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• W2252772083 abstract "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. 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. There is an abundant evidence that insulin resistance complicates chronic kidney disease (CKD) by interfering with processes that contribute to abnormalities in the metabolism of lipids and carbohydrates and loss of protein stores.1.Turcotte L.P. Fisher J.S. Skeletal muscle insulin resistance: roles of fatty acid metabolism and exercise.Phys Ther. 2008; 88: 1279-1296Crossref PubMed Scopus (119) Google Scholar, 2.Semenkovich C.F. Insulin resistance and atherosclerosis.J Clin Invest. 2006; 116: 1813-1822Crossref PubMed Scopus (322) Google Scholar, 3.Bailey J.L. Price S.R. Zheng B. et al.Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atroply.J Am Soc Nephrol. 2006; 17: 1388-1394Crossref PubMed Scopus (196) Google Scholar Loss of protein stores is emphasized because muscle is a major site of insulin resistance and this loss is largely initiated by defects in the intracellular signaling pathway that is initiated by insulin.4.Pham H. Utzschneider K.M. de Boer I.H. Measurement of insulin resistance in chronic kidney disease.Curr Opin Nephrol Hypertens. 2011; 20: 640-646Crossref PubMed Scopus (37) Google Scholar Clinically, metabolic defects uncovered in rodent models of insulin resistance can be identified in patients with nearly normal kidney function, as well as patients with end-stage renal disease.5.Fliser D. Pacini G. Engelleiter R. et al.Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease.Kidney Int. 1998; 53: 1343-1347Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar,6.DeFronzo R.A. Alvestrand A. Smith D. et al.Insulin resistance in uremia.J Clin Invest. 1981; 67: 563-568Crossref PubMed Scopus (465) Google Scholar As insulin resistance is present in non-diabetic patients with minimal renal insufficiency, it is generally agreed that insulin resistance in CKD or complications of CKD cause insulin resistance; the development of insulin resistance is not limited to diabetic nephropathy or specific kidney diseases. Instead, renal insufficiency results in interference with the intracellular signaling pathway initiated by insulin. The consequences of insulin resistance have been intensively studied and, recently, biochemical mechanisms causing insulin resistance have been elucidated. Because these mechanisms have been largely identified in animal models of CKD, they need to be corroborated in patients to determine how insulin resistance affects the metabolism of carbohydrates, lipid, and protein. The development of insulin resistance does not include defects in the binding of insulin to its receptor on cell membranes. Instead, insulin resistance results in ‘post-receptor defects’ that interfere with intracellular signaling processes.7.Friedman J.E. Dohm G.L. Elton C.W. et al.Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors.Am J Physiol. 1991; 261: e87-e94PubMed Google Scholar,8.Smith D. DeFronzo R.A. Insulin resistance in uremia mediated by postbinding defects.Kidney Int. 1982; 22: 54-62Abstract Full Text PDF PubMed Scopus (108) Google Scholar The defects in intracellular signaling result in several metabolic abnormalities. Understanding the development of insulin resistance is difficult because CKD and metabolic consequences of CKD (e.g., metabolic acidosis, increased glucocorticoid production, activation of inflammatory cytokines, or excess angiotensin II) each cause insulin resistance and older patients seem to be more susceptible to developing complications of CKD.9.May R.C. Kelly R.A. Mitch W.E. Mechanisms for defects in muscle protein metabolism in rats with chronic uremia: the influence of metabolic acidosis.J Clin Invest. 1987; 79: 1099-1103Crossref PubMed Scopus (290) Google Scholar, 10.Cai D. Yuan M. Frantz D.F. et al.Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB.Nat Med. 2005; 11: 183-190Crossref PubMed Scopus (1796) Google Scholar, 11.Hu Z. Wang H. Lee I.H. et al.Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice.J Clin Invest. 2009; 119: 7650-7659Google Scholar, 12.Zhang L. Du J. Hu Z. et al.IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting.J Am Soc Nephrol. 2009; 20: 604-612Crossref PubMed Scopus (189) Google Scholar, 13.DeFronzo R.A. Glucose intolerance and aging: evidence for tissue insensitivity to insulin.Diabetes. 