Understanding the cause of type 2 diabetes

Type 2 diabetes has long been thought to have heterogenous causes, even though epidemiological studies uniformly show a tight relationship with overnutrition. The twin cycle hypothesis postulated that interaction of self-reinforcing cycles of fat accumulation inside the liver and pancreas, driven by modest but chronic positive calorie balance, could explain the development of type 2 diabetes. This hypothesis predicted that substantial weight loss would bring about a return to the non-diabetic state, permitting observation of the pathophysiology determining the transition. These changes were postulated to reflect the basic mechanisms of causation in reverse. A series of studies over the past 15 years has elucidated these underlying mechanisms. Together with other research, the interaction of environmental and genetic factors has been clarified. This knowledge has led to successful implementation of a national programme for remission of type 2 diabetes. This Review discusses the paucity of evidence for heterogeneity in causes of type 2 diabetes and summarises the in vivo pathophysiological changes, which cause this disease of overnutrition. Type 2 diabetes has a homogenous cause expressed in genetically heterogenous individuals.