2036-P: Gut Microbes Regulate Insulin Clearance in Mice

Obesity and insulin resistance are associated with hyperinsulinemia, which is caused by increased insulin secretion and/or reduced insulin clearance. Impaired insulin clearance may be caused by ectopic lipid deposition in liver and skeletal muscle, the key sites of insulin clearance and degradation. Insulin is the key hormone regulating blood glucose. The composition of the intestinal microbiota can regulate aspects of diet-induced obesity and glucose metabolism. Here we found that the microbiota also regulates insulin clearance during prolonged diet-induced obesity. Male C57Bl/6J mice fed 45% high fat diet (HFD) for a prolonged period had impaired insulin clearance relative to chow fed mice as measured by insulin/C-peptide ratio during an oral glucose tolerance test. High fat fed mice also showed impaired insulin clearance measured after injection of insulin - mice fed chow or 45% HFD had plasma insulin concentration measured at 0, 5, 30, and 60 minutes following injection of human insulin and area under the curve calculated. Treatment of 45% HFD-fed mice with an antibiotic cocktail of Neomycin/Ampicillin for 2 weeks improved insulin clearance after insulin injection. Next, we colonized previously germ-free mice with the microbiota from chow or 45% HFD-fed “donor” mice for 6 weeks. The previously germ-free “recipient” mice colonized with feces-resident microbes from chow or HFD fed donors did not differ in insulin clearance when recipient mice were fed a chow diet. However, when colonized recipient mice were switched from chow to 45% HFD for 2 weeks the recipient mice colonized with microbes from 45% HFD fed donors showed impaired insulin clearance relative to recipient mice colonized with microbes from chow fed donors. Our results demonstrate that diet-induced changes in fecal microbes are an independent factor regulating insulin clearance. Diet-induced changes in the gut microbiota and consequent impaired insulin clearance may participate in hyperinsulinemia leading to exacerbated insulin resistance and obesity. Disclosure K.P. Foley: None. S. Zlitni: None. B.M. Duggan: None. B.D. Henriksbo: None. N.G. Barra: None. J.F. Cavallari: None. F. Forato Anhê: None. T. Lau: None. Y. Chen: None. J.D. Schertzer: None. Funding Canadian Institutes of Health Research