Glucokinase activity in diabetes: too much of a good thing?

Glucokinase catalyses the first step in glucose metabolism. It functions as a glucose sensor in the insulin-secreting pancreatic beta-cells.Activating mutations in glucokinase cause too much insulin secretion (hyperinsulinism), whereas inactivating mutations cause too little insulin release and varying degrees of diabetes. Glucokinase activators have been trialled as antidiabetic drugs but generally fail to enhance insulin secretion in the long term.Recent studies show it is a glucose metabolite and not glucose itself that causes the decline in beta-cell function in response to chronic hyperglycaemia or diabetes. This argues that glucokinase activation would exacerbate beta-cell decline in diabetes.Partial glucokinase inhibition prevents the hyperglycaemia-induced decline in beta-cell function in beta-cell lines and animal models of diabetes.