Glucokinase Mutations, Insulin Secretion, and Diabetes Mellitus

The glycolytic enzyme glucokinase plays a key role in glucose sensing by the insulin-secreting pancreatic beta-cells, and mutations in the gene encoding this enzyme are a common cause of maturity-onset diabetes of the young (MODY), a form of non-insulin-dependent diabetes mellitus characterized by autosomal-dominant inheritance and onset before 25 years of age. Twenty-eight different mutations in this gene have been identified in subjects with MODY. Clinical studies have shown that subjects with MODY due to mutations in glucokinase have elevated fasting and postprandial glucose levels with normal first-phase insulin secretory responses to intravenous glucose injection and normal insulin secretion rates over a 24-h period. However, the dose-response curve relating glucose and insulin secretion rate obtained during graded intravenous glucose infusions was shifted to the right in subjects with glucokinase mutations, indicating decreased sensitivity to glucose. In normal subjects, the beta-cell was most sensitive to an increase in glucose concentration between 5.5 and 6.0 mM, whereas in patients with glucokinase mutations, the maximum responsiveness was increased to 6.5 to 7.5 mM glucose. These studies indicate that glucokinase is an important component of the glucose-sensing mechanism of the beta-cell.