Puberty, diabetes, and the kidneys, when eustress becomes distress

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PROJECT SUMMARY / ABSTRACT: Diabetic kidney disease (DKD) is a common and serious complication in youth with 2 diabetes (T2D). Epidemiological data implicate puberty as a major accelerator of kidney injury in youth with obesity and diabetes, yet the mechanisms by which reproductive maturation results in kidney disease remain unknown. A better understanding of the pubertal mechanisms contributing to kidney disease is needed to promote preservation of native kidney function, especially in high-risk youth with obesity and/or T2D. We hypothesize that youth with obesity and/or T2D experience relative kidney hypoxia during puberty due to a metabolic mismatch between increased renal energy expenditure and impaired substrate metabolism. In turn, the kidney hypoxia results in loss of glomerular charge and size selectivity with increased transglomerular transport of protein, and kidney dysfunction. To address these hypotheses, we propose to design an accelerated longitudinal study in which we will enroll adolescents (8-14 years, 50% girls) with obesity and elevated hemoglobin A1c (HbA1c ≥6%) [n=60], and healthy normal weight controls [n=40] at Tanner (pubertal) stages 1-4 and examine them at baseline, 1 and 2-year follow-up. We will combine state-of- the-art magnetic resonance imaging (MRI) methods for quantifying kidney growth, oxygen availability and hemodynamic function with gold-standard measurements of glomerular filtration rate (iohexol clearance), renal plasma flow (p-aminohippurate clearance), glomerular size and charge selectivity (dextran and IgG/IgG4 clearance) and assessments of insulin sensitivity and mitochondrial function (intravenous glucose tolerance test and metabolomics). These experiments are designed to define the mechanisms contributing to kidney injury during puberty and identify novel risk factors and therapeutic targets to mitigate the development of obesity and diabetes-related nephropathy.