Introduction

Diabetes mellitus (DM) is a syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance, or both. It affects more than 120 million people world-wide, and it is estimated that it will affect 220 million by the year 2020. Diabetes is usually irreversible and, although patients can have a reasonably normal lifestyle, its late complications result in reduced life expectancy and major health costs. These include macrovascular disease, leading to an increased prevalence of coronary artery disease, peripheral vascular disease and stroke, and microvascular damage causing diabetic retinopathy and nephropathy. Neuropathy is another major complication.

Insulin structure and secretion

Insulin is the key hormone involved in the storage and controlled release within the body of the chemical energy available from food. It is coded for on chromosome 11 and synthesized in the beta-cells of the pancreatic islets. The synthesis, intracellular processing and secretion of insulin by the beta-cell is typical of the way that the body produces and manipulates many peptide hormones. After secretion, insulin enters the portal circulation and is carried to the liver, its prime target organ. About 50% of secreted insulin is extracted and degraded in the liver; the residue is broken down by the kidneys. C-peptide is only partially extracted by the liver (and hence provides a useful index of the rate of insulin secretion), but is mainly degraded by the kidneys.

An outline of glucose metabolism

Blood glucose levels are closely regulated in health and rarely stray outside the range of 3.5-8.0 mmol/L (63-144 mg/dL), despite the varying demands of food, fasting and exercise. The principal organ of glucose homeostasis is the liver, which absorbs and stores glucose (as glycogen) in the post-absorptive state and releases it into the circulation between meals to match the rate of glucose utilization by peripheral tissues. The liver also combines 3-carbon molecules derived from breakdown of fat (glycerol), muscle glycogen (lactate) and protein (e.g. alanine) into the 6-carbon glucose molecule by the process of gluconeogenesis.

Glucose production

About 200 g of glucose is produced and utilized every day. More than 90% is derived from liver glycogen and hepatic gluconeogenesis, and the remainder from renal gluconeogenesis.

The brain is the major consumer of glucose. Its requirement is 1 mg/kg bodyweight per minute, or 100 g daily in a 70 kg man. Glucose uptake by the brain is obligatory and is not dependent on insulin, and the glucose used is oxidized to carbon dioxide and water. Other tissues, such as muscle and fat, are facultative glucose consumers. The effect of insulin peaks associated with meals is to lower the threshold for glucose entry into cells; at other times, energy requirements are largely met by fatty-acid oxidation. Glucose taken up by muscle is stored as glycogen or broken down to lactate, which re-enters the circulation and becomes a major substrate for hepatic gluconeogenesis. Glucose is used by fat tissue as a source of energy and as a substrate for triglyceride synthesis; lipolysis releases fatty acids from triglyceride together with glycerol, another substrate for hepatic gluconeogenesis.

Hormonal regulation

Insulin is the major regulator of intermediary metabolism, although its actions are modified in many respects by other hormones. Its actions in the fasting and postprandial states differ. In the fasting state its main action is to regulate glucose release by the liver, and in the postprandial state it additionally facilitates glucose uptake by fat and muscle. The effect of counter-regulatory hormones (glucagon, epinephrine (adrenaline), cortisol and growth hormone) is to cause greater production of glucose from the liver and less utilization of glucose in fat and muscle for a given level of insulin.

Cell membranes are not inherently permeable to glucose. A family of specialized glucose-transporter (GLUT) proteins carry glucose through the membrane into cells.

• GLUT-1 – enables basal non-insulin-stimulated glucose uptake into many cells
• GLUT-2 – transports glucose into the beta-cell: a prerequisite for glucose sensing.
• GLUT-3 – enables non-insulin-mediated glucose uptake into brain neurones and placenta.
• GLUT-4 – enables much of the peripheral action of insulin. It is the channel through which glucose is taken up into muscle and adipose tissue cells following stimulation of the insulin receptor .

