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Prevention and rescue of diabetes by all-trans retinoid acid and exendin-4 in NOD mice with and without islet transplantation

Jyuhn-Huarng Juang¹, Yang-Hau Van²

¹Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital; ²Division of Endocrinology, Chang Gung Children’s Hospital, Taoyuan, Taiwan

Type 1 diabetic patients have progressive decrease in pancreatic beta-cell mass. Eventually, they are insulin deficient and depend on exogenous insulin for life. Recent studies showed new beta-cell formation occurred even after long-standing type 1 diabetes. Therefore, type 1 diabetes may be treated by targeting inhibition of beta-cell destruction and promotion of beta-cell regeneration. It has been shown that all-trans retinoid acid (ATRA) 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 beta cells and exerts antiapoptotic effect on beta cells. Thus we hypothesized that the ATRA and exendin-4 therapy may prevent and rescue diabetes in NOD mice with and without islet transplantation. In the first experiment, NOD/scid mice were intravenously transferred with splenocytes isolated from 12 week-old female NOD mice. After adopted transfer, mice were treated with ATRA (0.5 mg/mouse intraperitoneally qd), exendin-4 (3 mg/kg subcutaneously bid) or ATRA+exendin-4 for 6 weeks. In either ATRA or exendin-4 treated groups, all of recipient mice developed diabetes before 8 weeks. Only the combination of ATRA and exendin-4 delayed the onset of diabetes till 10-12 weeks (p<0.05). In the second experiment, NOD mice were treated with ATRA or exendin-4 after the onset of diabetes. All but one treated with ATRA remained diabetic and the survival time was not different among control (52±31 days), ATRA (45±19 days) and exendin-4 (62±34 days) groups. One mouse achieved normoglycemia after ATRA treatment and is alive for 366 days with periodic hyperglycemia. In the third experiment, diabetic NOD mice were transplanted with 300-600 islets from NOD/scid mice and then treated with ATRA or exendin-4. All mice remained diabetic and the survival time was not different among control (52±51 days), ATRA (101±101 days) and exendin-4 (48±19 days) groups. In conclusion, the combination of ATRA and exendin-4 is an effective intervention to prevent autoimmune diabetes. However, ATRA and exendin-4 alone did not prevent or rescue diabetes in NOD mice with and without islet transplantation.