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.

Exercise training raises high density lipoprotein cholesterol, lowers blood pressure, and leads to a 20 to 40% increase in insulin sensitivity by enhancing insulin action in skeletal muscles. Therefore, all diabetic patients should be encouraged to engage in 30 minutes of modest aerobic exercise (such as brisk walking, aerobics, swimming, or bicycling) three to four times per week. The intensity should be gauged to produce an increase in pulse rate to 60 to 70% of maximum, which can be calculated as 220 minus age. This level of exercise is referred to as “conversational exercise” because it is not intense enough to prevent the patient from conversing with a partner during the workout.

Exercise usually lowers blood glucose levels. If someone is a real competitive athlete, glucose levels will go up during competition due to adrenaline being released during this activity. Many times, the same person will have a low glucose level at a practice but a high one at a game even in the same sport. It takes a lot of insulin dose adjustments before normal glucose levels are achieved with exercise. There are many ways to deal with this. First, do the exercise without changing anything to see what happens. Many people prefer to take their pumps off for exercise. This can usually be worked out if the sport is not too long, like baseball or cross country running. If the patient is on injections, it is more difficult to address, but a plan needs to be developed. This patient may need to lower the bolus prior to the previous meal or snack or he/she may need to decrease the long acting insulin during the sport season. This makes it difficult to figure out what to do if there is no exercise that day as long-acting insulins (Lantus, Levimir) last for several days so changing based on the same day simply does not work for the patient. He or she would probably need to increase the fast-acting insulin on off days to counteract high glucose levels.

For athletes competing in sports, it is advisable to remove the pump during the sport (if using a pump), but reattach it as soon as the sport is over and replace at least 1 hour of basal insulin as a bolus. This will keep the glucose from rising within the first hour after the sport is finished. The Diabetes Research in Children Network (DirecNet) studied this and found that if the pump was kept on at the usual basal rate, hypoglycemia occurred, but if it was removed, hyperglycemia occurred very soon after the exercise was completed. Therefore, to prevent the hypoglycemia during exercise, pump should be removed or basal decreased significantly, but insulin needs to be replaced soon after exercise to prevent hyperglycemia. Exercise also cause delayed hypoglycemia in most patients with diabetes. In order to prevent this, patients are instructed to decrease basal rate at bedtime to 70 to 80% of their usual dose for 4 to 5 hours. This prevents nocturnal hypoglycemia in these patients. It was shown by Bussau, et al., that a sprint at the end of practice or a game reduces hypoglycemia due to increase in catecholamines. Since many athletes do this as part of their sport, it is no wonder that they come off the field with extremely high glucose levels that need to be corrected. Sprinting does raise glucose and many sports require sprinting.

Health-care providers must recommend exercise to their patients. The success rate is not very good for patients continuing an exercise plan, but if it is not discussed, the success rate is even poorer. Exercise is extremely difficult to maintain as is diet but if patients are not encouraged, they surely will not see any necessity for it. It should be addressed at every visit as a part of the visit. Sometimes hearing things over and over does eventually make a difference to a patient. Even if the motivation wears off, the patient will usually follow a plan for a while and if they are seen every 3 months, they may have more time that they exercise than they do not exercising. In a study at the Joslin Diabetes Center located at the University Health Care Center in Syracuse, NY, patients were asked to develop their own meal and exercise plan. At 2 and 6 months respectively, 89% and 92% of the participants felt that they were following the meal plan either some or most of the time. One hundred percent of respondents were able to determine their own exercise plan, with 98% indicating they could adhere to the plan, and 85.7% felt that the new plan would be easier than previous ones. At 2 and 6 months respectively, 70% and 73% felt that they were following their exercise plan either some or most of the time. Individualized meal and exercise plans can be successfully created by the patients themselves. In an integrative literature review, Dr. Nancy Allen, examined the literature on diabetes research using social cognitive theory (15) to determine its predictive ability in explaining exercise behavior and to identify key interventions that enhance exercise initiation and maintenance. The results showed that a statistically significant relationship between self-efficacy and exercise behavior was found in correlational studies. Results from the predictive study support the predictability of self-efficacy for exercise behavior. Self-efficacy was predictive of exercise initiation and maintenance over time. The evidence for successful interventions to increase self-efficacy and exercise behavior over time was inconclusive.

In conclusion everyone is in agreement that exercise is an important and even essential part of any diabetes management plan. It is also one of the most difficult parts of the regimen for patients to adhere to.

Notify the screener that you have diabetes and are carrying your supplies with you. Please note that while Transportation Security Administration is not currently requiring a prescription label, it recommends having the label available to identify the medication in order to expedite the security checkpoint screening process. The following diabetes-related supplies and equipment are allowed through the checkpoint once they have been screened:

• Insulin and insulin loaded dispensing products (vials or box of individual vials, jet injectors, pens, infusers, and preloaded syringes) that are clearly identified with a prescription label containing a name that matches the passenger’s name on his or her ticket.

•   Other liquid prescription medicines such as Smylin, Byetta, or a Glucagon Emergency Kit that are clearly identified with a prescription label containing a name that matches the passenger’s name on his or her ticket.

•   Note that essential nonprescription liquid medicines (such as regular insulin, where in some states a prescription to dispense is not required) should be clearly labeled.

•   Multiple containers of liquids and gels (including cake mate) to treat hypoglycemia. If containers are more than 3 oz, then passengers need to declare these items to security checkpoint personnel.

•   Unlimited number of unused syringes when accompanied by insulin or other injectable medication.

•   Blood glucose meters, blood glucose meter test strips, continuous blood glucose monitors, lancets, alcohol swabs, meter-testing solutions, and monitor supplies.

•   Insulin pump and insulin pump supplies (cleaning agents, batteries, plastic tubing, infusion kit, catheter, and needle).

•   Urine ketone test strips.

•   Unlimited number of used syringes when transported in Sharps disposal container or other similar hard-surface container.

In addition to the information providers above, it is recommended that passengers review Transportation Security Administration’s 9/26/06 Q&A (PDF) PersonswithDisabilitiesQuestionsandAnswers.pdf) regarding changes to liquids ban at airport security checkpoints.

Pump Wearers

Although insulin pump manufacturers indicate that pumps can safely go through airport security systems, pump wearers may request a visual inspection rather than walking through the metal detector or being hand-wanded. Note that this may subject you to closer scrutiny or a “pat-down.”

•   Advise the screener that the insulin pump cannot be removed because it is connected to a catheter inserted under your skin.

•   Insulin pumps and supplies must be accompanied by insulin with a label clearly identifying the medication.

If You Experience Hypoglycemia During the Security Procedure

Immediately inform screeners if you are experiencing low blood sugar and are in need of medical assistance.

If You Request a Visual Inspection of Your Supplies

You have the option of requesting a visual inspection of your insulin and diabetes associated supplies. Keep in mind that

•   you must request a visual inspection before the screening process begins otherwise your medications and supplies will undergo X-ray inspection.

•   you should separate your medication and associated supplies from your other property in a pouch or bag.

•   medications should be labeled so they are identifiable.

•   in order to prevent contamination or damage to medication and associated supplies and/or fragile medical materials, you will be asked at the security checkpoint to display, handle, and repack your own medication and associated supplies during the visual inspection process.

•   any medication and/or associated supplies that cannot be cleared visually must be submitted for X-ray screening. If you refuse, you will not be permitted to carry your medications and related supplies into the sterile area.

Contact Transportation Security Administration

If you have an immediate need while being screened, you should ask for a screener supervisor. You may also contact the Transportation Security Administration contact center to report unfair treatment or to obtain additional information by calling toll-free 866-289-9673 during the following hours of operation (all times are Eastern Standard Time):

•   Monday through Friday 8 a.m-10 p.m.

•   Saturday, Sunday, and Holidays 10 a.m.-6 p.m.

Complaints about discriminatory treatment (http://airconsumer.ost.dot.gov/ DiscrimComplaintsContacs.htm) by federal security screeners should be directed to Transportation Security Administration. Transportation Security Administration accepts complaints by mail to Transportation Security Administration, Transportation Security Administration Headquarters, 12th Floor, Room 1203 N, Transportation Security Administration-1, 400 Seventh St., SW, Washington, DC 20590.

In addition to filing a complaint with a federal agency, passengers alleging discriminatory treatment by air carrier personnel (pilots, flight attendants, gate agents, or check-in counter personnel) may download and print a complaint form and follow instructions provided by Department of Transportation’s (DOT’s) Web site (http://airconsumer. ost.dot.gov/problems.htm). They should also notify their airline carrier. Other consumer complaints may be directed to the Department of Transportation’s Office of Consumer Protection Division, 400 Seventh St., S.W., Washington, DC, 20590, U.S.A. More information on where passengers may file complaints for travel service problems, contact DOT by calling 1-800-255-1111.

The association recommends packing at least twice the number of supplies needed during travel, and bringing a quick-acting source of glucose to treat low blood glucose, as well as an easy to carry snack such as a nutrition bar. Carry or wear medical identification and carry contact information for your physician while traveling. It may also be helpful to have contact information for a health-care professional available at your destination, and be prepared to adjust medication when traveling in different time zones.

•   You should separate your medication and associated supplies from your other property in a pouch or bag.

•   Medications should be labeled so they are identifiable.

•   In order to prevent contamination or damage to medication and associated supplies and/or fragile medical materials, you will be asked at the security checkpoint to display, handle, and repack your own medication and associated supplies during the visual inspection process.

•   Any medication and/or associated supplies that cannot be cleared visually must be submitted for X-ray screening. If you refuse, you will not be permitted to carry your medications and related supplies into the sterile area.

Contact Transportation Security Administration

If you have an immediate need while being screened, you should ask for a screener supervisor.

In addition, blood glucose levels tend to increase while traveling in any mode, therefore, increase the basal rate by approximately 30% while traveling. If on injections, increase the bolus doses and may need more doses during travel. When traveling across time zones and wearing a pump, the time needs to be changed on arrival. This is essential to maintain basal rates at the right times of day. If on injections with Lantus or Levimir, these need to be adjusted by approximately 2 hr/day. If on NPH, it may need to be given as much as 3 hours earlier or later depending on the time zone.

If traveling to high altitudes, 3000 to 5000 m (10,000 to 16,000 ft), barometric pressure decreases linearly with increasing altitude. Inspired P02 at the summit of Mount Everest (8848 m) is < 30% of that at sea level. Acclimatization refers to the physiological changes that occur consequent to prolonged exposure to the hypoxia and low barometric pressure of altitude, and it includes hyperventilation, with the resultant respiratory alkalosis being reduced over time by compensatory renal bicarbonate excretion. Although erythrocyte levels also increase, this occurs much more slowly, over the course of several weeks. It is also important to note that acclimatization does not imply normalization because, despite continued hyperventilation, alveolar P02 levels remain well below that at sea level even in fully acclimatized individuals.

