Diabetes mellitus and other disorders of metabolism

Chapter 20 Diabetes mellitus and other disorders of metabolism

Diabetes mellitus

Hyperglycaemia, insulin and insulin action

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 (Fig. 20.1). 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. Figure 20.2 illustrates the cellular events triggering the release of insulin-containing granules. 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.

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 (Fig. 20.4). It consists of a dimer with two α-subunits, which include the binding sites for insulin, and two β-subunits, which traverse the cell membrane. When insulin binds to the α-subunits it induces a conformational change in the β-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.

Classification of diabetes

Diabetes may be primary (idiopathic) or secondary (Table 20.1). Primary diabetes is classified into:

Table 20.1 Aetiological classification of diabetes mellitus, based on classification by the American Diabetes Association (ADA)

Note: Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient.

(Adapted from ADA. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008; 31(Suppl 1):S55–S60.)

The key clinical features of the two main forms of diabetes are listed in Table 20.2. Type 1 and type 2 diabetes represent two distinct diseases from the epidemiological point of view, but clinical distinction can sometimes be difficult. The two diseases should from a clinical point of view be seen as a spectrum, distinct at the two ends but overlapping to some extent in the middle. Hybrid forms are increasingly recognized, and patients with immune-mediated diabetes (type 1) may, for example, also be overweight and insulin resistant. This is sometimes referred to as ‘double diabetes’. It is more relevant to give the patient the right treatment on clinical grounds than to worry about how to label their diabetes. The classification of primary diabetes continues to evolve. Monogenic forms have been identified (see p. 1007), in some cases with significant therapeutic implications. Although secondary diabetes accounts for barely 1–2% of all new cases at presentation, it should not be missed because the cause can sometimes be treated. All forms of diabetes derive from inadequate insulin secretion relative to the needs of the body, and progressive insulin secretory failure is characteristic of both common forms of diabetes. Thus, some patients with immune-mediated diabetes type 1 may not at first require insulin, whereas many with type 2 diabetes will eventually do so.

Table 20.2 The spectrum of diabetes: a comparison of type 1 and type 2 diabetes mellitus

  Type 1 Type 2


Younger (usually <30)

Older (usually >30)




Symptom duration



Higher risk ethnicity

Northern European

Asian, African, Polynesian and American-Indian

Seasonal onset




HLA-DR3 or DR4 in >90%

No HLA links


Autoimmune disease

No immune disturbance





Insulin deficiency

Partial insulin deficiency initially


± ketoacidosis

± hyperosmolar state


Always need insulin

Need insulin when beta cells fail over time


C-peptide disappears

C-peptide persists

Type 1 diabetes mellitus


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 often predate clinical onset by many years. Autoantibodies are also found in older patients with LADA and carry an increased risk of progression to insulin therapy.

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, and some HLA class I alleles also modify the risk conferred by class II susceptibility genes.

Autoimmunity and type 1 diabetes

Type 1 diabetes is associated with other organ-specific autoimmune diseases including autoimmune thyroid disease, coeliac disease, Addison’s disease and pernicious anaemia. Autopsies of patients who died following diagnosis of type 1 diabetes show infiltration of the pancreatic islets by mononuclear cells. This appearance, known as insulitis, resembles that in other autoimmune diseases such as thyroiditis. Several islet antigens have been characterized, and these include insulin itself, the enzyme glutamic acid decarboxylase (GAD), protein tyrosine phosphatase (IA-2) (Fig. 20.6) and the cation transporter ZnT8. Recent studies have shown that GAD immunotherapy has no benefit. The observation that treatment with immunosuppressive agents such as ciclosporin prolongs beta-cell survival in newly diagnosed patients has confirmed that the disease is immune-mediated.

Type 2 diabetes mellitus


Type 2 diabetes is a common condition in all populations enjoying an affluent lifestyle, and has increased in parallel with the adoption of a western lifestyle and increasing obesity. The four major determinants are increasing age, obesity, ethnicity and family history. In poor countries, diabetes is a disease of the rich, but in rich countries, it is a disease of the poor; obesity being the common factor. Glucose intolerance or frank diabetes may be present in a subclinical or undiagnosed form for years before diagnosis, and 25–50% of patients already have some evidence of vascular complications at the time of diagnosis. Onset may be accelerated by the stress of pregnancy, drug treatment or intercurrent illness. The overall prevalence within the UK is 4–6%, and the lifetime risk is around 15–20%. Type 2 diabetes is 2–4 times as prevalent in people of South Asian, African and Caribbean ancestry who live in the UK, and the life-time risk in these groups exceeds 30%. High rates also affect people of Middle Eastern and Hispanic American origin living western lifestyles. Obesity increases the risk of type 2 diabetes 80–100 fold, and this is reflected by the increasing prevalence of diabetes in different populations. On average, the inhabitants of affluent countries gain almost 1 g daily between the ages of 25 and 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 often due to reduced exercise rather than 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, particularly within high-risk ethnic groups, is a matter for concern.

