Abstract 398: Mice Containing the Human Gilbert’S Syndrome Mutation (UGT1A1*28) Are Resistant to the Development of Type II Diabetes and Deposition of Body Fat on a High Fat Diet

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Heme oxygenase-1 (HO-1) induction has been previously demonstrated to reduce body weight and prevent type II diabetes in obese mice. However, the role of increased bilirubin production in this response is unknown. Gilbert’s syndrome is derived from a mutation in the hepatic UGT1A1 gene which results in decreased conjugation and increased levels of plasma biliribin independent of changes in HO-1. In order to determine the role of increased plasma bilirubin on the development of type II diabetes and obesity, we placed mice whose only functioning UGT1A1 gene contained the human Gilbert’s syndrome mutation (UGT1A1*28, n=4) as well as C57BL/6J control mice (n=5) on a high fat (60%) diet for 35 weeks. Plasma bilirubin levels were significantly increased in the UGT*28 mice as compared to controls and averaged 1.65 ± 0.2 vs. 1.18 ± 0.1 mg/dL (P<0.05). UGT*28 mice exhibited significantly decreased body weights (14-17%, P<0.05) early (4-8 weeks) and late (29-32) after high fat feeding as compared to control mice. Fat mass as measured by Echo-MRI was significantly decreased by 15-20% on weeks 18,24,30,35 as compared to control mice (P<0.05). Lean mass was significantly increased by 7-10% in UGT*28 mice as compared to control mice at 18, 24, and 35 weeks (P<0.05). Fasting blood glucose levels in UGT*28 mice over the entire study were significantly lower as compared to control and averaged 94 ± 3 vs. 138 ± 9 mg/dL (P<0.05). Plasma insulin levels were also significantly decreased in UGT*28 mice over the study averaging 1.8 ± 0.1 vs. 2.9 ± 0.2 ng/mL (P<0.05). No differences in food intake or oxygen consumption were observed in UGT*28 mice as compared to control mice. These results suggest that moderate increases in plasma bilirubin can attenuate the increase in fat mass accumulation and normalize insulin sensitivity in response to a high fat diet.

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