Those who seem to do well and are successful on these climbs are those who are in excellent control (HbAlc < 7%) and have no complications. Acute mountain sickness can occur causing dizziness and nausea. This can effect glucose control. Symptoms of acute mountain sickness may mask symptoms of hypoglycemia in some people with diabetes. Diabetes control deteriorated in climbers consistently due to elevation and decreases in temperature. Climbing requires much preparation and consideration of the consequences.

Traveling should be fun and it should be an adventure, but to keep it that way, much planning needs to take place. Patients should discuss travel plans with their health-care provider well before taking the trip. This greatly reduces the risk of problems related to travel in those with diabetes. Make sure that all the guidelines that the ADA puts forth are followed. Always take twice as many supplies as necessary.

What is a sick day? Any day that you are not feeling well, having trouble eating your usual meals, or are experiencing a medical procedure or extreme emotional upset.

Why are sick days important? Diabetes is affected not only by what you eat and the insulin you take, but also by other hormones in the body. Hormones that work against insulin usually increase during illness or stress, causing the insulin you take to work less effectively. This is why illness and stress cause the blood sugar to rise. Diabetic ketoacidosis is a severe, life-threatening complication of diabetes that commonly occurs during illness or severe stress. This develops due to a lack of adequate insulin to fight the stress-related hormones.

What can I do ? The MOST important thing you can do during a sick day is to take your insulin. Even if you cannot eat, your body needs at least the insulin you take during a usual day, maybe even more. You should adjust your insulin as follows:

• Identify your longest-acting insulin. This is probably either glargine (Lantus), NPH, or Lente. Take your usual dose of this insulin, the same number of times during the day.

• Identify your shortest-acting insulin. This is probably lispro (Humalog), aspart (Novolog), or regular insulin. If you are not eating, do not take your usual doses of the short-acting insulin. Take the short-acting insulin as follows:

Add together your total daily dose of all insulin.

How many units of long-acting and short-acting insulin do I take in a typical day? units

Figure out 15% of this number (with a calculator, multiply your total daily dose x 0.15). If the result is a fraction, round up to the nearest unit. This is your “sick day dose”.

My “sick day dose” is: units of short-acting insulin.

When blood sugar is over 150 mg/dl, take this dose of short-acting insulin, at least 4 hours apart.

What should I eat? If you are able to, eat the way you usually do. If you are unable to eat normally, it is important to make sure you get enough fluid and carbohydrate (sugar).

Drink 4-6 ounces (4 ounces is half a cup) of fluid without calories every 30 minutes.

This fluid could include water, unsweetened hot or cold tea, or diet soft-drinks. This fluid is important to prevent dehydration.

Eat or drink 50 g of carbohydrate every 4 hours. To find the carbohydrate content in food/fluids, look at the nutritional label. Note the serving size, and the total carbohydrate.

For example, one can of (non-diet) soda contains 12 ounces and 43 g of carbohydrate. This carbohydrate (sugar) will provide you with energy to fight your illness, and help to prevent low blood sugar.

What else should I do during a sick day?

• Check your urine for ketones. When the body produces ketones (detectable in the urine) and your blood sugar is high, it means you are not taking enough insulin to stay in control during your illness.

If you have ketone strips, make sure they are not expired

If you do not have ketone strips, get some at the pharmacy (available without a prescription)

Check your urine for ketones several times daily while you are sick. If you are taking enough insulin and fluids, ketone levels should not be more than “small”

• Call your diabetes care provider (primary care physician, nurse practitioner, or diabetes educator) if:

You vomit (throw up) even once; ask for an antinausea medication. Suppositories work best if you are having trouble keeping food down. A prescription may need to be called in to your pharmacy. This could prevent a hospital stay.

You have an obvious infection. You may need an antibiotic.

Your illness lasts longer than 2 days

Your blood sugar is over 400 mg/dl, two times in a row, after you have taken your sick day dose of insulin and it should have had an effect.

You have “moderate” to “large” amounts of ketones in your urine and a blood sugar over 200 mg/dl for more than 8 hours, even after taking your sick day dose of insulin.

You feel very sick or are in pain.

You have abdominal pain, shortness of breath or trouble breathing, your family notices a fruity odor in your breath, or you become extremely sleepy or woozy.

Your diabetes care provider is:

Name:____________________________________________________________________

Office number:_____________________________________________________________

Emergency contact information:________________________________________________

Type 2 Diabetes

What is a sick day? Any day that you are not feeling well, having trouble eating your usual meals, or are experiencing a medical procedure or extreme emotional upset.

Why are sick days important? Diabetes is affected not only by what you eat and the insulin you take, but also by other hormones in the body. Hormones that work against insulin usually increase during illness or stress, causing the insulin you take to work less effectively. This is why illness and stress cause the blood sugar to rise. Severe high blood sugar requiring hospitalization can occur if proper care is not taken during illness.

What can I do? When you are sick, even if you are unable to eat normally, you must take your diabetes medication. If you take only pills for your diabetes, you need these even if you are unable to eat. Metformin (Glucophage), a common diabetes medication, can cause stomach upset if not taken with meals. If this happens to you, stop taking the metformin until you are able to eat again.

If you take insulin (either alone or in combination with diabetes pills), you still need to take it while you are sick. Even if you can not eat, your body needs at least the insulin you take during a usual day, maybe even more. You should adjust your insulin as follows:

• Identify your longest-acting insulin. This is probably either glargine (Lantus), NPH, or Lente. Take your usual dose of this insulin, the same number of times during the day.

• Identify your shortest-acting insulin. This is probably either lispro (Humalog), aspart (Novolog), or regular insulin. If you are not eating, do not take your usual doses of the short-acting insulin. Take the short-acting insulin as follows:

Add together your total daily dose of all insulin.

How many units of long-acting and short-acting insulin do I take in a typical day?_ _units

Figure out 15% of this number (with a calculator, multiply your total daily dose x 0.15). If the result is a fraction, round up to the nearest unit. This is your “sick day dose”.

My “sick day dose” is: _units of short-acting insulin.

When blood sugar is over 150 mg/dl, take this dose of short-acting insulin, at least 4 hours apart.

What should I eat? If you are able to, eat the way you usually do. If you are unable to eat normally, it is important to make sure you get enough fluid and carbohydrate (sugar).

• Drink 4-6 ounces (4 ounces is half a cup) of fluid without calories every 30 minutes. This fluid could include water, unsweetened hot or cold tea, or diet soft-drinks. This fluid is important to prevent dehydration.

• Eat or drink 50 g of carbohydrate every 4 hours. To find the carbohydrate content in food/fluids, look at the nutritional label. Note the serving size, and the total carbohydrate. For example, one can of (non-diet) soda contains 12 ounces and 43 g of carbohydrate. This carbohydrate (sugar) will provide you with energy to fight your illness, and help to prevent low blood sugar.

What else should I do during a sick day?

• If you normally take insulin, check your urine for ketones. When the body produces ketones (detectable in the urine) and your blood sugar is high, it means you are not taking enough insulin to stay in control during your illness.

if:

If you have ketone strips, make sure they are not expired

If you do not have ketone strips, get some at the pharmacy (available without a prescription)

Check your urine for ketones several times daily while you are sick. If you are taking enough insulin and fluids, ketone levels should not be more than “small” Call your diabetes care provider (primary care physician, nurse practitioner, or diabetes educator)

You vomit (throw up) even once; ask for an antinausea medication. Suppositories work best if you are having trouble keeping food down. A prescription may need to be called in to your pharmacy. This could prevent a hospital stay.

You have an obvious infection. You may need an antibiotic.

Your illness lasts longer than 2 days

Your blood sugar is over 400 mg/dl, two times in a row, after you have taken your sick day dose of insulin and it should have had an effect.

You have “moderate” to “large” amounts of ketones in your urine and a blood sugar over 200 mg/dl for more than 8 hours, even after taking your sick day dose of insulin.

You feel very sick or are in pain.

You have abdominal pain, shortness of breath or trouble breathing, your family notices a fruity odor in your breath, or you become extremely sleepy or woozy.

Your diabetes care provider is: Name:___________________

Office number:______________

Emergency contact information:.

When initiating the older patient on insulin, the advantages and concerns of treatment need to be reviewed. Aspects such as physical, mental, and visual problems must be carefully assessed; practical and safe glucose targets must be established based on the individual patient’s needs and capabilities. Insulin therapy must be individualized based on each patient’s glucose levels, prognosis related to coexisting medical conditions, and treatment goals.

Insulin is often initially used in combination with one or more oral agents. Basal insulin — intermediate- or long-acting — is initially started at bedtime and slowly increased to reach safe morning glucose targets and, if required, a second dose and/or additional fast-acting insulin is added during the day. Complex multiple-dose insulin regimens should be avoided unless essential. A wide variety of insulins is available, from very rapid-acting to very long-acting and premixed combination preparations.

The greatest risk of insulin therapy is hypoglycemia, and evidence suggests that frail older adults are at higher risk of serious hypoglycemia than are healthier, more functional older adults. A practical approach to improve benefit and reduce risk when using insulin therapy includes

■ Continuation of use of oral agents. There is evidence that it will enhance effectiveness of residual insulin, reduce glycemic variability, and may help with weight control.

■ Use of basal insulin early [neutral protamine Hagedorn (NPH) or glargine]. With a starting dose of 10 units bed time (HS) (5 units if frail) or up to 0.25 units/kg weight, then titrating weekly or biweekly to a goal of fasting blood glucose of 120 to 140 mg/dL.

■ Use of insulin analogs in patients who require prandial insulin because it may reduce the likelihood of hypoglycemia in those with variable food intake or unpredictable digestion/ absorption.

Time for supervised practice for those with motor or visual problems should be provided and can improve the accuracy of insulin administration. The patient’s insulin injection technique should be observed on a regular basis to detect a need for adaptive strategies such as additional lighting, magnification, and premixed syringes. Elderly subjects often make errors when trying to mix insulin on their own. The accuracy of insulin injections may be improved in older patients when they are treated with premixed insulin. Family members, home care nurses, and visiting nurses can assist with implementing these techniques at home.

Physician and educator attitudes are important factors in the acceptance of insulin therapy. Discussing the benefits and potential challenges of insulin therapy may help patients decide about whether to take insulin or not. The need of insulin can be presented as the treatment for the patient’s particular stage of diabetes. This approach may help overcome patient resistance to insulin use (i.e., fear of injection, pain, lipohypertrophy complexity of regimens, etc.). In addition, it is important to recognize and address the provider’s resistance related to lack of time and resources to supervise treatment, skepticism about the effectiveness of insulin, and perceived cardiovascular risk. Finally, understanding medical limitations associated with insulin use (weight gain and risk for hypoglycemia) may help overcome these barriers and target therapy more appropriately.