The insulin receptor

This is a glycoprotein (400 kDa), coded for on the short arm of chromosome 19, which straddles the cell membrane of many cells. It consists of a dimer with two alpha-subunits, which include the binding sites for insulin, and two beta-subunits, which traverse the cell membrane. When insulin binds to the alpha-subunits it induces a conformational change in the beta-subunits, resulting in activation of tyrosine kinase and initiation of a cascade response involving a host of other intracellular substrates. One consequence of this is migration of the GLUT-4 glucose transporter to the cell surface and increased transport of glucose into the cell. The insulin-receptor complex is then internalized by the cell, insulin is degraded, and the receptor is recycled to the cell surface.

Diabetes may be primary or secondary (Table 19.1). Although secondary diabetes accounts for barely 1-2% of all new cases at presentation, it should not be missed because the cause can often be treated. Type 1 diabetes (insulin-dependent diabetes mellitus) and type 2 diabetes (non-insulin-dependent diabetes mellitus) represent two distinct diseases from the epidemiological point of view, but clinical distinction can sometimes be difficult. The two diseases should, in clinical terms, be seen as a spectrum, distinct at the two ends but overlapping to some extent in the middle (Table 19.2). Varying degrees of insulin secretory failure may be present in both forms of diabetes. For example, some patients with immune-mediated diabetes may not at first require insulin, whereas many with type 2 diabetes will eventually do so.

Type 1 diabetes mellitus

Epidemiology

Table 19-1. Causes of secondary diabetes

Pancreatic disease

Cystic fibrosis

Chronic pancreatitis

Malnutrition-related pancreatic disease

Pancreatectomy

Hereditary haemochromatosis

Carcinoma of the pancreas

Endocrine disease

Cushing’s syndrome

Acromegaly

Thyrotoxicosis

Phaeochromocytoma

Glucagonoma

Drug-induced disease

Thiazide diuretics

Corticosteroid therapy

Atypical antipsychotics

Antiretroviral protease inhibitors

Insulin-receptor abnormalities

Congenital lipodystrophy

Acanthosis nigricans

Genetic syndromes

Friedreich’s ataxia

Dystrophia myotonica

Table 19-2. The spectrum of diabetes: a comparison of type 1 and type 2 diabetes mellitus

	Type 1 (insulin dependent)	Type 2 (non-insulin dependent)
Epidemiology	Younger (usually < 30 years of age)	Older (usually > 30 years of age)
	Usually lean	Often overweight
	Increased in those of Northern European ancestry	All racial groups. Increased in peoples of Asian, African, Polynesian and American-Indian ancestry
	Seasonal incidence
Heredity	HLA-DR3 or DR4 in > 90%	No HLA links
	30-50% concordance in identical twins	∼ 50% concordance in identical twins
Pathogenesis	Autoimmune disease:	No immune disturbance
	Islet cell autoantibodies	Insulin resistance
	Insulitis
	Association with other autoimmune diseases
	Immunosuppression after diagnosis delays beta-cell destruction
Clinical	Insulin deficiency	Partial insulin deficiency
	May develop ketoacidosis	May develop hyperosmolar state
	Always need insulin	Many come to need insulin when beta-cells fail over time
Biochemical	Eventual disappearance of C-peptide	C-peptide persists

Type 1 diabetes is a disease resulting in insulin deficiency. In western countries almost all patients have the immune-mediated form of the disease (type 1A). Type 1 diabetes is prominent as a disease of childhood, reaching a peak incidence around the time of puberty, but can present at any age. A ’slow-burning’ variant with slower progression to insulin deficiency occurs in later life and is sometimes called latent autoimmune diabetes of adults (LADA). This may be difficult to distinguish from type 2 diabetes. Clinical clues are: considerable weight loss, hyperglycaemia which fails to correct with diet and tablet treatment, the presence of strong or persistent ketonuria at diagnosis, and autoantibody tests indicating autoimmune disease. The highest rates of type 1 diabetes in the world are seen in Finland and other Northern European countries, with the exception of the island of Sardinia, which for unknown reasons has the second highest rate in the world. The incidence of type 1 diabetes appears to be increasing in most populations. In Europe the annual increase is of the order of 3-4%, and is most marked in children under the age of 5 years. A subtype of type 1 diabetes (type 1B) has recently been described in Japanese patients with an abrupt onset, no autoimmune disease and high serum pancreatic enzyme concentrations at diagnosis. This has not been described in other populations. WHO (1995) estimated that there are 19.4 million people with type 1 diabetes and that the number will rise to 57.2 million by 2025.

