Diabetic Complications in Germ-Free BTBR and BTBRob/ob mice
Obesity and metabolic syndrome are leading causes of type II diabetes, which is a growing epidemic and one of the major global health problems that we face in the 21st century. Obesity and diabetes are associated with an altered gut microbiota that further aggravates metabolic syndrome, and may promote inflammation and contribute to diabetic complications. The focus of this grant application is the role of the microbiome in modulating complications of diabetes. My collaborator, Charles Alpers (University of Washington), has recently characterized a new mouse model of type II diabetes, which develops several diabetic complications, notably diabetic nephropathy, as well as cardiomyopathy and retinopathy. BTBR WT mice develop pre-diabetes. When made leptin deficient, The BTBRob/ob mouse develops progressive obesity and type II diabetes. The novel aspect of this mouse model of type II diabetes is that these mice also develop clinical and morphologic features that closely mimic diabetic nephropathy in humans. Thus this model provides a tool to dissect factors that contribute not only to the development of insulin resistance and diabetes, but also end organ damage and specifically, diabetic nephropathy. To test whether the gut microbiome contributes to disease progression in these mice, we treated BTBR WT and ob/ob mice with broad spectrum antibiotics between 4-16 weeks of life. Antiobiotic treatment resulted in a significant improvement in pre-diabetes in WT mice, but paradoxical increased mortality and no improvement in severe diabetes in the ob/ob mice. Fialure to completely suppress gut microbes in the ob/ob mice was a complicating factor. We hypothesize that end organ complications from genetic obesity and diabetes will be improved by definitively eliminating the microbiome through the generation of germ-free mice. We will test our hypothesis with the following specific Aims: 1) To develop a GF model of pre-diabetes and diabetes in the BTBR and BTBRob/ob mice, and 2) To compare the development of pre-diabetes and diabetes in GF and conventional BTBR and BTBRob/ob mice.

The role of intestinal dysbiosis in diabetic nephropathy
Obesity and metabolic syndrome are leading causes of type II diabetes, which is a growing epidemic and one of the major global health problems that we face in the 21st century. Obesity and diabetes are associated with an altered gut microbiota that further aggravates metabolic syndrome, and may promote inflammation and contribute to diabetic complications. The focus of this grant application is the role of the microbiome in modulating complications of diabetes. My collaborator, Charles Alpers (University of Washington), has recently characterized a new mouse model of type II diabetes, which develops several diabetic complications, notably diabetic nephropathy, as well as cardiomyopathy and potential retinopathy. The BTBRob/ob mouse is leptin deficient, resulting in progressive obesity and type II diabetes. The novel aspect of this mouse model of type II diabetes is that these mice also develop clinical and morphologic features that closely mimic diabetic nephropathy in humans. Thus this model provides a tool to dissect factors that contribute not only to the development of insulin resistance and diabetes, but also end organ damage and specifically, diabetic nephropathy. Hypothesis: Studies with obese mice and humans indicate that these individuals have an altered microbiome, and that this altered microbiome can promote obesity, fatty liver disease, and diabetes. Similarly, diabetes is associated with changes in the microbiome in rodent models. We hypothesize that genetic obesity and diabetes cause changes in the gut microbiota (intestinal dysbiosis) that contribute to complications of diabetes. We will test our hypothesis with the following specific Aims. Specific Aim 1: To characterize the microbiome, and whether there is evidence of increased translocation and exposure to gut microbes in diabetic mice. Specific Aim 2: To determine whether BTBRob/ob mice have a diabetogenic microbiome that contributes to the development of diabetic nephropathy.

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