TABLE   Insulin Preparations

Abbreviation: NPH, neutral protamine Hagedorn (insulin).

Insulin is a hormone that plays a key role in regulating carbohydrate, protein, and fat metabolism. The main stimulus for its secretion is glucose, although many other factors including amino acids, catecholamines, glucagon, and somatostatin, are involved in its regulation. The secretion of insulin is not constant and peaks occur in response to the intake of food.

The major effects of insulin on carbohydrate homoeostasis follow its binding to specific cell-surface receptors on insulin-sensitive tissues, notably the liver, muscles, and adipose tissue. It inhibits hepatic glucose production and enhances peripheral glucose disposal thereby reducing blood-glucose concentration. It also inhibits lipolysis thereby preventing the formation of ketone bodies.

Therapy with insulin is essential for the long-term survival of all patients with type 1 diabetes mellitus. It may also be necessary in some patients with type 2 disease. The management of diabetes mellitus and the role of insulin in type 1 and type 2 disease is discussed. Insulin is generally the treatment chosen for all types of diabetes mellitus during pregnancy.

Choice of insulin. The different types of insulin and their formulations are described under Definitions, above. In some countries including the UK the commercially available preparations have been standardised to a single strength containing 100 units/mL a strength of 40 units/mL is still available in some other countries, and in others concentrated injections (500 units/mL) are available to enable high doses to be given subcutaneously in a small volume. All formulations can be given by subcutaneous injection, most by intramuscular injection, but only soluble insulins can be given by the intravenous route. The long-term management of diabetic patients usually involves the subcutaneous route. Syringes and needles for subcutaneous injection are preferably disposable. Pen-injector devices which hold the insulin in cartridge form and meter the required dose are becoming increasingly popular. Soluble insulin is often given by the intraperi-toneal route to patients on continuous ambulatory peritoneal dialysis. More recently, products supplying short-acting insulin by inhalation have been developed.

The various formulations of insulin are classified, according to their duration of action after subcutaneous injection, as short-, intermediate-, or long-acting. The exact duration of action for any particular preparation, however, is variable and may depend upon factors such as interindividual variation, the patient’s antibody status, whether the insulin is of human or animal origin, the dose, and the site of injection. Short-acting insulins are the soluble insulins, which have an onset after about 30 minutes to 1 hour, a peak activity at about 2 to 5 hours, and a duration of about 6 to 8 hours. Some analogues, such as insulins lispro and aspart, are also short-acting, with a faster onset and shorter duration of action than soluble insulin and are sometimes known as rapid-acting insulins. Intermediate-acting insulins include biphasic insulins, isophane insulins, and amorphous insulin zinc suspensions. In general these have an onset within about 2 hours, peak activity after about 4 to 12 hours, and a duration of up to 24 hours. Commercially available mixtures of soluble insulins and isophane insulins have activities which would normally place them within the intermediate-acting category. Mixed insulin zinc suspensions may be classified as either intermediate- or long-acting as the duration of action may be up to 30 hours the onset of action is generally 2 to 3 hours and the time to peak activity 6 to 15 hours. Long-acting insulins include crystalline insulin zinc suspensions and protamine zinc insulins. These generally have an onset after about 4 hours, a peak activity at about 10 to 20 hours, and a duration of up to 36 hours. The insulin analogues insulin glargine and insulin detemir are also long-acting. After intramuscular injection, the onset of action of all insulins is generally more rapid and the duration of action shorter.

The type of formulation, its dose, and the frequency of administration are chosen to suit the needs of the individual patient. Whatever the formulation, human insulin is generally used for all newly diagnosed diabetics.

Control. The dosage of insulin must be determined for each patient and although a precise dose range cannot be given a total dose in excess of about 80 units daily would be unusual and may indicate the presence of a form of insulin resistance. The dose should be adjusted as necessary according to the results of regular monitoring of blood concentrations (or occasionally urine concentrations) of glucose by the patient.

The WHO has recommended that the glucose concentration of venous whole blood under fasting conditions should be kept within the range of 3.3 to 5.6 mmol/litre (60 to 100 mg per 100 mL) and after meals should not be allowed to exceed 10 mmol/litre (180 mg per 100 mL) blood-glucose concentrations should not be allowed to fall below 3 mmol/litre (55 mg per 100 mL). In practice it seems to be generally acceptable for patients to aim for blood-glucose concentrations between 4 and 10 mmol/litre, with the understanding that occasional variations outside this range may occur. It should be remembered that the glucose concentrations in venous plasma, venous whole blood, and capillary whole blood may be slightly different. Control may also be determined by monitoring of glycosylated haemoglobin concentrations ideally the aim is an HbA_1c level of less than 7% or an HbA₁ of less than 8.8%, compared with normal ranges of 4 to 6% and 5 to 7.5% respectively. Insulin requirements may be altered by various factors (see Precautions, above). The aim of any regimen should be to achieve the best possible control of blood glucose by attempting to mimic as closely as possible the pattern of optimum endogenous insulin secretion. Many regimens involve the use of a short-acting soluble insulin with an intermediate-acting insulin, such as isophane insulin or mixed insulin zinc suspension, often given twice daily. It may sometimes be necessary, though, to give 3 or 4 injections daily to achieve good control and this typically involves giving a soluble insulin before meals and an intermediate- or long-acting insulin in the evening. A once-daily injection of an intermediate- or long-acting insulin is now generally considered to be acceptable only for those patients with type 2 diabetes mellitus who still retain some endogenous insulin secretion but nevertheless require insulin therapy, or for those patients with type 1 disease unable to cope satisfactorily with more intensive regimens. If a more intensive regimen is desired, continuous subcutaneous infusion may be employed using soluble insulin in an infusion pump. This delivers a constantbasal infusion of insulin supplying about half of the total daily requirements, the remainder being provided by patient-activated bolus doses before each meal. The technique has a limited place in the management of diabetes patients using it need to be well-motivated, reliable, and able to monitor their own blood glucose, and must have access to expert advice at all times. Formulations in which the insulin is in suspension are not suitable for continuous subcutaneous infusion and some brands of soluble insulin are unsuitable for this purpose because of the risk of precipitation in the pump catheter.

Ketoacidosis. Insulin is also an essential part of the emergency management of diabetic ketoacidosis. Only short-acting soluble insulins should be used. Treatment includes adequate fluid replacement, usually by infusing sodium chloride 0.9% initially, and the use of potassium salts to prevent or correct hypokalaemia. Insulin should be given by continuous intravenous infusion if possible, although other routes have also been used — for details of regimens see Diabetic Emergencies, under Diabetes Mellitus, below. Since insulin normally corrects hyperglycaemia before ketosis it is usually necessary to continue giving insulin once normoglycaemia has been achieved but to change the rehydration fluid to glucose-saline so that the additional glucose prevents the development of hypoglycaemia.

Administration. ADMINISTRATION ROUTES. The long-term management of diabetic patients usually involves injection by the subcutaneous route. The advice to diabetics has been to inject their insulin using a full-depth perpendicular injection.In many non-obese patients, however, such a technique can result in inadvertent intramuscular injection. Since insulin is absorbed more rapidly after intramuscular than subcutaneous injection, this may lead to greater day-to-day variability in blood-glucose control. In particular, overnight control may be inadequate if intermediate-acting preparations such as isophane insulin are used. Some therefore consider that extended-action insulins should be injected at an angle into a raised skin fold. Although injection of soluble insulin into muscle may produce a more physiological action profile, until more data are available a technique that ensures subcutaneous injection may be prudent with soluble insulins as well.The anatomic site of subcutaneous insulin injection is usually rotated in an attempt to decrease local adverse effects (see Adverse Effects, above). However, the rate of absorption varies between sites and such a practice may also contribute to day-to-day variability in blood-glucose concentrations. For example, large variations in blood-glucose concentrations have been reported on subcutaneous injection into the thigh. Some have suggested rotation of injection sites within an anatomic region, or possibly use of the same anatomic region for injections given at a specific time of day.

Jet injectors deliver insulin at high pressure across the skin into the subcutaneous tissue without use of a needle. The greater dispersion obtained gives more rapid absorption of short- and intermediate-acting insulins and consequently reduces the total duration of action. Mild pain, bruising, and bleeding may be a problem. Despite having been available for some years, there is little information about their benefits and risks and they are not widely used. However, results in a small study in women with gestational diabetes have suggested that jet injection may be associated with less variation in postprandial blood-glucose concentration and a lower incidence of insulin antibodies.Insulin preparations may also be given by intramuscular injection. Absorption is more rapid than from a subcutaneous injection. However, exercise may produce considerable variations in insulin absorption after intramuscular injection. Soluble insulins may be given intravenously this route is used in diabetic ketoacidosis, and also in surgery and labour. Intermittent pulsed intravenous insulin therapy added to a conventional subcutaneous regimen has been reported to improve symptoms of orthos-tatic hypotension and hypertension.

The subcutaneous and intravenous routes, and, rarely, the intramuscular route have all been used for the continuous administration of insulin (see Intensive Administration Regimens, below). Formulations of insulin for intranasal use are under investigation. They have been tried in both type 1 and type 2 diabetes, but bioavailability is low and variable. Absorption enhancers have been used to facilitate uptake of insulin from the nasal mucosa and local adverse effects are dependent, in part, on their irritancy. Similarly, buccal formulations are under investigation,and have become available in some countries. Devices for delivering insulin to the lungs via oral inhalation have been developed. Inhaled insulin is effective in maintaining glycaemic control in both type 1 and type 2 diabetes,although there is some evidence from longer-term studies that it is slightly less effective than subcutaneous injection however, patient acceptability is higher. It is given before meals as a short-acting insulin in patients also receiving intermediate or long-acting subcutaneous insulins or oral antidiabetics in type 2 diabetes it has also been used alone. UK recommendations from NICE are that it should be reserved for patients who are unable to start or intensify subcutaneous insulin therapy because of a marked, persistent fear of injections or severe difficulties with injection sites (for example, due to lipoatrophy). Data regarding the long-term safety of inhaled insulin also need to be collected, given reports of pulmonary effects and higher levels of insulin antibodies in people with type 1 diabetes. A few cases of primary lung malignancies have occurred in clinical trials of inhaled insulin, at a higher incidence than in comparator-treated patients. However, the number of cases was too small to determine whether these events were related to inhaled insulin, and all affected patients had a history of cigarette smoking. Endogenous insulin is delivered into the portal venous system, and then passes immediately to the liver where a large fraction of the insulin is extracted. The above routes of administration all deliver insulin into the peripheral circulation, with the risk of peripheral hyperinsulinaemia which has been considered a risk factor for atherosclerotic complications. Giving insulin via the intraperitoneal or oral routes may overcome this problem to some extent. Peritoneal insulin is used routinely in diabetics undergoing chronic ambulatory peritoneal dialysis, but has also been used for continuous administration (see Intensive Administration Regimens, below). Various formulations of insulin for oral delivery are also under investigation. Rectal or transdermal insulin has also been tried.

