Short- and long-term gliclazide effects on pancreatic islet cell function and hepatic insulin extraction in non-insulin-dependent diabetes mellitus

Abstract

Nine non-obese males with non-insulin-dependent diabetes mellitus (NIDDM) were evaluated before and after 3 and 12 months (6 patients) treatment with the second generation hypoglycemic sulfonylurea: gliclazide. They underwent an oral glucose tolerance test, intravenous glucose and arginine tests measuring plasma insulin and C-peptide responses. Pre-hepatic insulin production and insulin delivery to peripheral tissues were calculated by deconvolution techniques and hepatic extraction of insulin estimated. An improvement was observed in the β-cell function of the patients on gliclazide treatment: reduction of fasting plasma glucose associated with a progressive increase in C-peptide level but insulin levels decreased at 12 months, suggesting an increase in hepatic insulin extraction at this time. In the same way, while plasma glucose values after oral and i.v. glucose were greatly reduced at 3 and 12 months treatment, insulin did not change but C-peptide levels increased significantly at 12 month treatment. While the prehepatic insulin secretion rate increased progressively on gliclazide during all glucose challenges, the fractional hepatic insulin extraction fell after 3 and increased at 12 month treatment, with opposite changes in insulin delivered to peripheral tissues. Thus the insulinogenic effect of gliclazide could be masked during long-term administration by a concomitant effect of gliclazide which increases hepatic extraction of insulin. The maintenance of the responsiveness to the non-glucose secretagogue, arginine, as evaluated by the C-peptide levels, before and after correction of hyperglycemia, suggested improvement of β-cell sensitivity to glucose after sulfonylurea treatment. When plasma glucose levels during gliclazide therapy were matched by glucose infusion to the pretreatment fasting plasma glucose, the acute insulin and C-peptide responses to arginine were also increased again, indicating that the β-cells were resensitized to the potentiating effect of glucose after sulfonylurea. In conclusion, gliclazide treatment increases insulin secretion and alters hepatic insulin extraction. Because C-peptide kinetic studies were not performed, the derived data related to pancreatic insulin secretion and hepatic insulin extraction are tentative and should be accepted with caution.