Genetic predisposition

Genetic factors account for about one-third of the susceptibility to type 1 diabetes, with 35% concordance between monozygotic twins. The human leucocyte antigen (HLA) haplotypes DR3 and/or DR4 on chromosome 6 are associated with increased susceptibility to type 1 diabetes. Defective presentation of autoantigens derived from β cells probably underlies the autoimmunity.

Environmental factors

Reduced exposure to microorganisms in early childhood may limit maturation of the immune system and increase susceptibility to autoimmune disease (the ‘hygiene hypothesis’). Viral infections including mumps, Coxsackie B4, retroviruses, congenital rubella, cytomegalovirus and Epstein–Barr virus might cause some forms of type 1 diabetes. Bovine serum albumin (BSA—a constituent of cow’s milk) has been implicated in triggering type 1 diabetes, since infants who are given cow’s milk are more likely to develop type 1 diabetes in later life than those who are breastfed. Stress may precipitate type 1 diabetes by stimulating the secretion of counter-regulatory hormones and possibly by modulating immune activity.

Metabolic disturbances in type 1 diabetes

Patients with type 1 diabetes present when adequate insulin secretion can no longer be sustained. High glucose levels may be toxic to the remaining β cells so that profound insulin deficiency rapidly ensues. Insulin deficiency is associated with the metabolic sequelae shown in Figure 11.1. Hyperglycaemia leads to glycosuria and dehydration, which in turn induces secondary hyperaldosteronism. Unrestrained lipolysis and proteolysis result in weight loss, increased gluconeogenesis and ketogenesis. When generation of ketone bodies exceeds their metabolism, ketoacidosis results. Secondary hyperaldosteronism encourages urinary loss of K+. Thus patients usually present with a short history of hyperglycaemic symptoms (thirst, polyuria, fatigue and infections) and weight loss, and may have developed ketoacidosis.

Fig. 11.1 Pathophysiological basis of the symptoms and signs of uncontrolled diabetes mellitus.

Genetic predisposition

Genetic factors are important in the aetiology of type 2 diabetes; monozygotic twins have concordance rates approaching 100%. However, many genes are involved and the chance of developing diabetes is also influenced by environmental factors.

Environmental factors

Epidemiological studies indicate that type 2 diabetes is associated with overeating, especially when combined with obesity and under-activity. However, only a minority of obese people develop diabetes. Obesity probably acts as a diabetogenic factor in those who are genetically predisposed both to insulin resistance and to β-cell failure. The risk of developing type 2 diabetes increases tenfold in people with a body mass index (BMI) >30 kg/m².

Other risk factors

Age: Type 2 diabetes is principally a disease of the middle-aged and elderly. In the UK, it affects 10% of the population over 65, and over 70% of all cases of diabetes occur after the age of 50 yrs.

Pregnancy: During normal pregnancy, insulin sensitivity is reduced through the action of placental hormones. Repeated pregnancy may increase the likelihood of developing irreversible diabetes, particularly in obese women. Around 80% of women with gestational diabetes ultimately develop permanent diabetes.

Metabolic disturbances in type 2 diabetes

Relatively small amounts of insulin are required to suppress lipolysis, and some glucose uptake is maintained in muscle, so that weight loss and ketoacidosis are rare. Glycosuria occurs when the blood glucose concentration exceeds the renal threshold (10 mmol/l (180 mg/dl)). The severity of the classical ‘osmotic’ symptoms of polyuria and polydipsia is related to the degree of glycosuria. In type 2 diabetes, hyperglycaemia develops slowly and the renal threshold for glucose rises, so that osmotic symptoms are usually mild. Thus, patients are often asymptomatic, but usually present with a long history of fatigue, with or without osmotic symptoms.

In some patients, presentation is late and pancreatic β-cell function has declined to the point where there is profound insulin deficiency. These patients may present with weight loss, although ketoacidosis remains rare. Intercurrent illness, e.g. with infections, increases the production of counter-regulatory hormones (cortisol, growth hormone, catecholamines), resulting in more severe hyperglycaemia and dehydration (see hyperosmolar non-ketotic coma, p. 395). Dyslipidaemias are also common in patients with type 2 diabetes.

Glucose

Sensitive glucose-specific dipsticks are used to detect glycosuria, ideally on urine passed 1–2 hrs after a meal, since this will detect more cases of diabetes. However, glycosuria can be due to a low renal threshold. This is a benign condition, common during pregnancy and in young people. Glycosuria always warrants further assessment by blood testing using an accurate laboratory method. In some individuals a rapid but transitory rise of blood glucose follows a meal and the concentration exceeds the normal renal threshold. This response is benign and is described as a ‘lag storage’ blood glucose curve or alimentary glycosuria. It may occur after gastric surgery or in hyperthyroidism, peptic ulceration or hepatic disease. Glycosuria is common in normal pregnancy (increased glomerular filtration rate). However, it should never be ignored and gestational diabetes should be excluded.

Ketones

Ketonuria may be found in normal people who have been fasting, exercising or vomiting repeatedly, or those on a high-fat, low-carbohydrate diet. Ketonuria is therefore not pathognomonic of diabetes but, if it is associated with glycosuria, diabetes is highly likely.