INSULIN ANALOGUES AND PROINSULIN. Recombinant-DNA technology has enabled the production of insulin analogues with altered pharmacokinetic profiles. Most of the insulin in pharmaceutical preparations is in the form of hexamers, which require time to dissociate before absorption from a subcutaneous site. Substitution of amino-acid residues at the monomer-monomer interface has produced monomeric insulin analogues that retain the biological activity of insulin. Good results have been reported with an analogue, insulin lispro, in which the B28 and B29 residues are replaced with lysine and proline. This analogue is commercially available and has been widely reviewed. In comparative studies of insulin lispro versus soluble insulin given before meals to patients also receiving a long-acting insulin, insulin lispro was reported to result in good glycaemic control, and could be given immediately before meals (5 to 15 minutes) rather than 20 to 40 minutes before as with soluble insulin. There is a suggestion that it may result in fewer severe hypoglycaemic episodes in such regimens. However, an analysis of 10 clinical trials did not find any difference between insulin lispro and neutral insulin (Humulin R) with respect to overall adverse effects or development of long-term diabetic complications. (See also insulin aspart, below.) A few cases of response to insulin lispro in patients with severe insulin resistance have been reported. Insulin lispro has been complexed with protamine to produce an intermediate-acting form, which is available as a biphasic preparation.

Insulin aspart is another short-acting insulin analogue, with aspartic acid substituted for proline at position B28. It is also used immediately before meals and controls postprandial blood glucose concentrations at least as well as regular human insulin, and may cause fewer hypoglycaemic episodes. A meta-analysis involving 42 studies of insulin lispro or insulin aspart versus regular insulin found that there was evidence of a minor benefit of the analogues in improving HbA_1c values in adult patients with type 1 diabetes no superiority could be shown in patients with type 2 diabetes.

Insulin glulisine is another insulin analogue, with asparagine at position B3 replaced by lysine, and lysine at B29 replaced by glutamic acid. It also has a rapid onset and short duration of action.

Recombinant-DNA technology has also been used to produce a long-acting basal insulin analogue, insulin glargine, suitable for once-daily use. It is available as a solution at pH 4 on subcutaneous injection and neutralisation by tissue buffering processes, microprecipitates are formed that slowly release insulin glargine over 24 hours with no pronounced peak in concentration or in metabolic activity. Controlled studies have reported insulin glargine to be more effective than human isophane insulin in producing glycaemic control as part of a basal-bolus regimen, and to be associated with fewer hypoglycaemic episodes. Insulin detemir is another long-acting insulin analogue that may have some benefit over isophane insulin. It is a neutral soluble human insulin analogue in which the terminal amino acid at B30 has been replaced by a 14-carbon fatty acid chain. This allows insulin detemir to bind reversibly to albumin, producing slow absorption and a prolonged and consistent metabolic effect for up to 24 hours. It appears to be at least as effective as isophane insulin in maintaining overall glycaemic control but with less intra-patient variability, a similar or lower risk of hypoglycaemia, and less body-weight gain.

Proinsulin (the natural precursor of insulin) appears to be more active than insulin in suppressing the hepatic production rather than the peripheral uptake of glucose. It has therefore been studied particularly in patients with type 2 diabetes mellitus. However, development by some manufacturers has been suspended because of a higher rate of adverse cardiac effects in patients treated with proinsulin than in controls.

INTENSIVE ADMINISTRATION REGIMENS. Intensive insulin regimens aim to mimic more closely the physiological insulin pattern in which a basal insulin concentration is supplemented by a preprandial boost of insulin. Such intensive regimens are used to provide tight control in an attempt to avoid long-term complications.

Intensified insulin regimens have the advantage of improving the patient’s lifestyle and allowing flexibility in timing of meals. However, careful dietary control must still be maintained and regular monitoring of blood-glucose concentrations is an important component of such regimens. Therefore patients must be well-motivated, reliable, and able to monitor their own blood glucose, and must have access to expert 24-hour help. Although there are reports of success with intensive regimens in brittle (labile) diabetics, these patients are generally unlikely to benefit from such regimens.

In multiple-injection regimens, the basal insulin is provided by an injection of intermediate- or long-acting insulin given usually at night, and soluble insulin is given before each main meal. Systems for continuous administration may be designed on an open-loop or closed-loop delivery system. Open-loop systems comprise an infusion pump with the infusion rate programmed or controlled manually according to manual blood-glucose monitoring. Closed-loop systems (the ‘artificial pancreas’) consist of an insulin pump, a glucose sensor, and a computer for analysis of blood-glucose data. Systems for continuous administration have most commonly used the subcutaneous route, but intraperitoneal, intravenous, or intramuscular infusion have also been used. The most extensively used open-loop system is continuous subcutaneous insulin infusion (CSII) using an external pump. A battery-powered pump infuses soluble insulin via a subcutaneous catheter which is resited every 2 to 3 days. A background infusion is given at a predetermined rate, and preprandial bolus doses given using an override switch or manual drive. CSII provides better glycaemic control than conventional injection therapy, but may be only slightly more effective than optimised multiple daily injection therapy. Complications include erythema, abscess, or cellulitis at the injection site and, rarely, contact dermatitis to components of the giving set, pump malfunction, or precipitation of insulin and catheter obstruction. Pump therapy increases the risk of ketoacidosis and intensive regimens are associated with decreased hypoglycaemic awareness and more severe hypoglycaemic episodes compared with conventional therapy, although there is some suggestion that CSII might reduce the risk of severe hypoglycaemia compared with multiple daily injection therapy. If the pump fails or there is an acute increase in insulin requirements, the onset of ketoacidosis may be more rapid and more likely to be associated with dangerous hyperkalaemia than with conventional regimens because there is no depot of insulin.

Further development of open-loop delivery systems has been in the design of implantable insulin pumps. The first pumps delivered insulin at a constant basal rate, but variable rate models are now available. Studies’ have shown that intravenous or intra-peritoneal delivery of insulin from an implantable pump can produce excellent glycaemic control, and fewer episodes of severe hypoglycaemia than are associated with intensive subcutaneous multiple-injection regimens. The main problems associated with such therapy are pump slow-down or catheter obstruction due to aggregation of insulin within the device these can normally be corrected by procedures to flush the pump and catheter, although alternative insulin formulations (e.g. with poloxamer) have been investigated. Other problems may include fibrinous obstruction of the catheter or local intolerance of the pump.

Closed-loop continuous infusion systems are generally confined to research and experimental work because glucose sensors suitable for implantation are still being developed. However, results in animals have suggested that an alternative to such systems may be a vascularised artificial pancreas containing islet cells.

MIXING OF INSULINS. Mixtures of insulin with differing durations of action may be used in order to produce a more normal pattern of blood glucose variation than can be achieved with a single insulin. However, physicochemical changes in the mixture may occur, either immediately on mixing or over time, and the physiological response to the mixture may therefore be different than if the components were given separately. An early review suggested that insulins from different manufacturers should not be mixed, since formulation differences might render them incompatible. It is important that a consistent routine is followed in preparing and using such mixtures, and manufacturers advise that the shorter-acting insulin should be drawn into the syringe first, to avoid contamination of the vial with the longer-acting component. Pre-prepared mixtures are available from many manufacturers and may be preferable provided that the proportions are suited to the patient’s needs.

The American Diabetes Association has issued guidelines for mixing of insulins, including:

• patients well controlled on a particular mixed regimen should maintain their standard procedure for preparing doses

• no other medication or diluent should be mixed with insulin unless approved by the prescriber

• insulin glargine should not be mixed with other forms of insulin because of the low pH of its diluent

• currently available isophane and short-acting insulin formulations when mixed may be used immediately or stored for future use

• rapid-acting insulins (insulin aspart, insulin lispro) can be mixed with isophane, lente, and ultralente insulins. Ultralente insulins do not affect the onset of action of the rapid-acting component a slight decrease in absorption rate but not bioavailability is seen if rapid-acting insulins are mixed with isophane insulin but postprandial blood-glucose response is similar to that seen with mixtures of rapid-acting and ultralente insulin

• mixtures of rapid-acting insulin with an intermediate- or long-acting insulin should be injected within 15 minutes before a meal

• mixing of short-acting (soluble) and lente or ultralente insulin is not recommended, as zinc ions present in the lente insulin may bind with the short-acting insulin and delay its effects. The degree and rate of binding vary with the insulins used, and may not reach equilibrium for 24 hours if such mixtures are used the patient should standardise the interval between mixing and injection

• phosphate-buffered insulins (e.g. isophane insulin) should not be mixed with zinc-containing (lente or ultralente) insulins, as zinc phosphate may be precipitated, and the longer acting insulin may be partially and unpredictably converted to a short-acting form

Insulin formulations may change and the manufacturers should be consulted if their recommendations differ from those in the guidelines.

Diabetes mellitus. Insulin is the mainstay of the treatment of type 1 diabetes mellitus. For a discussion of the treatment of diabetes mellitus, including the contexts in which insulin is used. The possible role of tight glycaemic control with insulin to prevent the development of microvascular and macrovascular complications in patients with type 1 diabetes is discussed, while further discussion of specific regimens and approaches to insulin therapy is given under Administration, above.

