Insulin pumps

The use of insulin pumps is becoming increasingly common. Currently the most frequently used pumps are battery-powered devices that are filled with insulin and infuse it at a rate set by the wearer into the subcutaneous tissues (usually the stomach) via a length of plastic tubing and a needle. This is called continuous subcutaneous insulin infusion (CSII). Boluses can be given as required at meal times.

Implantable pumps, which infuse insulin into the peritoneum and are filled via a subcutaneous port, and whose rate of insulin infusion is set by a hand-held electronic communicator, have been tried and been successful in improving control. At present these devices depend on frequent blood glucose monitoring and dose adjustment. They therefore require a high level of patient commitment and understanding.

Closed loop systems, where the insulin pump can sense blood glucose levels and feedback to adjust the rate of infusion appropriately would act as an artificial pancreas. The appropriate glucose sensing technology and improved, more concentrated insulin preparations are yet to be developed, but are a real possibility.

Alternative insulin delivery

Inhaled, buccal and intranasal insulin aerosol preparations have already been developed. Concern exists about the possibility of pulmonary reactions to inhaled insulin, but safety data are reassuring so far and these preparations are currently undergoing phase 3 trials, with the possibility that the first preparation will be released in 2002.

Glucose sensing techniques

Non-invasive techniques for sensing glucose are being developed. The measurement of interstitial fluid glucose levels using a device called the GlucoWatch Automatic Glucose Biographer has already undergone initial trials in the USA. This technique could easily be applied to the development of a nocturnal hypoglycaemia alarm as well as providing regular daytime readings. The painless nature of the technique (glucose is forced onto the skin using a process called reverse iontophoresis) would also encourage compliance with monitoring requirements.

Techniques analysing glucose-related signals by spectrometry and implantable glucose sensors are also being developed.

Type 2 diabetes prevention

The identification and targeting of individuals at high risk of development of type 2 diabetes has proved feasible. Interventions to increase exercise and lose weight have been successful in preventing the development of the disease. The more widespread application of these findings may prove to be the best way forward in managing the impending epidemic.

Aims of diabetes care

The aims of diabetes care are as follows:

• To empower people with diabetes to manage and cope with their condition and to lead a life of normal length and fulfilment through: education; the development of understanding of their condition to allow them to cope with new challenges; and the provision of skills to adapt their lifestyle;

• The minimization of cardiovascular and microvascular risk;

• The early detection and management of complications.

Clinical staff and set-up

The diabetes team should comprise doctors, diabetes nurse, specialists/educators, dietitians and podiatrists. All members of the team should be accessible through the clinic. The clinic should have appropriate facilities to provide a range of services. These should include:

• Footcare;

• Education; Regular/annual review;

• Eye surveillance;

• Access to appropriate specialists;

• Written information for people with diabetes.

The use of protocols for diabetes care, structured patient records and a prompted recall system for annual review and eye review with prompts for both doctors and patients is extremely useful.

The basic information sheet used in the DiabCare project (Diabetes Care and Research in Europe) is shown in Image 37 as an example of a structured record that is useful both for recording the appropriate data and for extracting it to monitor performance.

Image 37. Patient basic information sheet.

Consultation organization

It is important to have a structure to the consultation so that all the necessary areas are covered. The plan in Table 7 outlines the appropriate areas to be covered at each type of review. Note that a history of vascular or neuropathic complications, including impotence, should be actively sought at annual review; whilst new problems, self-monitoring results, diet, smoking and exercise should be discussed at all reviews.

Table 7. Clinic organization: schedule for clinical review. This table summarizes the guidelines for monitoring in the text. Note that if someone already has proteinuria then ACR is not appropriate and monitoring of timed urinary albumin excretion would be more appropriate for measuring progression of disease

At the end of the consultation it is important to reach agreement on:

• The main points covered;

• Changes in therapy;

• Targets set;

• Interval to next review.

Education

“It is the responsibility of the diabetes team to ensure that the person with diabetes can lead the lifestyle of their educated choice, achieved through the three elements of empowerment: knowledge, behavioural skills and self-responsibility”

Provision of education

Education should be provided over three time frames:

1. At diagnosis:

• Basic information on diet, exercise and smoking cessation;

• Supportive information about the nature of diabetes and its outcomes;

• Minimum skills required to control the initial situation.

2. In the months following diagnosis:

• More comprehensive coverage;

• Targets of therapy;

• Eating out;

• Diabetic complications, arterial risk factors and foot care;

• Employment, insurance, driving and travel.

3. In the long term:

• Periodic reinforcement.

