Combination Therapy with Glucagon-Like Peptide-1 and Gastrin Restores Normoglycemia

Combination therapy with GLP-1 and gastrin restores normoglycemia. 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.

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.

The results showed that 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- (IFN-) to transforming growth factor-β1 (TGF-β1), and β-cells were protected from apoptosis.

From the results it was concluded that 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.

Published online ahead of print October 3, 2008, Diabetes.  DOI: 10.2337/db08-0688

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DID YOU KNOW: 
Diabetes affects 246 million people worldwide and is expected to affect some 380 million by 2025. – Each year another 7 million people develop diabetes.  – Diabetes is expected to cause 3.8 million deaths worldwide in 2007, roughly 6% of total world mortality, about the same as HIV/AIDS and malaria combined.

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