Youth versus adult-onset type 2 diabetic kidney disease: Insights into currently known structural differences and the potential underlying mechanisms

Type 2 diabetes (T2D) is a global health pandemic with significant humanitarian, economic, and societal implications, particularly for youth and young adults who are experiencing an exponential rise in incident disease. Youth-onset T2D has a more aggressive phenotype than adult-onset T2D, and this translates to important differences in rates of progression of diabetic kidney disease (DKD). We hypothesize that youth-onset DKD due to T2D may exhibit morphometric, metabolic, and molecular characteristics that are distinct from adult-onset T2D and develop secondary to inherent differences in renal energy expenditure and substrate metabolism, resulting in a central metabolic imbalance. Kidney structural changes that are evident at the onset of puberty also serve to exacerbate the organ's baseline high rates of energy expenditure. Additionally, the physiologic state of insulin resistance seen during puberty increases the risk for kidney disease and is exacerbated by both concurrent diabetes and obesity. A metabolic mismatch in renal energetics may represent a novel target for pharmacologic intervention, both for prevention and treatment of DKD. Further investigation into the underlying molecular mechanisms resulting in DKD in youth-onset T2D using metabolomics and RNA sequencing of kidney tissue obtained at biopsy is necessary to expand our understanding of early DKD and potential targets for therapeutic intervention. Furthermore, large-scale clinical trials evaluating the duration of kidney protective effects of pharmacologic interventions that target a metabolic mismatch in kidney energy expenditure are needed to help mitigate the risk of DKD in youth-onset T2D.