Introduction and Aims: The aims of these studies were to explore the scope of activity of oral DBI-500, an atypical glycolipid, in a murine model of prediabetic type 2 diabetes and obesity, and in two models of NASH.
Methods: Part 1. Male C57BL/6 mice (14 weeks old) that received a high fat diet were divided into 3 groups (8 - 9 per group) and were either dosed with up to 144 mg/kg, 72 mg/kg or matching placebo via once daily oral gavage for 7 days. Fasting glucose, body weight and gene expression analyses were performed. Part 2. NASH was induced in male C57BL/6 mice using a standard methionine/choline deficient diet. Concomitant with initiation of diet, 4 groups of 8 mice received either placebo, 80 or 40 mg/kg DBI-500 or 40 mg/kg + metformin every other day for 4 weeks per gavage. Part 3. NASH was induced by diet in apolipoprotein-E-deficient mice using western diet (WD). Dose groups of 5 dose groups of 8 mice were dose with DBI-500 (100, 50 or 25mg/kg, or 25mg+metformin).
Results: Part 1. Gene expression analysis of epidymal fat samples showed significant increases in PPAR-gamma and adiponectin expression with concomitant significant reduction in CD8+ expression. Blood glucose and body weight were reduced. Plasma levels of PAI-1 and CD40L were also significantly reduced. Part 2. MCD mice showed significant and dose dependent reduction in hepatic collagen. Part 3. In ApoE deficient mice, DBI-500 significantly reduced expression of hepatic alpha-SMA and TGF-beta1, and significantly increased PPAR-delta. BDI-500 also significantly increased HNF4-alpha.
Conclusions: DBI-500 is a potential once daily novel therapy for type two diabetes and NASH that also significantly reduces markers of cardiovascular risk. DBI-500’s capacity to increase expression of HNF4-alpha strongly indicates potential as combination treatment with FXR agonists.
A. Leighton: Stock/Shareholder; Self; Dale Biotech, Inc.