1979; 28: 1095-1101Crossref PubMed Scopus (493) Google Scholar Recent reports indicate that these different conditions share a common pathway that impairs insulin-initiated, intracellular signaling, and hence, to the development of insulin resistance. The intracellular signaling pathway that mediates the metabolic responses to insulin is well defined. Normally, insulin binding to its receptor is followed by phosphorylation of specific tyrosines in the insulin receptor and insulin receptor substrate-1 (IRS-1). This is followed by phosphorylation of phosphatidylinositol-3 kinase (PI3K) and the Akt kinase (p-Akt). In fact, the level of p-Akt in muscle are a marker of impaired insulin signaling: a low level of p-Akt in muscle signifies impaired insulin-initiated intracellular signaling resulting in defects in the uptake and metabolism of glucose and lipids plus protein degradation in muscle. In contrast, high levels of p-Akt in muscles stimulate glucose uptake and the synthesis of proteins in muscles while suppressing the degradation of muscle proteins (Figure 1). It is difficult to reproducibly assess insulin insensitivity or defects in insulin-stimulated intracellular signaling. Fliser et al.5.Fliser D. Pacini G. Engelleiter R. et al.Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease.Kidney Int. 1998; 53: 1343-1347Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar used an intravenous glucose tolerance test plus frequent measurements of blood glucose and insulin. They compared non-diabetic patients with minimal-to-advanced loss of kidney function by infusing glucose intravenously and measuring levels of blood glucose and insulin over 2.5 h. The group concluded that defects in insulin-mediated metabolism of glucose are present in patients with early stages of CKD and nearly normal serum creatinine levels. Recently, Jia et al.14.Jia T. Huang X. Qureshi A.R. et al.Validation of insulin sensitivity surrogate indices and prediction of clinical outcomes in individuals with and without impaired renal function.Kidney Int. 2014; 86: 383-391Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar reported that CKD patients (median glomerular filteration rate of 46 ml/min per 1.73 m2) can have insulin insensitivity that is detected during a modified oral glucose tolerance test. The ‘gold-standard’ for documenting insulin resistance is the euglycemic clamp test: patients are given an intravenous infusion of insulin to stimulate glucose uptake in body tissues. At the same time, glucose is infused intravenously at a rate that maintains a constant level of blood glucose. If this rate is high, it indicates the presence of increased insulin sensitivity; a low rate of glucose infusion documents insulin resistance. The euglycemic clamp test has been used by DeFronzo et al., to demonstrate that insulin resistance is present in end-stage renal disease patients, as well as in patients with complications of CKD such as metabolic acidosis.6.DeFronzo R.A. Alvestrand A. Smith D. et al.Insulin resistance in uremia.J Clin Invest. 1981; 67: 563-568Crossref PubMed Scopus (465) Google Scholar, 13.DeFronzo R.A. Glucose intolerance and aging: evidence for tissue insensitivity to insulin.Diabetes. 1979; 28: 1095-1101Crossref PubMed Scopus (493) Google Scholar, 15.DeFronzo R.A. Beckles A.D. Glucose intolerance following chronic metabolic acidosis in man.Am J Physiol. 1979; 236: e328-e334PubMed Google Scholar Unfortunately, the euglycemic clamp test is time consuming and requires trained personnel, so it is rarely used in clinical practice. Alternatively, the insulin suppression test can detect insulin resistance. It is based on infusing hormones/medications (i.e., octreotide, epinephrine, or propranolol) to suppress the release of endogenous insulin. At the same time, insulin and glucose are infused to achieve steady-state blood levels.4.Pham H. Utzschneider K.M. de Boer I.H. Measurement of insulin resistance in chronic kidney disease.Curr Opin Nephrol Hypertens. 2011; 20: 640-646Crossref PubMed Scopus (37) Google Scholar,16.Greenfield M.S. Doberne L. Kraemer F. et al.Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp.Diabetes. 1981; 30: 387-392Crossref PubMed Google Scholar The estimated insulin sensitivity in this test is inversely proportional to the steady-state blood glucose concentration.4.Pham H. Utzschneider K.M. de Boer I.H. Measurement of insulin resistance in chronic kidney disease.Curr Opin Nephrol Hypertens. 