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.

Peripheral blood

A low haemoglobin should always be considered in relation to:

• the white blood cell (WBC) count
• the platelet count
• the reticulocyte count (as this indicates marrow activity)
• the blood film, as abnormal red cell morphology may indicate the diagnosis.

Where two populations of red cells are seen, the blood film is said to be dimorphic. This may, for example, be seen in patients with ‘double deficiencies’ (e.g. combined iron and folate deficiency in coeliac disease, or following treatment of anaemic patients with the appropriate haematinic).

Bone marrow

Examination of the bone marrow is performed to further investigate abnormalities found in the peripheral blood (Practical box 8.1). Aspiration provides a film which can be examined by microscopy for the morphology of the developing haemopoietic cells. The trephine provides a core of bone which is processed as a histological specimen and allows an overall view of the bone marrow architecture, cellularity and presence/absence of abnormal infiltrates.

The following are assessed:

• cellularity of the marrow
• type of erythropoiesis (e.g. normoblastic or megaloblastic)
• cellularity of the various cell lines
• infiltration of the marrow
• iron stores.

Special tests may be performed: cytogenetic, immunological, cytochemical markers, biochemical analyses (e.g. deoxyuridine suppression test), microbiological culture.