The hyperglycemic and hyperinsulinemic combo gives you diabetic kidney disease immediately. Focus on “Combined acute hyperglycemic and hyperinsulinemic clamp induced profibrotic and proinflammatory responses in the kidney”

Abstract

diabetic kidney disease (DKD) is the leading cause of end-stage kidney failure in the United States (11). Clinically, nephropathy induced by diabetes is characterized by albumin in the urine and declining glomerular filtration rate. On histological examination, diabetic kidney disease is a glomerular disease defined by mesangial expansion, nodular sclerosis, arterial hyalinosis (arteriolar thickening by deposition of pink hyaline material) leading to glomerulosclerosis and tubulointerstitial fibrosis. DKD is caused by hyperglycemia (HG) as reducing the glycohemoglobin levels from 9 to 7% in patients with type 1 diabetes resulted in a greater than 50% decrease in nephropathy development (3). However, recent studies of patients with type 2 diabetes failed to show a significant reduction in DKD progression when the glycohemoglobin target was reduced below 7% (4). Many of us would like to understand the reason for this surprising difference in nephropathy development and progression. One interpretation is that hyperglycemia is just one of the factors that play a role in the development of diabetic complications in type 2 diabetes and that hyperinsulinemia (HI), insulin resistance, and adiponectin could be equally important. In the current edition of the journal, Mariappan et al. (8) examine the effect of acute (7 h) combined hyperglycemia and hyperinsulinemia on profibrotic and proinflammatory gene expression in rat kidneys (8). The authors describe an approximately twofold increase in urinary isoprostane levels indicative of increased renal oxidative stress under these conditions. They observed a significant increase in renal TGF-β expression and its downstream mediator phospho-Smad3 (8). The expression of fibronectin and β1-laminin was also increased even after this short period of HI/HG. Increased expression of phosphorylated mTOR, S6 kinase, ERK, eIF4E, eIF4A are likely responsible for the increased matrix protein synthesis and kidney enlargement. The authors went on to identify the TLR4/Myd88 and NF-κB pathways as responsible for the increased cytokine expression in the context of hyperglycemia and hyperinsulinemia. In summary, the authors provide compelling evidence that acute HI combined with HG regulate the expression of multiple pathways known to play roles in DKD development. Unfortunately, the authors neglected to provide results from control rats exposed to hyperglycemia or hyperinsulinemia alone; thus, we cannot fully conclude whether these effects are mediated by glucose or the increased insulin levels. For example, we are left to wonder whether reactive oxygen species release is higher in HG/HI animals or lower compared with HG rats. In addition, the length of the “acute” treatment warrants further scrutiny of the time course of these changes. Do changes occur only acutely or are they still evident after prolonged hyperglycemia? Are changes reversible after periods of normoglycemia or are changes sustained? Acute changes in cellular metabolism can cause changes in the epigenome by providing more or less substrate for the key histone or DNA modifying enzymes (7). Cells cultured in high glucose-containing medium sustain changes in their histone modification patterns, for example, at the NF-κB locus, that are likely responsible for its sustained increased expression (5, 6, 9). Future studies will be necessary to determine whether the observed changes are reversible or sustained once euglycemic environment is reestablished. The study by Mariappan et al. is significant as it highlights the critical role of hyperinsulinemia in the development of diabetic kidney disease. Indeed, on a cellular level, it is possible that in the setting of both HI and HG, insulin shifts even more glucose into the intracellular compartment providing substrate for the mitochondria and increasing the reactive oxygen species release. Furthermore, the study provides experimental evidence for the notion that acute fluctuations of glucose and insulin levels may be just as damaging to cells as chronic elevated glucose levels (2). For example, in animal models of diabetes, increased reactive oxygen species release and podocyte apoptosis are observed right around the time when hyperglycemia develops and neither of these changes is sustained (10). As we do not routinely treat the hyperglycemia in diabetic mouse models, glucose levels are relatively constant in these animals, which could contribute to the fact that the diabetic mouse models do not develop progressive renal function decline (1). Clinical studies also support the notion that glycemic variability is a critical factor in the development of complications. In summary, this study provides the first description of acute HI/HG-induced kidney damage. In the future, this new model can be used to examine the patho-mechanism of DKD and develop new therapeutic interventions.