When comparing with other chronic health conditions, from an experiential perspective, it is important to consider:

•   disease factors, including disease onset, disease progression;

•   regimen factors, including the complexity, the intrusiveness, the cost and the accessibility, and the side-effects that affect regimen adherence;

•   individual factors, including health beliefs and coping; and

•   comorbidpsychopathology.

Disease, regimen, and individual factors specific to Type 1 diabetes mellitus, although reviewed more comprehensively elsewhere, will be reviewed briefly in this chapter. Several psychological problems that are prevalent and problematic among individuals with Type 1 diabetes mellitus, depression, anxiety, and dysregulated eating, will each be reviewed in detail in the post.

The disease onset of Type 1 diabetes mellitus may vary in several ways. Some individuals may experience the vague and mildly distressing symptoms of increased thirst and urination, hunger, fatigue, and weight loss, and subsequently seek medical attention at which time they receive the diagnosis of Type 1 diabetes mellitus. In such cases, the symptoms are not extreme or greatly distressing, and the individual may perceive the news of the diagnosis and demand for ongoing treatment to be more distressing than the symptoms. In contrast, other individuals may develop diabetic ketoacidosis (diabetic ketoacidosis) (e.g., a serious and dangerous condition of high levels of ketones, which can result in coma and/or death) prior to diagnosis, and therefore experience the disease onset as more distressing and fear inducing. Additionally, many adults with Type 1 diabetes mellitus have been diagnosed as children or adolescents, and time since diagnosis is an important consideration. The regimen factors are likely to be more important than the disease factors regarding both coping and self-management success among individuals with Type 1 diabetes mellitus. The Type 1 diabetes mellitus self-management regimens, as described in more detail in other chapters, are reviewed here with respect to the specific demands they place on patients. Regardless of which exact regimen an individual uses, the Type 1 diabetes mellitus treatment is complex, multifactorial, and requires ongoing consistency. The exact regimen, in turn, poses particular challenges and offers particular benefits. In Table 1, the typical current Type 1 diabetes mellitus regimens are compared and contrasted regarding the factors involved in patient self-care.

Table Specific Self-Management Activities and Lifestyle Factors Relevant to Current Insulin Regimen

Within the literature addressing Type 1 diabetes mellitus treatment among adolescents and children, an important distinction has been made between adherence and self-management with accompanying activities and goals relevant to blood glucose management. Adherence represents the patient’s following of treatment instructions by medical providers, and self-management involves an active self-directed process, with elements divisible into process to execute the activities to reach self-management goals. This distinction emphasizes that, although self-management is a process collaborative with medical providers, it truly requires the patients and families to understand the factors that affect blood glucose [e.g., food intake (carbohydrates, fats), insulin dosage, timing of food intake and insulin dosage, blood glucose monitoring, exercise, stress], factors that affect prevention of complications (foot care, ophthalmologic screening), and actively manage these activities in their ongoing life. As highlighted in Table 1, the evolution of regimen, development of newer preparations of insulin (e.g., Glargine), and application of newer delivery methods (e.g., continuous subcutaneous insulin infusion [CSII] pumps) over the past 10 to 15 years, has greatly affected the self-management behaviors required for patients. As a result, many of the old stereotypes among the public, such as Type 1 diabetes mellitus management requiring the elimination of simple carbohydrates and/or severe restriction of carbohydrates, has become an obsolete assumption. For example, those using basal/bolus multiple daily injections (multiple daily insulin) or CSII pumps, who are accurate in their carbohydrate counting and appropriate use of insulin-to-grams of carbohydrate bolus ratios, may not need to limit carbohydrate intake at all. Although regimen such as multiple daily insulin and CSII pumps have reprieved some patients from requirements of older regimen, successful management continues to require the consistent process of active blood glucose monitoring, use of insulin boli to correct high blood glucose, counting of carbohydrates and use of insulin-to-gram of carbohydrate ratio boli, and other demanding activities to maintain optimal blood glucose.

The individual factors, such as intelligence, knowledge, culture, patient’s trust in medical profession, health beliefs, and coping, constitute the variables that interact with the disease and regimen factors overviewed above. For a full review of these issues, the reader is referred to Boyer. Here, a brief review of diabetes-specific knowledge and coping are provided.

Diabetes-Specific Knowledge

Since the treatment for Type 1 diabetes mellitus involves a complex regimen of self-management, the amount and accuracy of knowledge is imperative for patients’ adherence to treatment and glycemic control. The literature on knowledge among the pediatric Type 1 diabetes mellitus population becomes relevant, since those diagnosed as children or adolescents may receive most of their self-management training at diagnosis. Data indicates, however, that individuals show decrease in their maintenance and application of diabetes-specific knowledge over time, and reeducation becomes important. Although knowledge is related to self-management and glycemic control, it has also been found not to predict management outcome, as other factors interfere with the application of this knowledge over time. Some of these factors are discussed throughout the remainder of this chapter.

Coping

Due to the demand for active and strategic self-management of blood glucose among all treatments for Type 1 diabetes mellitus, the coping dispositions of patients and their families are of crucial importance. Empirical investigations regarding coping among those with Type 1 diabetes mellitus, and the relationship of coping to medical outcomes, have generally implied that active, approach-oriented coping dispositions show a better match with diabetes mellitus 1 self-management demands than passive, avoidant coping. Active coping corresponds with better quality of life among adults with diabetes, and better metabolic control among adolescents with Type 1 diabetes mellitus. Although much of the research investigating samples of patients with Type 1 diabetes mellitus are adolescent samples, these data are relevant to our discussion, as most adults with Type 1 diabetes mellitus have had the condition across their adolescent years, and may have developed coping dispositions that persist into adulthood. While some studies have shown that coping training interventions for adolescents produced reductions in diabetes-specific stress but not improvements in glycemic control, others have produced improvements in self-efficacy as well as metabolic control that maintained for 6 months following therapy. Simply put, it appears that individuals who manage stress by approaching the stressful condition, attempting to control the condition, and find the process of exerting strategic control to be distress-reducing are likely to be more easily successful managing Type 1 diabetes mellitus than those who reduce stress by avoiding the stressful condition, employing avoidant strategies to reduce the sense of threat and distress, and experience greater distress when approaching the stress-inducing context.

While the factors reviewed above, knowledge, coping, and self-management difficulties are relevant to any and all individuals with Type 1 diabetes mellitus, several psychological disorders have been shown to be more prevalent in those with Type 1 diabetes mellitus, and particularly problematic for self-management and glycemic control.

DEPRESSION

ANXIETY

DYSREGULATED EATING

CONCLUSION

Type 1 diabetes mellitus is a complicated disease, which can represent a significant stressor for the individual and his/her family. A comprehensive understanding of how this disease impacts psychological factors, and the impact of psychological factors on medical outcomes is crucial in understanding and managing this disease. A well-developed literature has investigated the comorbidity between Type 1 diabetes mellitus and several psychiatric diseases, and has shown that individuals with diabetes mellitus have a disproportionately higher rate of psychiatric disorders. Depression, anxiety, and dysregulated eating appear more prevalent among those with Type 1 diabetes mellitus, interfere with important outcomes such as quality of life, self-management, and glycemic control. In addition, psychological factors interact with adjustment to Type 1 diabetes mellitus, self-management, and metabolic control, even at subdiagnostic levels of symptomatology. Indeed, it appears nearly impossible to optimize medical outcomes without addressing the role of knowledge, coping, anxiety and mood, and dysregulated eating in the adult Type 1 diabetes mellitus population. Diabetes treatment teams must maintain a high suspicion for these factors among adults with Type 1 diabetes mellitus, screen carefully, and treat aggressively, so as to prevent these nonpathophysiological factors from rendering treatment ineffective.

Some individual studies have found that depression among those diagnosed with diabetes was vastly elevated, compared to the individuals without diabetes, with depression as high as six times higher for those with diabetes mellitus. In an epidemiological study of depression in individuals with Type 1 diabetes mellitus and type 2 diabetes mellitus, findings revealed that depression was three to four times more prevalent in this population than in the general population. These results suggest that 15% to 20%, or approximately one in five individuals with either Type 1 diabetes mellitus or type 2 diabetes mellitus are afflicted with depression. Furthermore, approximately 40% of individuals with diabetes mellitus have significantly elevated levels of depressive symptomatology, but are not clinically depressed.

The literature has developed enough to permit meta-analytic studies. Taken together, the evidence from 42 studies regarding rates of depression among those with Type 1 diabetes mellitus or type 2 diabetes mellitus indicates a 2.0 odds ratio for depression among those with diabetes. While these studies include both Type 1 diabetes mellitus and type 2 diabetes mellitus populations, the data did not suggest a difference between Type 1 diabetes mellitus and type 2 diabetes mellitus. For those with Type 1 diabetes mellitus, there appeared to be twice the rate of depression as among those without diabetes. There were, however, differences related to gender. Rates of depression were 28% among women with diabetes, and 18% among men with diabetes, but due to different base rates for depression among men and women without diabetes, the 2.0 odds ratio was consistent for both genders. A more recent review, investigating depression among only samples with Type 1 diabetes mellitus, and including rive additional studies since the Anderson and colleagues study, reported that 12% of those with Type 1 diabetes mellitus exhibited comorbid depression, compared with only 3.2% of the comparison group without diabetes. These data suggest that, among individuals with Type 1 diabetes mellitus, the rates of depression may be above three times the rate as those without diabetes mellitus. Indeed, 27% of children and adolescents diagnosed with Type 1 diabetes mellitus developed a major depressive episode during the 10 years after the diagnosis of Type 1 diabetes mellitus. These series of studies and the resulting meta-analytic reviews demonstrate that regardless of the exact degree of increased risk and prevalence, depression appears elevated in prevalence among those with Type 1 diabetes mellitus.

Given the elevated prevalence of depression among individuals with diabetes mellitus, a few studies have attempted to characterize the disorder further. In a study by Peyrot and Rubin, elevated depressive symptoms varied according to two factors: (/) nondiabetes specific (generic) factors and (//) diabetes-related factors. The researchers found higher rates of depression among women, individuals who were unmarried, and those with less education. Higher rates of depression were also found in individuals with three or more medical complications secondary to their diabetes (i.e., retinopathy, neuropathy, kidney disease, etc). Other studies have examined the relationship between social problems and depression in individuals with diabetes mellitus. Roy found that social problems are reported more often among individuals with Type 1 diabetes mellitus. Wilkinson and colleagues found that individuals reporting major social problems had significantly higher levels of psychiatric morbidity.

Relationship of Depression to Medical Outcomes

Of further concern is the relationship between comorbid depression and medical outcomes among those with Type 1 diabetes mellitus. Several studies have investigated the influence of depression on glycemic control and other adherence measures. Studies have found that individuals with diabetes mellitus and a history of depression showed significantly worse glycemic control as measured by glycosylated hemoglobin. Additionally, afew meta-analytic studies now exist and have shown a significant relationship between depression and poorer metabolic control among those with both Type 1 diabetes mellitus and type 2 diabetes mellitus. Not surprisingly, depression has also shown a relationship to greater complications of persistent hyperglycemia. Inquiry continues regarding the exact nature of this relationship between depression and hyperglycemia. One study sought to determine whether depression induced a decrease in diabetes self-care and whether changes in self-management mediated the relationship between depression and hyperglycemia. Although the inclusion of the score from the summary of diabetes self-care activities in regression analyses attenuated the relationship between depression and glycosylated hemoglobin among individuals with Type 1 diabetes mellitus, it did not account for a significant mediation of the depression -> hyperglycemia relationship. As such, continued investigation of this relationship is necessary, to determine the strength of the depression -> reduced self-management -> hyperglycemia mechanism, or evaluate other psychological and psychophysiological mechanisms for this relationship.

The course of depression in the diabetes mellitus population is chronic and severe, and the presence of depression in individuals with diabetes mellitus may significantly worsen the course of both disorders. There is sufficient data in the literature demonstrating the (0 increased prevalence of depression in the Type 1 diabetes mellitus population, (ii) deleterious impact of depression on medical outcomes, and (Hi) evidence that effective treatments exist. However, depression continues to be underdiagnosed and undertreated. In a study of nine primary care practices, 49% of patients with a diagnosis of either Type 1 diabetes mellitus or type 2 diabetes mellitus, reporting clinically significant depression in a systematic screening, were not diagnosed or treated. Only 43% of those patients who were appropriately diagnosed with depression were receiving antidepressant pharmacotherapy, and only 6.7% received four or more psychotherapy sessions during the previous year. This suggests that not only were many patients with depression not initially diagnosed, but those who were diagnosed were not adequately treated.

Treatment for Comorbid Depression and Diabetes

A few studies have examined the influence of psychopharmacology and psychotherapy on the treatment of depression in this population; however data remain scarce. Although the prevalence of major depression and diabetes is well established, there are no large-scale, randomized controlled clinical trials. Both antidepressant medications and cognitive behavioral therapy have demonstrated short-term effectiveness in the treatment of depression among diabetes mellitus individuals. The results seem promising with improvement towards a reduction in depressive symptoms, as well as improved glycemic control. As previously stated, data is available showing that depression has been shown to worsen medical outcomes for those with diabetes. Many of the treatment data for depression and diabetes show improvements in medical outcomes (i.e., improved metabolic control); however, depression treatment for those with comorbid depression and diabetes have not consistently shown improvement in patients’ self-management or glycemic control.

Pharmacological management of depression may be necessary for long-term or resistant depressive symptoms. Monoamine oxidize inhibitors and tricyclic antide-pressants are not commonly used to treat depression in persons with diabetes due to potential adverse side effects (e.g., short-term hyperglycemia, hypoglycemic unawareness, postural hypotension). Notably, a randomized clinical trial of nortriptyline revealed significant reductions in depression; however, there was an adverse effect on glucose control. Selective serotonin reuptake inhibitors appear to be the preferred antidepressant of choice for those with diabetes mellitus. However, Selective serotonin reuptake inhibitors are not without side effects. This class of drugs may alter the metabolism of certain oral hypoglycemics and certain drugs can be associated with weight gain. Effectiveness data suggest that Selective serotonin reuptake inhibitors are associated with both improved depressive symptoms and metabolic control. The SSRI, fluoxetine, has been evaluated for its efficacy on reducing depressive symptoms in both Type 1 diabetes mellitus and type 2 diabetes mellitus patients. An 8-week, randomized clinical trial found that fluoxetine significantly reduced depressive symptoms compared to placebo and trended towards better glycemic control.

Lack of statistical power is an important note of caution in interpreting the data on antidepressants on depressive symptoms in persons with diabetes. Most of the pharmacotherapy studies have too few participants to robustly measure symptom reduction and symptom burden from diabetes, and no long-term data are available.

Cognitive behavioral treatment has been shown useful in the treatment of depression in persons with diabetes; however, data is scant. This therapeutic approach modifies dysfunctional thinking, reduces negative emotions, trains stress reduction, and provides skill building in areas of deficit. Improvements in mood, quality of life, and coping were demonstrated in the only large-scale randomized clinical trial to date in type 2 diabetes mellitus adults. However, other data from less statistically robust studies exists. Cognitive behavioral therapy has shown effects through improved glycemic control and quality of life, and evidence suggests that cognitive-behavioral therapies techniques may prove beneficial in improving compliance to diabetes regimen.

Combined treatment of pharmacotherapy and psychotherapy has been found to be significantly more efficacious in reducing depressive symptoms than placebo alone .

Overall, with the limited data available, it appears that both psychopharmacological and psychotherapeutic approaches have beneficial effects on depression reduction in persons with diabetes, and may promote improvement in medical outcomes.

Additionally, some individuals experience anxiety directly related to Type 1 diabetes mellitus and self-management. Although most diabetic complications arise from persistent hyperglycemia, the immediate symptoms of hypoglycemia are much more perceptible subjectively and indeed frightening and uncomfortable. Fear of hypoglycemia has been observed among individuals with Type 1 diabetes mellitus. Fear of hypoglycemia has been found to be related to higher trait anxiety and greater perceived stress, past experiences with hypoglycemia, more daily variability in blood glucose, and poorer metabolic control. A self-report instrument, the hypoglycemic fear survey, has been developed to measure this phenomenon, and has demonstrated good internal consistency and temporal stability. Fear of hypoglycemia appears to have two components, each measured by the hypoglycemic fear survey, a cognitive worry component and a behavioral avoidance component. Patients may become persistently worried and fearful of hypoglycemia, and mistake the symptoms of anxiety for the similar symptoms of hypoglycemia, often experiencing persistent difficulty distinguishing whether these symptoms are due to low blood glucose or anxiety. In addition, this persistent fear induces some individuals to engage in avoidance behaviors such as overeating in response to early symptoms of low blood glucose, intentionally maintaining higher levels of blood glucose to create the perception of safety from hypoglycemia by underdosing their insulin relative to blood glucose levels or food intake.