Nutritional advice

Nutrition is central to the successful management of diabetes. It should form an integral part of all education programs. It should be made clear that a diabetic diet is high in carbohydrate and lower in fat than that currently followed by most of the population, but it is a healthy diet and no different from that recommended for everybody. The essentials of the diet are:

• Saturated fat to constitute < 10% of calories and polyunsaturated fat to constitute < 10% of calories;

• It is carbohydrate rich and high in fibre;

• Limit but do not completely exclude simple sugars;

• Protein to constitute < 15% of calories;

• Increase fresh fruit and vegetable consumption;

• Alcohol as part of total calorie intake is acceptable, but should be moderate and reduced in those with hypertension or hypertriglyceridaemia;

• Total calorie intake should be geared to achieving and maintaining a normal body mass index.

Exercise

Diabetic subjects should be advised that physical exercise:

• Can increase insulin sensitivity;

• Can decrease blood pressure;

• Can improve blood lipid control;

• Should be taken every 2-3 days for optimum effect;

• May increase the risk of acute and delayed hypoglycaemia, but that this is manageable.

The encouragement of increased levels of physical activity should be a routine part of diabetes care. The possibility of incorporating increased levels of activity into normal living should be explored, and more formal exercise, such as walking for 20-30 minutes a day on 3 or more days of the week, discussed.

Blood glucose monitoring

All people with type 2 diabetes should be performing some form of blood glucose monitoring. This can be with blood reagent strips, blood glucose meters or with urinalysis according to the individual’s need and capabilities. It should be explained that blood glucose monitoring is performed to:

• Educate regarding the effects of diet and exercise on blood glucose levels;

• Indicate satisfactory blood glucose control;

• Guide insulin dose adjustment and management of hypoglycaemia;

• Enable the patient to self-manage acute illness and new situations with appropriate changes in therapy.

Patients should be encouraged to keep a written record and to bring this with them to the clinic.

If they are using urine tests then these should be postprandial and the frequency tailored to the situation (at least once a week).

In acute illness, tests should be performed 4-8 times a day.

Patients using insulin should record blood glucose 1-4 times daily according to the situation. Some prefer to record 4 times a day on 2 days of the week but beware those that have 2 “good” days a week and relax their efforts at other times.

Cardiovascular risk assessment and management

Cardiovascular risk factors should be routinely assessed. These include smoking, blood pressure, blood lipids and glycaemic control. Variables such as the presence of microalbuminuria or left ventricular hypertrophy also increase the level of risk and should be taken into consideration. It should be remembered that cardiovascular risk factors are not managed in isolation but in combination, and intervention is multifactorial.

Clinic targets for blood glucose, blood lipids and blood pressure control are summarized in Table 8. The target levels may appear low, but are derived from the fact that a patient with type 2 diabetes may be at the same risk of a new cardiovascular event as someone who has already suffered a myocardial infarction. For a more detailed discussion on the management of multiple risk factors and risk assessment see the joint British recommendations on the prevention of coronary heart disease in clinical practice.

Integrated approach

Review the established arterial risk factors:

• Glycaemic control;

• Lipids;

• Blood pressure;

• Smoking;

• Body weight/abdominal adiposity;

• Family history;

• Urinary albumin excretion;

• Arterial/cardiac symptoms;

at diagnosis and then annually, or more frequently if symptoms are abnormal or treated (Table 7). If the subject has established cardiovascular disease or arterial risk factors in addition to type 2 diabetes then management of blood glucose, lipids and blood pressure should be aggressive and the patient should be started on aspirin. The algorithms in Images 38, 39 and 40 for blood glucose, lipid and blood pressure management should prove helpful.

Table 8. Targets for blood glucose, lipids and blood pressure in type 2 diabetes

Microvascular disease

The detection, surveillance and management of microvascular disease is one of the fundamental functions of the diabetes clinic. The beginning of this chapter provides a guide to a structured clinic and timing of reviews. Algorithms for the detection and management of eye, foot, renal and nerve damage are found in the site on complications.

Image 39. Lipid management.

Image 40. Blood pressure management.

Type 2 diabetes mellitus is a syndrome with many possible contributory factors — both genetic and environmental — that combine to produce the insulin resistance and β-cell failure defining this condition.

Genetic predisposition to type 2 diabetes

Evidence for the existence of genetic factors determining the development of type 2 diabetes comes from family studies, which show that:

• Concordance exists for type 2 diabetes of 60-100% in identical twins and 17% in non-identical twins;

• There is familial aggregation of cases; 80% of African Americans, 40% of Caucasians and 80% of Pima Indians with type 2 diabetes have a positive family history;

• The genetic component is usually polygenic and may account for up to 70% of the risk of developing the disease.