Type 2 diabetes is associated with central obesity, hypertension, hypertriglyceridaemia, a decreased HDL-cholesterol, disturbed haemostatic variables and modest increases in a number of pro-inflammatory markers. Insulin resistance is strongly associated with many of these variables, as is increased cardiovascular risk. This group of conditions is referred to as the metabolic syndrome (see p. 223). The International Diabetes Federation has proposed criteria based on increased waist circumference (or BMI >30) plus two of the following: diabetes (or fasting glucose >6.0 mmol/L), hypertension, raised triglycerides or low HDL cholesterol. On this definition, about one-third of the adult population has features of the syndrome, not necessarily associated with diabetes. Critics would argue that the metabolic syndrome is not a distinct entity, but one end of a continuum in the relationship between exercise, lifestyle and bodyweight on the one hand, and genetic make-up on the other, and that diagnosis adds little to standard clinical practice in terms of diagnosis, prognosis or therapy.


Abnormalities of insulin secretion and action

The relative role of secretory failure versus insulin resistance in the pathogenesis of type 2 diabetes has been much debated, but even massively obese individuals with a fully functioning beta-cell mass do not necessarily develop diabetes, which implies that some degree of beta-cell dysfunction is necessary. Insulin binds normally to its receptor on the surface of cells in type 2 diabetes, and the mechanisms of ‘insulin resistance’ are still poorly understood. Insulin resistance is, however, associated with central obesity and accumulation of intracellular triglyceride in muscle and liver in type 2 diabetes, and a high proportion of patients have non-alcoholic fatty liver disease (NAFLD), see page 303. It has long been stated that patients with type 2 diabetes retain up to 50% of their beta-cell mass at the time of diagnosis, as compared with healthy controls, but the shortfall is greater than this when they are matched with healthy individuals who are equally obese. In addition, patients with type 2 diabetes 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. An early sign is loss of the first phase of the normal biphasic response to intravenous insulin. Established diabetes is associated with hypersecretion of insulin by a depleted beta-cell mass. Circulating insulin levels are therefore higher than in healthy controls, although still inadequate to restore glucose homeostasis. Relative insulin lack is associated with increased glucose production from the liver (owing to inadequate suppression of gluconeogenesis) and reduced glucose uptake by peripheral tissues. Hyperglycaemia and lipid excess are toxic to beta cells, at least in vitro, a phenomenon known as glucotoxicity, and this is thought to result in further beta-cell loss and further deterioration of glucose homeostasis. Circulating insulin levels are typically higher than in non-diabetics following diagnosis and tend to rise further, only to decline again after months or years due to secretory failure, an observation sometimes referred to as the ‘Starling curve’ of the pancreas. Type 2 diabetes is thus a condition in which insulin deficiency relative to increased demand leads to hypersecretion of insulin by a depleted beta-cell mass and progression towards absolute insulin deficiency requiring insulin therapy. Its time course varies widely between individuals.

Monogenic diabetes mellitus

The genetic causes of some rare forms of diabetes are shown in Table 20.3. Considerable progress has been made in understanding these rare variants of diabetes. Genetic defects of beta-cell function (previously called ‘maturity-onset diabetes of the young’, MODY) are dominantly inherited, and several variants have been described, each associated with different clinical phenotypes (Table 20.4). These should be considered in people presenting with early-onset diabetes in association with an affected parent and early-onset diabetes in ~50% of relatives. They can often be treated with a sulfonylurea.

Table 20.3 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’s 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’s, 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

Genetic defects of beta-cell function

See Table 20.4

Infants who develop diabetes before 6 months of age are likely to have a monogenic defect and not true type 1 diabetes. Transient neonatal diabetes mellitus (TNDM) occurs soon after birth, resolves at a median of 12 weeks, and 50% of cases ultimately relapse later in life. Most have an abnormality of imprinting of the ZAC and HYMAI genes on chromosome 6q. The commonest cause of permanent neonatal diabetes mellitus (PNDM) is mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium-ATP channel.

Neurological features are seen in 20% of patients. Diabetes is due to defective insulin release rather than beta-cell destruction, and patients can be treated successfully with sulfonylureas, even after many years of insulin therapy.

Clinical presentation of diabetes

Presentation may be acute, subacute or asymptomatic.

Diagnosis and investigation of diabetes

Diabetes is easy to diagnose when overt symptoms are present, and a glucose tolerance test is hardly ever necessary for 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 20.1. Epidemiological studies show 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.

Mar 31, 2017 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Diabetes mellitus and other disorders of metabolism

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