DIABETIC EMERGENCIES. As discussed, diabetic ketoacidosis and hyperosmolar hyperglycaemic state are medical emergencies and should be treated immediately with fluid replacement and insulin. Potassium, and possibly phosphate, replacement may also be required, but bicarbonate should not be given unless acidaemia is very severe. In the UK the BNF recommends that insulin be given by intravenous infusion for diabetic ketoacidosis, as a solution of soluble insulin 1 unit/mL via an infusion pump. An infusion rate of 6 units/hour in adults and 0.1 units/kg per hour in children is recommended initially, with the rate doubled or quadrupled if the blood glucose concentration fails to decrease by about 5 mmol/litre per hour. When blood glucose concentrations have fallen to 10 mmol/litre the infusion rate can be reduced to 3 units/hour in adults or about 0.05 units/kg per hour in children, and continued, with glucose 5% to prevent hypoglycaemia, until the patient is ready to take food by mouth. The insulin infusion should not be stopped before subcutaneous insulin has been started. Potassium chloride is included in the infusion as appropriate to prevent insulin-induced hypokalaemia. If facilities for intravenous infusion are not available the insulin is given by intramuscular injection: in adults an initial loading dose of 20 units intramuscularly is followed by 6 units intramuscularly every hour until the blood glucose concentration falls to 10 mmol/litre, when the dose is given every 2 hours. Late hypoglycaemia due to insulin accumulation should be watched for and managed appropriately. In the USA the intramuscular or the subcutaneous route have been used as alternatives to intravenous insulin, with other appropriate management. One successful set of protocols for insulin dosage in diabetic ketoacidosis is as follows: an initial intravenous bolus of 0.15 units/kg is followed by infusion of 0.1 units/kg per hour if blood glucose does not fall by about 2.5 to 3.5 mmol/litre in the first hour the infusion rate is doubled every hour until this rate of decline is achieved. (A similar insulin regimen has proved effective in patients with hyperosmolar hyperglycaemic state.) When given by the intramuscular or subcutaneous routes an initial bolus of 0.4 units/kg is divided and given half by the intravenous route and half either intramuscularly or subcutaneously as appropriate. This is followed by 0.1 units/kg every hour intramuscularly or subcutaneously if response is inadequate it is replaced by an intravenous bolus of 10 units until blood glucose falls by 2.5 to 3.5 mmol/litre. In children intravenous infusion of 0.1 units/kg per hour is recommended, or if intravenous infusion is impractical an initial intramuscular bolus of 0.1 units/kg followed by 0.1 units/kg per hour either intramuscularly or subcutaneously. Treatment is continued at this rate until a serum-glucose concentration of about 12.5 mmol/litre is reached (or about 15 mmol/litre for hyperosmolar hyperglycaemic state), when the rate is decreased to 0.05 to 0.1 units/kg per hour until acidosis is controlled and subcutaneous insulin replacement treatment can be started.

TYPE 2 DIABETES MELLITUS. Traditionally the use of insulin in patients with type 2 diabetes has tended to be reserved for those who cannot be controlled by diet and oral antidiabetics alone. Given the possible association between circulating insulin and atherosclerotic cardiovascular symptoms there has been some concern about the use of exogenous insulin in insulin-resistant patients who are already hyperinsulinaemic. Furthermore, patients switched to insulin tend to gain weightwhich is undesirable in a frequently obese patient group. Insulin is nonetheless being used more frequently in type 2 patients. This is largely because of a trend toward more intensive regimens designed to produce tighter glycaemic control, on the hypothesis that, as in patients with type 1 disease, this will reduce the development and progression of diabetic complications. Results from the UK Prospective Diabetes Study, show that insulin is an effective option in type 2 diabetes, and confirm both the value of intensive therapy in retarding microvascular complications, and that oral therapy should be used before insulin in patients with primary diet failure.

In order to minimise the dose of insulin required, and any risks it may entail, it has been suggested that insulin therapy in type 2 diabetes should be combined with other measures including oral hypoglycaemic drugs. There has long been debate about the value of combined therapy, but a meta-analysis indicated that glycaemic control was better, and insulin requirements lower, in type 2 diabetics who received insulin with a sulfonylurea. For evidence that the insulin analogues insulin lispro and insulin as-part have no advantage over regular insulin in type 2 patients see Insulin Analogues, above.

Diagnosis and testing. PITUITARY FUNCTION. Insulin-induced hypoglycaemia has been used to provide a stressful stimulus in order to assess hypothalamic-pituitary function. The insulin stress or insulin-tolerance test has been used as a standard test for assessment of growth hormone or corticotropin deficiency. However, it is unpleasant, expensive, and not without risk, and is contra-indicated in patients with angina, heart failure, cerebrovascular disease, or epilepsy some recommend its use only when results of alternative tests are equivocal, and it should only be performed in specialist units under strict surveillance.

Hyperkalaemia. Insulin promotes the intracellular uptake of potassium. It is therefore used in the management of moderate to severe hyperkalaemia, when it is given with glucose.

Liver disorders. There have been reports of benefit from the use of insulin and glucagon in the treatment of liver disorders, based on their reported hepatotrophic effect. However, randomised studies have found no benefit from insulin and glucagon infusions in fulminant hepatic failure and acute alcoholic hepatitis.

Myocardial infarction. Discussions on the effects of insulin with glucose and potassium in the ischaemic heart, including its effect in reducing blood free fatty acids, have emphasised its potential benefits in left ventricular failure and cardiogenic shock. A meta-analysis of randomised controlled studies performed before the widespread use of thrombolytics found a reduction in mortality in recipients of glucose-insulin-potassium solutions. However, although a pilot study that included patients undergoing reperfusion (thrombolysis or percutaneous coronary intervention) reported benefit, this was not confirmed in larger randomised studies using standard glucose-insulin-potassium infusions. A further study found that routine use of such infusions in patients undergoing reperfusion had no effect on myocardial salvage, although some improvement was reported in diabetics.

Intensive glucose control, with insulin-glucose infusion followed by multiple daily subcutaneous insulin injections has been reported to reduce mortality in diabetics who suffered a myocardial infarction. A similar study of treatment after myocardial infarction included only patients with type 2 diabetes mellitus who were treated with routine care, or insulin-glucose infusion followed by either long-term subcutaneous insulin or standard glucose control. The study was stopped early due to slow patient recruitment, but results did suggest that although glucose concentration was a strong independent predictor of long-term mortality, the use of long-term insulin treatment did not improve survival compared with conventional treatment at similar levels of glucose control. An observational study in non-diabetics with hyperglycaemia suggested that intensive glucose control also improved outcomes in this population, but another study found no benefit. However, the glucose control achieved in this study was similar in both the intensive and the conventional treatment groups and an analysis based on blood glucose concentrations suggested that strict glucose control was beneficial.For the conventional management of myocardial infarction.

Neonatal hyperglycaemia. Hyperglycaemia is common in very immature neonates because of delayed or reduced insulin production. It can be treated by glucose restriction until glucose tolerance improves. However, this may not provide enough glucose to meet basal metabolic needs, and the use of an insulin infusion can allow sufficient glucose to be given. It has been suggested that insulin is best given intravenously in a separate, easily titratable solution because of the frequent fluctuations of requirement in these infants.

Overdosage with calcium-channel blockers. High-dose insulin, with glucose and potassium as required to maintain normal plasma concentrations of these, has been reported to be of value in the treatment of overdosage with calcium-channel blockers that has not been adequately managed with conventional therapy (which is described under Treatment of Adverse Effects under Nifedipine). A review of 13 reported cases found that various dosage regimens had been tried. These included bolus doses of insulin 10 to 20 units, and continuous infusions of 0.1 to 1 unit/kg per hour. The authors of one report have proposed a regimen that includes an initial intravenous bolus dose of insulin 1 unit/kg, followed by a continuous infusion of 0.5 units/kg per hour this may be increased to 1 unit/kg per hour if necessary.

Preparations

British Pharmacopoeia 2008: Insulin Aspart Injection; Insulin Lispro Injection; Protamine Zinc Insulin Injection

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1and 6.2: Biphasic Insulin Injection; Biphasic Isophane Insulin Injection; Insulin Zinc Injectable Suspension; Insulin Zinc Injectable Suspension (Amorphous); Insulin Zinc Injectable Suspension (Crystalline); Isophane Insulin Injection; Soluble Insulin Injection

The United States Pharmacopeia 31, 2008: Extended Insulin Human Zinc Suspension; Extended Insulin Zinc Suspension; Human Insulin Isophane Suspension and Human Insulin Injection; Insulin Human Injection; Insulin Human Zinc Suspension; Insulin Injection; Insulin Lispro Injection; Insulin Zinc Suspension; Isophane Insulin Human Suspension; Isophane Insulin Suspension; Prompt Insulin Zinc Suspension

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Argentina: Actrapid HM; Actrapid MC¤; Biohulin C; Biohulin N; Humalog; Humulin 70/30; Humulin L; Humulin NPH; Humulin R; Humulin U; Insulatard HM; Insulatard MC¤; Insuman N; Insuman R; Mixtard 30 HM; Monotard HM¤; Monotard MC¤

Australia: Actraphane HM¤; Actraphane MC¤; Actrapid MC¤; Actrapid; Humalog Mix 25; Humalog; Humulin 20/80, 30/70 and 50/50; Humulin L; Humulin NPH; Humulin R; Humulin UL; Hypurin Isophane; Hypurin Neutral; Initard Human¤; Initard¤; Insulatard Human¤; Insulatard¤; Insulin 2¤; Isotard MC¤; Lantus; Lente MC¤; Mixtard 20/80, 30/70, 50/50; Mixtard¤; Monotard MC¤; Monotard; NovoMix 30; NovoRapid; Protamine Zinc Insulin MC¤; Protaphane MC¤; Protaphane; Rapitard MC¤; Semilente MC¤; Ultralente MC¤; Ultratard; Velosulin¤

Austria: Actrapid HM; Depot-Insulin¤; Humalog Mix 25 and 50; Humalog; Huminsulin Basal; Huminsulin Long; Huminsulin Normal; Huminsulin Profil II and III; Huminsulin Ultralong; Insulatard HM; Insulatard¤; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman komb Typ 15, Typ 25, and Typ 50¤; Insuman Rapid; Komb-Insulin¤; Lente MC¤; Mixtard 30/70 and 50/50¤; Mixtard HM 10/90, 20/80, 30/70, 40/60, and 50/50; Monotard HM; Rapitard MC¤; Ultratard HM; Velosulin HM¤; Velosulin¤

Belgium: Actrapid HM; Humaject 30/70; Humaject NPH; Humaject Regular; Humalog; Humuline 20/80, 30/70, 50/50; Humuline Long; Humuline NPH; Humuline Regular; Humuline Ultralong; Initard Humanum¤; Insulatard HM; Insulatard-X Humanum¤; Lantus; Lente MC¤; Mixtard HM 10/90, 20/80, 30/70, 40/60, 50/50; Mixtard-X Humanum¤; Monotard HM; NovoMix 30; NovoRapid; Ultralente MC¤; Ultratard HM; Velosuline HM

Brazil: Actrapid MC; Biohulin 70/30, 80/20, and 90/10; Biohulin Lenta; Biohulin NPH; Biohulin Regular; Biohulin Ultralenta; Humalog Mix 25; Humalog; Humulin 70/30; Humulin Lenta; Humulin NPH; Humulin Regular; Insuman Comb 85N/15R and 75N/25R; Insuman N; Insuman R; Iolin NPH¤; Iolin Regular¤; Lantus; Monolin NPH¤; Monolin Regular¤; Monotard MC; Neosulin Lenta¤; Neosulin NPH¤; Neosulin Regular¤; Novolin 90/10, 80/20, and 70/30; Novolin L; Novolin N; Novolin R; Novolin U; NovoRapid; Protaphane MC