This fact that Fear of hypoglycemia is related to previous frequency and experiences with hypoglycemic episodes hypoglycemia and the pattern of persistent and intrusive worry about low blood glucose hypoglycemia, the anxious hyperarousal that accompanies this fearful cognition, and the resulting maladaptive behavioral attempts to avoid risk of hypoglycemia, has led some investigators to question whether this responding may constitute the symptom triad of posttraumatic stress.

In the only study to date, in which the full symptom triad of intrusive ideation, anxious hyperarousal, and avoidance, along with the criterion that these symptoms pose clinically significant interference with functioning, reported that 25% of individuals using basal/bolus insulin regimen (i.e., multiple daily insulin and CSII pumps) indicated symptoms consistent with current posttraumatic stress disorder related to hypoglycemia.

Relationship of Anxiety to Medical Outcomes

Furthermore, a meta-analysis assessing evidence of a relationship between anxiety and metabolic control found that, while overall results did not support a significant relationship, in studies using interviews to evaluate anxiety, anxiety did show significant relationship to glycemic control. It appears that when more rigorous assessment was utilized, a relationship between anxiety and hyperglycemia was detectable, although not supported by studies employing questionnaire assessment of anxiety.

Treatment for Comorbid Anxiety and Diabetes

While very few empirical studies have evaluated efficacy of treatment for anxiety among adults with Type 1 diabetes mellitus, one case study has demonstrated that cognitive-behavioral therapies may be useful, suggesting that cognitive-behavioral therapies may be as effective for this population as for others. Since anxiety greatly affects quality of life, since studies utilizing interview assessment of anxiety indicate that it interferes with medical outcomes for those with Type 1 diabetes mellitus, and since diabetes-specific anxiety and hypoglycemic fear may interfere with glycemic control, interventions to treat anxiety among those with Type 1 diabetes mellitus are greatly needed.

Despite the fewer studies regarding treatment of anxiety among those with diabetes mellitus 1 compared to the literature addressing depression, the existing evidence suggests that clinicians should have a high suspicion for anxiety among adults with Type 1 diabetes mellitus. In addition, the potential detriment regarding metabolic outcomes suggests that therapies to ameliorate anxiety are imperative.

For adolescents with Type 1 diabetes mellitus, diabetes self-care requires an unremitting focus on the balance among food, exercise, and insulin. Therefore, it is reasonable to speculate that people with Type 1 diabetes mellitus may often become more preoccupied with food and their own bodies than the average person. In general, adolescents with a chronic illness, such as Type 1 diabetes mellitus, generally report higher body dissatisfaction, and engage in more dangerous weight loss measures than those without a chronic illness.

Although intensive insulin therapy represents the most effective current regimen, it tends to cause a modest weight gain, and increases the risk for hypoglycemia (low blood sugar). When an individual has a hypoglycemic episode they must eat something to raise their blood sugar, thereby increasing their calorie consumption for the day. These side effects are generally mild and thought to be worth the health benefits that come with intensive insulin therapy. However, the increase in weight that can be caused both by an increase in caloric consumption due to hypoglycemia and the improvement in glycemic control can be upsetting and problematic for some people and, therefore, seems likely to be a risk factor for the development of disordered eating.

As a result of this need for hyperawareness about one’s body, combined with a higher base weight than average, it is not surprising that the rate of eating disorders among people with Type 1 diabetes mellitus is higher than among the general population. Current estimates suggest that approximately 16% of people with Type 1 diabetes mellitus suffer from a co-occurring eating disorder, and many more will suffer from subclinical levels of disordered eating. Research suggests that Type 1 diabetes mellitus may trigger the development of an eating disorder, as Type 1 diabetes mellitus may exacerbate body dissatisfaction following Type 1 diabetes mellitus diagnosis and treatment, in part to their higher-than-average base weight.

The diagnostic and statistic manual, (DSM-intravenous) identifies three forms of eating disorders: anorexia nervosa, bulimia nervosa, and eating disorder not otherwise specified. There is currently a debate about adding a fourth disorder, binge eating disorder, to the next revision of the DSM. A section below is devoted to each.

Anorexia

Anorexia is often the easiest of the eating disorders to diagnose because the physical symptoms are difficult to keep hidden. The symptoms, refusal to maintain a minimally normal body weight (characterized as less than 85% of what is appropriate for an individual’s height), an intense fear of gaining weight, severe disturbances and perceptions about the shape of the body, amenorrhea, preoccupation with food, the hoarding of food, concerns about eating in public, cooking for others but refusing to eat, and rigid thinking, may readily become apparent to family, friends, or medical professionals.

A meta-analysis that reviewed five controlled studies, found that individuals with Type 1 diabetes mellitus are at no greater risk for developing anorexia than the general population. However, an estimated 1% of all females develop anorexia at some point in their lives, and approximately 10% of people with anorexia will die from complications such as starvations, suicide, or an electrolyte imbalance, constituting the highest death rate of any mental illness. Therefore, observation and screening for those with Type 1 diabetes mellitus is imperative, even if the rates are not higher than among those without diabetes mellitus.

Anorexia can cause infertility, osteoporosis, and irritable bowel syndrome; however, for those with anorexia and Type 1 diabetes mellitus the risks are even greater. Women with diabetes and anorexia have a mortality rate of 34.6 per 1000 person-years, whereas those with anorexia without diabetes have only a 2.2 per 1000 person-years. This staggering difference highlights the essential need for physicians to screen for this disorder, regardless of its prevalence. In addition, people with diabetes face a slew of other potential complications. Skipping meals can put people with diabetes at risk for hypoglycemia, which can result in a variety of symptoms including mental confusion, impaired judgment, mood changes, seizures, coma, and possibly death.

Bulimia

Bulimia nervosa is characterized by episodes of binge eating, followed by a variety of compensatory methods to negate the increase in calories consumed (e.g., purging through vomiting, excessive exercise, using laxatives or enemas, starvation). A binge is defined as occurring during a discrete period of time, involves eating an amount of food that is significantly larger than what most people would eat during similar circumstances, and a sense of being out of control during the episode. Other symptoms that may become evident in the clinical setting include dehydration, abdominal pain, and the emergence of dental problems (as continuous vomiting wears away the tooth enamel).

Bulimia is diagnosed in approximately 1% to 3% of the population, with males displaying one-tenth the rate for females. Since individuals with bulimia often appear physically healthy and are not grossly underweight, prevalence may, in fact, be much higher. In addition, 30% of those with bulimia show a lifetime diagnosis of comorbid disorders, such as substance abuse or dependence disorde.

A meta-analysis of controlled studies composed of 748 persons with diabetes and 1587 female participants found that patients with Type 1 diabetes mellitus are significantly more likely to develop bulimia when compared to those without diabetes. In addition, it is also estimated that 60% to 80% of people with Type 1 diabetes mellitus engage in episodes of binging at a subclinical rate. This binging and purging behavior makes it incredibly difficult to keep blood glucose levels stable. This is because the activity of binging and purging makes it difficult to accurately gauge the amount of food a person is ingesting, and it becomes impossible to accurately assess the amount of insulin that is necessary. In addition, binges often include foods that are high in fats, which may have no immediate impact on blood sugar levels, but may cause them to rise hours later. The results of this can be disastrous. The inability of people with bulimia to keep their blood glucose levels stable can result in blood glucose levels that are perpetually too high, or too low. In turn, this leads to higher HbAlc levels and poorer overall glycemic control.

A recent study compared patients with Type 1 diabetes mellitus and bulimia, to those with Type 1 diabetes mellitus and binge eating disorder. Although both of these are serious forms of disordered eating, the study found that the presence of bulimia nervosa was highly associated with severe disturbances related to depression, anxiety, and eating disorders. In addition, the group with bulimia nervosa showed an overall higher rate or co-occurring mental disorders, psychosocial dysfunction and poorer overall glycemic control.

Eating Disorder Not Otherwise Specified

Some eating disorders have unique features that cause them to not fit one of the generally accepted categories of eating disorders (e.g., anorexia, bulimia). To address this problem, DSM-intravenous identifies a diagnosis known as eating disorder not otherwise specified (ED-NOS). Examples of eating disturbances that would fit this diagnostic profile include a person who purges after eating only a small amount of food or a person who has lost a significant amount of weight by starving themselves but their weight still technically falls in a healthy range.

The most common ED-NOS seen in people with Type 1 diabetes mellitus is the reduction of insulin dosage to lose weight. Studies have found that up to 30% of adolescents with Type 1 diabetes mellitus have intentionally reduced or omitted their insulin doses to control weight in adolescence or young adulthood. We have observed several variations of this in the clinical setting: (/) episodically omitting insulin administration; (//) consistently under dosing for meals and snacks; or {Hi) the omission of a bolus for meals albeit maintenance of basal doses by those using insulin pumps or basal/bolus formats of injection regimen (with Glargine basal doses and “per-meal” bolus injections with analogue insulin).

When this happens, blood glucose becomes hyperglycemic and ketones appear in the urine as body fat is broken-down for energy, placing individuals at greater risk for ketoacidosis, nephropathy, and other diabetic complications. Of tremendous clinical difficulty is that, despite the negative impact of insulin omission on glycemic control and risk for potentially irreversible complications, this tactic does successfully result in weight loss. For individuals with Type 1 diabetes mellitus who are rigidly fixated upon weight loss, to the exclusion of long-term DMl-related health concerns, diagnosis and treatment of the eating disorder become imperative.

Relationship of Dysregulated Eating to Medical Outcomes

An eating disorder can be a life-threatening illness for anyone, but for a person with diabetes it is even more dangerous. Eating disorders greatly increase the mortality and morbidity rate among people with Type 1 diabetes mellitus. The majority of research has found that having an eating disorder is linked to increased medical complications for people with diabetes. As a result, screening for eating disorders should be implemented as part of routine care for people with diabetes in order to prevent the development or exacerbation of diabetes related complications secondary to dysregulated eating patterns. Multiple self-report measures that are reliable and valid are available to assist with screening and diagnosis of dysregulated eating; however, most are not specific to those with diabetes.

Treatment for Comorbid Diabetes and Dysregulated Eating

Once an eating disorder or any pattern of disordered eating is diagnosed, treatment should begin immediately. Patients may require inpatient treatment in either a medical or psychiatric hospital, if their eating disorder is particularly severe, or their health is at immediate risk. An example of this circumstance, which is most relevant to people with diabetes, is a person who has intentionally omitted so much insulin from their regimen that they have entered a state of ketosis and require an intravenous insulin drip in order to normalize their blood sugar.

After immediate physical danger has been eliminated or ruled out, long-term treatment can begin. Because of the increased risks associated with having both Type 1 diabetes mellitus and an eating disorder, an interdisciplinary team should be utilized in order to address the complex nature of the problem. Ideally, the team should include a psychotherapist, diabetes educator, endocrinologist, and nutritionist. These professionals should be in regular communication with each other in order to ensure that treatment is progressing; and the physical, emotional and psychological needs of the patient are all being addressed. Depending on the age and circumstances of the patient, family, group, and/or couples therapy may be appropriate as well.

One small study compared 9 young women with bulimia nervosa who were receiving in-patient treatment to 10 young women with bulimia nervosa who were not. These patients were reassessed 3 years after treatment by examining their body mass index, HbAlc results, and psychological test scores. Patients who had received inpatient treatment had lower HbAlc results and demonstrated lower scores on measures assessing depression, anxiety, and binge eating and purging behaviors. Although the small sample size of this study makes it difficult to discern how generalizable the results are, these preliminary findings do suggest that inpatient treatment may be a more helpful form of treatment for women with diabetes who are suffering from bulimia nervosa.

That an HbAlc of < 7% can be achieved in the person with Type 1 diabetes mellitus has been clearly demonstrated in the Diabetes Control and Complications Trial (Diabetes Control and Complications Trial). Furthermore, this study demonstrated that improved glycemic control with intensive insulin therapy in patients with Type 1 diabetes mellitus leads to graded reduction in retinopathy, nephropathy, and neuropathy on complications. The Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study of Diabetes Control and Complications Trial subjects has more recently demonstrated that intensive insulin therapy also reduces cardiovascular morbidity and mortality.

As early as 1993, the Diabetes Control and Complications Trial research group recommended that intensive diabetes treatment be instituted in most individuals with Type 1 diabetes mellitus, unless contraindications to doing so existed. Furthermore, the Diabetes Control and Complications Trial demonstrated that intensive therapy is most effective in preventing complications when introduced during the first 5 years of diabetes. In 303 subjects with early Type 1 diabetes mellitus and residual beta-cell function who were randomly assigned to intensive or conventional therapy, those receiving intensive therapy were slower to lose residual beta-cell function than the conventional therapy group (risk reduction 57%) (4). In addition, intensive therapy in those with residual beta-cell function resulted in a lower HbAlc, a 50% reduction in risk for retinopathy progression, and a lower risk for severe hypoglycemia compared to those who received intensive therapy but did not have residual beta-cell function. It seems abundantly clear that intensive therapy should be implemented as early as possible, and be maintained for as long as possible in Type 1 diabetes mellitus.

The health-care provider must tailor an individualized insulin regimen for each person with Type 1 diabetes mellitus to enable targeted blood glucose control. In order to be successful in this regard, it is essential to have an understanding of the normal physiologic pattern of insulin secretion, the currently available insulin preparations and safe and effective methods for both initiating and adjusting the insulin therapy regimen. This chapter will provide a discussion of each of these key elements of insulin therapy for adults with Type 1 diabetes mellitus.

PHYSIOLOGIC INSULIN SECRETION

While the person with Type 1 diabetes mellitus has an absolute deficiency in ability to secrete insulin from the pancreatic beta cell, it is helpful to understand physiologic insulin secretion as we prescribe an insulin regimen to optimally meet the daily needs of the Type 1 diabetes mellitus patient.

Basal Insulin

The normal concentration of insulin measured by radioimmunoassay in the peripheral venous plasma of fasting humans who do not have diabetes is 0 to 70 (iIJ/mL (0-502 pmol/L). Basal insulin secretory profiles reveal a pulsatile pattern of hormone release, with small secretory bursts occurring about every 9 to 14 minutes, superimposed upon greater amplitude oscillations of about 80 to 150 minutes. The amount of insulin secreted in the basal state averages 1 U/hr.

The Prandial Insulin Response

Meals, particularly those incorporating carbohydrates and/or other nutritional stimuli of insulin secretion may induce up to a 4- to 10-fold increase in insulin secretion when compared to the basal state, which usually lasts for 2 to 3 hours before returning to the baseline. Rise in blood glucose concentration following intravenous administration of glucose cause a burst in secretion that peaks within 3 to 5 minutes and subsides within 10 minutes and is known as “first phase” insulin release (FPIR). If the blood glucose concentration remains high, then the rise in insulin secretion is sustained in a second-phase of insulin release. The average amount of insulin secreted per day in a normal human is about 40 U (287 nmol).

Loss of pulsatile insulin secretion is one of the earliest signs of beta-cell dysfunction in patients destined to have Type 1 diabetes mellitus. By the time of diagnosis, beta-cell insulin secretion is negligible to absent. Therefore, one should assume that the individual with Type 1 diabetes mellitus has absolute insulin deficiency and will always require exogenous insulin therapy to prevent ketogenesis and uncontrolled hyperglycemia due to gluconeogenesis.

When prescribing insulin for the person with Type 1 diabetes mellitus, one will attempt to mimic these physiologic basal-bolus patterns of insulin secretion. In order to safely and effectively do so, the prescriber must have a sound knowledge of currently available insulins.

TYPES OF INSULINS

With advances in recombinant DNA technology, it is now possible to produce large quantities of insulin with an amino acid structure identical to that of human insulin using strains of genetically altered Escherichia coli bacteria or yeast. All forms of insulin have identical physiologic effects. Insulins differ in their rapidity of time to onset of action, the time from subcutaneous injection to peak of action, and their duration of action.