Type 1 diabetes belongs to a family of HLA-associated immune-mediated organ-specific diseases. Genetic susceptibility is polygenic, with the greatest contribution from the HLA region. Autoantibodies directed against pancreatic islet constituents appear in the circulation within the first few years of life, and predate clinical onset by many years. Autoantibodies are also found in older patients with LADA and predict progression to insulin therapy in this group.

Genetic susceptibility

Type 1 diabetes is not genetically predetermined, but increased susceptibility to the disease may be inherited.

Inheritance

The identical twin of a patient with type 1 diabetes has a 30-50% chance of developing the disease. Since twins with identical genes may never develop the disease, non-genetic factors must also be involved. Children of people with type 1 diabetes have an increased chance of developing type 1 diabetes. The risk of developing diabetes by age 20, curiously, is greater with a diabetic father (3-7%) than with a diabetic mother (2-3%). If one child in a family has type 1 diabetes, each sibling has a ∼ 6% risk of developing diabetes by age 20. If siblings are HLA-identical (share the same HLA type as the affected child), the risk rises to about 20%. Longer-term follow-up has, however, shown that the lifetime risk of diabetes in first-degree relatives is considerably greater than this.

HLA system.

The HLA genes on chromosome 6 are highly polymorphic and modulate the immune defence system of the body. More than 90% of patients with type 1 diabetes carry HLA-DR3-DQ2, HLA-DR4-DQ8, or both, as compared with some 35% of the background population. All DQB1 alleles with an aspartic acid at residue 57 confer neutral to protective effects with the strongest effect from DQB1*0602 (DQ6), while DQB1 alleles with an alanine at the same position (i.e. DQ2 and DQ8) confer strong susceptibility. Genotypic combinations have a major influence upon risk of disease. For example HLA DR3-DQ2/HLA DR4-DQ8 heterozygotes have a considerably increased risk of disease. The presence or absence of certain HLA class I alleles substantially modifies the risk conferred by class II susceptibility genes.

Other gene regions.

Genome-wide searches for regions conferring susceptibility to, or protection against, type 1 diabetes have been carried out, and 10-20 regions of interest have been identified. These are designated IDDM1 (HLA locus), IDDM2 and so on. It is already clear that individually these make a much smaller contribution to genetic susceptibility than the HLA region. An intensive search to identify these genes and their products continues.
A DNA region close to the insulin gene on chromosome 11 is designated IDDM2, and short, intermediate and long insertions have been reported. Homozygosity of the short (class I) allele is found in some 80% of patients with type 1 diabetes as against 40% of controls.
The CTLA-4 gene has also been implicated in type 1 diabetes and might be a common factor in a variety of HLA-associated autoimmune conditions.

Autoimmunity and insulin-dependent diabetes mellitus

Several pieces of evidence suggest that type 1 diabetes is an immune-mediated disease. These include the HLA associations described above, and associations with other organ-specific autoimmune diseases including autoimmune thyroid disease, Addison’s disease and pernicious anaemia. Autopsies of patients who died soon after diagnosis show infiltration of the pancreatic islets by mononuclear cells. This appearance, known as insulitis, resembles that in other autoimmune diseases such as thyroiditis. Autoantibodies directed against islet constituents are also present in some 90% of newly presenting patients. A number of islet antigens have been characterized, and include insulin itself, the enzyme glutamic acid decarboxylase (GAD), and the intracellular portion of two islet peptides from the tyrosine phosphatase family. Confirmation of the autoimmune nature of the disease came from the observation that treatment with immunosuppressive agents such as ciclosporin following diagnosis prolongs beta-cell survival.

Environmental factors

The incidence of childhood type 1 diabetes is rising steadily, suggesting that environmental factor(s) are involved in its pathogenesis. Early exposure to enteroviruses such as Coxsackie B4 has often been suspected, but the role of viruses in the causation of the disease has yet to be confirmed. It has also been suggested that a cleaner environment with less early stimulation of the immune system in childhood may increase susceptibility for type 1 diabetes, as for atopic/allergic conditions (the hygiene hypothesis).