Single-gene defects causing the clinical picture of type 2 diabetes (but now classified as type 3 diabetes) have been identified but are very rare. These include the gene defects causing MODY (maturity onset diabetes of the young) and maternally transmitted mitochondrial DNA abnormalities. Their study is of interest in further unravelling the pathogenesis of the disease.

Environmental factors in susceptibility to type 2 diabetes

Obesity

Obesity is defined as a body mass index (BMI) of >30 kg/m and is the environmental risk factor most widely recognized as being associated with type 2 diabetes. It is becoming increasingly common in western societies with more than 50% of adults in the UK being overweight and 17% of men and 19.3% of women obese.

Image 4. Relationship of average fatness and prevalence of diabetes in subjects over 29 years of age in 10 countries. Produced with permission from reference 4.

Obesity alone is neither a necessary nor a sufficient condition for the development of type 2 diabetes: most obese patients do not develop diabetes, nor are all patients with type 2 diabetes obese. Obesity is, however, very strongly associated with the development of type 2 diabetes, especially truncal obesity, which reflects increased visceral fat deposition. Evidence for this association comes from various sources:

• The prevalence of type 2 diabetes increases in proportion to the level of obesity in a population (Image 4);

• The risk of type 2 diabetes increases exponentially with a BMI of >23 kg/m (a person with a BMI of >35 kg/m has a 40-fold increase in risk for developing type 2 diabetes, equating to a lifetime risk of =50%) (Image 5);

• Waist circumference of >40 inches is associated with a 3.5-fold increase in the 5-year incidence of type 2 diabetes. This effect is additive to that of obesity (Image 6);

• The BMI can explain approximately 30% of the total variance in insulin sensitivity, insulin resistance being an important feature of type 2 diabetes.

Image 5. Body mass index (BMI) and relative risk of diabetes among a cohort of 27983 American men aged 40-75 years. Risk (compared with a BMI of < 23 kg/m ) is adjusted for age, smoking and family history of diabetes. Produced with permission from reference 5.

Image 6. Effects of body mass index (BMI) and central obesity (measured as waist:hip ratio, WHR) on age-standardized prevalence of type 2 diabetes mellitus. Data are from Mauritian men and women: similar relationships have been shown in many studies of other ethnic groups. From reference 6.

How does obesity cause type 2 diabetes? In obesity, particularly truncal obesity, there are increased stores of intra-abdominal fat, which is prone to lipolysis. How this might lead to type 2 diabetes is outlined in Image 7.

Physical inactivity

Lack of physical exercise, starting in childhood, is probably the most important factor in the current epidemic of childhood and adult obesity and is also an important factor in the development of type 2 diabetes. Regular exercise improves insulin sensitivity by increasing glucose uptake into muscle and if undertaken regularly in early adult life reduces the risk of development of type 2 diabetes.

Image 7. Possible aetiological links between obesity and type 2 diabetes.

Thrifty phenotype (Barker-Hales hypothesis)

This concept relates to the possible long-term effects of fetal malnutrition and the notion that people of low birthweight are at increased risk of developing type 2 diabetes, hypertension, dyslipidaemia (raised triglycerides and low HDL cholesterol), procoagulant tendencies and ultimately ischaemic heart disease.

It is hypothesized that nutritional deficits in fetal and early infant life may both compromise the function of B cells and induce insulin resistance. Deficiency of protein and amino acids critical to β-cell growth and insulin secretion into late fetal life may be important in leading to inadequate β-cell development, but the possible basis of insulin resistance is unknown. These defects, programmed in utero, come to the fore if obesity and insulin resistance then develop during adult life when type 2 diabetes may result.

Biochemical defects of type 2 diabetes

Insulin resistance

Insulin resistance is the inability of insulin to produce its usual biological effects at concentrations that are effective in normal subjects. Insulin sensitivity varies widely amongst both normoglycaemic and hyperglycaemic individuals but is generally more pronounced in those with type 2 diabetes and is crucial to the development of the condition.

There are three principal tissues involved in the insulin resistance of type 2 diabetes:

• Skeletal muscle, which is responsible for 75% of glucose disposal following a carbohydrate meal; most of this is used for glycogen synthesis. In type 2 diabetes insulin resistance in skeletal muscle appears to be due to defects at post-receptor sites affecting both glycogen synthesis and oxidative glucose disposal;

• The liver, whose excessive production of glucose is the main source of fasting and basal hyperglycaemia in type 2 diabetes.

This would normally be suppressed by insulin and by hyperglycaemia itself, but both these effects are diminished in type 2 diabetes; • The adipocyte, where insulin resistance prevents basal insulin levels from suppressing lipolysis. Non-esterified fatty acid (NEFA) concentrations rise; the effects of this are summarized in Image 7.