Canada: Humalog Mix 25; Humalog; Humulin 20/80, 30/70; Humulin L; Humulin N; Humulin R; Humulin U; Iletin II Pork Lente; Iletin II Pork NPH; Iletin II Pork Regular; Iletin Lente¤; Iletin NPH¤; Iletin Regular¤; Iletin Semilente¤; Iletin Ultralente¤; Initard 50/50¤; Insulatard NPH Human¤; Insulatard NPH¤; Insulin-Toronto (Regular)¤; Lente Insulin¤; Mixtard 15/85, 30/70, 50/50¤; Mixtard 30/70¤; Novolin 10/90, 20/80, 30/70, 40/60, 50/50; Novolin Lente; Novolin NPH; Novolin Toronto; Novolin Ultralente; NovoRapid; PZI Iletin¤; Semilente Insulin¤; Ultralente¤; Velosulin (Regular)¤; Velosulin Human¤

Chile: Actrapid HM; Actrapid¤; Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insulatard HM; Insulatard¤; Insuman N; Insuman R; Lantus; Lenta¤; Mixtard HM¤; Monotard HM

Czech Republic: Actrapid HM; Humalog Mix 25 and 50; Humalog NPL; Humalog; Humulin L; Humulin M3; Humulin N; Humulin R; Humulin U; Hypurin Bovine Isophane; Hypurin Bovine Protamin Zink Sulfat; Hypurin Porcin Neutral; Insulatard HM; Insuman Basal; Insuman Komb Typ 15, Typ 25, and Typ 50; Insuman Rapid; Lantus; Mixtard HM 10, 20, 30, 40, 50; Monotard HM; NovoMix 30; NovoRapid; Ultratard HM; Velosulin HM

Denmark: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70; Humulin NPH; Humulin Regular; Humutard Ultra¤; Insulatard; Insuman Basal; Insuman Comb 25; Insuman Rapid; Mixtard 10/90, 20/80, 30/70, 40/60, and 50/50; Monotard; NovoMix 30; NovoRapid; Velosulin

Finland: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70¤; Humulin NPH; Humulin Regular; Humutard Ultra¤; Humutard; Insulin Lente MC¤; Insulin Lyhyt¤; Insulin Pitka¤; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Lantus; Mixtard 10, 20, 30, and 50; Monotard; NovoMix 30; NovoRapid; Protaphane; Ultratard; Velosulin¤

France: Actraphane HM¤; Actrapid HM; Apidra; Durasuline¤; Endopancrine 100¤; Endopancrine 40¤; Endopancrine Protamine¤; Endopancrine Zinc Protamine¤; Humalog Mix 25 and 50; Humalog; Insulatard Nordisk¤; Insulatard; Insuline NPH¤; Insuline Semi Tardum¤; Insuline Tardum MX¤; Insuline Ultra Tardum¤; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Intermediaire 100%¤; Insuman Intermediaire 25/75¤; Insuman Rapid; Lantus; Lente MC¤; Levemir; Lillypen Profil 10, 20, 30, and 40¤; Lillypen Protamine Isophane¤; Lillypen Rapide; Mixtard 10, 20, 30, 40, and 50 HM; Mixtard¤; Monotard¤; NovoMix 30; NovoRapid; Orgasuline 30/70¤; Orgasuline NPH¤; Orgasuline Rapide¤; Protaphane HM¤; Rapitard MC¤; Semilente MC¤; Ultralente MC¤; Ultratard¤; Umuline Profil 30; Umuline Protamine Isophane (NPH); Umuline Rapide; Umuline Zinc Compose¤; Umuline Zinc¤; Velosulin; Velosuline¤

Germany: Actraphane 10/90, 20/80, 30/70, 40/60, 50/50; Actrapid; B-Insulin; Basal-H-Insulin¤; Berlinsulin H 20/80, 30/70; Berlinsulin H Basal; Berlinsulin H Normal; Depot-H-Insulin¤; Depot-H15-Insulin¤; Depot-Insulin Horm¤; Depot-Insulin S¤; Depot-Insulin¤; H-Insulin¤; H-Tronin¤; Humalog Mix 25 and 50; Humalog; Huminsulin Basal; Huminsulin Long¤; Huminsulin Normal; Huminsulin Profil II and III; Huminsulin Ultralong¤; Insulatard Human; Insulatard MC¤; Insulin Basal; Insulin Comb 30/70; Insulin Monotard HM; Insulin Novo Semilente MC; Insulin Rapid; Insulin S; Insulin SNC; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Komb-H-Insulin¤; Komb-Insulin S¤; Komb-Insulin¤; L-Insulin SNC¤; L-Insulin¤; Lantus; Lente¤; Mixtard 30/70; Mixtard¤; Monotard; NovoMix 30; NovoRapid; Protaphane; Rapitard¤; Semilente; Ultralente¤; Ultratard HM; Velasulin Human¤; Velasulin MC¤; Velasulin¤; Velosulin

Greece: Actraphane HM¤; Actrapid HM; Humalog Mix 25; Humalog; Humulin Lente; Humulin M2, M3; Humulin NPH; Humulin Regular; Humulin Utralente; Lantus; Mixtard 10, 20, 30, 40, and 50; Monotard HM; NovoMix 30; NovoRapid; PenMix 10, 20, 30, 40, or 50¤; Protaphane HM; Ultratard

Hong Kong: Actrapid HM; Actrapid MC¤; Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insulatard MC¤; Lantus; Mixtard 20 and 30 HM; Monotard HM; Monotard MC¤; NovoRapid; Protaphane HM; Protaphane MC¤; Ultratard HM

Hungary: Humalog M25 and M50; Humalog; Humulin L; Humulin M1, M2, M3, M4; Humulin N; Humulin R; Humulin U; Insulin Actrapid; Insulin Insulatard; Insulin Mixtard 10, 20, 30, 40, 50; Insulin Monotard; Insulin Semilente; Insulin Ultratard; Monotard MC; NovoRapid

India: Actrapid; Human Actrapid; Human Insultard; Human Mixtard 30 and 50; Human Monotard; Lantus; Lentard; Mixulin; Rapidica; Rapimix; Wosulin Biphasic 30/70 and 50/50; Wosulin-N; Wosulin-R; Zinulin

Ireland: Actrapid; Humalog Mix 25 and 50; Humalog; Human Actraphane¤; Human Initard 50/50¤; Human Protaphane¤; Human Velosulin¤; Humulin I; Humulin Lente; Humulin M3; Humulin S; Humulin Zn; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Rapid; Lantus; Levemir; Mixtard 10, 20, 30, 40, and 50; Monotard; Neulente¤; Neuphane¤; NovoMix 30; NovoRapid; Ultratard; Velosulin¤

Israel: Humalog Mix 25; Humalog; Humulin 70/30, 80/20; Humulin N; Humulin R; Humulin U¤; Lantus; NovoMix 30; NovoRapid

Italy: Actraphane HM 10/90, 20/80, 30/70, 40/60, 50/50; Actrapid HM; Bio-Insulin 30/70 and 50/50¤; Bio-Insulin I¤; Bio-Insulin L¤; Bio-Insulin R¤; Bio-Insulin U¤; Humalog Mix 25; Humalog; Humulin 30/70 and 50/50; Humulin I; Humulin L; Humulin R; Humulin U; Lantus; Lenta MC¤; Monotard HM; NovoRapid; Protaphane HM; Rapitard MC¤; Ultratard HM

Japan: Humacart 3/7; InnoLet 10R, 20R, 30R, 40R, and 50R; InnoLet N; InnoLet R; Monotard; NovoLet 10R,20R, 30R, 40R, 50R¤; NovoLet N¤; NovoLet R¤; Novolin 10R, 20R, 30R, 40R, and 50R; Novolin N; Novolin R; Novolin U; NovoRapid; Penfill N; Penfill R; Penfill 10R, 20R, 30R, 40R, 50R; Velosulin

Malaysia: Actrapid; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Insulatard; Lantus; Mixtard 30 HM; Monotard HM¤; NovoRapid; Ultratard HM¤

Mexico: Anilusin¤; Humalog Mix 25; Humalog; Humanilusin¤; Humulin 70/30, 80/20; Humulin L; Humulin N; Humulin R; Insulex¤; Insuman 100N; Insuman 15R/85N, 25R/75N, and 50R/50N; Insuman R; Lantus; Novolin 30/70; Novolin L; Novolin N; Novolin R; Prodiabin-N

Netherlands: Actrapid; Humaject 10/90, 20/80, 30/70, 40/60, 50/50¤; Humaject NPH¤; Humaject Regular¤; Humalog Mix 25; Humalog; Humuline NPH; Humuline Zink¤; Humuline 20/80, 30/70; Humuline; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Isuhuman Basal¤; Isuhuman Comb 15, Comb 25, Comb 50¤; Isuhuman Infusat¤; Isuhuman Rapid¤; Mixtard 10, 20, 30, 40, and 50; Monotard; NovoRapid; Ultratard; Velosulin

Norway: Actrapid; Humalog Mix 25; Humalog; Humulin Mix 30/70¤; Humulin NPH; Humulin Regular¤; Insulatard; Insulin Basal¤; Insulin Infusat¤; Insulin Komb 25/75¤; Insulin Rapid¤; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Lantus; Mixtard 10/90, 20/80, 30/70, 40/60, 50/50; Monotard; NovoMix 30; NovoRapid; Ultratard; Velosulin¤

New Zealand: Actrapid; Humalog Mix 25¤; Humalog; Humulin 70/30, 80/20; Humulin L; Humulin N; Humulin R; Humulin U¤; Insulatard MC; Lantus; Mixtard 30 or 50; Monotard; NovoRapid; PenMix 10, 20, 30, 40, or 50; Protaphane; Ultratard; Velosulin HM; Velosulin MC

Portugal: Actrapid; Humalog; Humulin Lenta; Humulin M1, M2, M3, M4, M5; Humulin NPH; Humulin Regular; Humulin Ultralenta; Insulatard; Isuhuman Basal; Isuhuman Comb 25; Isuhuman Rapid; Mixtard 10, 20, 30, 40, and 50 HM; Monotard; Ultratard

Russia: Actrapid HM (Актрапид НМ); Actrapid MC (Актрапид MC); Biosulin N (Биосулин Н); Biosulin R (Биосулин Р); Humalog (Хумалог); Humulin M3 (Хумулин М3); Humulin NPH (Хумулин НПХ); Humulin Regular (Хумулин Регуляр); Insulidd L (Инсулидд Л); Insulidd N (Инсулидд Н); Insulidd R (Инсулидд Р); Insulin Lt (Инсулин Лт); Insulin Maxirapid (Инсулин Максирапид); Insuman Basal (Инсуман Базал); Insuman Comb 25 (Инсуман Комб 25); Insuman Rapid (Инсуман Рапид); Lantus (Лантус); Levulin L (Левулин Л); Levulin N (Левулин Н); Levulin R (Левулин Р); Mixtard 30 HM (Микстард 30 НМ); Monotard MC (Монотард Нм); NovoRapid (Новорапид); Protaphane HM (Протафан НМ)

