• A number of different pathological mechanisms produce chronic hyperglycaemia, the hallmark of clinical diabetes

• These mechanisms produce different patterns of presentation and therefore different types of diabetes

• Important pathways include autoimmune destruction of beta cells in type 1 diabetes, and insulin resistance with gradual decline in beta cell function in type 2

• Diabetes may also result from drug therapy or from systemic disease affecting other organs as well as the pancreas

• There is increasing interest in the classification of sub-types of diabetes, which is assisting in the personalisation of treatments for affected individuals


Diabetes mellitus is not one disease. It is defined as chronic hyperglycaemia that may be caused by one or more of numerous underlying processes. Some of these cause diabetes directly by interfering with beta cell function or through significant defects in insulin action. In other cases diabetes is part of a more general disorder affecting many other organs or systems. Examples include some endocrinopathies, drug- or chemical-induced diabetes; diabetes related to certain infections and diabetes associated with certain genetic syndromes.

Although one might argue that management of diabetes is empirical and that knowledge of the underlying causes does not alter management for most patients, this is changing. For some distinct sub-types of diabetes, there are clinical implications for the patient and their family. In the future, this is likely to lead to increasing personalisation of drug therapy.

Type 1 diabetes

Type 1 diabetes results from destruction of the beta cells in the islet cells of Langerhans in the pancreas (Figure 2.1). This usually results in more or less absolute deficiency of insulin. In most cases, this is due to autoimmune destruction of the islets. This results from a combination of genetic susceptibility and poorly understood environmental triggers that initiate the disease process. It is believed that this process starts a long time before the illness actually presents. There is, therefore, an opportunity for prevention of diabetes in the future in this group of patients. Type 1 diabetes is far more common in those with a history of other autoimmune disorders such as coeliac disease, thyroid disease, pernicious anaemia and Addison's disease. If there is a strong family history of any of these disorders, the risk of type 1 diabetes in these families is higher.

Genetic factors predisposing to type 1 diabetes

The strong concordance of type 1 diabetes in monozygotic twins suggests a major role for genetic factors. The major

Figure 2.1 Beta cell destruction after 50 years of type 1 diabetes.

histocompatibility complex antigens are thought to be important. Most type 1 patients show either DR3 or DR4, whilst DR2 is thought to be protective against diabetes.

Autoantibodies in type 1 diabetes

Islet cell autoantibodies are present at diagnosis but will gradually decline and disappear in ensuing years. This means that if there is diagnostic uncertainty, islet cell antibodies can be checked early during presentation. Specific tests have been devised recently including anti-GAD (glutamate decarboxylase) antibodies and also anti-IAP (inhibitor of apoptosis protein) antibodies. The presence of both together is associated with a significantly higher risk of developing type 1 diabetes.

The use of these tests in clinical practice is restricted to situations where there is doubt about the diagnosis of the type of diabetes and to distinguish from type 2 diabetes. Clinically, the implication is that if the tests are negative the patient might then not require insulin. Attempts to prevent type 1 diabetes in these susceptible individuals has thus far not proved successful.

Type 2 diabetes

Type 2 diabetes is a complex heterogeneous condition and recent genetic studies have revealed numerous sub-types. Children presenting with mild hyperglycaemia present diagnostic problems as they may have latent slowly progressing type 1 diabetes. These children may then progress to requiring insulin. On the other hand, with increasing prevalence of obesity more children are now presenting with type 2 diabetes, particularly from ethnic minorities. In the USA, in some areas, up to 50% of children with diabetes are now presenting with the type 2 form.

Latent autoimmune diabetes in adults (LADA) is thought to comprise about 5% of all patients with type 2 diabetes. These people have autoantibodies usually seen in type 1 diabetes, but their clinical presentation is like someone with type 2 diabetes. This is a group that may present an excellent opportunity for subsequent prevention of diabetes if an effective intervention can be developed to prevent further beta cell destruction.


Monogenic diabetes (previously referred to as maturity onset diabetes in the young, MODY)

Monogenic diabetes is the term used for a collection of conditions that cause diabetes now shown to result from single gene defects. One feature of these conditions is that they show autosomal dominant inheritance patterns where the disease appears to be vertically transmitted (e.g. through several generations). It is also diagnosed before the age of 25 years, but, unlike type 1 diabetes patients, monogenic diabetes patients do not often require insulin for at least 5 years after diagnosis. Genetic testing in these cases can confirm the particular sub-type of diabetes. This can have significant clinical implications. Patients with HNF1a (hepatocyte nuclear factor 1a) mutations, for example, exhibit exquisite sensitivity to sulphonylureas and can be successfully treated with tablets. Knowledge of the mutation, therefore, can help in the management of this disorder, even in children who would otherwise have been put onto insulin. This is also one form of type 2 diabetes where we would use a sulphonylurea in preference to metformin when initiating therapy. Patients with HNF1| have renal cysts. Patients with glucokinase mutations are less common but the diagnosis is significant for the individual and their families. Such patients are much less likely to develop complications of diabetes because they mainly have mild fasting hyperglycaemia without significant post meal hyperglycaemia.

Maternally inherited diabetes with deafness (MIDD)

This is a form of diabetes due to mutations in mitochondria, most commonly related to 3243A > G mitochondrial DNA mutation. Mitochondria in an individual are inherited from the mother rather than from the father, therefore one clue would be evidence of strong maternal transmission of diabetes, particularly when this is associated with a sensorineural deafness. Some patients may also have peripheral vision problems, particularly night blindness. These patients often require insulin.

Figure 2.2 Lipodystrophy affecting the buttocks (a) but not the abdomen (b).


It has been known for a long time that marked defects in adipose tissue distribution may be associated with diabetes. For example, complete absence of subcutaneous adipose tissue as in generalised lipodystrophy or partial lipodystrophies with absence of fat in the face and torso are associated with diabetes and dyslipidaemia. However, more recently a much more common disorder of adipose tissue distribution, familial face-sparing lipodystrophy has been recognised. These patients often have excess fat on the face, neck, abdomen and also visceral fat. They show marked lack of fat in the gluteal area and in the limbs (Figure 2.2). Often patients also have acanthosis nigricans, seen particularly in the axilla or the back of the neck (Figure 2.3). These patients present with an insulin-resistant diabetes, often with hypertriglyceridaemia. Marked hypertriglyceri-daemia can be a risk factor for pancreatitis and should be managed with low-fat diet and lipid-lowering medication.

Other insulin-resistant syndromes

Other rarer causes of insulin-resistant syndromes may present in childhood, with failure to thrive, growth problems and also acanthosis nigricans. Paradoxically, these children may exhibit fasting hypoglycaemia and yet once they develop diabetes may require large doses of insulin to control hyperglycemia. If such disorders are suspected, referral to a specialist will be required as the management can be quite difficult.

Figure 2.3 Acanthosis nigricans in the axilla (a) and behind the neck (b).

Further reading

Jafar-Mohammadi B, McCarthy MI. Genetics of type 2 diabetes mellitus and obesity - a review. Ann Med 2007;18:1-9.

Lindgren CM, McCarthy MI. Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. Nat Clin Pract Endocrinol Metab 2008;4:156-63.

Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 2008;4:200-13. Epub 2008 Feb 26. Review.

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