When insulin is injected, six monomers are associated in a hexameric form. The time it takes for the hexamer to dissociate into monomers, which can be absorbed across the capillary basement membrane is a strong determinant of the time of onset of action, peak levels in the circulation, and duration of action. For example, regular insulin must first dissociate into dimers, then into monomers, a process that takes 30 to 60 minutes following administration of a subcutaneous shot. This phenomenon accounts for the need to dose regular insulin 30 to 45 minutes prior to a meal if it is to attenuate the postprandial glycemic excursion. On the other hand, rapid-acting insulin analogs dissociate more quickly into monomeric form following injection. This results in their shorter time to onset of action and ability to dose with the meal, or even at the end of a meal.

COMPONENTS OF THE PHYSIOLOGIC INSULIN REGIMEN

Insulins are divided for practical purposes into two broad categories, basal and bolus, based on their pharmacokinetics. Physiologic insulin replacement attempts to mimic normal insulin secretion patterns, and is used to meet an individual’s total daily insulin requirement that consists of the sum of basal, prandial, and correction dose insulin requirements.

Basal insulin refers to exogenous insulin per unit of time necessary to prevent unchecked gluconeogenesis and ketogenesis. It provides a constant background level of insulin that controls blood glucose overnight while the patient sleeps and between meals when they are not eating and the meal bolus insulin action has waned. When dosed appropriately, basal insulin should not cause hypoglycemia if/when the patient does not eat or ingests less food than was anticipated during a meal. In treating Type 1 diabetes mellitus, basal insulin needs will most commonly be met by: injection of once daily insulin glargine; once or twice daily insulin detemir; or by rapid-acting or regular insulin delivered subcutaneously via an insulin pump.

The term bolus insulin incorporates both prandial and correction doses of insulin. Bolus insulin is preferentially provided as one of the rapid-acting insulin analogs, e.g., aspart, glulisine and lispro, or may be provided as short-acting regular insulin. Prandial or meal insulin refers to insulin which covers the postmeal glycemic excursion. Efforts are made to match meal insulin doses to anticipated carbohydrate intake, which will be achieved either by a consistent carbohydrate meal plan or by “carbohydrate counting.” The latter refers to counting the number of grams of carbohydrate to be taken in a meal and calculating an appropriate dose of insulin to take with the food. An individualized carbohydrate to insulin ratio is based upon an estimate of known insulin sensitivity. (Further details are discussed below in the section on pattern management.)

Correction- or supplemental-dose insulin is used to treat hyperglycemia that occurs before or between meals despite administration of routine daily doses of basal and prandial insulin, and is taken in addition to these standing doses. When the patient with diabetes is ill or stressed, total daily insulin requirements commonly increase. This increase in insulin requirement is a result of release of insulin counter-regulatory hormones, predominantly cortisol and catecholamines, and to a lesser extent glucagon and growth hormone, which are released in the physiologic endogenous stress response. If correction-dose insulin is needed at bedtime, it should be administered at a reduced dose compared to other times of day to reduce risk of nocturnal hypoglycemia.

Table Salient Features of Insulin Preparations

Patients with diabetes mellitus 1 have absolute insulin deficiency and therefore require basal insulin replacement at all times to prevent diabetic ketoacidosis, even when they are unable to eat. Withholding basal insulin from the patient with Type 1 diabetes mellitus results in a rapid rise in blood glucose, by as much as 29 to 60 mg/dL/hr, with accompanying onset of ketonemia in approximately 2 to 3 hours, leading inevitably to diabetic ketoacidosis.

Basal Insulins: Long-Acting and Intermediate-Acting Insulins

Even during an overnight fast, the normal pancreas continues to secrete insulin. Basal insulin suppresses hepatic glucose production and ketogenesis and maintains near normoglycemia in the fasting state. When administered subcutaneously, basal insulins have a delay of 2 to 6 hours from time of injection into the subcutaneous depot that determines their individual time to onset and duration of action. In the setting of Type 1 diabetes mellitus, subcutaneous basal insulin is most commonly used in combination with bolus prandial insulin doses administered prior to each meal in the multiple daily insulin regimen. Basal insulins for subcutaneous injection may be broadly categorized into long-acting and intermediate-acting insulins. The salient features of each of the currently available basal insulins will now be overviewed.

Long-Acting Insulins

Insulin Glargine (Lantus). Glargine is a recombinant human insulin analog. It differs from human insulin in that asparagine at position A21 is replaced by glycine, and two arginines are added to the C-terminus of the beta chain. Because of these changes, insulin glargine is soluble in an acidic environment and forms a stable hexamer precipitate in the neutral pH environment upon injection into subcutaneous tissue. The hexamer precipitate allows for a delay in the onset of action and a constant release of insulin over a 24-hour period with no pronounced peak. It thus serves to provide basal insulin action over the course of a day. The mechanism of action of glargine is similar to that of human insulin, and on a molar basis its glucose-lowering effects are similar to those of human insulin. Because glargine is provided in an acid solution, it cannot be mixed with other forms of insulin as it would alter their absorption profiles. Its acidity also accounts for discomfort with injection in a small proportion (2.7%) of users. In clinical trials in patients with Type 1 diabetes mellitus, glargine when compared to twice daily NPH insulin has been associated with a reduced risk of hypoglycemia (particularly nocturnal hypoglycemia). Hypoglycemia is less likely to occur with once daily glargine dosing when it is taken in the morning. In about 10% to 20% of patients with diabetes mellitus 1, glargine must be taken twice daily to provide 24-hour coverage of basal insulin needs. In a smaller proportion of patients, there may be a modest peak approximately 2 hours after injection. In a comparison study between insulin glargine and detemir in adults with type 2 diabetes mellitus, insulin glargine showed a better adjusted HbAlc than that seen with insulin detemir (6.92% vs. 7.13%, respectively, p = 0.035).

Insulin Detemir (Levemir)

Also, a recombinant human insulin analog, detemir, which has a 14-carbon fatty acid (myristic acid) covalently bound to lysine at position B29 and threonine at position B30, is omitted. Fatty acid acylation enhances detemir’s affinity to albumin. Albumin binding allows for a protracted duration of effect predominantly via delayed absorption from the subcutaneous adipose tissue depot at the injection site. Detemir’s duration of action is longer than that of neutral protamine Hagedorn (NPH) insulin (Table 1). In one study, a detemir dose of 0.29 U/kg provided the same effect as 0.3 U/kg NPH, but with a longer duration of action (16.9 hours vs. 12.7 hours, respectively). The duration of action for insulin detemir increases dose dependently from 5.7 hours at a low dose (0.1 U/kg) to 23.2 hours at a high dose (1.6 U/kg). Detemir’s duration of action in some cases is less than 24 hours. This is particularly so when the total daily insulin requirement is low (< 0.1 U/kg/day) as may be the case in Type 1 diabetes mellitus. Therefore in persons with Type 1 diabetes mellitus, particularly those who are lean, detemir may need to be dosed twice daily to effectively meet basal insulin requirements.

Detemir has been shown to effect glycemic control in several controlled noninferiority clinical trials in Type 1 diabetes mellitus patients on a basal-bolus regimen when used either twice or once daily. Detemir is associated with less risk of hypoglycemia, particularly nocturnal hypoglycemia when compared to NPH insulin.

Data have demonstrated consistently across clinical trials to date in diabetes mellitus 1 that patients treated with detemir have less weight gain than those using NPH. Data regarding weight comparison for detemir versus glargine have not yet been published for Type 1 diabetes mellitus. For type 2 diabetes mellitus, it has recently been reported in a large observational (PREDICTIVE) study’s German subgroup analysis that modest clinical weight reduction (0.8 ± 0.2 kg, p < 0.0001) was observed when patients were transitioned from a glargine ± oral agent regimen to detemir. In addition, less weight gain was observed when detemir was compared to glargine for 26 weeks in a recent report from the 2006 International Diabetes Foundation meeting in adults with type 2 diabetes mellitus (+1.3 kg vs. 2.6 kg, respectively). The mechanism underlying detemir’s modestly favorable weight effects have not been elucidated to date. It has been suggested that enhanced activity in the brain may suppress appetite and/or that it may exhibit greater effects in the liver than in the periphery, thus restoring a more physiological mode of insulin action.

Intermediate-Acting Insulin

NPH insulin (Humulin N; Novolin N). NPH or isophane insulin is a crystalline suspension of insulin with protamine and zinc. Combination with protamine and low concentrations of zinc enhance the aggregation of insulin into dimers and hexamers after subcutaneous injection. A depot is formed after injection and the insulin is released slowly, providing an intermediate-acting insulin with a slower onset of action and a longer duration of activity (12-16 hours) than that of regular insulin. The duration of action of NPH insulin is variable; rarely some patients may require only one NPH injection daily; while others require three or more injections daily. NPH insulin is equipotent to the other basal insulins. NPH has variable absorption and peaks both of which can predispose to hypoglycemia, particularly when a meal is delayed or food intake is curtailed. For these reasons, NPH insulin is not commonly used in an multiple daily insulin regimen for Type 1 diabetes mellitus.

Bolus Insulins: Rapid-Acting Insulin Analogs and Regular and Inhaled Insulins

Rapid-Acting Insulin Analogs

Rapid-acting insulins are generally preferred as the bolus insulin of choice in intensive glycemic control regimens. Their rapid time to onset of action allows injection immediately before meals, whereas regular insulin must be given 30-45 minutes before meals to optimally match the glycemic excursions after a meal. The rapid-acting analogs glulisine and lispro are also indicated for injection at the end of or up to 15 minutes following a meal, which confers the potential for increased flexibility in meal scheduling and allows the person with Type 1 diabetes mellitus to take the meal-time insulin following eating. This latter feature is particularly useful when the caloric intake for a given meal is not certain, e.g., when eating out or when ill, as the analog may be dosed after the meal to match actual carbohydrate intake.

Conversely, the one clinical setting in which rapid-acting analogs may not be preferred is when they are to be given to meet all of the patient’s insulin requirements for a period of time, e.g., during acute illness, or when nothing is to be taken by mouth after midnight for a procedure the next day or when there will be a prolonged NPO period following surgery after an insulin drip is discontinued. The rapid-acting analogs have a relatively shorter duration of action (up to 4 hours) when compared to regular insulin. It is therefore preferable to continue basal insulin or use an insulin drip under such circumstances when at all possible. If this cannot be done, then rapid-acting insulin analogs must be dosed every 4 hours to prevent diabetic ketoacidosis, or the patient can take regular insulin every 6 hours until the usual basal insulin regimen can be resumed. This consideration is more likely to be an issue of concern in the hospital rather than in the outpatient setting. (Further discussed under sick day adjustments below.)

A meta-analysis of 42 randomized controlled trials (involving 5925 patients with Type 1 diabetes mellitus) that compared rapid-acting insulin analogs to regular insulin showed only a minor benefit of the rapid-acting insulin analogs in terms of HbAlc reduction. A moderate increase in the dose of basal insulin may be required when a patient is switched from regular insulin to a rapid-acting insulin for premealtime dosing, in order to meet insulin requirements between meals when the action of the rapid-acting analog has waned that were previously being met by the tail of action of regular insulin.

Regular insulin and the rapid-acting analogs are equipotent. In clinical trials comparing regular insulin to the rapid-acting insulin analogs, improvements in overall glycemic control have been similar; however, the rapid-acting insulin analogs may be superior to regular insulin in improving overall glycemic control when they are used via CSII.

The rapid-acting insulins are also particularly useful in addressing unexpectedly high blood glucose levels (e.g., between meals or in the setting of stress) because they will lower glucose levels more rapidly and without the prolonged effect of regular.

The teratogenicity and long-term safety profile of rapid-acting insulins in pregnancy are unknown, except for insulin aspart, which has been recently granted a category B pregnancy rating for Type 1 diabetes mellitus by the Food and Drug Administration (FDA).

Insulin Lispro (Humalog). It is also of recombinant DNA origin. It is Lys (B28), Pro (B29) insulin. The effect of this amino acid rearrangement is to reduce the capacity of the insulin to self-aggregate in subcutaneous tissues, resulting in behavior similar to that of monomeric insulin. This allows more rapid absorption from the subcutaneous depot following injection. Given intravenously, the pharmacokinetic profiles of lispro and human regular insulin are similar. Lispro was the first available rapid-acting insulin analog that closely matches circulating insulin levels to the time course of the increase in plasma glucose seen after ingestion of a carbohydrate-rich meal. Frequency of hypoglycemia is lower with premeal lispro than with regular insulin (6.4 episodes/30 days vs. 7.2 episodes/30 days, respectively). The rapid onset of action of insulin lispro is not blunted by mixing with NPH insulin just before injection. A meta-analysis of patients with Type 1 diabetes mellitus found that the incidence of severe hypoglycemia was 30% lower in patients treated with insulin lispro (« = 2327) when compared to regular insulin (« = 2339). Insulin lispro can also be administered via external CSII pumps. Pharmacodynamically, insulin lispro has an onset of glucose-lowering activity in 5 to 15 minutes and reaches mean peak plasma concentrations at 60 minutes when given subcutaneous. It has a duration of action of about 2 to 4 hours. After subcutaneous administration, the half-life of insulin lispro is about 1 hour. Intermittent subcutaneous injections of insulin lispro may be given within 15 minutes prior to or immediately after a meal because of its fast onset of action.

Insulin Aspart (Novolog). It differs from human insulin by substitution of aspartic acid for proline at position B28. This substitution also leads to a more rapid onset and duration of action analogous to those seen with insulin lispro when compared to regular insulin. Insulin aspart is administered by subcutaneous injection and is also approved for delivery via external CSII pump. Insulin aspart has an onset of action of about 15 minutes. It is therefore given immediately before meals (start meal within 5-10 minutes after injection). Insulin aspart has a peak glucose lowering effect at 60 minutes and exhibits a duration of action of roughly 2 to 4 hours. The half-life of insulin aspart following subcutaneous injection is about 80 minutes (34). On January 29, 2007 the FDA approved a pregnancy category B rating for insulin aspart [rDNA origin] injection, indicating that adequate clinical studies of its use in pregnant women have not revealed increased risks to the fetus. The approval was based on data from a study conducted at 63 sites in 18 countries (« = 322), showing that changes in glycated hemoglobin and rates of maternal hypoglycemia were comparable with insulin aspart and human regular insulin. Although the study was not large enough to evaluate the risk for congenital malformations, the use of insulin aspart compared with human regular insulin yielded fewer preterm deliveries (P < .053), consistently low rates of major hypoglycemia, a decreased risk for neonatal hypoglycemia (glucose < 2.6 mmol/L) requiring treatment, and reduced risks to the fetus. Outcomes with insulin aspart are comparable to those of human regular insulin.

Insulin Glulisine (Apidra™). It is produced by recombinant DNA technology utilizing a nonpathogenic laboratory strain of E. coli (K12). Insulin glulisine differs from human insulin in that asparagine at position B3 is replaced by lysine and the lysine at position B29 is replaced by glutamic acid. Insulin glulisine may be mixed with NPH insulin (Apidra should be drawn into the syringe first). Insulin glulisine is administered by subcutaneous injection and can be used for administration via external CSII pumps. Insulin glulisine has an onset of action of approximately 5 to 15 minutes, and also has a peak glucose lowering effect at 1 hour. The apparent half-life of insulin glulisine after subcutaneous administration is 42 minutes, compared to 86 minutes for regular human insulin. Intermittent subcutaneous injections of insulin glulisine may be given within 15 minutes before to 20 minutes after starting a meal.

Short-Acting Insulin [Regular Insulin (Humulin R; Novolin R)]

Regular Insulin. It consists of zinc insulin crystals in monomeric form in a clear solution. After subcutaneous injection it tends to self-associate, first into dimers and then into hexamers that must then dissociate prior to absorption as only the monomers and dimers can be absorbed to any appreciable degree (42). This results in a 30- to 60-minute delay in the time to its onset following subcutaneous injection, which practically speaking limits its flexibility in terms of convenience of time of administration relative to meals for the patient. Furthermore, since the peak glycemic response to a mixed meal is between 2 to 4 hours after ingestion, regular insulin may peak too late to allow targeted control of postprandial hyperglycemia. Finally, there is also a potential for hypoglycemia to develop as a late sequelae some hours after a meal, due to regular’s longer duration of action, which

often further limits ability to titrate it to tight postmeal blood glucose goals. Regular insulin can be administered via the intravenous, intramuscular, or subcutaneous routes, and it is used in CSII pumps.

The onset of action of regular insulin (100 U/mL) after subcutaneous administration begins approximately 30 minutes after injection with maximal effects occurring 2 to 4 hours later. The apparent plasma half-life following subcutaneous administration is approximately 1.5 hours with a duration of action of 6 to 8 hours. subcutaneous regular insulin must be given 30 to 45 minutes before a meal to allow matching of the insulin action to the postprandial blood glucose rise.