Protein

Dipstick testing will detect urinary albumin >300 mg/l and can indicate renal disease or urinary infection in people with diabetes.

Glucose

Laboratory blood glucose testing is cheap and highly reliable. Capillary blood glucose can also be measured with a portable electronic meter, used to monitor diabetes treatment. Glucose concentrations are lower in venous than in arterial or capillary (fingerprick) blood. Whole blood glucose concentrations are lower than plasma concentrations because red blood cells contain relatively little glucose. Venous plasma values are the most reliable for diagnostic purposes.

Glycated haemoglobin

Glycated haemoglobin (Hb) provides an accurate and objective measure of glycaemic control over a period of 2 mths. It is used to assess glycaemic control, but is not sufficiently sensitive to make a diagnosis of diabetes.

The non-enzymatic covalent attachment of glucose to Hb (glycation) increases the amount in the HbA_1c fraction relative to non-glycated adult Hb (HbA₀). The rate of formation of HbA_1c is directly proportional to the blood glucose concentration; a rise of 1% in HbA_1c corresponds to an increase of 2 mmol/l in blood glucose. HbA_1c concentration reflects blood glucose over the erythrocyte lifespan (120 days), but is affected more by recent events.

HbA_1c estimates may be erroneously diminished in anaemia and pregnancy, and may be difficult to interpret in uraemia and haemoglobinopathy. In clinical practice, HbA_1c is measured once or twice yearly to assess glycaemic control and provides an index of risk for developing diabetic complications.

Blood lipids

The concentration of serum lipids—total, LDL and HDL cholesterol and triglycerides—is another important index of metabolic control in diabetic patients and should be measured at diagnosis and regularly thereafter.

Establishing the diagnosis of diabetes

In a symptomatic patient, the diagnosis may be confirmed by a random plasma glucose concentration ≥11.1 mmol/l (200 mg/dl) or a fasting plasma glucose concentration ≥7 mmol/l (126 mg/dl). In an asymptomatic patient two samples are required. An oral glucose tolerance test (OGTT) is indicated when plasma glucose levels are elevated but not diagnostic of diabetes: fasting range 6.1–7.0 mmol/l (110–126 mg/dl), or random plasma glucose range 7.8–11.0 mmol/l (140–199 mg/dl). The WHO criteria for diagnosing diabetes mellitus are shown in Box 11.2 and are based on the risk of developing microvascular disease. Patients who do not meet the criteria for diabetes may have ‘impaired glucose tolerance’ (IGT) or ‘impaired fasting glucose’ (fasting glucose 6.1–6.9 mmol/l (110–125 mg/dl)). These patients have an increased risk of progression to frank diabetes and of macrovascular disease.

Stress hyperglycaemia occurs when conditions impose a burden on the pancreatic β cells, e.g. during pregnancy, infection or treatment with corticosteroids. It usually disappears after the acute illness has resolved, but blood glucose should be remeasured.

When diabetes is confirmed, other investigations should include:

Clinical assessment

Hyperglycaemia causes:

Uncontrolled diabetes is associated with an increased susceptibility to infection and patients may present with skin infections. A history of pancreatic disease (particularly with alcohol excess) makes insulin deficiency more likely.

The clinical features of the two main types of diabetes are compared in Box 11.3. Overlap occurs particularly in age at onset, duration of symptoms and family history. Typical type 2 diabetes increasingly occurs in obese young people. Older adults may have evidence of autoimmune activity against β cells, a slowly evolving variant of type 1 diabetes (LADA). More than 70% of patients with type 2 diabetes are overweight, 50% have hypertension and hyperlipidaemia is common.

Management

Educating patients: This can be achieved by a multidisciplinary team (doctor, dietitian, specialist nurse and podiatrist) in the outpatient setting. However, patients requiring insulin initially need daily advice and possibly admission to hospital. They need to learn how to measure insulin doses, give their own injections, and adjust the dose depending on glucose monitoring, exercise, illness and hypoglycaemia. They must understand the principles of diabetes, recognise the symptoms of hypoglycaemia, and receive advice about risks of driving with diabetes.

Self-assessment of glycaemic control: Urine testing has limitations, as persistent hyperglycaemia may be masked and hypoglycaemia not detected. However, it is inexpensive and may suffice for those with well-controlled type 2 diabetes or those treated with diet alone. Those treated with insulin should be taught to perform capillary blood glucose measurements at home. This permits patients to make appropriate adjustments in treatment on a day-to-day basis. Thus changes in routine can be accommodated, ketoacidosis avoided and dietary compliance encouraged while avoiding hypoglycaemia. Blood glucose monitoring is expensive and may not be justified in many people with type 2 diabetes.

Advice to patients with IGT

Therapeutic goals

The aim of treatment is to achieve as near normal metabolism as is practicable. The recommended target HbA_1c is ≤7%, to minimise vascular complications. However, type 2 diabetes progresses in severity with time, making this target difficult to achieve. In addition, strict control in type 1 diabetes increases the risk of hypoglycaemia. Glycaemic targets should therefore be appropriate; strict control may be inappropriate in the very young, the elderly and people with cancer. Desirable blood glucose targets are:

Treatment of hypertension and dyslipidaemia is often required following assessment of cardiovascular risk. Targets are: