Box 1. Box 1 The diversity of diabetes mellitus

The term 'diabetes mellitus' covers a wide variety of conditions that are linked only by shared symptoms arising from high levels of blood sugar. That diversity may be crudely partitioned^{2, 3, 11, 12} into type 2 (adult-onset) and the less-common type 1 (juvenile-onset). The respective prevalences among diabetics in the United States are 90–95% and 5–10%. Both diseases centre on the hormone insulin, which is responsible for mediating the uptake by cells of glucose from the blood.

Type 1 diabetes (insulin-dependent diabetes mellitus) is an autoimmune disease in which autoantibodies destroy the pancreatic-islet cells that synthesize insulin. Patients are thin, produce little or no insulin, and are prone to ketosis, a particular metabolic imbalance. They carry certain gene types — the HLA alleles DR3, DR4 or both — that encode particular components of the immune system. Type 2 diabetes (non-insulin-dependent diabetes mellitus) involves altered insulin secretion and insulin resistance. Patients are often obese and are not subject to ketosis. They do produce insulin but become insulin-resistant — that is, unable to respond effectively to it.

Distinguishing the two forms can be complicated, however, because there is early-onset type 2 and late-onset type 1. Type 2 diabetes is itself very heterogeneous, both genetically and in the associated pathological and physiological symptoms. The disease arises from at least 60 identified genetic disorders, united only by the common feature of high blood-glucose levels due to insulin resistance. This heterogeneity reinforces the evolutionary puzzle: genes that predispose the bearer to type 2 diabetes must really convey some advantage, because they have evidently been preserved independently many times by natural selection. The 'thrifty gene' hypothesis, according to which such genes allow efficient food utilization in times of plenty, in preparation for famine, provides a possible explanation.