Regular insulin is approved for intravenous administration. When given intravenous, its onset of action is within 15 minutes with maximal effects occurring 15 to 30 minutes after injection. The plasma half-life of intravenous regular insulin is approximately 5 to 6 minutes and its duration of action is 30 to 60 minutes. This short half-life and duration of action has important practical implications. When a patient with Type 1 diabetes mellitus is being treated with an intravenous insulin infusion, e.g., for diabetic ketoacidosis, it is imperative to give the first shot of subcutaneous insulin at the time of drip discontinuation with sufficient lag time prior to stopping the intravenous to allow time to onset of the insulin that was given subcutaneous. This step must be taken, as there is rapid dissipation of the intravenous insulin’s action when the drip is stopped, in order to prevent gluconeogenesis and ketogenesis.

Finally, regular insulin has been developed for administration via inhalation (see below) and is in product development for possible delivery as an oral spray for absorption via the buccal mucosa.

Inhaled Insulin (Exubera). Inhaled insulin has been approved for use in the management of Type 1 diabetes mellitus in adults. It causes a rapid rise in serum insulin concentration (similar to that which occurs after subcutaneous aspart or glulisine are injected, and faster than that seen with subcutaneous regular insulin). It has a slightly longer duration of action than the rapid analogs.

The FDA has to date approved one inhaled insulin product and delivery device, Exubera. In this system, insulin powder is packaged in a foil blister, which is inserted into the device. A 1-mg capsule of Exubera provides the equivalent of about 2.7-3 U of insulin; the 3-mg capsule provides about 8 U. When the device is activated, the blister is pierced and the insulin powder is dispersed into a cloud in a chamber, which the patient then inhales through a mouthpiece. The bioavailability of this inhaled insulin preparation is approximately 10% to 20% that of a subcutaneously injected insulin dose. Decreased bioavailability is due to a combination of factors: loss of the insulin powder (~30%) through retention in the blister and the inhalation device, deposition in the oropharynx (~20%), and the tracheobronchial tree (~ 10%). Forty percent of an inhalation is delivered to the alveolar spaces from where it passes across the alveolar capillary membrane to the circulation. Exhalation of particles, breakdown by enzymes, and elimination by macrophages also have some impact on bioavailability. Bioavailability may vary among insulin delivery systems, amongst patients, and even within the same patient.

In a 6-month randomized trial of Type 1 diabetes mellitus patients (mean age 29 ± 14) in which premeal inhaled (« = 163) was compared with subcutaneous regular insulin (« = 165), mean glycosylated hemoglobin was reduced to a similar degree in the inhaled and subcutaneous insulin groups [-0.3% and -0.1%, respectively; adjusted difference -0.16% (CI -0.34 to 0.01)], with a similar percentage (23.3% in the inhaled insulin group vs. 22% in the subcutaneous group) of subjects achieving Ale < 7. Although 2-hour postprandial glucose reductions were comparable between the groups, fasting plasma glucose levels declined more in the inhaled than in the subcutaneous insulin group [the mean adjusted change in FPG was -35 mg/dL in the inhaled group, whereas in the subcutaneous group, there was a slight increase in FPG (4 mg/dL); adjusted treatment group difference -39.53 mg/dL (CI -57.50 to -21.56)]. Inhaled insulin was associated with a lower overall hypoglycemia rate [9.3% (inhaled) vs. 9.9% (subcutaneous) (risk ratio [RR] 0.94 [CI 0.91-0.97])] but higher severe hypoglycemia rate [6.5% vs. 3.3% (RR 2.00 [CI 1.28-3.12])] when compared to regular insulin before meals.

A systematic review of six randomly controlled trials comparing inhaled insulin with rapidly acting injections (three in Type 1 diabetes mellitus and three in type 2 diabetes mellitus) concluded that glycemic control was equivalent, but that patient satisfaction and quality of life was greater with inhaled insulin. These studies were limited in length (12 and 24 weeks), therefore long-term safety and/or pulmonary effects could not be established.

Clinical trials of to date, have been designed as noninferiority studies, therefore ability of inhaled insulin to enable attainment of glycemic goals (A1C < 6.5-7.0%) known to be effective in preventing long-term complications has not yet been fully assessed.

From the nonpulmonary perspective, both intradose variability in insulin absorption and the difficulty in making precise dose adjustments [Exubera allows variation by 1 mg (three regular insulin equivalent units) at a time] may preclude the use of inhaled insulin for Type 1 diabetes mellitus patients managed with intensive insulin regimens. Two other inhaled insulin delivery devices that are in development and clinical trials testing at present will each use a novel delivery system that may allow increased flexibility in dosing moving forward. The Type 1 diabetes mellitus patient who uses inhaled insulin also needs to take subcutaneous basal insulin.

Safety issues related to Exubera may be classified as nonpulmonary and pulmonary. Nonpulmonary risks include hypoglycemia, which is similar to that seen with use of other insulins. Several studies have found an increase in insulin antibodies with inhaled insulin, compared with those receiving subcutaneous insulin. Patients with Type 1 diabetes mellitus had higher levels of antibodies than those with type 2 diabetes mellitus. The presence of insulin antibodies had no correlation with HbAlc level, change in insulin dose, or incidence of hypoglycemia. The clinical significance of the presence of these insulin-binding antibodies is not yet established.

With regards to pulmonary effects, inhaled insulin has been under intense and ongoing scrutiny in terms of potential impact on pulmonary function as it has moved through the development, clinical trials, and approval processes. The most common pulmonary symptom associated with inhaled insulin is a nonproductive cough, that is reported more frequently in patients taking inhaled insulin than in those in the comparison group receiving subcutaneous insulin or oral agents [risk ratio, 3.52 (CI, 2.23-5.56); 16.9% vs. 5.0%, respectively]. There were no differences between patients with Type 1 diabetes mellitus or type 2 diabetes mellitus. Cough occurred within seconds to minutes after administration of inhaled insulin; it was mild and was not associated with changes in pulmonary function. Cough was noted early in the treatment course (within the first month) and diminished in frequency and severity over time. Cough may be seen in up to 21% of persons using Exubera inhaled insulin, compared to 4% to 8% for patients not using it.

Diabetes mellitus is known to affect the lung. The underlying mechanism(s) that cause change are unclear. Mediators of inflammation, such as IL-1, IL-6, and TNF are associated with insulin resistance. Reduction in inflammatory markers with tight glucose control has been reported implicating diabetes itself as a cause of systemic inflammation. It is possible that this inflammatory process is involved in the pathophysiology of diabetes related lung disease. It has also been postulated that lack of insulin in lung tissue causes increased oxidative stress and the production of free radicals. Pulmonary function test changes are seen in diabetes patients. When compared with nondiabetic adults, individuals with diabetes mellitus have some reduction in pulmonary function, namely lower average values for FVC and FEVi. Glycemic control is not felt to be as important to this deterioration as is the duration of the diabetes. Sandier and associates demonstrated that the lower mean DLCO/alveolar ventilation in diabetes patients was associated with a lower pulmonary capillary blood volume, hypothesized to be due to pulmonary microangiopathy, premature lung aging, or glycosylation-induced alterations in hemoglobin-carbon monoxide reaction rates (74).

In clinical trials, Type 1 diabetes mellitus patients receiving inhaled insulin had a decline in FEVi from baseline when compared to those in a comparison group treated with subcutaneous regular insulin [weighted mean difference, -0.031 L (CI -0.043 L to -0.020 L)]. The modest decline in FEVi seen with inhaled insulin was statistically significant. The decrease in FEVi was slowly progressive over the first 6 months but stabilized in studies of up to 2 years’ duration. Among patients with Type 1 diabetes mellitus, inhaled insulin was associated with a greater decrease in DLCO from baseline than was subcutaneous insulin [weighted mean difference, — 0.902 mL/min/mmHg (CI, -1.546 to -0.258 mL/min/mmHg)]). The decline in diffusing capacity of the lung for carbon monoxide (DLCO) was evident in studies of 24 weeks duration or less, although there was no difference in the 2-year study. In a 12-week crossover trial, DLCO returned to baseline after patients were switched back to subcutaneous insulin. Among patients with type 2 diabetes mellitus, there was no difference in DLCO from baseline between the inhaled insulin group and the comparison group in studies up to 2 years in duration. The modest decrease in DLCO does not have any recognized clinical correlates.

Before starting inhaled insulin, a baseline spirometry should be obtained. Following initiation of inhaled insulin therapy, repeat spirometry is recommended at 6 months and then yearly as long as there is no deterioration in pulmonary function.

Inhaled insulin is contraindicated in patients with any degree of pulmonary compromise. Pathology of the lung as well as other exogenous factors play a crucial role in the absorption, delivery, and systemic exposure of inhaled insulin. Several pulmonary conditions impact systemic exposure to inhaled insulin. In chronic smokers, the alveolar-capillary membrane is more permeable, increasing absorption of insulin by two- to fivefold; chronic obstructive pulmonary disease increases exposure by about 50%. Asthma decreases it by 20% to 30%. Acute smoking attenuates absorption, perhaps due to reversible constriction of the airways. Active smokers should not be started on inhaled insulin, and previous smokers must demonstrate at least 6 months of abstinence. It is also known that passive smoking decreases exposure to inhaled insulin by 20% to 30%.

DETERMINANTS OF INSULIN EFFICACY

Factors Determining Absorption of Subcutaneously Administered Insulin in the Ambulatory Patient

Understanding variables that influence rates of absorption of insulin from the subcutaneous injection depot enables one to develop a clear understanding of how they will act to impact blood glucose and of the importance of consistent timing of doses with regards to time of day and to meals. The degree of absorption of any insulin dose, both among patients and in the same patient, can vary from day to day by as much as 25% to 50%, leading to unexplained fluctuations in glycemic control. This effect is greatest with long-acting insulins and least with regular, lispro, aspart, and glulisine insulin. There is some suggestion that day-to-day variability of absorption is less with insulin determir compared to glargine, but the clinical significance of this observation has not been established.

Factors that influence insulin absorption include: the time course of dissociation of injected insulin in the subcutaneous depot, size of the subcutaneous depot, site of the injection, subcutaneous blood flow, impact of exercise on uptake from the injection site, presence of hypertrophy or atrophy in the subcutaneous injection site, and the presence of anti-insulin antibodies.

Time Course of Dissociation

As has already been mentioned, the time it takes for the insulin to dissociate into monomers, which can be absorbed directly across the capillary basement membrane is a strong determinant of its time to onset of action, to peak levels in the circulation, and its duration of action. For example, regular insulin must first dissociate into dimers, then into monomers, a process that takes 30 to 60 minutes following administration of a subcutaneous shot and is maximal 2 to 4 hours following delivery of the dose. On the other hand, rapid-acting insulin analogs dissociate more quickly into monomeric form following injection, which results in their shorter time to onset of action and an ability to dose these analogs with a meal.

Insulin Type

The type of insulin administered determines the time of onset, peak activity, and duration of action of subcutaneous administration.

Size of the Subcutaneous Insulin Depot

Variability in absorption is increased and net absorption is reduced with increasing size of the subcutaneous depot. While it is not common for the adult with Type 1 diabetes mellitus to be on high doses of insulin, in the patient who is taking large number of units of insulin in a given dose, e.g., over 50 to 100 U in a single injection, it is preferred to split the shot into two equally divided doses to decrease the size of the depot, thereby promoting efficacy and reducing absorption variability.

Injection Technique

Both the angle of needle entry and the depth of penetration affect the rate of insulin absorption. Very shallow insertion can cause a painful intradermal injection that will not be well absorbed. In comparison, a perpendicular injection in a lean area may result in an intramuscular injection, from which absorption is more rapid.

The recommended insulin injection technique is to use an area of the body in which about 2.5 cm (1 in.) of subcutaneous fat can be pinched between two fingers. The syringe, with a 0.5-inch microflne (27 G) or ultraflne (29 G or 31 G) needle, is inserted perpendicular to the pinched-skin up to the hilt and the insulin is then injected. The needle should be held in place for several seconds before being withdrawn to avoid insulin leakage after withdrawal of the needle.

Site of Injection

Potential sites for injection are the upper arms, abdominal wall, thighs, and buttocks. Insulin is absorbed most rapidly from the abdominal wall, slowest from the leg and buttock, and at an intermediate rate from the arm. At any of these sites, the rapidity of insulin absorption varies inversely with subcutaneous fat thickness.

Rate of Subcutaneous Blood Flow

The degree of absorption is also impacted by the rate of subcutaneous blood flow. Insulin absorption is reduced by smoking and increased by any increase in skin temperature induced by such things as exercise, saunas or hot baths, and local massage. These variations are more marked with regular and rapid-acting insulins than with long-acting insulins.

POTENTIAL COMPLICATIONS OF INSULIN THERAPY

PHYSIOLOGIC REPLACEMENT THERAPY INSULIN REGIMENS

INSULIN DOSING ADJUSTMENTS AND PATTERN MANAGEMENT

GUIDELINES FOR DOSING CORRECTION/SUPPLEMENTAL INSULIN

SPECIFIC PRACTICAL GUIDELINES FOR PATTERN MANAGEMENT

Core Insulin Adjustment Guidelines

Core insulin adjustment guidelines will address basic recommendations for correction of hypoglycemia, hyperglycemia, variations in food intake or level of physical activity, and days when the patient is sick or stressed. When glycemic control is suboptimal and both hyperglycemia and hypoglycemia are present, one should first address hypoglycemia and correct it. This approach is recommended for several reasons. First and foremost, the short-term hypoglycemia is a safety issue. In addition, if hyperglycemia is due to rebound from hypoglycemic episodes, e.g., nocturnal hypoglycemia leading to high fasting blood glucose or to sequential extra correction doses of insulin, then increasing the insulin dose to treat highs will only exacerbate the tendency for hypoglycemia, perpetuating a vicious cycle of lows and highs.

Adjusting for Hypoglycemia

In evaluating episodes of hypoglycemia, one must first establish whether the lows are explained or unexplained as this will impact whether or not insulin doses need to be adjusted as the corrective action of choice. An exploration of variables that may be causing the hypoglycemia should be undertaken. Is the hypoglycemia explained by a decreased food intake, e.g., skipped meal or bedtime snack; an increase in the number of insulin doses taken, e.g., serial correction doses to treat a high; an increase in the number of units of insulin taken in a dose, e.g., a large correction dose; or by an increase in physical activity? If the explanation was an isolated occurrence, then the corrective action is to try and avoid the circumstances that caused it, e.g., to carry a snack when it is likely a meal will be skipped. If it is known that the explanation is going to be an ongoing phenomenon, e.g., beginning of an effort to lose weight through a cut in caloric intake or initiation of a regular exercise program, then the responsible insulin is adjusted downward to avoid further recurrences, per the general guidelines for basal and bolus insulin adjustment discussed earlier in this section.

Guidelines for Treating Hypoglycemia

Simple carbohydrate is taken to treat hypoglycemia. The patient should be advised to avoid indiscriminately ingesting large quantities of food or calories-containing beverages (such as regular soda or juice) in response to symptoms of hypoglycemia, as this will contribute to subsequent hyperglycemia. In general for blood glucose of 51 to 70 mg/dL, treatment with 10 to 15 g of fast-acting carbohydrate is recommended; blood glucose less than or equal to 50 mg/dL is treated with 20 to 30 g. blood glucose should be retested 15 minutes after carbohydrate ingestion and repeat treatment taken as needed, based upon the blood glucose result. The patient should also be advised to eat a more substantial snack or a meal that was missed or is late following initial treatment of a hypoglycemic reaction. This will prevent a recurrence. Once blood glucose is more than 70 to 80 mg/dL, the patient can generally safely take an appropriate prandial dose to cover carbohydrate intake with the next scheduled meal to be eaten.

Adjusting for Hyperglycemia

Insulin doses will be adjusted upward when a pattern demonstrating hyperglycemia at a given time of day is present for 2 to 3 days in a row at the same time of day and the hyperglycemia is unexplained by increased food intake, inactivity, or the somogyi phenomenon (rebound hyperglycemia).

