Abstract
BackgroundActivating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidase-IV (DPP-IV). We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on β-cell regeneration in diabetic mice.Materials & MethodsDiabetes in C57BL/6 mice was induced by streptozotocin. PSN632408 and sitagliptin alone or in combination were administered to diabetic mice for 7 weeks along with BrdU daily. Nonfasting blood glucose levels were monitored. After treatment, oral glucose tolerance test (OGTT), plasma active GLP-1 levels, β-cell mass along with α- and β-cell replication, and β-cell neogenesis were evaluated.ResultsNormoglycemia was not achieved in vehicle-treated mice. By contrast, 32% (6 of 19) of PSN632408-treated diabetic mice, 36% (5 of 14) sitagliptin-treated diabetic mice, and 59% (13 of 22) diabetic mice treated with PSN632408 and sitagliptin combination achieved normoglycemia after 7 weeks treatment. Combination therapy significantly increased plasma active GLP-1 levels, improved glucose clearance, stimulated both α- and β-cell replication, and augmented β-cell mass. Furthermore, treatment with combination therapy induced β-cell neogenesis from pancreatic duct-derived cells.ConclusionOur results demonstrate that combining a GPR119 agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating β-cell regeneration and reversing diabetes.
Highlights
Progressive impairment of pancreatic b-cell function and decline in b-cell mass result in relative or absolute insulin deficiency and hyperglycemia, the primary basis of all diabetic manifestations [1,2,3]
Our results demonstrate that combining a G-protein coupled receptor 119 (GPR119) agonist with a DPP-IV inhibitor may offer a novel therapeutic strategy for stimulating b-cell regeneration and reversing diabetes
We examined the efficacy of combining a GPR119 agonist (PSN632408) with a DPP-IV inhibitor in C57BL/6 mice with STZ-induced diabetes
Summary
Progressive impairment of pancreatic b-cell function and decline in b-cell mass result in relative or absolute insulin deficiency and hyperglycemia, the primary basis of all diabetic manifestations [1,2,3]. GLP-1 is rapidly degraded and inactivated by dipeptidylpeptidaseIV (DPP-IV), a serine protease present in soluble form in circulation. DPP-IV inhibitors, such as sitagliptin, play a major role in preventing degradation of endogenous active GLP-1 and are being assessed extensively in clinical settings for their long-term efficacy in improving b-cell function in humans with type-2 diabetes mellitus [8,9]. DPP-IV inhibitors are the only agents in clinical use that increase endogenous GLP-1 levels [10,11]. Activating G-protein coupled receptor 119 (GPR119) by its agonists can stimulate glucagon like peptide-1 (GLP-1) release. We studied the efficiency of combining PSN632408, a GPR119 agonist, with sitagliptin, a DPP-IV inhibitor, on b-cell regeneration in diabetic mice
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