Different Effects of Glyburide and Glipizide on Insulin Secretion and Hepatic Glucose Production in Normal and NIDDM Subjects

Abstract

Glyburide (GB) and glipizide (GZ) differ in their pharmacokinetics, but it is not known whether they also differ in mode of action. To examine this question, 10 young healthy subjects and 6 non-insulin-dependent diabetic (NIDDM) patients participated in each of three studies: 1) infusion of saline for 120 min followed by a 100-min hyperglycemic (125 mg/dl) clamp; 2) 120-min primed continuous infusion of GZ followed by a 100-min hyperglycemic clamp; and 3) 120-min primed continuous infusion of GB followed by a 100-min hyperglycemic clamp. The GB and GZ infusions were continued throughout the hyperglycemic clamp. Similar plasma concentrations of GB and GZ were obtained in both groups. All studies were performed with [3-3H]glucose to allow quantification of hepatic glucose production. When administered under basal conditions of glycemia, the acute phase (0-10 min) of plasma insulin and C-peptide increase in both control and NIDDM subjects was twice as great with GZ compared with GB (P less than .01). During the hyperglycemic-clamp studies performed in normal subjects, both GB and GZ increased the first- (1.6-fold) and second- (2.2-fold) phase plasma insulin responses more than hyperglycemia alone. During the hyperglycemic clamp in NIDDM subjects, the first-phase plasma insulin response was absent, and the second-phase insulin response was markedly impaired. Neither GB nor GZ improved first-phase insulin secretion in the NIDDM patients. In both NIDDM and control subjects, the effects of hyperglycemia and sulfonylurea drugs (both GB and GZ) on the first- and second-phase plasma insulin responses were simply additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term gliclazide treatment improves the in vitro glucose-induced insulin release in rats with Type 2 (non-insulin-dependent) diabetes induced by neonatal streptozotocin

“…Although one has to be cautious in relating findings obtained in diabetic animal models to diabetic patients, our results in the n0-STZ and n5-STZ (group B) rats agree with clinical reports which conclude that chronic sulfonylurea therapy augments both basal and stimulated first phase insulin secretion in Type 2 diabetes by increasing islet sensitivity to glucose [15,16,41] while the acute sulfonylurea administration does not significantly improve their first phase insulin secretion [42].…”

Reduction of insulin resistance by combined kidney-pancreas transplantation in Type 1 (insulin-dependent) diabetic patients

“…Blood cyclosporin concentration was measured by RIA utilizing monoclonal antibodies to recognize native cyclosporin A (Cyclo-Trac, Incstar Co., Stitlwater, Minn., USA) [42]. Plasma 3-3H-glucose specific radioactivity was measured in duplicate on the supernatants of Ba(OH)JZnSO4 precipitates, after total evaporation to eliminate 3H-water (Somogyi's method) [26]. Urinary nitrogen excretion was measured by Kjeldhal's method [23].…”

Evidence that insulin can directly inhibit hepatic glucose production

“…The difference in the magnitude of the two responses was statistically significant (p < 0.03), providing further support for the view that insulin can directly inhibit HGP, independent of any change in flow of substrates from periphery to liver. [Diabetologia (1997[Diabetologia ( ) 40: 1300[Diabetologia ( -1306 Keywotds Liver, insulin, portal system, C-peptide, tolbutamide.Evidence has been published showing that hepatic glucose production (HGP) is decreased following the infusion of either insulin or sulfonylurea compounds [1][2][3][4], and this is generally assumed to be due to a direct effect of insulin on the liver. However, the results of two recent studies in dogs [5,6] of insulin, suggesting that the ability of insulin to inhibit HGP may be mediated through its peripheral action on substrate flow to the liver.…”