If the hyperglycemia is explained by an increased food intake or a decline in physical activity, it is preferable to correct the underlying lifestyle indiscretion rather than to raise the insulin dose(s). If fasting hyperglycemia is present, and particularly if fasting hyperglycemia is seen in association with wide variation in blood glucose values, including the presence of normal and/or lower values, one must exclude the possibility that the highs represent rebound in response to nocturnal hypoglycemia. This distinction is accomplished by asking the patient to check a blood glucose reading between 2 and 3 AM to see if it is normal. If the overnight blood glucose is high, then it is appropriate to adjust the basal insulin dose upward to move blood glucose levels toward the desired target range. If this value is low, it demonstrates that nocturnal hypoglycemia with subsequent rebound is the likely cause of the fasting highs, and the appropriate insulin adjustment is a reduction by 10% to 20% in the basal insulin that is acting at this time of night, e.g., once daily glargine or detemir dose or the evening dose of twice daily dosed insulin NPH or detemir.

Adjusting Insulin for Variations in Food Intake

In order that postprandial blood glucose levels will be optimized, it is necessary for the provider and the patient to have an understanding of the relationship between the caloric content, and in particular the carbohydrate content of the meal, as the latter is the major contributor to the postprandial glycemic excursion. Prandial insulin dose will be matched with the anticipated or actual carbohydrate content of the meal. In the consistent carbohydrate meal plan, the number of grams of carbohydrate included in a given meal from day to day will be kept constant, thus allowing a prespecifled insulin dose prescribed to be taken with the meal to control the postmeal glucose excursion. The nutritionist diabetes educator will typically provide a meal plan that incorporates in the range of 30 to 45 g of carbohydrate with each of breakfast and lunch and 45 to 60g of carbohydrate daily with dinner, depending on the patient’s total daily caloric intake. The bedtime snack will contain 15 or more grams of carbohydrate if it is to be taken with a dose of insulin.

The second method whereby insulin doses are matched to carbohydrate content of the meals is carbohydrate counting in which a predetermined insulin-to-carbohydrate ratio is matched to the premeal anticipated or postmeal known carbohydrate content. Carbohydrate counting requires the patient to count grams of carbohydrate and estimate insulin doses based on carbohydrate intake. An average of 1 U of short- or rapid-acting insulin will dispose off 10 to 15 g (one starch equivalent) of carbohydrate, with a range of 0.5 to 2.0 U. In the adult with Type 1 diabetes mellitus, where the total daily insulin requirement is typically not very high and insulin resistance is not present, it is generally safe to start with an insulin-to-carbohydrate ratio of 1 U of insulin for every 15 g of carbohydrate. This method allows flexibility in the content of each meal. The patient can increase the amount of insulin taken with the meal, e.g., if eating out, or to reduce it in the event that a meal will be small or one does not feel like eating.

The insulin-to-carbohydrate ratio will account for insulin sensitivity relative to the postprandial glycemic excursion. It is important to note that insulin-to-carbohydrate ratios can vary with time of day, and that they are affected by stress, illness, and variations in physical activity. One should also note that the dawn phenomenon often induces a state of relative insulin insensitivity in the early morning, in which case it may be necessary to provide one insulin-to-carbohydrate ratio for the patient to take with breakfast, e.g., 1/10 and another ratio for the other meals of the day, e.g., 1/12 or 1/15 to appropriately match each to individual requirements.

Several formulae may also be applied to calculate an individual insulin-to-carbohydrate ratio: the 450 or 500 rule and the weight method. The 500 or the 450 rule may be used when a dose of insulin given before a meal results in postprandial blood glucose levels in the target range. The insulin-to-carbohydrate ratio by the 450 or 500 rule is calculated as follows:

•   Rapid-acting insulin (aspart, glulisine, or lispro)-to-carbohydrate ratio = 500 divided by TDDI.

•   Regular insulin-to-carbohydrate ratio = 450 divided by TDDI.

As an example, if the individual TDD is 50 U and the patient uses a regimen with prandial rapid-acting then the insulin-to-carbohydrate ratio would be 500 divided by 50 or 1 U of analog for 10 g of carbohydrate.

Table Weight-Based Insulin to Carbohydrate Ratios

The weight method for determining the insulin-to-carbohydrate ratio uses assignment of a ratio from a table based upon the patient’s weight to provide the insulin-to-carbohydrate ratio.

Whichever method of matching insulin-to-carbohydrate content of the meal is used, it is important to assess the impact of the dose on postmeal blood glucose levels by checking a finger-stick value 60 to 90 minutes after a dose of rapid-acting insulin analog has been given with a meal or 2 hours after the meal if regular insulin is provided as the prandial insulin. If this value is high, and a consistent carbohydrate diet is being used, the premeal insulin bolus dose will be raised by 10% to 20%. If the postmeal blood glucose is above target and if an insulin-to-carbohydrate ratio is used to determine the premeal dose, the ratio will be increased, typically in 2 to 5 g increments, e.g., from 1/15 to 1/12 or 1/10, depending upon the rise in magnitude of the blood glucose after the meal. Conversely, when blood glucose following a meal is lower than desired, the number of units of insulin given per gram of carbohydrate prior to the meal will be reduced.

Adjusting Insulin for Changes in Activity/Exercise

Increased levels of physical activity, including formal exercise, impact blood glucose control by promoting movement of glucose into glycogen stores in the peripheral tissues. The entry of glucose into skeletal muscle is increased during exercise via an insulin-independent increase in the number of GLUT 4 transporters in muscle cell membranes. This increase in glucose entry persists for several hours after exercise and regular exercise training can produce prolonged periods of time where insulin sensitivity is increased. Exercise can precipitate hypoglycemia in diabetes not only because of the increase in muscle uptake of glucose but also because absorption of injected insulin is more rapid during exercise. Patients with diabetes will often need to either take in extra calories or reduce their insulin dosage when they exercise. If body weight is a concern, it is preferable to lower insulin doses in anticipation of exercise rather than to ingest extra calories to prevent hypoglycemia. Determination of the optimum insulin regimen for the patient with diabetes mellitus 1 for exercise will be facilitated by careful blood glucose monitoring in the periexercise period until insulin requirements are determined and appropriate insulin doses for these times have been determined. blood glucose testing is recommended before, during, and after the activity to monitor the patient’s response to exercise. Exercise-induced hypoglycemia may occur many hours after the activity as glycogen stores are repleted. This is particularly true following intense exercise, such as weight lifting and/or prolonged periods of aerobic exercise such as long-distance running or biking.

If exercise is planned, insulin dosages will be adjusted in anticipatory fashion in order to decrease risk for hypoglycemia either during or following the period of increased physical activity. It is not uncommon for the patient with Type 1 diabetes mellitus who exercises regularly to have one insulin regimen for exercise days and another for days on which exercise is not undertaken. Premeal rapid-acting or regular insulin can be reduced 25% to 50% for moderate levels of planned postprandial activity. If the activity is strenuous, the patient may need additional carbohydrate along with the reduction in premeal insulin. Patients using insulin pumps can temporarily lower the basal rate by 20% to 40% for sustained periods of exercise, particularly those lasting over 60 minutes. A reduction in the basal rate by 25% during postexercise hours may also be necessary to avoid postexercise hypoglycemia. Suspending the basal rate for more than one hour is not recommended in the insulin deficient patient who has Type 1 diabetes mellitus as ketogenesis may develop.

If exercise is unplanned, ingestion of additional carbohydrate will be necessary (15-30 g of carbohydrate for every 30 to 45 minutes of moderate exercise). It is also important to note that it is always necessary for the patient with diabetes to maintain adequate hydration during exercise as dehydration has a negative impact on insulin sensitivity.

Adjusting Insulin for Illness or During Periods of Stress: Sick Day Rules

Stress and illness clearly impact glycemic control. In the patient with Type 1 diabetes mellitus, release of insulin counterregulatory hormones under such circumstances will typically lead to hyperglycemia. Indeed progressive development of hyperglycemia without other aggravating factors may indicate that an illness, e.g., urinary tract infection or viral syndrome is in its prodromal stages. Careful questioning of the patient about symptoms that suggest underlying illness is part of a thorough assessment under these circumstances. It is necessary for the patient to have a plan of action to enable glycemic control on sick days.

Diabetes education for the adult patient with Type 1 diabetes mellitus should include a thorough grounding in the general principles of sick day management, which includes the following:

•   Checking finger-stick BGs every 4 hours if not eating, or before meals and bedtime if eating discrete meals.

•   Check 2 to 3 AM blood glucose if running high at bedtime or nocturnal hypoglycemia is suspected.

•   Take all usual prescribed doses of basal insulin glargine or detemir, with adjustment in basal dose(s) as described below.

•   Reduce NPH insulin doses by 1/3 to 1/2 if food intake curtailed (to prevent hypoglycemia when the NPH peaks).

•   Take usual meal insulin doses if eating well with a correction insulin dose if premeal blood glucose is high; if not eating well, decrease meal insulin dose by 50% and consider taking at the end of the meal after assuring that the food is eaten.

•   Maintain hydration.

•   Check urine for ketones.

•   If vomiting and cannot keep food or liquids down, go to the emergency room.

Table Practical Guidelines for Insulin Adjustment in Adults with Type 1 Diabetes Mellitus^a

Multiple daily insulin insulin dose adjustments are made to minimize hyperglycemia on sick days or during periods of stress.

•   If all BGs are running high, basal insulin dose(s) will be adjusted upward by 20% increments.

•   Correction or supplemental doses of insulin will be given in addition to basal and prandial insulin doses when hyperglycemia is present. Correction or supplemental doses of insulin will be determined by calculation of a correction dose based on the total daily insulin requirement, e.g., by the rule of 1800 or as 10% of the TDDI if urine is dip negative for ketones and as 20% of the total daily insulin requirement if there are ketones in the urine (as discussed earlier), or by use of a correction dose scale.

•   As with all insulin doses prescribed, it is essential to review the impact of sick day doses given to an individual patient and to revise these doses per BGs obtained to assure that they lower blood glucose appropriately while minimizing risk of hypoglycemia.

CSII dose adjustments

•   When the patient is being treated with an insulin pump, the sick day insulin dose adjustments are to increase the basal insulin rate by about 50% and the bolus insulin doses by 20%.

HOSPITAL MANAGEMENT

The principles of using physiologic insulin replacement to mimic normal insulin secretion patterns that are used in the outpatient with Type 1 diabetes mellitus generally are applied in hospital management of adults with Type 1 diabetes mellitus as well.

Hypoglycemia

The normal physiologic response to hypoglycemia includes early suppression of insulin secretion, release of glucagon and catecholamines, and later release of cortisol and growth hormone. It is important to understand that persons with Type 1 diabetes mellitus have alterations in the physiologic suppression of insulin and release of glucagon expected in response to low blood glucose, which impairs ability to return blood glucose levels to normal. These pathophysiologic alterations are present in as few as 5 years after Type 1 diabetes mellitus develops. In addition, hypoglycemia itself impairs the autonomic nervous system activation that is expected when hypoglycemia occurs, further impairing the patient’s response. For a full discussion of the pathophysiology of insulin counterregulatory responses in Type 1 diabetes mellitus.

Hypoglycemia is the most serious complication of intensive insulin replacement regimens and often will be the factor that limits ability to achieve intensive targeted glucose control. In the Diabetes Control and Complications Trial, patients in the intensive treatment group had a threefold greater risk (62%) of severe hypoglycemia when compared to those in the conventional treatment group (19%) (p < 0.001). It is therefore important to make efforts to prevent hypoglycemia from occurring in adults with Type 1 diabetes mellitus.

Practically speaking, mild hypoglycemic reactions that the patient senses and can treat are not uncommonly associated with intensive insulin therapy. Severe hypoglycemia with neuroglycopenia can however lead to confusion, aggressive behavior, loss of consciousness, seizures, coma, and death. Severe reactions may also result in motor vehicle accidents and serious falls with traumatic injuries. Certain patients, particularly those adults with long-standing Type 1 diabetes mellitus and autonomic neuropathy, may not subjectively sense any symptoms of hypoglycemia even in the presence of dangerously low-glucose concentrations. The presence of recurrent severe hypoglycemia is an indication to liberalize blood glucose targets, i.e., raise both the lower and upper limits of the target blood glucose range in order to prevent such occurrences. Risk of insulin-induced hypoglycemia can be reduced if the patient is carefully educated about recognition of his/her individual warning signs of hypoglycemia and/or of their blunting or absence as applicable, and know how to treat hypoglycemic reactions appropriately. If hypoglycemic unawareness is present, a family member and/or work colleague or friend(s) should be instructed in recognition of the signs and symptoms of hypoglycemia and in use of a glucagon emergency kit. In patients with advanced end-stage microvascular or macrovascular diabetes complications in whom the benefit of intensive glucose control is less clear, one may also consider liberalization of blood glucose targets in order to avoid increased risk of hypoglycemia that is inherent in intensive insulin treatment

regimens. Despite the higher risk of severe hypoglycemia with intensive insulin therapy, in the Diabetes Control and Complications Trial serial neuropsychological testing showed no long-term changes in cognitive function.

In Type 1 diabetes mellitus patients treated with Exubera, the frequency of all hypoglycemic episodes was similar to those treated with subcutaneous regular insulin over 12 and 24 weeks of therapy (5.58% vs. 5.4%, respectively). However, the rate of severe hypoglycemia [defined as that requiring assistance by another, involving a neurological symptom (memory loss, confusion, irrational behavior, unusual difficulty walking, seizure, loss of consciousness) and associated with an SMBG < 50 mg/dL or in the absence of SMBG, that which was reversible with oral carbohydrate, subcutaneous glucagon or intravenous glucose] was twice as frequent with insulin Exubera [6.5 vs. 3.3; RR 2.00 (CI 1.28 to 3.12)], compared with subcutaneous regular.

Treatment for mild hypoglycemia consists of 15 to 30 g of a rapidly absorbed source of carbohydrate such as 4 ounces of juice or regular soft drink, 4 ounces of skim milk, a small tube of gel cake frosting, or commercially available glucose tablets or gels. A finger-stick blood glucose check and the ingestion of carbohydrate is repeated every 15 to 20 minutes until the blood glucose level has returned to normal. Rapid-acting carbohydrate should be followed by a snack or by a meal that was missed or is due in order to prevent hypoglycemic recurrence.

In addition to the availability of glucose tablets, hard candy, or other sources of a readily absorbable form of carbohydrate, it is recommended that all patients with Type 1 diabetes mellitus should have emergency glucagon kits available at home and at work, assuming that there are people who can be trained in their use. In the event of an unconscious hypoglycemic reaction, 0.5 to 1 mg of glucagon given intramuscularly rapidly raises the plasma glucose concentration to an acceptable range and avoids the difficulties and dangers associated with attempting to get a comatose, stuporous, or disoriented individual to ingest glucose by mouth. Again, once the patient has sufficiently recovered from the episode, a snack or meal should be eaten.

Weight Gain

Improvement in glucose control with a reduction in glycosuria is often associated with weight gain as loss of calories in the urine is reduced. Increased food intake to treat or prevent recurrent hypoglycemia can also contribute to weight gain. Insulin itself may stimulate appetite. Recent data from clinical trials for insulin detemir consistently show slightly less weight gain when compared to NPH (as discussed in the insulin section earlier in this chapter). Mechanism(s) underlying a potential for less weight gain with insulin detemir are unknown. Data from mouse models suggest that dysregulation of insulin action at the level of the insulin receptor and downstream signaling targets in the central nervous system are associated with obesity and diabetes. In the brain, intact insulin signaling via the IRS-PI 3-kinase pathway is essential for nutrient homeostasis and appetite regulation as pharmacological inhibition of insulin signaling, especially in the hypothalamus, leads to obesity-induced diabetes. Keeping in mind that clinical trials have shown that insulin detemir therapy is characterized by weight stability or even modest weight loss, it has been hypothesized that in addition to activating the insulin-signaling cascade in peripheral tissues detemir may also activate cerebral insulin signaling. It is known that albumin directly penetrates into the cerebrospinal fluid across choroids plexus epithelial cells. In this model, it is postulated that detemir’s cerebral action may be enhanced due to its attached fatty acid chain. The long-term clinical significance of this modest but reproducible weight advantage that has been seen in clinical trials with detemir remains to be determined.

Exacerbation of Retinopathy

Intensive therapy slows the rate of development and progression of mild to moderate retinopathy. In addition, in the Diabetes Control and Complications Trial it was found that retinopathy occasionally worsens in the first year after initiation of intensive therapy, which manifests as an increase in the number of soft exudates (due to retinal infarcts in the superficial layers). This is felt to represent the closure of small retinal blood vessels that were narrowed but previously patent. Correction of hyperglycemia lowers plasma volume, which places marginal vessels at-risk. Increased availability of insulin-like growth factor-1 (IGF-1) may also contribute.