Pre-type 1 diabetes and prevention of type 1 diabetes

Prospective studies of first-degree relatives of children with diabetes have shown that islet autoantibodies appear in the circulation in the first few years of life – demonstrating that the process culminating in diabetes is initiated very early – and many years before diagnosis. Further, they can predict development of the disease, especially when present in combination. The ability to predict the disease has opened the way to possible disease prevention, but trials using injected or oral insulin or nicotinamide have all proved unsuccessful.

This is relatively common in all populations enjoying an affluent lifestyle. The four major determinants are increasing age, obesity, ethnicity and family history. Large differences in prevalence exist based on these characteristics. In poor countries diabetes is a disease of the rich, but in rich countries it is a disease of the poor. The disease may be present in a subclinical form for years before diagnosis. The onset may be accelerated by the stress of pregnancy, drug treatment or intercurrent illness. Estimates of prevalence using the WHO criteria would suggest an overall prevalence of around 2% within the UK. Within the UK, type 2 diabetes is three to four times as prevalent in people of South Asian, African and Caribbean ancestry. High rates have also been found in people of middle Eastern or Hispanic American origin living western lifestyles. Unfortunately, people in westernized countries gain on average nearly 1 gram in weight every day of their adult life between the ages of 25-55 years. This gain, due to a tiny excess in energy intake over expenditure – 90 kcal or one chocolate-coated digestive biscuit per day – is the result of reduced exercise in a population rather than of increased food intake. Further, our sedentary lifestyle means that the proportion of obese young adults is rising rapidly, and epidemic obesity will create a huge public health problem for the future. The increasing numbers of obese adolescents presenting with type 2 diabetes is already a matter for concern in the USA and other parts of the world. Diabetes prevalence increases with age and 10% of people of Northern European stock will develop diabetes by the age of 70. This proportion rises towards 30% in those with a family history of diabetes and in those from some ethnic groups.

The insulin resistant state seen in type 2 diabetes tends to cluster with other conditions which increase cardiovascular risk. These include: hypertension, obesity, hypertriglyceridaemia, a decreased HDL-cholesterol, and the skin condition acanthosis nigricans. High insulin levels are characteristic. This has been called the insulin resistance syndrome, syndrome X or the metabolic syndrome. It seems likely that this is not a distinct entity but one end of a continuum in the relationship between exercise, lifestyle and bodyweight on the one hand, and individuals’ genetic make-up on the other – resulting in a state associated with adverse clinical consequences. About a third of the adult population have features of the syndrome, not necessarily associated with diabetes.

Genetics

Population-based studies show identical twins of patients with type 2 diabetes have a greater than 50% chance of developing diabetes; the risk to non-identical twins or siblings is of the order of 25%. These observations confirm a genetic component to the disease. Type 2 diabetes is a polygenic disorder, but the genes responsible for the great majority of cases have yet to be identified. This situation seems set to change, and as genetic causes are discovered the phenotypic differences between people currently lumped together as having ‘type 2 diabetes’ will probably be explained.

The genetic causes of some rare forms of type 2 diabetes are shown in Table 19.3.

A rare variant of type 2 diabetes is referred to as ‘maturity-onset diabetes of the young’ (MODY). This is dominantly inherited. Five variants have been described. The different MODY genotypes are associated with different clinical phenotypes (Table 19.4). MODY should be considered in young people presenting with a typical family history (diabetes affecting a parent and 50% expression of the disease in the family) plus a form of early-onset diabetes which appears easy to control.

Environmental factors: early and late

Table 19-3. Rare genetic causes of type 2 diabetes

Disorder	Features
Insulin receptor mutations	Obesity, marked insulin resistance, hyperandrogenism in women, acanthosis nigricans (areas of hyperpigmented skin)
Maternally inherited diabetes and deafness (MIDD)	Mutation in mitochondrial DNA. Diabetes onset before age 40. Variable deafness, neuromuscular and cardiac problems, pigmented retinopathy
Wolfram syndrome (DIDMOAD – diabetes insipidus, diabetes mellitus, optic atrophy and deafness)	Recessively inherited. Mutation in the transmembrane gene, WFS1. Insulin-requiring diabetes and optic atrophy in the first decade. Diabetes insipidus and sensorineural deafness in the second decade progressing to multiple neurological problems. Few live beyond middle age
Severe obesity and diabetes	Alström, Bardet-Biedl and Prader-Willi syndromes. Retinitis pigmentosa, mental insufficiency and neurological disorders
Disorders of intracellular insulin signalling. All with severe insulin resistance	Leprechaunism Rabson-Mendenhall syndrome Pseudoacromegaly Partial lipodystrophy: lamin A/C gene mutation

