Transgenic UDP‐glucuronosyltransferase 1 mice are protected from obesity‐induced type 2 diabetes

Abstract

Obesity-induced type 2 diabetes is a growing human health issue in Western societies. Fibrates are PPARα agonists used to treat dyslipidemia and diabetes and are targeted by glucuronidation for elimination. Initially, to examine the effects of PPARα agonists on human UDP-glucuronosyltransferase 1 (UGT1) regulation, transgenic human UGT1 mice (Tg-UGT1) were treated with the fibrate WY-14643. Oral administration of WY-14643 to Tg-UGT1 mice induced UGT1A1 and 1A4 in the liver. To examine the contribution of human glucuronidation towards obesity-induced type 2 diabetes, wild type (WT) and Tg-UGT1 male mice were fed a normal diet or a 35% fat diet (HFD) for 16 weeks. Mass gain was monitored and diabetic status established by insulin and glucose tolerance tests and serum insulin levels. There was no difference in mass gain between male WT or Tg-UGT1 mice on HFD. Obese WT mice were insensitive to insulin, retained elevated blood glucose levels, and displayed hyperinsulinemia, indicating the onset of type 2 diabetes. Interestingly, obese Tg-UGT1 mice were insulin sensitive and displayed normal blood glucose clearance. Blood insulin levels for obese Tg-UGT1 mice were similar to WT and Tg-UGT1 males on normal diets. To determine if human UGT1A expression correlated with protection from type 2 diabetes, human UGT1A protein levels were measured by Western blot analysis. UGT1A1 and UGT1A4 in the small intestine were down-regulated in obese Tg-UGT1 mice. While it is not clear why down-regulation of the human UGT1A proteins might protect against obesity-induced type 2 diabetes, the reduction may lead to reduced clearance and increase the potential for toxicity of drugs in diabetic patients. (Supported by USPHS grants GM49135 and ES10337)