Despite the early exacerbation of retinopathy seen in the Diabetes Control and Complications Trial, there was clear evidence of benefit from intensive therapy when patients with mild to moderate nonpro-liferative retinopathy were followed for 9 years. Specifically, the incidence of worsening retinopathy in intensively treated patients was higher than in those receiving conventional therapy at 1 year (7.4% vs. 3%) but much lower at 9 years (25% vs. 53%).

Insulin Allergy

Allergy to recombinant human (rDNA) and biosynthetic insulin preparations is a rare complication of insulin therapy. Insulin antibodies of high titers were observed in many patients treated with early insulin preparations containing proinsulin, C-peptide, and other peptide contaminants. Immunoglobulin G-insulin antibodies in very high titers can lead to immune-mediated insulin resistance, which is now extremely rare.

Currently, the prevalence of allergic reactions during insulin treatment is around 2%, but less than one-third of reported events are considered related to insulin itself.

Transition from animal insulins to rDNA insulins has markedly decreased the incidence of allergic reactions. Allergenicity of the insulin molecule itself is felt to be attributed to the chemical structure of the terminal part of the beta chain. Other causes of insulin therapy associated allergic responses are other components of insulin preparations, including protamine, additives such as cresol or zinc, and latex.

Insulin antibodies of the immunoglobulin G and immunoglobulin E type are reported in low titers in patients treated exclusively with human insulin. Frequency and levels of immunoglobulin G-insulin antibodies are identical in patients treated either with biosynthetic or semisynthetic human insulin preparations. Allergic symptoms to human insulin are now found in less than 1% of de novo-treated patients. Overall immunological complications of insulin therapy have decreased significantly during the last two decades and are now predominantly observed in patients with interrupted insulin therapy.

The most common manifestation of allergic reactions to insulin consists of local wheal-and-flare reactions at the site of injection. Occasionally, more generalized allergic reactions occur, and even more rarely anaphylactic reactions. Mild local allergic reactions to insulin can be treated by first trying a switch to an alternative insulin preparation, or with antihistamines or by the addition of low doses of dexamethasone to the insulin vial. More severe reactions require desensitization. In the future, anti-immunoglobulin E treatment with omalizumab may offer another alternative to these patients.

Lipodystrophy: Lipoatrophy and Lipohypertrophy

Repeated insulin injections at a site sometimes lead to dystrophic change. Atrophy of subcutaneous fatty tissue known as lipoatrophy. Lipoatrophy is an immune complication of insulin therapy, which is not often seen seen since the development of the current human insulin preparations and insulin analogs. It was reported previously in 10% to 55% of patients treated with nonpurified bovine/porcine insulin preparations, but has almost disappeared since the advent of human insulins. In fact, injection of these newer preparations directly into the atrophic area often resulted in restoration of normal contours. Even with the purified human insulins, hypertrophy of subcutaneous fatty tissue may be a problem if one injects repeatedly at the same site. This complication of insulin therapy may be largely avoided by broad rotation of subcutaneous shot or CSII pump insertions sites. Lipohypertrophy that is problematic may be treated by liposuction.

Conventional Insulin Therapy

Conventional insulin therapy is used to describe simpler, usually fixed dose insulin regimens, such as single daily injections, or two injections per day of regular and NPH insulin, either mixed together in the same syringe or provided as a premix of insulins, which are given in prespecified doses before breakfast and dinner. Such regimens are based on the concept that each of the insulin components in the two doses is covering insulin needs for one-quarter of the day and results in a single peak of insulin absorption. Such mixed-split regimens are not physiologic. In addition, conventional insulin therapy is unlikely to enable achievement of target HbAlc levels in patients with Type 1 diabetes mellitus and are no longer recommended unless the adult with Type 1 diabetes mellitus cannot or will not comply with an intensive insulin regimen.

Intensive Insulin Therapy

In patients with Type 1 diabetes mellitus and deficiency of endogenous insulin production, the exogenous insulin regimen will be designed to simulate as closely as possible the multiphasic profile of insulin secretory responses to meals and snacks present in normal subjects in order to enable targeted glycemic control. The term intensive insulin therapy is used to describe more complex insulin administration regimens in which basal insulin therapy is combined with bolus doses of insulin given three or more times daily timed to correspond with ingestion of meals and/or snacks. When the intensive insulin therapy is delivered by subcutaneous injection, the regimen is known as a multiple daily injection (multiple daily insulin) regimen. Intensive insulin therapy is also delivered by continuous subcutaneous insulin infusion (CSII) using an external insulin pump. Currently in the United States, approximately 25% to 30% of persons with Type 1 diabetes mellitus are treated with insulin pumps.

In multiple daily insulin, basal insulin is delivered as once or twice daily long-acting or twice daily intermediate-acting insulin and in CSII basal insulin is delivered in continuous fashion. In both multiple daily insulin and CSII, bolus/meal insulin is delivered as discrete doses in conjunction with food intake, by shot in the multiple daily insulin regimen and by activation of a bolus for delivery by the insulin pump in CSII.

In one trial comparing CSII using insulin aspart versus multiple daily insulin with insulin aspart and glargine, CSII therapy resulted in lower glycemic exposure [40% lower for CSII than multiple daily insulin as measured by area under the curve (AUC) glucose > 80 mg/dL and AUC glucose > 140 mg/dL] without increased risk of hypoglycemia [CSII: 92% (73% for nocturnal hypoglycemia), multiple daily insulin: 94% (72% for nocturnal hypoglycemia)], as compared with multiple daily insulin (93).

Considerations in the Decision to Intensify Insulin Therapy

As mentioned earlier in this chapter, studies suggest that intensive therapy should be started as early as possible following the diagnosis of diabetes mellitus 1 and that it has clear benefits for patients with Type 1 diabetes mellitus when implemented at any time in the course of the disease. It is important to consider the practical aspects of such a regimen in the discussion with the adult patient with Type 1 diabetes mellitus who is to intensify insulin therapy. Following are the issues for consideration:

•   A commitment by the patient to follow the regimen is required. It will be necessary to manage and coordinate diet, activity, insulin administration, and blood glucose monitoring. Algorithms for insulin administration in multiple daily insulin management of Type 1 diabetes mellitus involve frequent monitoring of the blood glucose concentration, generally at a frequency of four or more times per day.

•   The incidence of hypoglycemia may be increased up to threefold in patients with Type 1 diabetes mellitus managed with intensive insulin regimens.

•   Weight gain is more likely with intensive insulin therapy regimens, which can limit patient compliance, particularly in women. Addition of pramlintide (Symlin) to the therapeutic regimen can help mitigate postprandial hyperglycemia and may allow weight loss rather than gain as hyperglycemia is controlled in some patients. Its ability to increase satiety, slow gastric emptying, and suppress glucagon secretion can impact postprandial hyperglycemia when used in combination with insulin therapy.

•   The cost of intensive insulin therapy is about three times that of conventional treatment, based upon an analysis of the Diabetes Control and Complications Trial. On the other hand, intensive therapy is associated with a lower incidence of costly chronic complications. Formal economic analyses have demonstrated that intensive therapy is cost-effective for the treatment of diabetes.

Multiple daily insulin Insulin Regimen

Long-Acting Basal Insulin Once (or Twice) Daily with Rapid-Acting Bolus Insulin Before Each Meal

This multiple daily insulin basal-bolus insulin regimen simulates the pattern of insulin production, which occurs physiologically in the person without diabetes. Basal insulin action will most commonly be provided by insulin glargine or detemir. Insulin glargine will generally be given once daily for control of fasting and premeal glucose levels. This dose is given at the same time daily and may be delivered either at bedtime, or with breakfast or dinner. It is a practical consideration to allow the patient to select which of these times of day he/she would be most likely to consistently take the basal insulin glargine dose to assure adherence to the regimen. In a small percentage of patients, the duration of action of glargine is not a full 24 hours, which then necessitates twice daily shots to provide continuous basal insulin action. Insulin detemir is given once or twice daily. Typically for the lean patient with Type 1 diabetes mellitus whose total daily insulin requirement is modest (and particularly if under 0.1 U/kg/day), twice daily dosing of insulin detemir is used. As discussed in the insulin section above, clinical trials dosing of detemir in Type 1 diabetes mellitus, which demonstrated safety and efficacy were carried out using both once and twice daily dosing of detemir. When dosed twice daily, insulin detemir is typically given with breakfast and at bedtime or at dinner time, depending upon which of the latter times would evenly distribute the timing of the twice daily doses. When used once daily, insulin detemir is typically dosed in the same fashion as described for insulin glargine, although it should be noted that currently in the United States, it is formally indicated only for PM dosing when prescribed once daily.

In the patient who is taking either insulin glargine or detemir as a once daily dose, a pattern whereby a rise in blood glucose levels in the hours prior to the time for administration of the basal insulin dose for the day, that is not attributable to the intake of food or reduction in the prior meal’s insulin dose, suggests that the basal insulin action is waning and that twice daily dosing is indicated.

Bolus doses of rapid-acting insulin analog are preferred in the multiple daily insulin regimen due to their rapid time to onset of action, which allows dosing with the meal, rather than regular insulin, which must be given with a 30 to 45 minute lag time if dosed premeal. The rapid-acting analogs will provide insulin coverage to control postmeal glycemic excursions. They may also be given if a carbohydrate containing snack is to be taken. As mentioned earlier and as discussed below under insulin adjustment recommendations for variations in meal portion size and carbohydrate content in detail, the meal bolus of insulin is generally matched to the carbohydrate content of the meal, either through implementation of a consistent carbohydrate diet or by using carbohydrate counting to match insulin dose to the meal’s carbohydrate content.

Alternative multiple daily insulin Regimens

Alternative multiple daily insulin regimens using NPH insulin have been described; however, they are generally not used widely for treating persons with diabetes mellitus 1 since the advent of the long-acting basal insulins, which when dosed once or twice daily have essentially no peak effect, thereby conferring lesser risk of hypoglycemia than an NPH-containing insulin regimen. In such regimens, three shots of NPH given at breakfast, dinner, and bedtime are used to meet the basal insulin requirement combined with two shots of rapid-acting bolus insulin delivered with breakfast and with dinner. The third dose of NPH insulin at bedtime in this multiple daily insulin regimen takes into account the observation that in individuals with Type 1 diabetes mellitus, the duration of action of the intermediate-acting insulin given before dinner is insufficient to control blood glucose in the early morning hours. Attempts to increase the dose of intermediate-acting insulin at dinner would expose the patient to a greater risk of hypoglycemia in the middle of the night, hence the incorporation of a modest dose of NPH at bedtime provides sufficient insulin action to control glycemia in the morning while minimizing risk of nocturnal hypoglycemia.

Practical Guidelines for Calculation of Insulin Doses for the multiple daily insulin Regimen

When undertaking calculation of insulin doses for initiation of therapy for any insulin regimen, one must be cognizant of the variability in total daily insulin requirements among individuals and within a given individual, and of the variation in a given insulin’s lag time to onset of action, time to peak, and duration of action. It is also necessary to be aware in the event of making a switch from one type of regimen to another of the level of blood glucose control prior to the time of change. In all of the practical guidelines presented in this chapter for insulin dosing, dosing suggestions are based on evidence presented in the literature and a conservative consensus of opinion designed to assure safety and avoid hypoglycemia at the time of introduction of the new insulin regimen. Close monitoring of finger-stick blood glucose values and insulin doses at the time of such transitions must be undertaken in order to monitor safety and effectiveness of the insulin regimen and to facilitate adjustments as needed to enable attainment of glycemic control targets.

Initiating Insulin Therapy in Type 1 diabetes mellitus

Most newly diagnosed patients with Type 1 diabetes mellitus can be started on a total daily dose (TDD) of 0.2 to 0.4 U of insulin/kg/day, although many may ultimately require 0.5 to 1.0 U/kg/day. In the event of newly diagnosed Type 1 diabetes mellitus with presentation in diabetic ketoacidosis, the total daily insulin requirement will be determined at the time of discontinuation of intravenous insulin infusion treatment. Approximately half (40-50%) of the calculated total daily insulin dose is given as basal either as once per day long-acting basal insulin (glargine or detemir) or as twice daily detemir insulin. The once daily long-acting basal insulin, as previously mentioned is generally given either at bedtime or in the morning; however, it may also be given at dinner time if this will be most convenient for the patient. The remainder of the TDD is then given as rapid-acting (preferred) or regular insulin, divided into before-meal bolus doses. The dose of bolus insulin to be taken before each meal is then allocated as 10% to 15% of the total daily insulin requirement with each meal and a smaller percentage, e.g., 3% to 5% with a snack. If there is a clear difference in the carbohydrate content or insulin requirement for given meals, then the distribution of prandial insulin may be tailored to accommodate the difference(s), e.g., if postbreakfast hyperglycemia is a challenge and lunch typically a smaller meal, one may choose to apportion 20% to 25% of the daily prandial insulin for breakfast, 10% to 15% for lunch, 15% to 20% for dinner, and 3% to 5% for the bedtime snack. Premeal dosages of bolus insulin can also be calculated based on the dietary intake (i.e., 1-2 units of insulin per 10-15 g of carbohydrate). These doses will subsequently be adjusted per usual meal size and content, as well as per how activity and exercise patterns impact individual BGs, as described in the insulin adjustment section below.

Converting from a Conventional Insulin Therapy Regimen to an multiple daily insulin Regimen

It is generally advisable to reduce the total daily basal insulin dose (units) when long-acting basal insulin is to be started at the time of conversion from twice daily NPH by 20% from the previous total daily basal NPH doses. This is particularly important if any episodes of hypoglycemia have been occurring and/or there has been a tendency for BGs to be at the lower limit of the patient’s target range on the prior intermediate insulin regimen in order to prevent hypoglycemia. If switching from twice daily doses of NPH insulin to once daily insulin glargine when the BGs have not been well-controlled, one may prescribe a glargine dose that is equivalent to the total number of units of NPH insulin that were being given daily.

If the patient switches from short-acting insulin (regular) to rapid-acting insulin (lispro, aspart, or glulisine), the dose of the rapid-acting insulin may need to be reduced and the dose of basal insulin may need to be increased, to compensate for the pharmacokinetic differences among these types of insulins, and in particular for the longer tail of regular insulin action that may provide some insulin effect between meals that the rapid-acting analog will not.

CSII by External Insulin Pump

An alternative method of delivering an intensive insulin therapy basal-bolus regimen is by CSII via an external pump. The insulin is delivered through a fine catheter from the pump to a subcutaneous insertion site. The pump delivers insulin as a preprogrammed, variable rate basal infusion as well as patient-directed boluses given before meals or snacks or in response to elevations in blood glucose concentration outside the prespecifled target range.

The basal insulin infusion rate for the adult patient with Type 1 diabetes mellitus commonly falls between 0.2 to 1 U/hr, although it can be higher. The basal rate can be programmed either to continue at a constant rate over the 24-hour period or more commonly to increase and decrease at predetermined times of the day to prevent anticipated excursions in the blood glucose concentration, for example, morning rises in glucose associated with the dawn phenomenon. Typically the patient with Type 1 diabetes mellitus will require anywhere from 3 to 4 or more alternative basal rates to enable tight glycemic control. Pumps provide the ability to use multiple alternative basal profiles to deal with recurrent patterns that require adjustment of insulin doses (e.g., menstruation, weekend lifestyle, and a variety of levels of exercise/activity). In addition they offer profiles, such as dual wave bolus or extended bolus to accommodate anticipated variations in eating patterns, e.g., for eating a large or extended multicourse meal.

Only rapid-acting or regular insulin is used in the insulin pump. Adjustments to the basal insulin infusion rate or changes in the size and timing of the insulin boluses generally allow more timely responses in blood glucose concentration than are seen when adjustments are made to doses of intermediate-acting or long-acting insulin. All of these features confer a potentially greater flexibility for the patient in terms of lifestyle and insulin dosing. It has been suggested that use of lispro insulin may lead to a lower risk of hypoglycemia than the other rapid insulin analogs and/or regular insulin in pumps.

Considerations in the Decision to Start CSII Pump Therapy

There are some practical considerations that the patient and provider must consider together when weighing a decision to use an insulin pump:

•   Patients treated with insulin pump therapy must always monitor glucose frequently (four or more times daily) and must always be alert to the possibility of failure of the infusion system, otherwise unexplained hyperglycemia develops.

•   The pump insertion set must be changed every 24 to 72 hours to assure uninterrupted insulin delivery and to prevent insertion site infections as described below.

