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.

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We investigated the role of CD4+CD25+FoxP3+ regulatory T cells on diabetes resistance in aged NOD mice that do not develop diabetes in pathogen-free housing. At 60 weeks age, <80% NOD mice developed diabetes. Adoptive transfer of lymphocytes from diabetic mice to aged nodiabetic NOD mice did not significantly increase the onset of diabetes. When 1x107 lymphocytes from age NOD mice were co-transferred with 5x106 lymphocytes from diabetes NOD mice into NOD.scid mice, all mice developed diabetes at 6 weeks. When 2x107 lymphocytes from aged NOD mice were co-transferred, none developed diabetes at 6 weeks and only 50% NOD.scid mice developed diabetes at 12 weeks. When 1x106 CD4+CD25- T cells was cotransferred with 5x106 lymphocytes from diabetic NOD mice, diabetes was developed in all NOD.scid mice. When 1x106 CD4+CD25+ T cells were used, only 17% mice developed diabetes at 12 weeks. The percentages of CD4+CD25+Foxp3+ T cells in the pancreatic lymph nodes, spleen and peripheral blood were 20.1±5.3%, 14.6±4.1% and 9.8±3.5% in aged NOD mice; 5.8±1.5%, 8.6±0.7% and 6.4±1.7% in control diabetic NOD mice. When a low dose of cyclosphamiade was given, diabetes was developed in 75% young NOD mice and in 18% aged NOD mice. However, when the high dose was given, 58% aged NOD mice had diabetes and CD4+CD25+Foxp3+ T cells in pancreatic lymph nodes were 7.0±1.7%. Our data demonstrated that immunoregulation through CD4+CD25+Foxp3+ T cells mediated the resistance of diabetes in aged NOD mice.

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