Genetic basis of insulin resistance

Insulin resistance is associated with obesity, but it also has a genetic component. This is suggested by the fact that relatives of patients with type 2 diabetes may be insulin resistant even if young, non-obese and tolerant to glucose, and 50% of first-degree relatives of patients with type 2 diabetes are insulin resistant 30-40 years before they develop diabetes.

In 1962, based largely on work with the Pima Indians of the Arizona desert, Neel proposed the “thrifty gene hypothesis”. This suggests that the obese type 2 diabetes genotype somehow conferred a survival advantage, explaining the persistence of type 2 diabetes. In populations that experience periodic famine a gene operating to favour fat storage during times of abundance might be beneficial — the “thrifty gene”. With the advent of the westernized lifestyle with relatively little physical activity and an abundance of energy-rich food, this previously advantageous gene would predispose to obesity, insulin resistance and the development of type 2 diabetes.

β-Cell failure

Insulin resistance alone does not explain the whole picture, since subjects who are extremely insulin resistant (particularly the obese) do not develop type 2 diabetes. These individuals manage to maintain normal glucose levels by increasing insulin secretion to overcome the effects of insulin resistance. In type 2 diabetes insulin levels may be above, below or within the normal non-diabetic range but these levels are always too low, because they are in the face of hyperglycaemia, which would push levels higher in non-diabetic counterparts.

Insulin resistance is therefore the abnormality that unmasks β-cell failure and so leads to type 2 diabetes.

Several defects have been identified in insulin processing and secretion that indicate β-cell dysfunction and herald β-cell failure:

• A moderate reduction is seen in β-cell numbers in the islets of type 2 diabetic subjects;

• Islet amyloid polypeptide is co-secreted with insulin and may compromise islet cell function if overproduced. Amyloid deposits are found in increased amounts in the islets of subjects with type 2 diabetes;

• Pulsatility of insulin secretion is disordered in subjects with type 2 diabetes. As well as indicating β-cell dysfunction, this may impair insulin sensitivity;

• There is loss of the first phase of insulin secretion, i.e. the shortlived surge of insulin release that follows an acute challenge (by increased glucose levels). The first phase is a more efficient signal than the second phase (prolonged secretion if the secretagogue challenge is sustained) and is lost in patients with impaired glucose tolerance and type 2 diabetes. In established type 2 diabetes the second phase is also impaired;

• Circulating levels of insulin precursors (proinsulin and its split products) are increased, indicating abnormalities of insulin processing.

Causes of β-cell failure

As with insulin resistance, this appears to be partly genetic and partly acquired. Evidence for the role of genetic factors comes from the finding of characteristic abnormalities in the pattern of insulin secretion in non-diabetic first-degree relatives of patients with type 2 diabetes. Purely genetic causes of β-cell dysfunction that alone cause hyperglycaemia (whether or not insulin resistance is present) are responsible for MODY, now classified separately as type 3 diabetes. Several environmental factors leading to β-cell failure have also been postulated. Hyperglycaemia impairs insulin secretion (gluco-toxicity) and helps to raise blood glucose in established type 2 diabetes; conversely, controlling hyperglycaemia can help to improve remaining β-cell function. Raised levels of NEFA, found in type 2 diabetes, have also been shown to damage B cells (lipotoxicity). An association between intrauterine growth retardation and impaired β-cell function has been postulated (the Barker-Hales hypothesis) on the basis of epidemiological studies (page 15).

Image 8. The natural history of type 2 diabetes.

The natural history of type 2 diabetes

The development of type 2 diabetes may be broken down into several distinct stages (Image 8). Initially, insulin resistance leads to increased glucose and non-esterified fatty acid (NEFA) levels. Insulin secretion increases to control these abnormalities. This compensatory response reaches a maximum that probably corresponds to the clinical state of impaired glucose tolerance. Thereafter, if the metabolic stress on the β-cell continues, the β-cells begin to fail and are unable to compensate by secreting sufficiently increased amounts of insulin, and blood glucose can no longer be prevented from rising into the diabetic range. With the glucotoxicity of persistent hyperglycaemia and the other factors mentioned above, β-cell failure progresses and insulin levels fall (Image 9).

The aetiology of type 2 diabetes is summarized in Image 10.

Image 9. The Starling curve of the pancreas. Insulin secretion increases to overcome insulin resistance, then reaches a plateau as β-cell failure intervenes and falls as the strain on the β-cells exerts its toll.

Image 10. Aetiology of type 2 diabetes.