Sir Hans Krebs Prize Lecture: Metabolic Regulation of Insulin Secretion in Health and Disease

Diabetes is a major global health problem that affects >450 million people worldwide. All forms of diabetes are characterised by chronic hyperglycaemia that results from insufficient insulin release from pancreatic beta-cells. The ATP-sensitive potassium (KATP) channel plays a central role in insulin secretion in both health and disease. Glucose normally stimulates insulin secretion via its metabolism. Metabolically generated ATP binds to, and thereby closes, KATP channels, leading to calcium-dependent electrical activity, calcium influx and insulin release. This process fails in diabetes.

Gain-of-function mutations that impair KATP channel inhibition by ATP cause a rare form of diabetes that develops shortly after birth (neonatal diabetes). Their identification has enabled many patients with neonatal diabetes to switch from insulin injections to sulphonylurea drugs (that block KATP channel activity) with considerable improvement in their clinical condition and quality of life. 

Type 2 diabetes (the most common form of the disease) involves both a genetic predisposition and lifestyle factors, develops with age and is associated with a progressive decline in beta-cell function. Impaired metabolic regulation of the KATP channel also appears to play a key role in type 2 diabetes. First a common genetic variant that causes a tiny reduction in the ATP sensitivity of the channel predisposes to type 2 diabetes. Second, current studies show that chronic hyperglycaemia contributes to the progressive loss of beta-cell function by impairing oxidative metabolism, and thus ATP production. This produces a vicious spiral that drives the progression from impaired glucose tolerance to type 2 diabetes. Only a small elevation of blood glucose is needed to initiate this effect. Our studies also show it is a glucose metabolite (rather than glucose itself) that is responsible, propose a possible pathway for how this metabolite impairs beta-cell function, and suggest a potential novel therapy to reduce/halt beta-cell decline.

 

krebs lecture 2023 poster