Influence of gliclazide on glucose-stimulated insulin release in man

Abstract

Although sulfonylureas (SU) are widely used in the management of patients with non-insulin-dependent diabetes mellitus (NIDDM), there is still debate about their mechanism of action on the pancreatic β cell. It is unclear whether the effect of SU on insulin release is additive to the effect of glucose, or whether SU act by increasing pancreatic β-cell sensitivity to glucose (a shift in the dose-response curve of glucose-stimulated insulin release without a change in maximum release). To address this issue, we assessed the influence of the SU gliclazide on glucose-stimulated insulin release in eight healthy male volunteers. Sixty-minute hyperglycemic glucose clamps (blood glucose levels: 8 mmol/L, a submaximal stimulus; and 32 mmol/L, a maximally stimulating concentration) were performed with and without prior oral administration of gliclazide (80 mg) 30 minutes before the glucose clamp. Mean plasma C-peptide increment at 5 minutes (first-phase secretion) obtained during the 8-mmol/L hyperglycemic clamp, was higher on the gliclazide study day than on the control day (1.07 ± 0.10 v 0.88 ± 0.10 mmol/L, P < .05), whereas no difference in plasma C-peptide response was observed during the 32-mmol/L hyperglycemic clamp. Mean plasma C-peptide increment obtained at the end (60 minutes; (second-phase secretion) of the 8-mmol/L hyperglycemic clamps was higher on the gliclazide study day than on the control day (1.36 ± 0.13 v 1.09 ± 0.09 mmol/L, P < .02). No difference was observed in plasma C-peptide response at the end of the 32-mmol/L hyperglycemic glucose clamps. There was a trend toward an increase by gliclazide in the ratio between plasma C-peptide increment obtained at 5 minutes (first-phase) during the 8-mmol/L glucose clamp and the plasma C-peptide increment obtained at 5 minutes during the 32-mmol/L glucose clamp (0.86 ± 0.09 v 0.07 ± 0.09, .10 > P > .05, gliclazide and control study days, respectively). Gliclazide also increased the ratio of the plasma C-peptide increments obtained at 60 minutes (second-phase) during the two hyperglycemic clamps (0.28 ± 0.01 v 0.23 ± 0.02, P < .05). We conclude that the SU gliclazide enhances insulin secretion by increasing pancreatic β-cell sensitivity to glucose, since it augmented the response to a submaximally stimulating blood glucose concentration, but not to a maximally stimulating blood glucose concentration.