What is the role of glycemic control in the etiology of diabetic nephropathy?

Updated: Oct 09, 2019
  • Author: Vecihi Batuman, MD, FASN; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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Glycemic control reflects the balance between dietary intake and gluconeogenesis and tissue uptake or utilization through storage as glycogen or fat and oxidation. This balance is regulated by insulin production from the β cells in the pancreas. Insulin regulates serum glucose through its actions on liver, skeletal muscle, and fat tissue. When there is insulin resistance, insulin cannot suppress hepatic gluconeogenesis, which leads to hyperglycemia. Simultaneously, insulin resistance in the adipose tissue and skeletal muscle leads to increased lipolysis and reduction in disposal of glucose causing hyperlipidemia in addition to hyperglycemia.

Evidence suggests that when there is insulin resistance, the pancreas is forced to increase its insulin output, which stresses the β cells, eventually resulting in β-cell exhaustion. The high blood glucose levels and high levels of saturated fatty acids create an inflammatory medium, resulting in activation of the innate immune system, which results in activation of the nuclear transcription factors-kappa B (NF-κB), and release of inflammatory mediators, including, interleukin (IL)–1β and tumor necrosis factor (TNF)–α, promoting systemic insulin resistance and β-cell damage as a result of autoimmune insulitis. Hyperglycemia and high serum levels of free fatty acids and IL-1 lead to glucotoxicity, lipotoxicity, and IL-1 toxicity, resulting in apoptotic β-cell death.

Hyperglycemia also increases the expression of transforming growth factor-β (TGF-β) in the glomeruli and of matrix proteins, specifically stimulated by this cytokine. TGF-β and vascular endothelial growth factor (VEGF) may contribute to the cellular hypertrophy and enhanced collagen synthesis and may induce the vascular changes observed in persons with diabetic nephropathy. [7, 8] Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes. [9]

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