Chronic DPP-IV inhibition with PKF-275-055 attenuates inflammation and improves gene expressions responsible for insulin secretion in streptozotocin induced diabetic rats.
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.
Delhi Institute of Pharmaceutical Sciences and Research, Pushp Vihar, Sector-3, MB Road, New Delhi 110 017, India. atul_akarte123@rediffmail.com
Atul Sureshrao
AS
Akarte
B P
BP
Srinivasan
Sonia
S
Gandhi
Sushant
S
Sole
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001798:Blood Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000235:genetics; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D009573:Nitrites / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
C569631:1-((2-adamantyl)amino)acetyl-2-cyano-(S)-pyrrolidine, monohydrochloride; D001786:Blood Glucose; D001798:Blood Proteins; D054873:Dipeptidyl-Peptidase IV Inhibitors; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D009566:Nitrates; D009570:Nitriles; D009573:Nitrites; D011759:Pyrrolidines; D012333:RNA, Messenger; C495683:Slc2a2 protein, rat; C495694:Slc2a4 protein, rat; D014409:Tumor Necrosis Factor-alpha; D052216:Glucagon-Like Peptide 1; D006003:Glycogen; D000218:Adamantane