Abstract

Objective. Glucagon-like peptide-1 (GLP-1) and gastrin promote pancreatic β-cell function, survival and growth. Here we investigated whether GLP-1 and gastrin can restore the β-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 following treatments, after which pancreatic insulin content and β-cell mass, proliferation, neogenesis, and apoptosis were measured. Insulin auto-antibodies were measured and adoptive transfer of diabetes as well as 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, β-cell mass, and insulin-positive cells in pancreatic ducts, and β-cell apoptosis was decreased. Insulin auto-antibodies 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-γ (IFN-γ) to transforming growth factor-β1 (TGF-β1), and β-cells were protected from apoptosis.

Conclusions. Combination therapy with GLP-1 and gastrin restores normoglycemia in diabetic NOD mice by increasing the pancreatic β-cell mass and downregulating the autoimmune response.