Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Reversing New-Onset Diabetes in NOD mice by Combining Sitagliptin with GW9508, a GPR40 and GPR120 Dual Agonist (#154)

A Ansarullah 1 , Yan Lu 1 , Martha Holstein 1 , Brittany DeRuyter 1 , Alex Rabinovitch 1 , Zhiguang Guo 1
  1. Sanford Research/USD, Sioux Falls, SD, United States

GPR120 is expressed on the intestinal L cells and some immune cells (macrophages). Activating GPR120 has an anti-inflammatory effect and stimulates GLP-1 release. GPR40 is abundantly expressed in β cells and intestinal L cells. DPP-IV inhibitor also has an anti-inflammatory effect and inhibits GLP-1 degradation. In this study, we investigated the effect of combining sitagliptin with GW9508, a GPR40 and GPR120 dual agonist, on reversing new-onset diabetes in NOD mice. New-onset diabetic NOD mice were orally treated either with sitagliptin at 30 mg/kg, or GW9508 at 5 mg/kg, or in combination twice a day, for up to 6 weeks. Nonfasting blood glucose level was determined. CD4+CD25+FoxP3+ T cells, Th17 T cells, and plasma GLP-1 were measured. Diabetes was reversed in 12.5% of mice treated with vehicle for GW9508 (DMSO), in 53.3% of mice treated with GW9508, in 45.4% of mice treated with sitagliptin, and in 75.0% of mice treated with GW9508 and sitagliptin. The insulitis score was significantly lower in GW9508 and sitagliptin treated mice. The percentage of CD4+CD25+FoxP3+ T cells in pancreatic lymph nodes was significantly increased in sitagliptin alone treated mice and in GW9508 and sitagliptin combination treated mice (P<0.05) but not in GW9508 alone treated mice compared to control mice. The percentage of IL-17+ cells and IL-17+CD4+ T cells in pancreatic lymph nodes and the ratio of IL-17+CD4+ cells/ CD4+CD25+Foxp3+ T cells were significantly decreased in GW9508 and sitagliptin treated mice (P<0.01). The percentage of insulin+/BrdU+ β cells and insulin+/Ki67+ β cells in islets were significantly increased compared to prediabetic NOD mice (P<0.01). Our studies demonstrated that GW9508 and sitagliptin improve the reversal of diabetes in new-onset diabetic NOD mice through modulating inflammation and stimulating β cell regeneration. Combining a DPP-IV inhibitor with a GPR40/GPR120 agonist is a new therapeutic approach for treating type 1 diabetes.