Ameliorating Effects of Sulfonylurea Drugs on Insulin Resistance in Otsuka Long-Evans Tokushima Fatty Rats

Abstract

OLETF (Otsuka Long-Evans Tokushima Fatty) rats are characterized by obesity-related insulin resistance, which is a phenotype of type 2 diabetes. Sulfonylurea drugs or benzoic acid derivatives as inhibitors of the ATP-sensitive potassium (KATP) channel are commercially available to treat diabetes. The present study compared sulfonylurea drugs (glimepiride and gliclazide) with one of benzoic acid derivatives (repaglinide) in regard to their long-term effect on ameliorating insulin sensitivity in OLETF rats. Each drug was dissolved and fed with drinking water from 29 weeks of age. On high glucose loading at 45 weeks of age, response of blood glucose recovery was the greatest in the group treated with glimepiride. On immunohistochemistry analysis for the Kir6.2 subunit of KATP channels, insulin receptor β-subunits, and glucose transporters (GLUT) type 2 and 4 in liver, fat and skeletal muscle tissues, the sulfonylurea drugs (glimepiride and gliclazide) were more effective than repaglinide in recovery from their decreased expressions in OLETF rats. From these results, it seems to be plausible that KATP-channel inhibitors containing sulfonylurea moiety may be much more effective in reducing insulin resistance than those with benzoic acid moiety. In contrast to gliclazide, non-tissue selectivity of glimepiride on KATP channel inhibition may further strengthen an amelioration of insulin sensitivity unless considering other side effects.

Modulatory effect of S-allylcysteine on glucose metabolism in streptozotocin induced diabetic rats

“…The hypoglycemic potency of SAC was comparable glyclazide, a standard hypoglycemic drug. Glyclazide has long been used to treat diabetes and is known to act by stimulating insulin secretion through action on the pancreatic b-cells (Jeong-Kwon Park et al, 2008). Hexokinase is an insulin-dependent and insulin-sensitive enzyme and are almost completely inhibited or inactivated in diabetic rat liver in the absence of insulin (Gupta et al, 1997).…”

Effects of Fluvastatin on the Pharmacokinetics of Repaglinide: Possible Role of CYP3A4 and P-glycoprotein Inhibition by Fluvastatin

“…Cholesterol-lowering agents such as HMG-CoA rductase inhibitors could be co-administered with antidiabetic agents for the treatment of hyperlipidemia induced by diabetes [9,17,21]. Based on the broad overlap in the substrate specificities as well as their co-localization in the small intestine, the primary site of absorption for orally administered drugs, cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp) are recognized as a concerted barrier to drug absorption [22,23].…”