期刊
KIDNEY INTERNATIONAL
卷 88, 期 6, 页码 1233-1239出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2015.305
关键词
cell signaling; chronic kidney disease; inflammation; insulin resistance
资金
- VA Career Development Award from the United States Department of Veterans Affairs, Biomedical Laboratory Research and Development Program [1IK2 BX002492]
- NIH [R37 DK37175]
- Norman S. Coplon extramural research grant of Satellite Health
- American Diabetes Association [1-11-BS-194]
- Diabetes Research Center [P50-DK079638]
Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identify the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids, and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging, and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to the activation of different E3 ubiquitin ligases, which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD.
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