Chronic DPP-IV inhibition with PKF-275-055 attenuates inflammation and improves gene expressions responsible for insulin secretion in streptozotocin induced diabetic rats.

Abstract

Inhibitors of dipeptidyl peptidase-4 (DPP-IV), a key regulator of the actions of incretin hormones, exert antihyperglycemic effects in type 2 diabetic patients. A major question concerns the potential ability of long term DPP-IV inhibition to have beneficial disease-modifying effects, specifically to attenuate loss of pancreatic β-cell mass due to oxidative stress induced inflammation. Here, we investigated the effects of a potent and selective DPP-4 inhibitor, an analog of vildagliptin (PKF-275-055), on glycemic control, pancreatic β-cell mass, genes and proteins expressions, tumor necrosis factor-alpha, and nitric oxide in an n2-STZ diabetic model of rat with defects in insulin sensitivity and secretion. To induce NIDDM, streptozotocin (STZ) 90 mg/kg was administered i.p. to a group of 2 days old pups. Diabetic rats were administered orally with vildagliptin analog PKF-275-055. Saline treated animals served as diabetic control. Significant and dose-dependent correction of postprandial hyperglycemia was observed in diabetic rats following 8 weeks of chronic therapy. Treatment with PKF-275-055 showed increased the number of insulin-positive β-cells in islets and improved the expressions of genes and proteins are responsible for insulin secretions. In addition, treatment of rats with PKF-275-055 significantly increased insulin content, glycogen content and total proteins content; and decreased the inflammatory markers i.e. nitric oxide and TNF-alpha. The present studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor having potential to reduce inflammation that might be a potential agent for type 2 diabetes.

• Authors: Atul Sureshrao Akarte, B P Srinivasan, Sonia Gandhi, Sushant Sole
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 47 Issue 2 Pg. 456-63 (Sep 29 2012) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 22800967 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• 1-((2-adamantyl)amino)acetyl-2-cyano-(S)-pyrrolidine, monohydrochloride
• Blood Glucose
• Blood Proteins
• Dipeptidyl-Peptidase IV Inhibitors
• Glucose Transporter Type 2
• Glucose Transporter Type 4
• Hypoglycemic Agents
• Insulin
• Nitrates
• Nitriles
• Nitrites
• Pyrrolidines
• RNA, Messenger
• Slc2a2 protein, rat
• Slc2a4 protein, rat
• Tumor Necrosis Factor-alpha
• Glucagon-Like Peptide 1
• Glycogen
• Adamantane

Topics

• Adamantane (analogs & derivatives, pharmacology, therapeutic use)
• Animals
• Blood Glucose (analysis)
• Blood Proteins (metabolism)
• Diabetes Mellitus, Experimental (drug therapy, metabolism, pathology)
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology, therapeutic use)
• Gene Expression Regulation (drug effects)
• Glucagon-Like Peptide 1 (genetics)
• Glucose Transporter Type 2 (genetics, metabolism)
• Glucose Transporter Type 4 (genetics, metabolism)
• Glycogen (metabolism)
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Inflammation (drug therapy, metabolism, pathology)
• Insulin (blood, metabolism)
• Insulin Secretion
• Liver (drug effects, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Nitrates (metabolism)
• Nitriles (pharmacology, therapeutic use)
• Nitrites (metabolism)
• Pancreas (drug effects, metabolism, pathology)
• Pyrrolidines (pharmacology, therapeutic use)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Tumor Necrosis Factor-alpha (blood)