Combination Therapy With Glucagon-Like Peptide-1 and Gastrin Restores Normoglycemia in Diabetic NOD Mice

Abstract

OBJECTIVE-Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic ␤-cell function, survival, and growth. Here, we investigated whether GLP-1 and gastrin can restore the ␤-cell mass and reverse hyperglycemia in NOD mice with autoimmune diabetes.RESEARCH DESIGN AND METHODS-Acutely diabetic NOD mice were treated with GLP-1 and gastrin, separately or together, twice daily for 3 weeks. Blood glucose was measured weekly and for a further 5 weeks after treatments, after which pancreatic insulin content and ␤-cell mass, proliferation, neogenesis, and apoptosis were measured. Insulin autoantibodies were measured, and adoptive transfer of diabetes and syngeneic islet transplant studies were done to evaluate the effects of GLP-1 and gastrin treatment on autoimmunity.RESULTS-Combination therapy with GLP-1 and gastrin, but not with GLP-1 or gastrin alone, restored normoglycemia in diabetic NOD mice. The GLP-1 and gastrin combination increased pancreatic insulin content, ␤-cell mass, and insulinpositive cells in pancreatic ducts, and ␤-cell apoptosis was decreased. Insulin autoantibodies were reduced in GLP-1-and gastrin-treated NOD mice, and splenocytes from these mice delayed adoptive transfer of diabetes in NOD-scid mice. Syngeneic islet grafts in GLP-1-and gastrin-treated NOD mice were infiltrated by leukocytes with a shift in cytokine expression from interferon-␥ to transforming growth factor-␤1, and ␤-cells were protected from apoptosis. CONCLUSIONS-Combination

DsAAV8-mediated expression of glucagon-like peptide-1 in pancreatic beta-cells ameliorates streptozotocin-induced diabetes

“…Zhang et al 5 have demonstrated that continuous infusion of GLP-1 in pre-diabetic NOD mice results in significant delay in the onset of diabetes as a result of increased beta-cell proliferation coupled with decrease in beta-cell apoptosis. Furthermore, combination therapies using GLP-1 or exendin-4 with gastrin, 48 anti-lymphocyte serum 49 or anti-CD3 immunotherapy 50 have been shown to restore normoglycemia in acutely diabetic NOD mice by increasing insulin stores and reducing beta-cell apoptosis. Thus, GLP-1-receptor agonists may be useful in therapeutic management of individuals with either type-1 or type-2 diabetes.…”

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