2011; 20: 640-646Crossref PubMed Scopus (37) Google Scholar A third method of identifying insulin resistance and β-cell function is based on the fasting values of blood insulin and glucose, the homeostatic model of insulin resistance.4.Pham H. Utzschneider K.M. de Boer I.H. Measurement of insulin resistance in chronic kidney disease.Curr Opin Nephrol Hypertens. 2011; 20: 640-646Crossref PubMed Scopus (37) Google Scholar The technique is insufficiently sensitive to detect insulin resistance reliably in a small group of patients, and it has been used mainly to assess insulin resistance in large numbers of subjects. The homeostatic model of insulin resistance shortcoming is its reliance on static measurements of fasting plasma insulin and glucose. Reportedly, comparisons of homeostatic model of insulin resistance and the euglycemic clamp technique reveal a reasonable correlation (i.e., r=0.88).17.Matthews D.R. Hosker J.P. Rudenski A.S. et al.Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentration in man.Diabetologia. 1985; 28: 412-419Crossref PubMed Scopus (25595) Google Scholar,18.Reaven G.M. The insulin resistance syndrome: definition and dietary approaches to treatment.Annu Rev Nutr. 2005; 25: 391-406Crossref PubMed Scopus (402) Google Scholar Additional details of tests of insulin resistance are provided by Pham et al.4.Pham H. Utzschneider K.M. de Boer I.H. Measurement of insulin resistance in chronic kidney disease.Curr Opin Nephrol Hypertens. 2011; 20: 640-646Crossref PubMed Scopus (37) Google Scholar The genesis of insulin resistance has been studied intensively for two reasons: first, inflammation is often associated with insulin resistance and abnormal metabolism of protein, carbohydrate, and lipids.19.Zhang L. Pan J. Dong Y. et al.Stat3 activation links a C/EBPdelta to myostatin pathway to stimulate loss of muscle mass.Cell Metab. 2013; 18: 368-379Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar,20.Wang X.H. Hu Z. Hu J.P. et al.Insulin resistance accelerates muscle protein degradation: activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling.Endocrinology. 2006; 147: 4160-4168Crossref PubMed Scopus (439) Google Scholar Second, the presence of insulin resistance is associated with an increased risk of atherosclerosis even in patients with mild degrees of CKD. The atherosclerosis risk is linked to increased circulating monocytes and decreased high-density lipoprotein cholesterol.6.DeFronzo R.A. Alvestrand A. Smith D. et al.Insulin resistance in uremia.J Clin Invest. 1981; 67: 563-568Crossref PubMed Scopus (465) Google Scholar, 19.Zhang L. Pan J. Dong Y. et al.Stat3 activation links a C/EBPdelta to myostatin pathway to stimulate loss of muscle mass.Cell Metab. 2013; 18: 368-379Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 21.Ganda A. Magnusson M. Yvan-Charvet L. et al.Mild renal dysfunction and metabolites tied to low HDL cholesterol are associated with monocytosis and atherosclerosis.Circulation. 2013; 127: 988-996Crossref PubMed Scopus (51) Google Scholar, 22.Shoelson S. Leo J. Goldfine A. Inflammation and insulin resistance.J Clin Invest. 2006; 116: 1793-1801Crossref PubMed Scopus (103) Google Scholar, 23.Pereira B.J. Sundaram S. Snodgrass B. et al.Plasma lipopolysaccharide binding protein and bactericidal/permeability increasing factor in CRF and HD patients.J Am Soc Nephrol. 1996; 7: 479-487PubMed Google Scholar, 24.Hotamisligil G.S. Arner P. Caro J.F. et al.Increased adipose tissue expression of tumor necrosis factor-a in human obesity and insulin resistence.J Clin Invest. 1996; 95: 2409-2415Crossref Scopus (2964) Google Scholar To understand how inflammation is related to insulin resistance, investigators have examined biochemical responses of macrophages, adipocytes or skeletal muscle to determine how inflammation can stimulate the production of inflammatory cytokines and how the cytokines might interfere with the functions of insulin.22.Shoelson S. Leo J. Goldfine A. Inflammation and insulin resistance.J Clin Invest. 2006; 116: 1793-1801Crossref PubMed Scopus (103) Google Scholar, 23.Pereira B.J. Sundaram S. Snodgrass B. et al.Plasma lipopolysaccharide binding protein and bactericidal/permeability increasing factor in CRF and HD patients.J Am Soc Nephrol. 1996; 7: 479-487PubMed Google Scholar, 25.Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.Science. 1993; 259: 87-91Crossref PubMed Scopus (6138) Google Scholar, 26.Feinstein R. Kanety H. Papa M.Z. et al.Tumor necrosis factor-a suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates.J Biol Chem. 1993; 268: 26055-26058Abstract Full Text PDF PubMed Google Scholar, 27.Kimmel P.L. Phillips T.M. Simmens S.J. et al.Immunologic function and survival in hemodialysis patients.Kidney Int. 1998; 54: 236-244Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar For example, patients in the early stages of CKD exhibit high levels of circulating proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6 (IL-6), interferon-γ, and lipopolysacchride.23.Pereira B.J. Sundaram S. Snodgrass B. et al.Plasma lipopolysaccharide binding protein and bactericidal/permeability increasing factor in CRF and HD patients.J Am Soc Nephrol. 1996; 7: 479-487PubMed Google Scholar, 28.Meuwese C.L. Snaedal S. Halbesma N. et al.Trimestral variations of C-reactive protein, interleukin-6 and tumour necrosis factor-alpha are similarly associated with survival in haemodialysis patients.Nephrol Dial Transplant. 2011; 26: 1313-1318Crossref PubMed Scopus (68) Google Scholar, 29.Zhang L. Rajan V. Lin E. et al.Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease.FASEB J. 2011; 25: 1653-1663Crossref PubMed Scopus (225) Google Scholar, 30.Spoto B. Leonardis D. Parlongo R.M. et al.Plasma cytokines, glomerular filtration rate and adipose tissue cytokines gene expression in chronic kidney disease (CKD) patients.Nutr Metab Cardiovasc Dis. 2012; 22: 981-988Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Although these circulating pro-inflammatory cytokines are produced by kidney, adipocytes, the liver, or muscles, the triggers stimulating their production are not clear.12.Zhang L. Du J. Hu Z. et al.IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting.J Am Soc Nephrol. 2009; 20: 604-612Crossref PubMed Scopus (189) Google Scholar, 19.Zhang L. Pan J. Dong Y. et al.Stat3 activation links a C/EBPdelta to myostatin pathway to stimulate loss of muscle mass.Cell Metab. 2013; 18: 368-379Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 29.Zhang L. Rajan V. Lin E. et al.Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease.FASEB J. 2011; 25: 1653-1663Crossref PubMed Scopus (225) Google Scholar There are at least two reasons to investigate how inflammation-stimulated defects affect metabolism. First, circulating cytokines can interfere with biochemical pathways resulting in insulin resistance and its metabolic consequences; and second, CKD-induced increases in circulating cytokines are associated with a significant risk of cardiovascular disease and death.5.Fliser D. Pacini G. Engelleiter R. et al.Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease.Kidney Int. 1998; 53: 1343-1347Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar, 22.Shoelson S. Leo J. Goldfine A. Inflammation and insulin resistance.J Clin Invest. 2006; 116: 1793-1801Crossref PubMed Scopus (103) Google Scholar, 28.Meuwese C.L. Snaedal S. Halbesma N. et al.Trimestral variations of C-reactive protein, interleukin-6 and tumour necrosis factor-alpha are similarly associated with survival in haemodialysis patients.Nephrol Dial Transplant. 2011; 26: 1313-1318Crossref PubMed Scopus (68) Google Scholar How does chronic inflammation induced by CKD cause insulin resistance? We uncovered a novel pathway by which inflammatory mediators (e.g., tumor necrosis factor-α or Il-6) cause insulin resistance.22.Shoelson S. Leo J. Goldfine A. Inflammation and insulin resistance.J Clin Invest. 2006; 116: 1793-1801Crossref PubMed Scopus (103) Google Scholar,31.Thomas S.S. Dong Y. Zhang L. et al.Signal regulatory protein-alpha interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease.Kidney Int. 2013; 84: 308-316Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Initially, we used a RNA microarray analysis to examine potential mediators of insulin resistance in muscles of a mouse model of CKD. There was a 5.2-fold increase in the expression of a transmembrane glycoprotein, SIRP-α, in muscles of mice with CKD.31.Thomas S.S. Dong Y. Zhang L. et al.Signal regulatory protein-alpha interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease.Kidney Int. 2013; 84: 308-316Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar SIRP-α was shown to interact directly with the insulin receptor in muscles of mice with CKD. The interaction reduced phosphorylation of tyrosines present in both the insulin receptor and IRS-1, and the decrease in tyrosine phosphorylation reduced insulin signaling in muscle cells. As IRS-1 phosphorylation was also reduced, we concluded that a low value of IRS-1 caused insulin resistance by interrupting insulin-stimulated intracellular signaling. The trigger of increased SIRP-α expression in muscle is activation of the NF-κB pathway. When the NF-κB pathway was inhibited, there was a sharp decrease in SIRP-α expression plus increased tyrosine phosphorylation and activation of the insulin receptor and IRS-1. The responses were shown to be physiologically relevant because suppression of NF-κB sharply reduced SIRP-α expression. There also was inhibition of the proteolytic activity of the ubiquitin–proteasome system (UPS) preventing muscle protein losses.31.Thomas S.S. Dong Y. Zhang L. et al.Signal regulatory protein-alpha interacts with the insulin receptor contributing to muscle wasting in chronic kidney disease.Kidney Int. 2013; 84: 308-316Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Other triggers of insulin resistance include uremic toxins. For example, accumulation of p-cresyl sulfate in patients with CKD or in animal models of CKD resulted in impaired insulin-stimulated intracellular signaling.32.Koppe L. Pillon N.J. Vella R.E. et al.p-Cresyl sulfate promotes insulin resistance associated with CKD.J Am Soc Nephrol. 2013; 24: 88-99Crossref PubMed Scopus (174) Google Scholar Furthermore, when normal mice were treated with p-cresyl sulfate, insulin resistance developed and lipids accumulated in muscle and liver.32.Koppe L. Pillon N.J. Vella R.E. et al.p-Cresyl sulfate promotes insulin resistance associated with CKD.J Am Soc Nephrol. 2013; 24: 88-99Crossref PubMed Scopus (174) Google Scholar Specifically, p-cresyl sulfate administration resulted in an 83% increase (P<0.001) in the lipid content of skeletal muscles of mice and this response was principally derived from white adipose tissue. There also was a 23% (P<0.05) increase in the lipid content of livers.32.Koppe L. Pillon N.J. Vella R.E. et al.p-Cresyl sulfate promotes insulin resistance associated with CKD.J Am Soc Nephrol. 2013; 24: 88-99Crossref PubMed Scopus (174) Google Scholar A similar ectopic redistribution of lipids developed in mice with CKD. Notably, the stimulus for developing insulin resistance in mice with CKD was the release of adipokines and cytokines from adipose tissues. In fact, it was found that redistribution of lipids to muscle increased reactive oxygen species and activated serine/threonine kinases (JNK, IKK, and P38 MAPK). These responses are relevant because each of these inflammatory factors can initiate insulin resistance.33.Qatanani M. Lazar M.A. Mechanisms of obesity-associated insulin resistance: many choices on the menu.Genes Dev. 2007; 21: 1443-1455Crossref PubMed Scopus (549) Google Scholar In cultured 3T3-L1 adipocytes or human adipocytes, addition of p-cresyl sulfate has been associated with suppression of lipogenesis and stimulation of lipolysis.32.Koppe L. Pillon N.J. Vella R.E. et al.p-Cresyl sulfate promotes insulin resistance associated with CKD.J Am Soc Nephrol. 2013; 24: 88-99Crossref PubMed Scopus (174) Google Scholar Thus, increased levels of the uremic toxin, p-cresyl sulfate stimulate inflammation and reactive oxygen species generation leading to changes in insulin-stimulated intracellular signaling, and hence, insulin resistance.33.Qatanani M. Lazar M.A. Mechanisms of obesity-associated insulin resistance: many choices on the menu.Genes Dev. 2007; 21: 1443-1455Crossref PubMed Scopus (549) Google Scholar An increase in circulating aldosterone occurring in patients with CKD produces a different mechanism of insulin resistance.34.Mitch W.E. Wilcox C.S. Disorders of body fluids, sodium and potassium in chronic renal failure.Am J Med. 1982; 72: 536-550Abstract Full Text PDF PubMed Scopus (108) Google Scholar,35.Hosoya K. Minakuchi H. Wakino S. et al.Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans.Kidney Int. 2014; 87: 749-760Abstract Full Text Full Text PDF Scopus (28) Google Scholar There is an inverse relationship between an increasing level of circulating aldosterone and declining kidney function.35.Hosoya K. Minakuchi H. Wakino S. et al.Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans.Kidney Int. 2014; 87: 749-760Abstract Full Text Full Text PDF Scopus (28) Google Scholar In a prospective, randomized, placebo-controlled study evaluating non-diabetic patients with stages 2–5 CKD, the efficacy of the aldosterone inhibitor, spironolactone, was evaluated. The trigger initiating an increase in mineralocorticoid receptor activation resulting in insulin resistance has been shown to be an increase in the accumulation of asymmetric dimethyl arginine. This molecule was found to impair insulin signaling in adipose tissues of rodents with CKD and it accumulates in patients or mice with CKD. The insulin resistance associated with excess asymmetric dimethyl arginine levels can be reversed by treating rodents or humans with spironolactone.35.Hosoya K. Minakuchi H. Wakino S. et al.Insulin resistance in chronic kidney disease is ameliorated by spironolactone in rats and humans.Kidney Int. 2014; 87: 749-760Abstract Full Text Full Text PDF Scopus (28) Google Scholar An excess of urea has also been implicated as a mechanism causing insulin resistance at least in cultured 3T3-L1 adipocytes.36.D'Apolito M. Du X. Zong H. et al.Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure.J Clin Invest. 2010; 120: 203-213Crossref PubMed Scopus (160) Google Scholar In adipocytes, it was found that adding a high concentration of urea stimulated the production of both reactive oxygen species and O-linked beta-N-acetylglucosamine. In mice, toxic responses to reactive oxygen species and O-linked beta-N-acetylglucosamine were largely eliminated by treatment with an antioxidant mimetic, superoxide dimutase catalase. Administration of the antioxidant also prevented the development of insulin resistance. These interesting examples of uremic toxin-generated insulin resistance plus the efficacy and safety of administering an antioxidant mimetic need to be evaluated in patients. Otherwise, the relationship of putative toxins to mechanisms that develop into metabolic abnormalities of CKD will remain speculative. Metabolic acidosis is another consequence of CKD that has been associated with the development of insulin resistance.15.DeFronzo R.A. Beckles A.D. Glucose intolerance following chronic metabolic acidosis in man.Am J Physiol. 1979; 236: e328-e334PubMed Google Scholar, 37.Graham K.A. Reaich D. Channon S.M. et al.Correction of acidosis in hemodialysis decreases whole-body protein degradation.J Am Soc Nephrol. 1997; 8: 632-637PubMed Google Scholar, 38.Reaich D. Graham K.A. Channon S.M. et al.Insulin mediated changes in protein degradation and glucose utilization following correction of acidosis in humans with CRF.Am J Physiol. 1995; 268: e121-e126PubMed Google Scholar Although only relatively small groups of patients have been rigorously studied to discern responses to correcting acidosis, the responses to metabolic acidosis are of special interest because improving acidosis in patients with CKD can preserve their muscle mass while slowing the loss of kidney function.39.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (634) Google Scholar In CKD, metabolic acidosis develops not only because the ability to excrete acid is limited but also because excess acid is produced when patients with CKD eat protein-rich foods, especially foods with increased sulfa-containing amino acids and phosphorylated proteins and lipids.40.Leal V.O. Delgado A.G. Leite M. et al.The influence of renal function and the diet on acid-base status in chronic kidney disease patients.J Renal Nutr. 2009; 19: 178-182Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,41.Dobre M. Rahman M. Hostetter T.H. Current status of bicarbonate in CKD.J Am Soc Nephrol. 2014; 26: 515-523Crossref PubMed Scopus (80) Google Scholar Fortunately, metabolic acidosis can be corrected simply by administering supplemental NaHCO3 or by changing the diet of patients with CKD to incorporate less meat and m" @default.
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• W2252772083 date "2015-12-01" @default.
• W2252772083 modified "2023-09-30" @default.
• W2252772083 title "Molecular mechanisms of insulin resistance in chronic kidney disease" @default.
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• W2252772083 doi "https://doi.org/10.1038/ki.2015.305" @default.
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