•   There is a risk of infection at the subcutaneous insertion site. Infections may occur on average once annually per patient even when best of practices for insertion and site care are used. Such infections are usually minor and can be treated by changing the site of infusion and using a topical antibiotic; a short course of oral antibiotics may also sometimes be required. If an insertion site abscess develops, surgical drainage in conjunction with antibiotic treatment will be necessary.

•   Because rapid-acting insulin is most commonly used, pump failure as a result of mechanical malfunction or catheter-related problems can quickly result in severe hyperglycemia with ketoacidosis that will develop in a matter of hours, as mentioned earlier, in the patient with Type 1 diabetes mellitus.

•   The initial cost of an insulin pump itself is high ($4500-6000 in 2007). One must then also purchase pump supplies on an ongoing basis. The relatively recently released patch, OmniPod pump system requires a lesser initial payment for the PDA device that controls Pod functions and programs insulin dosing (~ $600). Single 72-hour use Pod units are then purchased in prospective fashion on a monthly basis for about $35 each, spreading out cost. Most health-insurance payors will cover 80% to 100% of the cost of a CSII pump system and supplies.

•   Some patients consider pump to be uncomfortable, embarrassing, or otherwise awkward.

Calculation of Initial Insulin Doses for CSII Pump Therapy

Basal will typically be delivered to meet between 40% and 50% of the patient’s total daily insulin requirement. The balance of the daily requirement is given as premeal bolus doses, which will control postprandial glucose excursions. In a patient with reasonably controlled previous multiple daily insulin injection regimen (e.g., Ale < 7.0%), the initial total daily dose of insulin (TDDI) administered by pump may be 10% to 20% less than the TDD of the previous regimen, as absorption of insulin from the subcutaneous delivery site is more efficient. Conversely, patients with a prior trend to hyperglycemia may start with the same TDD as they had been using with their subcutaneous injection regimen. In general, as in the multiple daily insulin regimens described earlier, approximately one-half of the total daily insulin dose is administered as basal insulin apportioned equally at the time of start up into an hourly delivery rate by dividing the desired total daily basal insulin dose by 24 hours to determine the number of units of insulin to be delivered per hour. For most patients, basal rates are in the range of 0.01 to 0.015 U/kg/hr (i.e., for a 60-kg woman approximately 0.6 to 0.9 U/hr), but they can range from under 0.5 to more than 2.0 U/hour. Premeal boluses for pump initiation may be estimated as follows: 20% for breakfast, 10% for lunch, 15% for dinner, and 5% for bedtime snack, or may be determined by carbohydrate counting and an individualized insulin-to-carbohydrate ratio.

The total daily basal rate can alternatively be calculated by multiplying the patient’s weight (in kg) by 0.3. Assuming that this basal rate represents 50% of the total daily insulin requirements for the person with Type 1 diabetes mellitus, an equivalent number of units of insulin used for basal delivery can be distributed between meal insulin boluses as described for multiple daily insulin above or again will alternatively be calculated using carbohydrate counting ratios.

Controlled clinical trials have indicated that on an average, intensive insulin regimens that use multiple insulin injections lead to levels of glucose control similar to those achieved with the insulin pump. On the other hand, there are some patients who never achieve adequate control with multiple daily injections but experience dramatic improvements with pump therapy. According to the Clinical Practice Recommendations of the American Diabetes Association, the insulin pump should be used only by candidates strongly motivated to improve glucose control and willing to work with their health-care provider in assuming substantial responsibility for their day-to-day diabetes self-management.

Implantable Insulin Infusion Pumps

A surgically implanted programmable pump is available in the European Union (EU) and is under investigation in the United States. Studies in patients with both Type 1 diabetes mellitus and type 2 diabetes mellitus have found that this pump system results in glycemic control equivalent to that of multiple daily insulin injections.

The implantable pump has the advantage, compared with intensive regimens using injections or external pumps, of a lower incidence of severe hypoglycemia (4 episodes/100 patient-years vs. 33 episodes/100 patient-years with multiple daily injections in patients with Type 1 diabetes mellitus) and less day-to-day fluctuation in blood glucose concentrations, less weight gain, and better quality of life. These advantages may occur, in part, because implantable pumps deliver into the peritoneal cavity or intravascularly, where absorption into the hepatic portal circulation provides more physiologic insulin delivery to the liver. Systemic insulin levels are lower than those that result when subcutaneous (subcutaneous) insulin shots are used.

Implantable pumps are prone to catheter blockage that may be due to either their slow rate of insulin delivery or increased macrophage activation in some patients. In addition, anti-insulin antibodies occur more commonly with continuous intraperitoneal insulin infusion (CPU) than with CSII.

Numerous clinical circumstances can lead to changes in insulin requirements. These circumstances commonly involve: variations in food intake (portion size and carbohydrate content) and/or timing, exercise frequency, timing and level of intensity, days the patient is ill or stressed, changes in concomitant medications, (e.g., addition or withdrawal of glucocorticoids to/from the treatment regimen), and stage of the menstrual cycle. Even in the patient who adheres to the comprehensive diabetes management regimen, there will be times when blood glucose levels will shift, resulting in high and/or low blood glucose patterns. Finally, pregnancy will necessitate tight glycemic control and frequent adjustments in insulin doses to keep glucoses in target range. In all of these circumstances it will be appropriate for the health-care provider and the patient to evaluate the reasons that have led to suboptimal control in order to make adjustments in the subcutaneous insulin or lifestyle regimen to enable attainment and maintenance of target blood glucose levels. It is also extremely useful, when possible, to make anticipatory insulin adjustments when a recurring circumstance, e.g., exercise will occur in order to avoid loss of control moving forward.

Successful pattern management requires a close collaboration between the patient and the diabetes-care provider team. The Diabetes Control and Complications Trial and recent clinical trials in type 2 diabetes mellitus have demonstrated that, with appropriate education and the provision of insulin treatment algorithms, adult patients are able to self-titrate their insulin doses to achieve treatment targets identified by the patient and their care team.

The goals of pattern management are several fold. It will identify blood glucose trends that are outside target ranges by time of day; all variables that may have contributed to hyperglycemia or hypoglycemia; and provide strategies for safe and effective adjustments in insulin dose(s) that will return blood glucose to, or maintain blood glucose within desired ranges. For practical purposes, insulin adjustment guidelines may be broken into core and advanced adjustments. Basic insulin adjustment guidelines will target correction of low- and high-blood glucose levels, including those which occur on “sick” days, and incorporate core lifestyle considerations in order to (/) optimize the match between prandial insulin and carbohydrate intake to enable postprandial glycemic control and (//) necessary changes in insulin doses for routine exercise. Advanced insulin adjustment guidelines will address such circumstances as travel, perimenstrual patterns, glucocorticoid therapy, and dialysis days.

Establishing Individual blood glucose Goals and Times of Day for blood glucose Monitoring

When embarking on the process of pattern management, one must first establish glycemia-related targets and times of day that finger-stick blood glucose measurements will be performed for the individual patient. It is key to establish with the patient that the recommended goals are acceptable. Selecting mutually agreeable blood glucose goals will help to assure adherence to the prescribed regimen.

Individual targets must always be set for fasting and postprandial glucose and for HbAlc. It may be necessary to lay out stepwise goals for reaching targets over time, particularly if current levels of control are far removed from recommended values, or the patient has concerns regarding the recommended targets. Fear of hypoglycemia as a result of increase in insulin doses and “not feeling right/well” if blood glucose values are lowered to beyond a perceived threshold level are examples of reasons patients may cite as concerns regarding intensification of the insulin regimen that may necessitate stepping of goals and further education to enable them to become comfortable with increasing insulin doses.

Table Recommended Glycemia-Related Targets

One additional concept that is increasingly recognized as a glycemia-related target is glycemic variability. This measure quantifies variation in blood glucose range over the time period of analysis. The concept of glycemic variability acknowledges the fact that HbAlc is an average of BGs in the 2 to 3 months preceding its measurement and that a normal value does not necessarily mean that all BGs have been within the prespecified target range. For example, if a patient has had numerous episodes of both hypoglycemia and hyperglycemia, the HbAlc may appear to be at target because it represents an average of all blood glucose values whether they be high, low, or within the target range. Glucose fluctuation, particularly during postprandial periods and during other times when blood glucose values swing, has been shown to exhibit a triggering effect on oxidative stress when compared to chronic sustained hyperglycemia. Free radical production in turn is implicated in the pathways that lead to hyperglycemic-induced vascular damage. Mean amplitude of glucose excursion (MAGE) correlates with free radical production and magnitude of glucose fluctuations.

Standard deviation from the average blood glucose may be used in clinical practice as a marker for MAGE. An initial goal for glycemic variability is suggested by Hirsch as twice the standard deviation (standard deviation) should be less than the average blood glucose level (standard deviation x 2 < average blood glucose). Even more desirable would be an average glucose level exceeding three times the standard deviation (standard deviation x 3 < average blood glucose). The standard deviation is calculated and reported by many of the currently available blood glucose monitor software programs.

All glycemia-related goals are also subject to modification in the presence of extenuating clinical circumstances such as blunted glycemic awareness, particularly if there is a history of hypoglycemia-related unconscious reactions or seizures, recurrent otherwise severe hypoglycemia, unstable cardiac status, end-stage renal disease, and the frail elderly warrant consideration of less tight glycemic control targets. For example, if a patient has unconscious hypoglycemic reactions, it may be quite appropriate to accept a target blood glucose range of 140 to 200 in order to minimize risk of recurrences.

FSBG measurements will in general be checked a minimum of four times daily in patients being managed with intensive insulin therapy regimens, and not uncommonly even more frequently. The times of day that it is desirable to see representative blood glucose values are those times that will enable meaningful adjustments in insulin doses or the lifestyle regimen. Typical times for checking are fasting and premeals to assess the appropriateness of basal insulin dosing, 60 to 90 minutes after a meal to assess the impact of premeal insulin doses, and 2 to 3 am in order to assess the level of glycemic control overnight as it affects one’s ability to move basal insulin doses up or down to optimize nocturnal blood glucose control. Patients should be encouraged to gather sample blood glucose readings from each of these time points when there is a question about the appropriateness of particular insulin doses and/or prior to office visits so that the health-care provider will have sufficient information to be able to assist in determining if the current insulin regimen is optimal. Those who will check less frequently should be advised to vary the times of day they are checking so that information from each of these times points is sampled.

In the initial stages of education, at a minimum, patients learning pattern management and self-titration of insulin doses should be encouraged to keep detailed records of blood glucose results, meal content, meal timing, activity, and exercise, etc. This will allow the diabetes team and the patient to learn the impact of these elements on glycemic control and insulin requirements. The patient should record comments in the blood glucose diary whenever BGs are above or below target at the time that the blood glucose value is noted, so that recall of circumstances that may have made the sugar high or low will be accurate. Insulin doses will then be adjusted, as is appropriate, based on identified relationships amongst blood glucose, food intake, and changes in activity.

Insulin Adjustment Guidelines

General Principles

Insulin adjustment is an art that should be guided by the science of what is known about how each component insulin of the total daily insulin requirement acts and how lifestyle and other variables impact blood glucose levels. Insulin adjustment guidelines are grounded in a sound knowledge of the pharmacokinetics of insulin, as discussed earlier in this chapter. When blood glucose levels are outside target ranges and it is determined that an adjustment in insulin dosing is necessary, knowledge of the action curves of the insulins that the patient is taking will guide the decision as to how to adjust the insulin regimen appropriately. The information presented in the following section is a composite of published information on this topic and a consensus of the accumulated clinical experience of the authors in caring for adult patients with Type 1 diabetes mellitus. We have attempted in presenting this information to provide a practical framework upon which the reader may build and convey to one’s patients the nuts and bolts of pattern management insulin adjustments.

For the patient with diabetes mellitus 1 on an multiple daily insulin regimen or using an insulin pump, the underlying principles for adjusting the insulin regimen are essentially the same. Fasting BGs that are not well-controlled will be corrected by adjusting the basal insulin dose(s), i.e., if the fasting blood glucose is low, the basal insulin dose will be decreased and if the fasting blood glucose is high, the basal insulin dose will be increased. Postmeal BGs that are not well-controlled will be corrected by adjusting the premeal insulin dose.

Table General Principles for Adjusting the Insulin Regimen

If the postmeal blood glucose is low, then the bolus insulin dose given prior to the meal will be reduced; if the postmeal blood glucose is high, then the bolus insulin dose given prior to the meal will be increased. Insulin doses will be changed up or down by 10% to 20% or per a prespecifled dose adjustment formula or algorithm whenever required, based on the presence of hyperglycemia or hypoglycemia, respectively. In the outpatient setting, it is typical to wait several days in order to determine trends and/or patterns in BGs by time of day before making changes to the prescribed insulin regimen. This practice is known as pattern management.

Guidelines for Basal Insulin Adjustment

In the multiple daily insulin regimen when the basal insulin is once daily glargine or detemir, the dose will be adjusted based upon the fasting blood glucose. When the basal insulin is twice daily detemir or NPH the evening dose will be adjusted if the fasting blood glucose is not at target and if the predinner blood glucose is not at target, the morning NPH dose will be changed.

In CSII, basal insulin rates are adjusted empirically based on glucose monitoring results. Certain time periods during the day may require higher, while other periods may require lower infusion rates depending on individual factors including lifestyle and the dawn phenomenon. Two to four basal rates are routinely applied to meet insulin requirements over the course of a 24-hour period. For example, patients often need a lower basal rate between bedtime and 3 am and a higher basal rate between 3 am and the time they get up in the morning to attenuate the dawn phenomenon. An intermediate basal rate may be needed during the rest of the day. Adjustments to the basal rate(s) are usually made in 10% to 20% increments in order to affect clinically meaningful changes in blood glucose levels. Anticipatory changes in basal infusion rates should be made about 1 to 2 hours before a change in plasma blood glucose level is required, e.g., prior to exercise.

Guidelines for Prandial-Bolus Insulin Adjustment

Rapid-acting insulin analogs are preferred for use as the meal-time bolus insulin in the intensive insulin regimen for the person with Type 1 diabetes mellitus for several reasons. They may be given at the time that the meal will be eaten, rather than 30 to 45 minutes before the meal, as is necessary with regular insulin. The rapid-acting analogs may also be given at the end of or even up to 20 minutes after a meal, as discussed earlier in this chapter. This feature is particularly useful if the amount of food that will be eaten is uncertain. As the rapid-acting analogs peak 60 to 90 minutes after being taken, a finger-stick blood glucose is taken 60 to 90 minutes after the meal to assess the appropriateness of the bolus insulin dose that was delivered. The premeal insulin dose can then be adjusted to control postprandial glucose levels, i.e., if the postmeal blood glucose is above the patient’s postmeal blood glucose goal, or rises by more than 25 to 50 mg/dL from the premeal value, the meal bolus can be increased and conversely, if the postmeal blood glucose is lower than desired, the premeal bolus insulin dose will be reduced.

Practically speaking, for the patient who is either not able, for example due to time constraints, or not willing to check postprandial BGs, one may adjust the premeal insulin dose based on the blood glucose prior to the next meal, as has been done in some Exubera and Apidra trials with good results.

In the Type 1 diabetes mellitus patient who is being treated with conventional mixed, split subcutaneous insulin therapy rather than multiple daily insulin (e.g., two injections per day of mixed rapid-acting or regular and NPH insulin), adjustments in the prandial component of the prebreakfast dose are made based on the postbreakfast or prelunch blood glucose, changes in the intermediate-acting insulin component of the am dose will be based on the presupper blood glucose. To make adjustments in the presupper doses of insulin, the prandial component of the presupper insulin dose will be determined by the postsupper or bedtime blood glucose levels, whereas the NPH insulin component of the presupper dose is based on 3 am and/or fasting blood glucose levels.

Several methods for determining Correction or supplemental doses of insulin are in use; however, studies to determine their specific safety and efficacy are lacking. Each method will take into account the patient’s relative sensitivity to insulin, either through an association with the known TDD of insulin being taken or the patient’s body weight. A key point to make regarding any method whereby Correction or supplemental doses of insulin of insulin are used is that the impact on blood glucose for an individual must be carefully monitored and the Correction or supplemental doses of insulin adjusted as necessary if it does not lower the blood glucose as expected or if it leads to hypoglycemia. This will require monitoring before and after the initial Correction or supplemental doses of insulin recommended is taken to allow determination of the most appropriate Correction or supplemental doses of insulin for the individual patient.