An association has been noted between low weight at birth and at 12 months of age and glucose intolerance later in life, particularly in those who gain excess weight as adults. The concept is that poor nutrition early in life impairs beta-cell development and function, predisposing to diabetes in later life. Low birthweight has also been shown to predispose to heart disease and hypertension in later life.

Table 19-4. Maturity-onset diabetes of the young (MODY)

	HNF-4a (MODY 1)	Glucokinase (MODY 2)	HNF-1a (MODY 3)	IPF-1 (MODY 4)	HNF-1b (MODY 5)
Chromosomal location	20q	7p	12q	13q	17q
Proportion of all MODY cases	5%	15%	70%	< 1% (MODY)	2%
Onset	Teens to thirties	Present from birth	Teens/twenties	Teens to thirties	Teens/twenties
Progression	Progressive hyperglycaemia	Little deterioration with age	Progressive hyperglycaemia	Progression unclear	Progression unclear
Microvascular complications	Frequent	Rare	Frequent	Few data	Frequent
Other features	None	Reduced birthweight	Sensitivity to sulphonylureas	Pancreatic agenesis in homozygotes	Renal cysts Proteinuria Renal failure

The glucokinase gene is intimately involved in the glucose-sensing mechanism within the pancreatic beta-cell. The hepatic nuclear factor (HNF) genes and the insulin promoter factor-1 (IPF-1) gene control nuclear transcription in the beta-cell where they regulate its development and function. Abnormal nuclear transcription genes may cause pancreatic agenesis or more subtle progressive pancreatic damage

There is no evidence of immune involvement in the pathogenesis of type 2 diabetes, but as noted earlier, a proportion of late-onset patients carry islet auto-antibodies directed against GAD at diagnosis, and these are more likely to progress to insulin therapy. Such cases are probably type 1 diabetes masquerading as type 2 diabetes.

A recent development is the recognition that subclinical inflammatory changes are characteristic of both type 2 diabetes and obesity. In diabetes, high-sensitivity C-reactive protein (CRP) levels are elevated in association with raised fibrinogen and increased plasminogen activator inhibitor-1 (PAI-1), and contribute to cardiovascular risk. Circulating levels of the proinflammatory cytokines TNF-α and IL-6 are elevated in both diabetes and obesity. Use of anti-inflammatory agents might potentially reduce the vascular risk associated with both conditions.

Abnormalities of insulin secretion and action

There has been considerable controversy as to the relative role of secretory failure versus insulin resistance in the pathogenesis of type 2 diabetes, but both factors are involved. Although insulin can bind normally to its receptor on the surface of cells in type 2 diabetes, unknown abnormalities attenuate insulin signalling within the cell, producing ‘insulin resistance’. An excess accumulation of intracellular triglyceride in muscle and liver in type 2 diabetes may contribute to this resistance. Type 2 diabetes develops when a person cannot secrete enough insulin to overcome this burden of insulin resistance. Depleted numbers of beta-cells are thus in a state of high output failure. This leads to increased glucose production from the liver (owing to inadequate suppression by insulin) and inadequate uptake of glucose peripherally.

Patients with type 2 diabetes retain up to 50% of their beta-cell mass at the time of diagnosis. In addition, almost all show islet amyloid deposition at autopsy, derived from a peptide known as amylin or islet amyloid polypeptide (IAPP) which is co-secreted with insulin. It is not known if this is a cause or consequence of beta-cell secretory failure. Abnormalities of insulin secretion manifest early in the course of type 2 diabetes. Normal subjects have a biphasic insulin response to intravenous glucose, but the first-phase insulin response is lost as hyperglycaemia develops, and insulin secretion in response to oral glucose is delayed and exaggerated. The majority of patients manifest reduced insulin secretion relative to the prevailing glucose concentration, and progressive beta-cell loss occurs in many patients, although not to the extent seen in type 1 diabetes. It is not known whether this is due to ‘exhaustion’ of surviving beta-cells or to some independent process of damage.

