Effects of All-Trans Retinoid Acid and Exendin-4 on Islet Transplantation in NOD Mice

Abstract Type 1 diabetes usually develops due to autoimmune destruction of β-cells in the pancreas. It has been shown that all-trans retinoid acid (ATRA), a potent derivative of vitamin A, hinders the development of autoimmune diabetes by inducing immune tolerance status. In addition, exendin-4, a glucagon-like peptide-1 receptor agonist, stimulates growth and differentiation of β-cells and exerts anti-apoptotic effect on β-cells. Thus, we hypothesized that the ATRA and exendin-4 therapy may improve the outcome of islet transplantation in non-obese diabetic (NOD) mice. After the onset of diabetes, each NOD mouse was transplanted with 300 or 600 islets isolated from NOD/severe combined immunodeficient (SCID) mice with or without treatment of ATRA (0.5 mg intraperitoneally every other day) and/or exendin-4 (3 μg/kg subcutaneously twice daily) for 6 weeks. After 300 or 600 NOD/SCID islet transplantation without any other treatment, all NOD recipients remained diabetic. However, the lowest blood glucose level in mice transplanted with 600 but not 300 islets was significantly lower than those without islet transplantation ( P < .05), although their survival time was comparable. Among recipients treated with ATRA, exendin-4, ATRA and exendin-4, and without treatment, their lowest blood glucose levels and survival time were not different. However, one recipient treated with ATRA survived for 223 days with intermittent hyperglycemia and the other who was treated with ATRA and exendin-4 achieved normoglycemia. In conclusion, islet transplantation lowered blood glucose levels in diabetic NOD mice. With a few exceptions, treatment with ATRA and exendin-4 alone or in combination in islet recipients could not reverse diabetes or prolong survival.