A novel long acting DPP-IV inhibitor PKF-275-055 stimulates β-cell proliferation resulting in improved glucose homeostasis in diabetic rats

• Published in: Biochemical pharmacology 2012-01, Vol.83 (2), p.241-252
• Main Authors: Akarte, Atul Sureshrao, Srinivasan, B.P., Gandhi, Sonia
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Adamantane - chemistry; Adamantane - pharmacology; Adamantane - therapeutic use; Animals; apoptosis; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Cell Proliferation - drug effects; Diabetes; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - pathology; Diabetes. Impaired glucose tolerance; Dipeptidyl peptidase-IV; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; gastric emptying; Glucagon like peptide -1; glucose; glucose tolerance tests; glycation; glycemic effect; half life; homeostasis; Homeostasis - drug effects; Homeostasis - physiology; hypoglycemia; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - enzymology; Insulin-Secreting Cells - pathology; Medical sciences; Nitriles - chemistry; Nitriles - pharmacology; Nitriles - therapeutic use; noninsulin-dependent diabetes mellitus; patients; pharmacology; Pharmacology. Drug treatments; Pyrrolidines - chemistry; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Rats; Rats, Wistar; secretin; streptozotocin; therapeutics; β-cell regeneration
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2011.10.003

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined chronic (once-a-day dosing for 8 weeks) effects of the DPP-4 inhibitor PKF-275-055 (1, 3, and 10 mg/kg) on β-cell regeneration and plasma DPP-IV activity, intact GLP-1, glucose, and insulin after an oral glucose load in neonatal wistar rats injected with streptozotocin (STZ) (n2-STZ model), a recognized model of type 2 diabetes. In streptozotocin induced diabetic rats, PKF-275-055 (3, and 10 mg/kg) significantly reduced glucose excursion during the oral glucose tolerance test conducted 2 h and 10 h after administration, with increases in plasma insulin and active glucagon-like peptide-1 (GLP-1) levels and significantly inhibited (> 50% inhibition) plasma DPP-IV activity during both the 1st and 2nd OGTT in diabetic rats. In contrast, PKF-275-055 (1–10 mg/kg) did not cause hypoglycemia in fasted normal rats. Furthermore, PKF-275-055 significantly inhibited advance glycation end product (HbA1c), HOMA-Index, gastric emptying and small intestinal transit rates, with significance at doses of 1 mg/kg or higher. Immunological staining showed PKF-275-055 stimulates β-cell regeneration and reduces pancreatic cell apoptosis in diabetic treated rats. The present preclinical studies indicate that PKF-275-055 is a novel selective DPP-IV inhibitor with long-acting antidiabetic effect that might be a potential agent for type 2 diabetes