ABNORMAL REGULATION OF HEPATIC GLUCOSE OUTPUT IN MATURITY-ONSET DIABETES OF THE YOUNG CAUSED BY A SPECIFIC MUTATION OF THE GLUCOKINASE GENE

A subtype of maturity-onset diabetes of the young (MODY) is caused by mutations of the glucokinase gene, an enzyme expressed in pancreatic b eta-cells and the liver. To assess the consequences of a functional al teration of glucokinase at the level of the liver, endogenous (hepatic ) glucose production and glucose cycling (an indirect assessment of he patic glucokinase activity) were measured with 2-H-2 glucose and 6,6-H -2 glucose in patients who developed MODY because of the V203A mutatio n of glucokinase, and in control subjects at similar levels of glycemi a, Measurements were performed in the postabsorptive state and after i ngestion of C-13-labeled glucose, In the postabsorptive state, MODY pa tients had normal glucose production (10.9 +/- 1.3 vs, 11.3 +/- 0.6 mu mol . kg(-1) . min(-1)) but decreased glucose cycling (0.6 +/- 0.3 vs , 1.5 +/- 0.3 mu mol . kg(-1) . min(-1): P < 0.05) when compared with control subjects, However at plasma glucose and insulin levels similar to those observed in MODY patients, control subjects' glucose product ion was markedly lower (3.2 +/- 1.5 mu mol . kg(-1) . min(-1)). After glucose ingestion, endogenous glucose production was reduced by only 2 9% in MODY patients compared with 80% in control subjects at a similar level of hyperglycemia (P < 0.05), This suggests that the V203A mutat ion of glucokinase results in decreased activity of glucokinase in liv er cells, Thus endogenous glucose production is inadequately inhibited by hyperglycemia in MODY patients, possibly as a result of impaired h epatic glucokinase activity. These alterations contribute to the patho genesis of hyperglycemia.