INSULIN SECRETORY ABNORMALITIES IN SUBJECTS WITH HYPERGLYCEMIA DUE TOGLUCOKINASE MUTATIONS

Pancreatic beta-cell function was studied in six subjects with mutatio ns in the enzyme glucokinase (GCK) who were found to have elevated fas ting and postprandial glucose levels in comparison to sis normoglycemi c controls. Insulin secretion rates (ISRs) were estimated by deconvolu tion of peripheral C-peptide values using a two-compartment model and individual Cpeptide kinetics obtained after bolus intravenous injectio ns of biosynthetic human C-peptide. First-phase insulin secretory resp onses to intravenous glucose and insulin secretion rates over a 24-h p eriod on a weight maintenance diet were not different in subjects with GCK mutations and controls. However, the dose-response curve relating glucose and ISR obtained during graded intravenous glucose infusions was shifted to the right in the subjects with GCK mutations and averag e ISRs over a glucose range between 5 and 9 mM were 61% lower than tho se in controls. In the controls, the beta cell was most sensitive to a n increase in glucose at concentrations between 5.5 and 6.0 mM, wherea s in the patients, with GCK mutations the point of maximal responsiven ess was increased to between 6.5 and 7.5 mM. Even mutations that resul ted in mild impairment of in vitro enzyme activity were associated wit h a > 50% reduction in ISR. The responsiveness of the beta cell to glu cose was increased by 45% in the subjects with mutations after a 42-h intravenous glucose infusion at a rate of 4-6 mg/kg per min. During os cillatory glucose infusion with a period of 144 min, profiles from the subjects with mutations revealed reduced spectral power at 144 min fo r glucose and ISR compared with controls, indicating decreased ability to entrain the beta cell with exogenous glucose. In conclusion, subje cts with mutations in GCK demonstrate decreased responsiveness of the beta cell to glucose manifest by a shift in the glucose ISR dose-respo nse curve to the right and reduced ability to entrain the ultradian os cillations of insulin secretion with exogenous glucose. These results support a key role for the enzyme GCK in determining the in vivo gluco se/ISR dose-response relationships and define the alterations in beta- cell responsiveness that occur in subjects with GCK mutations.