Novel Paradigms in Diabetic Complications

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DESCRIPTION (provided by applicant): Diabetic kidney disease is recognized as the leading cause of excess mortality in the population with type 1 diabetes. The prevailing theory is that excess calories are processed via the mitochondria resulting in accumulation of superoxide radicals via the electron transfer chain. However, our exciting data generated from live animal imaging demonstrates a completely opposite set of conclusions. There is actually a dramatic reduction of superoxide radicals in response to a high caloric state in tissues prone to diabetic complications. To determine if reduced mitochondrial function also occurs in humans, we evaluated the urine metabolome and found that patients with diabetes and kidney disease had reduced metabolites related to mitochondrial function. In the present proposal we will use two large well characterized cohorts of patients from the FinnDiane Study and the CRIC study to demonstrate the role of these urine metabolites in determining future renal disease. We will also identify if epigenetic modification of the PGC1a promoter may underlie the reduction in mitochondrial function in patients and in animal models. Using a systems biology and imaging approach we will link the reduction in mitochondrial function with alterations in the metabolome and epigenome in the kidney and the urine. This application will be a paradigm shifting approach to the medical challenge of hyperglycemia induced kidney disease. PUBLIC HEALTH RELEVANCE: The renal complications of diabetes are perhaps the number one public health problem facing industrialized nations. By identifying the urine metabolome and epigenome in patients with type 1 diabetes and kidney disease we hope to gain a better understanding of the basis of kidney complications of type 1 diabetes.