South Africa: Actraphane HM; Actrapid HM; Humalog Mix 25; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Humulin U¤; Lantus; Mixtard 20/80; Monotard HM; NovoMix 30; NovoRapid; Protaphane HM; Ultratard HM

Singapore: Actrapid HM; Humalog Mix 25; Humalog; Humulin 30/70; Humulin L; Humulin N; Humulin R; Insulatard HM; Lantus; Mixtard 20, 30, 50 HM; Monotard HM¤; NovoMix 30; NovoRapid; Ultratard HM¤

Spain: Actrafan HM¤; Actrap MC¤; Actrapid; Combitard Humana 15/85¤; Humalog Mix 25 and 50; Humalog NPL; Humalog; Humaplus 30/70; Humaplus NPH; Humaplus Regular; Humulina 10:90, 20:80, 30:70, 50:50; Humulina Lenta¤; Humulina NPH; Humulina Regular; Humulina Ultralenta¤; Insulatard NPH¤; Insulatard; Lantus; Lente MC¤; Meztardia Humana 50/50¤; Meztardia Nordi¤; Mixtard 10, 20, 30, 40, and 50; Mixtard 30/70¤; Monotard¤; Monotard; NovoMix 30; NovoRapid; Protafan HM¤; Rapitar MC¤; Semilen MC¤; Ultrale MC¤; Ultratard; Velosulin Humana¤; Velosulin¤

Sweden: Actrapid; Humalog Mix 25 and 50; Humalog; Humulin Mix 30/70; Humulin NPH; Humulin Regular; Humutard¤; Insulatard; Insuman Basal; Insuman Comb 25; Insuman Infusat; Insuman Rapid; Isuhuman Basal¤; Isuhuman Comb 25/75, 50/50¤; Isuhuman Infusat¤; Isuhuman Rapid¤; Lantus; Mixtard 10/90, 20/80, 30/70, 40/60, 50/50; Monotard; NovoMix 30; NovoRapid; Ultratard; Velosulin

Switzerland: Actraphane HM¤; Actrapid HM; Actrapid MC; Humalog; Huminsulin Basal (NPH); Huminsulin Long; Huminsulin Normal; Huminsulin Profil III; Huminsulin Ultralong; Hypurin 30/70 Mix; Hypurin Isophane; Hypurin Neutral; Initard Humaine¤; Initard¤; Insulatard HM; Insulatard MC; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Infusat; Insuman Rapid; Lantus; Lente MC¤; Levemir; Mixtard 30 MC; Mixtard HM 10, 20, 30, 40, 50; Monotard HM; NovoMix 30; NovoRapid; Rapitard MC¤; Semilente MC; Ultralente MC¤; Ultratard HM; Velosulin HM; Velosulin MC¤

Thailand: Actrapid HM; Humalog Mix 25¤; Humalog¤; Humulin 70/30¤; Humulin N¤; Humulin R¤; Insulatard; Lantus; Mixtard 20, 30, 50 HM; Monotard HM; NovoMix 30; NovoRapid; Ultratard HM¤

United Arab Emirates: Jusline 70/30; Jusline N; Jusline R

United Kingdom: Actrapid; Apidra; Humaject I¤; Humaject M1, M2, M3, M4, M5¤; Humaject S¤; Humalog Mix 25 and 50; Humalog; Human Actraphane¤; Human Initard 50/50¤; Humulin I; Humulin Lente¤; Humulin M3; Humulin S; Humulin Zn¤; Hypurin 30/70; Hypurin Isophane; Hypurin Lente; Hypurin Neutral; Hypurin Protamine Zinc; Hypurin Soluble¤; Initard 50/50¤; Insulatard; Insuman Basal; Insuman Comb 15, 25, and 50; Insuman Rapid; Lantus; Lentard MC¤; Levemir; Mixtard 10, 20, 30, 40, and 50; Monotard¤; NovoMix 30; NovoRapid; PenMix 10/90, 20/80, 30/70, 40/60, 50/50¤; Pork Actrapid; Pork Insulatard; Pork Mixtard 30; Pur-in Isophane¤; Pur-in Mix 15/85, 25/75, 50/50¤; Pur-in Neutral¤; Rapitard MC¤; Semitard MC¤; Ultratard¤; Velosulin¤; Velosulin

United States: Apidra; Exubera; Humalog Mix 75/25 and 50/50; Humalog; Humulin 70/30, 50/50; Humulin BR¤; Humulin L; Humulin N; Humulin R; Humulin U Ultralente; Insulatard NPH Human¤; Insulatard NPH¤; Lantus; Lente Iletin I¤; Lente Iletin II; Lente L¤; Lente; Levemir; Mixtard Human 70/30¤; Mixtard¤; Novolin 70/30; Novolin L¤; Novolin N; Novolin R; NovoLog Mix 70/30; NovoLog; NPH Iletin I¤; NPH Iletin II; Protamine, Zinc & Iletin I¤; Regular Iletin I¤; Regular Iletin II; Semilente Iletin I¤; Semilente¤; Ultralente Iletin I¤; Ultralente U¤; Ultralente; Velosulin Human BR¤; Velosulin¤

Venezuela: Humalog; Humulin 70/30; Humulin L; Humulin N; Humulin R; Insuman N; Insuman R; Novolin 70/30; Novolin L; Novolin N; Novolin R

Choice of insulin regimens

It is preferable to use human insulin in diabetic pregnancy, although a very small minority of patients who are still using animal insulins, because of hypoglycaemic unawareness, maybe reluctant to change. Porcine insulin is probably acceptable but bovine insulin is best avoided as it can produce significant levels of insulin antibodies that freely cross the placenta. These have been implicated as a cause of infant morbidity possibly affecting β-cell function of the fetus and influencing neonatal insulin secretion. Whilst the current insulin analogues possess theoretically attractive properties for pregnancy, none are licensed for use in pregnancy. Some of the short-acting analogues are being used more widely, seemingly without problems.

Once daily insulin regimens

These would seldom be appropriate in pregnant mothers with diabetes established before pregnancy, but single daily injections of an intermediate-duration insulin before breakfast maybe very effective in some women with type 2 or mild gestational diabetes. Such individuals can usually produce sufficient insulin in a fasting state overnight to maintain normoglycaemia and thus an intermediate insulin, e.g., an isophane, such as Humulin I (Lilly), Insulatard (Novo-Nordisk) would be suitable. Additional short-acting or soluble insulin, e.g., Actrapid (Novo-Nordisk) or Humulin S (Lilly) may be added later as a fast-acting component to counter postprandial hyperglycaemia. The use of such regimens significantly reduces the incidence of fetal macrosomia in women with gestational diabetes when compared with treatment by diet alone.

The newer short-acting insulin analogues insulin lispro (Humalog (Lilly)) and insulin aspart (Novorapid (Novo-Nordisk)) have rapid absorption characteristics that provide a peak insulin concentration more rapidly than obtained with human insulin. This results in lower postprandial plasma glucose concentrations. This is therapeutically attractive in the context of the increased insulin resistance associated with pregnancy. However, it is unknown whether these analogue insulins are teratogenic. Maternally derived insulin can only cross the placenta if antibody bound. In clinical trials with insulin lispro, there has been no observed increase in antibody response. This means little insulin transfer from mother to fetus and thus no likely increased risk for congenital malformations. A multicentre, multinational study in 500 pregnancies exposed to insulin lispro (Humalog) during organogenesis showed no increase in malformation rates.

Anxieties have been expressed that the use of insulin lispro during pregnancies complicated by diabetes may accelerate retinopa-thy through its influence on the IGF-1 (insulin-like growth factor 1) system. This seems unlikely as insulin lispro binds to the IGF-1 receptor with an affinity of only about 1/1000 that of IGF-1 and with an affinity of only about 1.5 times human insulin. Insulin aspart (Novorapid) has only 69% IGF-1 activity that of human insulin. Whilst remaining unlicensed for use in pregnancy these analogues are being used increasingly in some centres.

Twice daily combinations of short- and intermediate-acting insulins

This type of regimen is still fairly widely used outside pregnancy -although diminishing in preference to basal prandial regimens -and is perfectly capable of providing adequate control during pregnancy as well. The usual combinations are a soluble insulin with an isophane insulin. Pre-mixed formulations of these insulins should be avoided in pregnancy as they do not afford sufficient flexibility. It is preferable to change women using these to free-mixing their insulins during the preconception period. The ability to change the proportion of short- to intermediate-acting insulin is important because as pregnancy progresses, the required balance between the two may change with increasing insulin resistance. Frequently it is found that hyperglycaemia before breakfast cannot be resolved by increasing the evening dose of isophane insulin without incurring frequent hypoglycaemia during the night, partly as a result of continued glucose usage in the fetoplacental unit. The general solution to this is to divide the evening injection, taking the short-acting insulin with the evening meal and the intermediate insulin at bedtime. Similarly, as gestation progresses, the proportion of short-acting insulin required may increase, reflecting increased insulin resistance, and to control postprandial hyperglycaemia in the afternoon it often becomes necessary to abandon the morning dose of intermediate insulin in preference to an additional lunch-time injection of short-acting insulin. From 36-week onwards, there is a tendency for the fasting blood glucose concentration to fall, which may require reduction or even omission of the evening injection of intermediate insulin. Sudden dramatic falls in insulin requirements at this time should alert the clinicians to the possibility of placental insufficiency sufficient to threaten the pregnancy.

Multiple daily insulin injections

Many younger patients with diabetes already employ such regimens, using pen-type insulin delivery devices. It is a particularly satisfactory means of achieving excellent metabolic control which is readily understood by the patient and can easily be altered to cope with variations in diet and activity. Generally, a short-acting insulin is administered with each of the main meals of the day and an isophane is given at bedtime. Close self-monitoring is essential for this type of regimen, but this will not differ from what is required for pregnancy anyway. Unfortunately, glargine insulin (Lantus (Sanofi-Aventis)), whilst commonly used in both type 1 and type 2 diabetes, is unlicensed for pregnancy and in view of theoretical considerations is not being recommended for use in pregnancy. It has a sixfold higher binding affinity for IGF-1 receptors, and experimental studies suggest an increased mitogenicity on tumour cell lines at high dosage. Until large-scale studies have demonstrated that placental transfer of glargine insulin is similar to the transfer of human insulin, and there is no increased risk to the fetus, this agent is not recommended. Its use is perhaps only justified where severe hypoglycaemia has been a problem, and there must be full discussion of the safety issues with the patient. Furthermore, this means that patients established on glargine insulin have to be switched back to an isophane basal insulin in the preconception period, or immediately an unplanned pregnancy is detected. Detimir insulin (Levemir (Novo-Nordisk)), another long-acting insulin analogue, does not have increased IGF-1 activity, so may eventually prove to be an attractive long-acting insulin alternative, but again is currently unlicensed for use in pregnancy.