One method for determining starting correction insulin doses is to determine the dose as a simple percentage of the total number of units of insulin (basal plus bolus) that makes up the patient’s TDDI. Typically, the correction dose will be 10% of the TDDI. If marked hyperglycemia is present and/or urine ketones are positive, the correction dose will be 20% of the TDDI, rounded down to the nearest unit. For example, if the basal insulin dose is 14 U of glargine and the meal dose is 5 U of insulin aspart with breakfast, 3 U with lunch, and 4 U with dinner, the total daily dose of insulin is 26 U. A Correction or supplemental doses of insulin for moderate elevation in blood glucose would be 2 U of rapid-acting insulin and for more marked hyperglycemia, if urine ketones are present, would be 4 U of rapid-acting insulin. This correction dose will be taken in addition to a usual basal and/or bolus insulin dose to be taken whenever the finger-stick blood glucose is above a predesignated target value for that time of day.

A second method in widespread use was developed by Paul Davidson and applies an insulin correction factor. It is known as the rule of 1800 when a rapid-acting insulin analog is used and the rule of 1500 when regular insulin is used as the Correction or supplemental doses of insulin.

Table Sample Correction/Supplemental Dose Scale for Insulin Administration

At bedtime and/or overnight, reduce the correction dose by half (50%), or take____units. (If this amount of insulin is less than one unit, do not take a dose.)

“For fingerstick glucose that is over 150 mg/dL or over______, take a correction insulin dose as shown on the selected scale in addition to your usual basal and meal insulin doses. Requires < 40 units insulin daily; or < 70 kg weight. Requires 40-99 units insulin daily; or 71-99 kg weight. Requires > 100 units insulin daily; or > 100 kg weight.

The correction factor calculated will provide an estimation of the number of mg/dL that 1 U of the correction insulin will lower the blood glucose. The Correction or supplemental doses of insulin will be the same insulin being used as prandial insulin for the patient. To calculate the correction factor for rapid-acting insulin analogs, 1800 is divided by the TDDI. For example, if a patient has a TDDI of 45 U, then the insulin correction factor would be: 1800 divided by 45 = 40. And 1 U of rapid-acting insulin would be expected to lower the blood glucose by 40 mg/dL. If the patient has a premeal blood sugar of 180 mg/dL and wants to correct to 100 mg/dL or cause the value to fall by 80 mg/dL, then the patient would take an extra 2 U of (80 mg/dL lowering divided by 40 mg/dL expected from 1 U correction dose) added to the number of units to be taken to cover the carbohydrates to be consumed in the meal.

Finally, a Correction or supplemental doses of insulin scale may be prescribed for the patient. Such scales will provide incremental, discrete stepped doses of insulin to be taken in response to progressively higher blood glucose levels, typically rising by 50 mg/dL/step on the scale. The correction dose scale differs from sliding scale insulin conceptually in two ways: (/) the selected dose of insulin will be given in addition to the prescribed basal plus prandial insulin doses to correct hyperglycemia and (//) the correction dose scale will factor in a surrogate measure of the patient’s known insulin sensitivity (i.e., TDDI or weight). Correction or supplemental doses of insulin scales are stratified as low, medium, or high dose with the option to provide an individualized scale.

EDUCATION

Diabetes education is required for all who are diagnosed with diabetes regardless of kind of diabetes or the age of the patient. Diabetes education does not ensure that patients will follow instructions and do everything that they are asked to do. Education is necessary but patients should be able to make the decision as to what they are willing to do to maintain or improve their health. Educators need to remember that just because someone decides that they will not follow directions for care, education was wasted. Everyone deserves to make an informed decision. Diabetes self-management training should be reimbursed as part of the care of the patient with diabetes since it is an enormous part of the treatment plan.

The scope of practice for diabetes educators defines the specialty and provides a framework for appropriate and effective practice of the specialty. This statement on the scope of practice for diabetes educators is not a static set of rules and definitions; rather, it is a fluid framework that adjusts to reflect the multidisciplinary nature of diabetes care, the evolving body of knowledge and evidence for effective interventions, and the ever-changing (and increasingly challenging) health-care environment.

DIABETES EDUCATOR’S SCOPE OF PRACTICE

All health-care providers need sufficient diabetes knowledge to provide safe, competent care to persons with or at risk for diabetes. As management of diabetes becomes increasingly complex, it is imperative that diabetes health-care professionals are well educated and appropriately credentialed. Expertise in diabetes care develops through experience, continuing education, individual study, and mentorship.

Diabetes educators use established principles of teaching and learning theory and lifestyle counseling to help clients confidently and effectively manage the disease. Instruction is individualized for persons of all ages, incorporating cultural preferences, health beliefs, and preferred learning styles of the client.

Behavior change directed at successful diabetes self-management was formally adopted as the desired outcome of Diabetes self-management training in 2002 (24). Seven specific self-care behaviors, known collectively as The American Association of Diabetes Educators 7 Self-Care Behaviors™, along with five core outcome measures, have been defined to guide the process of Diabetes self-management training.

The primary goal of diabetes education is to provide knowledge and skill training that helps individuals identify barriers and facilitates problem-solving and coping skills to achieve effective self-care behavior and behavior change. It is the position of the American Association of Diabetes Educators that all educators should measure the American Association of Diabetes Educators 7 Self-Care Behaviors, both for individuals and in the aggregate, at least twice: pre- and postintervention. The American Association of Diabetes Educators 7 Self-Care Behaviors are listed below:

1.  Healthy eating

2.  Being active

3.  Monitoring

4.  Taking medications

5.  Problem solving

6.  Healthy coping

7.  Reducing risks

Additional follow-up measurements are ideal and should be applied as appropriate to the practice setting. By adopting the American Association of Diabetes Educators 7 Self-Care Behaviors, educators are able to determine their effectiveness with individuals and populations, compare their performance with established benchmarks, and measure and quantify the unique contribution that Diabetes self-management training plays in the overall context of diabetes care.

American Association of Diabetes Educators

OUTCOMES MEASUREMENT STANDARDS

In the September/October issue of The Diabetes Educator American Association of Diabetes Educators published its position statement on standards for outcomes measurement of diabetes self-management education.

Seven diabetes self-care behavior measures determine the effectiveness of diabetes self-management education at individual, participant, and population levels. Diabetes self-care behaviors should be evaluated at baseline and then at regular intervals after the education program. The continuum of outcomes, including learning, behavioral, clinical, and health status, should be assessed to demonstrate the interrelationship between DSME and behavior change in the care of individuals with diabetes.

Individual patient outcomes are used to guide the intervention and improve care for that patient. Aggregate population outcomes are used to guide programmatic services and for continuous quality improvement activities for the DSME and the population it serves.

PRACTICE OPTIONS

Three practice options, which may overlap, are available to health-care professionals who choose to specialize in diabetes care:

1.  Diabetes educator

2.  Certified diabetes educator

3.  Board certified in advanced diabetes management

These classifications are differentiated by educational preparation, formal credentialing, professional practice regulations, and the clinical practice environment. It is the position of the American Association of Diabetes Educators that all diabetes educators work toward formal certification. The diabetes educator and Certified diabetes educator are chiefly concerned with and actively engaged in the process of Diabetes self-management training. The Board certified in advanced diabetes management incorporates skills and strategies of Diabetes self-management training into the more comprehensive clinical management of people with diabetes. Differences in the preparation, scope, and practice of diabetes educators (certified or not) and the Board certified in advanced diabetes management may make dual credentialing desirable for some. For example, a diabetes educator or Certified diabetes educator may also have the Board certified in advanced diabetes management credential, provided he or she meets the academic and practice requirements for Board certified in advanced diabetes management certification. Conversely, the Board certified in advanced diabetes management may not necessarily be a diabetes educator as defined here. A more comprehensive description of each classification is given below.

Diabetes educators are health-care professionals who have achieved a core body of knowledge and skills in the biological and social sciences, communication, counseling, and education and who have experience in the care of people with diabetes. Mastery of the knowledge and skills required to become a diabetes educator are obtained through formal and continuing education, individual study, and mentorship. The role of the diabetes educator can be assumed by professionals from a variety of health disciplines, including, but not limited to, registered nurses, registered dietitians, pharmacists, physicians, mental health professionals, podiatrists, optometrists, and exercise physiologists. The diabetes educator is an integral partner in the diabetes care team.

The diabetes educator understands the impact of acute or chronic problems on a person’s health behaviors and lifestyle, and on the teaching Aearning process. Such appreciation is essential for the development of a comprehensive plan for continuing education and cost-effective, self-care management.

Members of the various health disciplines who practice diabetes education bring their particular focus to the educational process. This widens or narrows the scope of practice for individual educators as is appropriate within the boundaries of each health profession, which may be regulated by national or state agencies or accrediting bodies. Regardless of discipline, the diabetes educator must be prepared to provide clients with the knowledge and skills to effectively manage his or her diabetes. Diabetes educators must possess a body of knowledge that spans across disciplines in order to provide comprehensive Diabetes self-management training. For example, dietitians who are diabetes educators provide instruction for insulin injection, insulin dosing, and medication side effects as well as providing nutrition counseling. Exercise physiologists in the diabetes educator role may help clients develop a meal plan, and pharmacists may provide counseling and instruction about foot care.

Diabetes educators may assume responsibilities beyond providing Diabetes self-management training to individuals. Program management; case management; clinical management; health-care consultancy with other providers, organizations, and industry; public and professional education; public health and wellness promotion; and research in diabetes management and education are all important roles assumed by diabetes educators.

CDEs, in addition to fulfilling the requirements of a diabetes educator, meet the academic, professional, and experiential requirements set forth by the National Certification Board for Diabetes Educators (NCBDE). The NCBDE defines the criteria for certification as a diabetes educator. As part of the application process, a diabetes educator must document that he or she meets all the criteria for certification. An accepted applicant must demonstrate competency in the required body of knowledge and skills by means of a written examination. Certification is valid for a period of 5 years, and is maintained either through repeat examination or through documented participation in relevant continuing education activities every 5 years.

Board certified in advanced diabetes management is a credential available since 2001. The Board certified in advanced diabetes management credential is the first advanced-practice certification offered to members of more than one discipline. Nurse Practitioners, Clinical Nurse Specialists, dietitians, and registered pharmacists may apply. Recognizing that nonnursing health-care professionals participate in diabetes care, the task force acknowledged the need for an advanced diabetes manager credential that includes nutrition and pharmacy as well as nursing.

Four discipline-specific examinations are offered for the Board certified in advanced diabetes management credential, reflecting the practice of comprehensive clinical management of individuals with diabetes. Candidates must document at least 500 hours of recent advanced-practice diabetes care. They must demonstrate skill in performing complete and/or focused assessments, recognizing and prioritizing complex data, and providing therapeutic problem-solving, counseling, and regimen adjustments for people with diabetes.

The educational preparation required to take the exams is as follows: a master’s degree in nursing is required for clinical nurse specialists and nurse practitioners, dietitians must have a relevant clinical master’s degree, and registered pharmacists must have a doctorate of pharmacy degree. Upon verification of eligibility, candidates sit for a discipline-specific written examination administered by the American Nurses Credentialing Center. Certification is valid for 5 years. Recertification is by reexamination or through qualified continuing education activities as defined by the American Nurses Credentialing Center. Additional information about certification and recertification can be obtained directly from the American Nurses Credentialing Center.

The Board certified in advanced diabetes management practice is characterized by autonomous assessment, problem identification, planning, implementation, and evaluation of diabetes care, within the guidelines for Board certified in advanced diabetes management practice set by the individual discipline. The process of using assessment data to independently derive a diagnosis or problem list is a key distinguishing aspect of Board certified in advanced diabetes management practice. A diabetes care professional with a Board certified in advanced diabetes management credential may or may not be a Certified diabetes educator. As diabetes education is an integral part of diabetes care and management, the professional with the Board certified in advanced diabetes management credential necessarily incorporates aspects of Diabetes self-management training into his or her practice, either directly or through referral to another qualified diabetes educator.

NUTRITION

EXERCISE

TRAVEL

WEATHER

Most people with diabetes do not understand the effect of weather on blood glucose control. When the weather is cold, glucose level may rise due to constriction of blood vessels. This constriction decreases the absorption of insulin from the subcutaneous tissue. Sometimes glucose level may drop during cold weather due to the amount of shivering that someone does. Shivering decreases glucose levels due to increased metabolic rate. Hot weather tends to lower glucose levels due to the dilation of the blood vessels. This helps the insulin to be absorbed faster than usual. Glucose levels frequently drop in the spring when temperatures begin to rise. This is something to be aware of so that it can be avoided or, at least, greatly limited.

HYPERGLYCEMIA

If a patient is treated with an insulin pump and glucose levels are elevated to > 250 mg/dL in the fasting state, the patient must be instructed to change the site immediately since he or she does not know how long insulin has not been infused for. If the patient is staying at home, he or she can correct the glucose and wait 1 to 2 hours for it to decrease to the normal range. If this does not happen, site needs to be changed immediately. The danger of not doing this is ketoacidosis and it can be avoided with careful attention to glucose levels > 250 mg/dL. At other times of the day, the correction should be made and glucose retested in 1 to 2 hours to make sure that glucose is coming down into the normal range. If moderate or large ketones are present or nausea, the correction should be doubled, as patients are very insulin resistant in this stage of ketosis. I strongly suggest that the patient then double the basal rate for 2 to 3 hours to bring the glucose back into the normal range quickly. If hyperglycemia occurs in those on injections, they simply need to correct with fast-acting insulin based on their correction factor.

SICK DAYS

When a patient with diabetes is ill, glucose levels tend to rise due to increased levels of cortisol. If glucose levels are elevated and a patient is on a pump, basal insulin should be increased by means of a temporary rate with an increase of 30 to 50%. If not on a pump, more frequent doses of fast-acting insulin need to be given every 3 to 4 hours. Some patients become hypoglycemic when ill. In this case, the temporary rate should be decreased by 30 to 50% until glucose levels begin to rise. If glucose levels remain low and insulin is discontinued for more than 1 hour, ketones can occur. If glucose continues to drop despite decreasing or stopping insulin, and patient is nauseous and/or vomiting, a small dose of glucagon (20 to 30 units) can be given to raise glucose level for a few hours. This may keep someone out of the hospital and at home where they are much more comfortable.

MENSTRUATION

In most women, glucose levels tend to rise the week before onset of menses. A different basal rate can be set into the pump to accommodate this rise in glucose. The basal profile can be changed back once menses begins. This makes life a little easier when the different basal profiles are already in the pump so that the woman does not need to do it on a monthly basis. If on injections, fast-acting insulin probably needs to be increased to cover meals and higher glucose values before onset of menses. The basal insulin is difficult to adjust because it takes a couple of days to equilibrate and this could cause hypoglycemia when menses occurs.

SMOKING

Everyone is aware of the long-term effects of smoking and these are all increased in those with diabetes. The acute effects of smoking are frequently overlooked. When someone with diabetes smokes a cigarette, blood vessels constrict and insulin is poorly absorbed. Most people who smoke grab a cigarette right after consuming a meal. This is extremely problematic since the insulin is not getting absorbed well, but the food is. This leads to high postprandial glucose levels. When smoking ceases, the blood vessels dilate causing the patient to absorb insulin quickly. This happens after the food has been digested causing subsequent low blood glucose levels. Patients who smoke with diabetes, therefore, have very erratic glucose levels with many hypo and hyperglycemic episodes.

MARIJUANA USE

Use of marijuana is similar to smoking cigarettes except it has the added effect of increasing appetite so people eat more food and either forget to cover it with insulin or just do not care. It is also difficult to detect hypoglycemia when high on marijuana.

COCAINE USE

When using cocaine, most people lose their interest in eating at all. They also forget to take insulin and begin to care only about the next fix. This is tragic for anyone, but for someone with diabetes it is particularly worrisome. If insulin is taken but the person does not eat, hypoglycemia occurs. If insulin is ignored, ketoacidosis occurs. Both are worrisome and scary.

ALCOHOL USE

Use of alcohol is tricky as well. This is the most commonly used drug. The problems with alcohol and diabetes are as follows:

1.  Drinking alcohol masks the symptoms of hypoglycemia.

2.  While detoxing alcohol the liver will not perform its usual job of glycogenolysis. If glucose falls dangerously low, the liver will not counter-regulate as it is too busy detoxing the alcohol and this is its first priority. It is important to remember that this is the one time that counter-regulation will not occur. Basal rates should be decreased by approximately 20% when going to sleep after a night of drinking. In this way, hypoglycemia is avoided. If a patient is on injections, a snack would need to be consumed before going to sleep. More than two alcoholic beverages should not be consumed by anyone but especially those with diabetes as it can be much more dangerous for him or her.