Fig 1: Schematic hypothesis for growth-induced progression derived from the fa/fa model. Nutrition-induced insulin and insulin-like growth factors (IGF-1/2) activate their individual receptors (insulin receptors [IRA and IRB], IGF-1R and IGF-2R, and their hybrid receptors comprising combinations of IR and IGF-1R proteins53. IGF-1 availability and local function is regulated through 6 different IGF1 binding proteins (IGFBPs1–6). Cell growth occurs through GF-induced activation of the mTORC1 complex which simultaneously senses nutrient availability including amino acids (leucine, arginine) and glucose30,31,54. In fa/fa rats high level nutrient intake drives high growth factor expression from birth resulting accelerated body and organ growth. IGF-1 promotes both glomerular volume enlargement and hyperfiltration29,55–57. Glomerular enlargement requires podocytes to hypertrophy to cover the expanding filtration surface with foot processes through increased protein synthesis via mTORC1 kinase-induced phosphorylation/activation of S6 kinase which in turn phosphorylates ribosomal S6. Thus, the collaboration between growth factors, nutrients, glomerular volume and podocytes represents the core components of a “progression initiation mechanism” (see the shaded box). Podocyte hypertrophic stress is represented in this report by the triad of high level podocyte ribosomal S6 phosphorylation, relative down-regulation of the podocyte-specific transcript nephrin versus podocin, and accelerated podocyte detachment into the filtrate. Glomerular volume increase and accelerated podocyte detachment both drive reduced podocyte density. The level of reduced podocyte density in concert with podocyte stress determines amount of albumin leak through the filter, and thereby degree of albuminuria. Mesangial expansion reduces the filtration area required for foot process coverage to preserve filter integrity, but when podocyte density reduction reaches critically low values fibrosis supervenes at sites of podocyte depletion. In parallel, pancreatic islet beta cells hypertrophy to increase insulin release to adapt to increasing insulin resistance, but eventually fail and become depleted in association with loss of blood glucose control. This in turn leads to the cardinal features of diabetes mellitus (polyuria, polydipsia and weight loss). Thus, parallel failure of two structurally and functionally complex long-lived cell types with limited capacity for replacement (pancreatic beta cells and podocytes) represent the diabetes-associated nephropathy phenotype. Hyperglycemia itself through oxidant injury or other mechanisms could also potentially contribute to podocyte detachment through various signaling pathways, mTORC1 complex activation via glucose sensors, or direct glucose toxicity effects7. However, in the fa/fa rat hyperglycemia itself did not appear to be required either to initiate podocyte injury or to sustain the progression mechanism once it was established. Hence the interaction between hyperglycemia and podocyte loss is represented by dashed lines in the schematic.