Continuous subcutaneous insulin infusion

Open-loop subcutaneous insulin infusion with miniature pumps can achieve near-normal glycaemic control in appropriately selected patients. However, multiple injection regimens remain a simpler solution that can achieve very similar results and continuous subcutaneous insulin infusion is potentially more dangerous in pregnancy. Severe hypoglycaemia is a significant risk and the rapid development of ketoacidosis may occur in the event of pump failure. This option should be considered very carefully and probably only undertaken in centres with extensive pump experience.

The pharmacokinetic profile of regular human insulin is such that most patients on insulin therapy require multiple daily injections to maintain glycemic control. Regular insulin has an onset of action of 0.5–1 hour after subcutaneous injection, reaches a peak effect in 2–3 hours, and has an effective duration of action of 3–6 hours (Table 4). The semisynthetic insulin analogs currently available have been developed to simulate endogenous insulin secretion more closely, and other agents are in development to provide a peakless pharmacokinetic profile.

The rapid-acting insulin analog lispro was introduced in 1996. After subcutaneous administration, insulin lispro is absorbed more quickly than regular human insulin, having an almost immediate onset of action and reaching peak levels within 1 hour. With its improved absorption profile, insulin lispro can be administered 15 minutes or less prior to a meal, compared to 30–45 minutes with regular insulin. The duration of action of insulin lispro is comparable to that of regular insulin. A meta-analysis of randomized clinical trials comparing human regular insulin and insulin lispro found that insulin lispro was significantly more effective in controlling postprandial glycemia control, without increasing the incidence of hypoglycemic episodes; there were no differences between the two insulin preparations in maintaining basal glycemic control or HbA1c levels. For individuals with type 2 diabetes and sufficient insulin reserve to cover meal-stimulated glucose production, postprandial insulin is relatively less important than basal insulin in maintaining glycemic control. Nonetheless, insulin lispro and other rapid-acting analogs can improve convenience when mealtime therapy is necessary. A new insulin formulation containing lispro and Neutral Protamine Lispro (NPL) in a ratio of 25%/75% was recently compared with human insulin 70/30. Twice daily administration of the new lispro formulation, 75% NPL and 25% lispro, called Humalog Mix 75/25, resulted in improved postprandial glycemic control, comparable overall glycemic control, and the convenience of administration immediately before meals.

Another rapid-acting insulin analog in development is insulin aspart. Clinical studies comparing insulin aspart with regular human insulin have demonstrated that the time-action profile of insulin aspart more closely resembles physiologic postprandial insulin release and improved postprandial glucose control.

The intermediate-acting insulins, neutral protamine Hagedorn (NPH) and lente insulins, have a longer pharmacokinetic profile than regular insulin, with onset of action of 2–4 hours, peak effect after 4–12 hours, and duration of action up to 20 hours. These agents offer one approach to basal insulin therapy for patients with moderate type 2 diabetes; some patients may need additional doses of a short-acting insulin for meal coverage.

Ultralente insulin is the only currently available long-acting insulin. Its onset of action is 6–10 hours, and the timing of a peak effect is dose dependent; the maximal duration of action is 24–30 hours. Long-acting insulin is both useful and convenient for basal insulin therapy. Many patients with type 2 diabetes can maintain glycemic control with only one or two daily injections of ultralente insulin and can manage postprandial excursions with endogenous insulin secretion or doses of short-acting insulin. However, ultralente insulin does not mimic endogenous basal secretion, i.e., continuous insulin release without significant peaks and troughs in serum levels. Long-acting insulin analogs are being developed to better achieve the peakless profile of endogenous insulin secretion.

Insulin glargine (Lantus), approved by the FDA, is a long-acting human insulin analog that can provide an effective basal supply. It is produced by recombinant DNA technology using nonpathogenic E. coli as the production organism. Insulin glargine differs from human insulin in that the amino-acid asparagine at position A-21 has been replaced by glycine, and additionally two arginines are added to the C-terminus of the B chain.

This insulin provides a relatively constant concentration/time profile over 24 hours with no pronounced peak. Insulin glargine is administered as a single injection at bedtime. In clinical trials with both type 1 and type 2 patients, Insulin glargine as a single subcutaneous injection was shown to have similar efficacy and similar rates of hypoglycemia when compared to one and two injections of NPH insulin. Insulin glargine’s potency is approximately the same as human insulin. However, it should be remembered that its duration of action is 24 plus hours. In contrast to other insulins, insulin glargine was shown to have no relevant difference in absorption from the abdominal, deltoid, or thigh after subcutaneous administration.

Insulin glargine can be used in patients with intensive insulin regimens who have type 1 disease, and may be an appropriate first insulin for patients with type 2 disease. Insulin glargine may also be appropriate therapy along with oral agents in patients with type 2 disease.

In summary, compared to human insulin, Basal Insulin Glargine (Lantus) shows clinical benefits that include once-daily dosing because of its prolonged duration of action and smooth, peakless time-action profile; comparable or better glycemic control; lower risk of clinically important hypoglycemic events, and a similar safety profile.

Other long-acting insulin analogs are in earlier stages of development, including a C16 fatty-acid-acylated analog. Researchers are also exploring another approach to basal glycemic control that targets hepatic glucose production, which may be responsible for fasting hyperglycemia in patients with type 2 diabetes. Hepatospecific insulin analogs are being developed that could reduce hepatic glucose production but exert minimal effect on peripheral glucose disposal.

Introduction

A new form of insulin will soon be available that may make life easier for many diabetics who require daily insulin injections. Called Lantus, it is the first long-acting recombinant human insulin analog with once-daily administration and 24-hour glucose-lowering power to be approved by the FDA. Aventis Pharmaceuticals, the manufacturer of Lantus, received FDA approval for the drug on April 24, 2000.

Lantus (insulin glargine [rDNA origin] injection) is indicated for the treatment of adults and children with type 1 diabetes mellitus, and adults with type 2 diabetes mellitus who require long-acting insulin for control of hyperglycemia. Just one injection a day provides a relatively constant concentration/time profile over a 24-hour period.

How It Works

Lantus is a recombinant human insulin analog that can be administered once daily at bedtime for people with type 1 or type 2 diabetes. The chemical structure of Lantus regulates its release from the subcutaneous tissue into circulation, providing a relatively constant profile with no pronounced peak and a glucose-lowering effect over 24 hours. The longer duration of action of Lantus is directly related to its slower rate of absorption and supports once-daily subcutaneous administration.

Insulin and its analogs lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

Clinical Study Results

Controlled clinical trials showed that Lantus demonstrated similar levels of efficacy, with regard to metabolic control, as Neutral Protamine Hagedorn (NPH) human insulin. In clinical studies, Lantus showed a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH human insulin.

In two randomized controlled clinical studies, more than 1,100 adult patients with type 1 diabetes received either basal bolus treatment with Lantus once daily or NPH human insulin once or twice daily for 28 weeks. Regular human insulin was administered before each meal. Lantus was administered at bedtime, and NPH human insulin was administered either once at bedtime or twice, in the morning and at bedtime. In another study, 619 patients with type 1 diabetes were treated for 16 weeks with basal bolus insulin where insulin lispro was used before each meal. Lantus was administered at bedtime and NPH insulin was administered once or twice daily. In all three of these studies, Lantus and NPH human insulin had a similar effect on glycohemoglobin with a similar overall rate of hypoglycemia. These studies established the efficacy of Lantus in adults with type 1 diabetes.

A randomized controlled clinical study was performed to evaluate Lantus in 349 pediatric patients with type 1 diabetes (ages 6-15 years). Patients were treated for 28 weeks with a basal bolus insulin regimen where regular human insulin was used before each meal. Lantus was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Similar effects on glycohemoglobin and the incidence of hypoglycemia were observed in both treatment groups, establishing the efficacy of Lantus in pediatric patients with type 1 diabetes.

Lantus was also evaluated in 570 adults with type 2 diabetes over a 52-week period as part of a regimen of combination therapy with insulin and oral antidiabetic agents. Lantus administered once daily at bedtime was as effective as NPH human insulin administered once daily at bedtime in reducing glycohemoglobin and fasting glucose. Another study of 518 type 2 diabetics who did not use oral antidiabetic agents showed that Lantus was as effective as either once-daily or twice-daily NPH human insulin in reducing glycohemoglobin and fasting glucose, with a similar incidence of hypoglycemia.

What the Patient Should Know

Human insulin therapy may be associated with hypoglycemia, worsening of diabetic retinopathy, lipodystrophy, skin reactions (such as injection-site reaction, pruritus, and rash), allergic reactions, sodium retention, and edema. Hypoglycemia is the most common adverse effect of insulins, including Lantus. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes.

Any change in insulin should be made cautiously and only under medical supervision. In clinical studies of adult patients, there was a higher incidence of treatment-emergent injection-site pain (2.7% Lantus versus 0.7% NPH). Pain at the injection site was usually mild and did not result in discontinuation of therapy.

Lantus must not be diluted or mixed with any other insulin or solution, as it may result in a delayed onset of action.

Lantus (insulin glargine [rDNA origin] injection) is indicated for the treatment of adults and children with type 1 diabetes mellitus, and adults with type 2 diabetes mellitus who require long-acting insulin for control of hyperglycemia. Just one injection a day controls blood sugar (glucose) levels for a full 24 hours.

Lantus is a “recombinant human insulin analog” — a manmade insulin that closely mimics human insulin. The chemical structure of Lantus regulates its release from the tissue under the skin into the bloodstream, providing a glucose-lowering effect that lasts for 24 hours. The longer duration of action of Lantus is directly related to its slower rate of absorption.

Several controlled clinical trials have shown that Lantus is as effective as human insulin for controlling blood sugar levels. Moreover, the incidence of hypoglycemia – low blood sugar – was lower in patients who used Lantus than in those who took regular insulin. Lantus was effective in adults and children with type 1 (insulin-dependent) diabetes as well as adults with type 2 diabetes who need insulin injections to control their blood sugar.

Like other insulins, Lantus is associated with some side effects. Insulin therapy may be associated with hypoglycemia, worsening of diabetic retinopathy (a disorder of the retina of the eye), skin reactions (such as injection-site reaction, itching and rash), allergic reactions and retention of fluid. Hypoglycemia is the most common adverse effect of insulin, including Lantus. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes.

Any change in insulin should be made cautiously and only under medical supervision. In clinical studies of adult patients, there was a higher incidence of injection-site pain in patients who used Lantus than in those who took regular insulin. However, pain at the injection site was usually mild and did not result in discontinuation of therapy.

Lantus must not be diluted or mixed with any other insulin or solution as it may result in a delayed onset of action. Patients should inform their health care providers about any other medications they might be taking since they may alter the way Lantus works in the body.