Overview and prevention

Whether an individual develops type 2 diabetes or not is largely due to genetic factors. When a person develops diabetes depends on lifestyle and is more relevant. Diabetes diagnosed in a man between the ages of 40-59 can cause a reduction in life expectancy by 5-10 years. In contrast, type 2 diabetes diagnosed after the age of 70 has little appreciable effect on life expectancy in men. Clinical trials have shown that diet, exercise or agents such as metformin have a marked effect in deferring the onset of type 2 diabetes.

Acute and subacute presentations often overlap.

Acute presentation

Young people often present with a 2- to 6-week history and report the classic triad of symptoms:

• polyuria – due to the osmotic diuresis that results when blood glucose levels exceed the renal threshold
• thirst – due to the resulting loss of fluid and electrolytes
• weight loss – due to fluid depletion and the accelerated breakdown of fat and muscle secondary to insulin deficiency.

Ketonuria is often present in young people and may progress to ketoacidosis if these early symptoms are not recognized and treated.

Subacute presentation

The clinical onset may be over several months or years, particularly in older patients. Thirst, polyuria and weight loss are typically present but patients may complain of such symptoms as lack of energy, visual blurring (owing to glucose-induced changes in refraction), or pruritus vulvae or balanitis that is due to Candida infection.

Complications as the presenting feature

These include:

• staphylococcal skin infections
• retinopathy noted during a visit to the optician
• a polyneuropathy causing tingling and numbness in the feet
• erectile dysfunction
• arterial disease, resulting in myocardial infarction or peripheral gangrene.

Asymptomatic diabetes

Glycosuria or a raised blood glucose may be detected on routine examination (e.g. for insurance purposes) in individuals who have no symptoms of ill-health. Glycosuria is not diagnostic of diabetes but indicates the need for further investigations. About 1% of the population have renal glycosuria. This is an inherited low renal threshold for glucose, transmitted either as a Mendelian dominant or recessive trait.

Physical examination at diagnosis

Evidence of weight loss and dehydration may be present, and the breath may smell of ketones. Older patients may present with established complications, and the presence of the characteristic retinopathy is diagnostic of diabetes. In occasional patients there will be physical signs of an illness causing secondary diabetes (Table 19.1).

Diabetes is easy to diagnose when overt symptoms are present, and a glucose tolerance test is not necessary for most clinical purposes. The oral glucose tolerance test has, however, allowed more detailed epidemiological characterization based on the existence of separate glucose thresholds for macrovascular and microvascular disease. These correspond with the levels for the diagnosis of impaired glucose tolerance (IGT) and diabetes as specified by the WHO criteria set out in Box 19.1.

Box 19.1 WHO diagnostic criteria – 1999

WHO criteria are: Fasting plasma glucose > 7.0 mmol/L (126 mg/dL) Random plasma glucose > 11.1 mmol/L (200 mg/dL) One abnormal laboratory value is diagnostic in symptomatic individuals; two values are needed in asymptomatic people. The glucose tolerance test is only required for borderline cases and for diagnosis of gestational diabetes.

The glucose tolerance test – WHO criteria
	Normal	Impaired glucose tolerance	Diabetes mellitus
Fasting	Less than 7.0 mmol/L	Less than 7.0 mmol/L	More than 7.0 mmol/L
2 h after glucose	Less than 7.8 mmol/L	Between 7.8 and 11.0 mmol/L	11.1 mmol/L or more

Adult: 75 g glucose in 300 mL water. Child: 1.75 g glucose/kg bodyweight. Only a fasting and a 120-min sample are needed. Results are for venous plasma – whole blood values are lower.

Epidemiological studies have shown that for every person with known diabetes, there is another undiagnosed in the population. A much larger proportion fall into the intermediate category of impaired glucose tolerance.

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