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Representing as it does the majority of people with diabetes worldwide, type 2 diabetes is unfortunately the least satisfactory of the classifications. This reflects the fact that there are likely to be many aetiological and patho-physiological routes to developing a condition of sustained, survivable hyperglycaemia. How are we likely to make progress in further dissecting this large group into clinically relevant aetiological subgroups?

1. Further definition of specific types. It is possible that, lurking among the type 2 diabetic population, are a number of as yet unrecognised single-gene syndromes. As the genetic effort to identify such monogenic diseases intensifies, some such conditions will emerge9. While they may be important, they are unlikely to represent a large proportion of people with what we currently call type 2 diabetes.

2. Classification on pathophysiology. As we gain more insight into the pathophysiological features of type 2 diabetes, we may achieve a meaningful definition of sub-phenotypes that may prove useful. For many years researchers have sub-grouped subjects into those predominantly characterised by insulin secretory dysfunction versus those with insulin resistance. This will continue to be useful but, unfortunately, interpretation is often difficult because of the effect that disease progression, whatever its initial aetiology, has on beta-cell function. Newer insights into sub-phenotypes may come from new technology, e.g. measurement of intramyocellular triacylglycerol10, serum adiponectin11 etc.

3. Role for polygenic determinants. The great promise of polygenics has yet to be fulfilled. However, there are signs of life. Thus, a frameshift mutation in an immune signalling protein, NOD2, has recently been found in ~6% of patients with Crohn's disease versus ~2% of controls12. Presumably such subjects will now be studied intensively for differences in their natural history and response to treatment compared to Crohn's patients who do not have this mutation. An intronic polymorphism in the calpain 10 gene has been hailed as the first type 2 diabetes polygene13. However, the situation is complex, with inconsistent findings in other studies14 and no clear mechanism of action as yet being defined. A common polymorphism in PPAR7 appears to reduce the risk of type 2 diabetes15. The search is continuing and more polymorphic variants contributing susceptibility to type 2 diabetes will undoubtedly be found.

4. Gene-environment interaction. The role of non-genetic effects in producing type 2 diabetes should not be underestimated. Undoubtedly, dietary factors and physical inactivity play a role16. There is increasing realisation that they will interact with particular genotypes. Thus we have recently demonstrated an interaction between dietary fat type and the common PPAR7 polymorphism with the beneficial effects of a high unsaturated/saturated fat intake in terms of adiposity and fasting insulin being confined to those with the PPAR7 Ala12 genotype17.

5. Need for a multidimensional classification. In the future, we may not simply be able to use a pithy, but meaningless, phrase to 'classify' a patient's diabetes. We may need to classify an individual according to the genotypes at particular loci and incorporate quantitative measure of risk factors such as diet and level of physical activity. This may be demanding but should lead to individualised therapy, not only with drugs but also with specific diet and exercise prescriptions.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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