Kidney energetics in the development of nephropathy in type 1 diabetes
**Rationale: Sites affected by the vascular complications of diabetes, share a high requirement for fuel production (ATP) by mitochondria and consume vast amounts of oxygen for their normal function. However, in individuals with type 1 diabetes, there is emerging evidence that organs prone to complications are not able to sufficiently compensate for the effects of diabetes on fuel generation. **We aim to: 1) Obtain kidney images of fuel (lactate/fatty acids; 1H-MR) and energy storage content (ATP; 31P-MR) from young T1D individuals (15-18 yrs) with and without evidence of early kidney dysfunction and match these to urinary metabolites and urinary cell energetics. 2) Use human kidney cells (proximal tubular cells and podocytes) derived from nephrectomy to better understand mitochondrial energy generation in type 1 diabetes. **Expected outcomes: These studies will provide in situ evidence of kidney fuel usage and storage early in the course of clinical nephropathy in T1D. These images will be matched with urinary profiles of energetic substrates and urinary cell function to evaluate less invasive markers of fuel usage by the kidney. In addition, data on renal mitochondrial dysfunction in human nephrectomy samples will be obtained from patients with and without type 1 diabetes and in various age groups to increase our understanding of the association between renal disease and mitochondrial dysfunction in type 1 diabetes.

Genetic susceptibility to mitochondrial function as a risk factor for diabetic nephropathy
**Rationale: A significant proportion of individuals with type 1 diabetes (T1D) will develop kidney disease, a major risk factor for myocardial infarction and stroke. Since this is not seen in all individuals with T1D, it is postulated that risk for kidney disease could be inherited. However it is difficult to obtain sufficient numbers of subjects to complete large scale screening to enable analysis of traits/genes which increase risk for kidney disease. These studies are also often limited by the parameters used to stratify groups such as albuminuria which can spontaneously regress and/or significantly change over time in individuals with T1D. The kidneys have a high requirement for fuel production (ATP) by mitochondria and consume vast amounts of oxygen for their normal function. However, in individuals with type 1 diabetes, there is emerging evidence that the kidney may not be able to sufficiently compensate for the effects of diabetes on fuel generation and that this may contribute to kidney disease. **In this pilot and feasibility study, we aim to: 1) Use a unique genetic reference platform, the Collaborative Cross Gene Mine to study two traits which associate with kidney disease in T1D, glomerular filtration rate and mitochondrial energy generation by the kidneys. **Expected outcomes: At the completion of this proposal, we will have addressed the novel hypothesis that genetic susceptibility to mitochondrial dysfunction is an important determinant of kidney function in T1D. We suggest that by understanding the association between genes which determine glomerular filtration rate as well as ATP generation by mitochondria, we may discover novel genes and pathways associated with the development of diabetic nephropathy. These could then be investigated in other models and in individuals with T1D, leading to a greater understanding of the pathogenesis of nephropathy in these individuals.

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