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Exendin-4 Modulates Diabetes Onset in Nonobese Diabetic Mice

Department of Medicine (I.H., L.L.B., D.J.D.), Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Medicine (P.P.), Sunnybrook Health Sciences Centre, and Department of Medicine (I.H., L.L.B., P.P., D.J.D.), the Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada M5G 1X5

Address all correspondence and requests for reprints to: Dr. D. J. Drucker, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.

Activation of the glucagon-like peptide-1 receptor (GLP-1R) is associated with expansion of β-cell mass due to stimulation of cell proliferation and induction of antiapoptotic pathways coupled to β-cell survival. Although the GLP-1R agonist Exenatide (exendin-4) is currently being evaluated in subjects with type 1 diabetes, there is little information available about the efficacy of GLP-1R activation for prevention of experimental type 1 diabetes. We examined the consequences of exendin-4 (Ex-4) administration (100 ng once daily and 2 µg twice daily) on diabetes onset in nonobese diabetic mice beginning at either 4 or 9 wk of age prior to the onset of diabetes. Ex-4 treatment for 26 wk (2 µg twice daily) initiated at 4 wk of age delayed the onset of diabetes (P = 0.007). Ex-4-treated mice also exhibited a significant reduction in insulitis scores, enhanced β-cell mass, and improved glucose tolerance. Although GLP-1R mRNA transcripts were detected in spleen, thymus, and lymph nodes from nonobese diabetic mice, Ex-4 treatment was not associated with significant changes in the numbers of CD4+ or CD8+ T cells or B cells in the spleen. However, Ex-4 treatment resulted in an increase in the number of CD4+ and CD8+ T cells in the lymph nodes and a reduction in the numbers of CD4+CD25+Foxp3+ regulatory T cells in the thymus but not in lymph nodes. These findings demonstrate that sustained GLP-1R activation in the absence of concomitant immune intervention may be associated with modest but significant delay in diabetes onset in a murine model of type 1 diabetes.