Exendin-4 treatment of nonobese diabetic mice increases beta-cell proliferation and fractional insulin reactive area.

OBJECTIVE: The notion of combining immunomodulatory agents with the incretin exendin-4 (Ex-4) has seen considerable favor as a potential therapy for the reversal of type 1 diabetes in man. While the addition of Ex-4 provides modest improvement to the effectiveness of immunological-based monotherapies in reversing hyperglycemia in the nonobese diabetic (NOD) mouse, the mechanism of action underlying this effect remains controversial and formed the basis for this investigation. RESEARCH DESIGN AND METHODS: Female NOD mice with new onset diabetes received either Ex-4 (0.2 microg) or saline via daily intraperitoneal injection for 30 days. To maintain viability after diagnosis of diabetes, animals also received subcutaneous insulin pellets. When persistent hyperglycemia returned, animals were sacrificed and histological studies performed to assess beta-cell proliferation (BrdU+/insulin+; Ki67+/insulin+) and fractional insulin reactive area. RESULTS: Ex-4-treated animals experienced diabetes reversal rates no better than controls. Despite this, Ex-4-treated mice demonstrated increased fractional insulin area (P=.035) and beta-cell proliferation as evidenced by elevated BrdU (P=.0001) and Ki67 staining (P=.04) with insulin co-localization. Also noteworthy, Ex-4-treated mice had poor weight gain following diagnosis in comparison to saline-treated animals (P=.003). CONCLUSIONS: Ex-4 monotherapy (0.2 microg daily-10 microg/kg per day) in NOD mice with new onset diabetes increases beta-cell proliferation and fractional insulin area. Ex-4 remains a promising component of combination therapies for type 1 diabetes. Additional studies are needed to identify a dose that maximizes beta-cell proliferation and minimizes potential side effects.