Most of the basic components of the metabolic syndrome, namely type 2 diabetes mellitus, hypertension, obesity, or low high-density lipoprotein cholesterol levels, apart from being major risk factors for cardiovascular disease have been also associated with an increased risk of chronic kidney disease. However, several epidemiologic studies conducted over the past years suggest that the central component of the syndrome, insulin resistance, as well as compensatory hyperinsulinemia are independently associated with an increased prevalence of chronic kidney disease. In addition, background studies support the existence of several pathways linking insulin resistance and hyperinsulinemia with kidney damage. Insulin per se promotes the proliferation of renal cells and stimulates the production of other important growth factors such as insulin-like growth factor-1 and transforming growth factor beta. Insulin also upregulates the expression of angiotensin II type 1 receptor in mesangial cells, thus enhancing the deleterious effects of angiotensin II in the kidney, and stimulates production and renal action of endothelin-1. Moreover, insulin resistance and hyperinsulinemia are associated with decreased endothelial production of nitric oxide and increased oxidative stress which have been also implicated in the progression of diabetic nephropathy. This review analyzes the above and other potential mechanisms, through which insulin resistance and hyperinsulinemia can contribute to renal injury.

Sarafidis PA, Nilsson PM: The metabolic syndrome: a glance at its history. J Hypertens 2006;24:621–626.
Reaven GM: Banting Lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595–1607.
American Diabetes Association: Diabetic nephropathy. Diabetes Care 2000;23(suppl 1):S69–S72.
Steinke JM, Sinaiko AR, Kramer MS, Suissa S, Chavers BM, Mauer M: The early natural history of nephropathy in type 1 diabetes. III. Predictors of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients. Diabetes 2005;54:2164–2171.
Garg JP, Bakris GL: Microalbuminuria: marker of vascular dysfunction, risk factor for cardiovascular disease. Vasc Med 2002;7:35–43.
Bakris GL: Clinical importance of microalbuminuria in diabetes and hypertension. Curr Hypertens Rep 2004;6:352–356.
Mykkanen L, Zaccaro DJ, Wagenknecht LE, Robbins DC, Gabriel M, Haffner SM: Microalbuminuria is associated with insulin resistance in nondiabetic subjects: the Insulin Resistance Atherosclerosis Study. Diabetes 1998;47:793–800.
Kim CH, Kim HK, Park JY, Park HS, Hong SK, Park SW, Lee KU: Association of microalbuminuria and atherosclerotic risk factors in non-diabetic subjects in Korea. Diabetes Res Clin Pract 1998;40:191–199.
Niskanen L, Laakso M: Insulin resistance is related to albuminuria in patients with type II (non-insulin-dependent) diabetes mellitus. Metabolism 1993;42:1541–1545.
Forsblom CM, Eriksson JG, Ekstrand AV, Teppo AM, Taskinen MR, Groop LC: Insulin resistance and abnormal albumin excretion in non-diabetic first-degree relatives of patients with NIDDM. Diabetologia 1995;38:363–369.
Bianchi S, Bigazzi R, Nenci R, Campese VM: Hyperinsulinemia, circadian variation of blood pressure and end-organ damage in hypertension. J Nephrol 1997;10:325–333.
Wirta OR, Pasternack AI, Mustonen JT, Koivula TA, Harmoinen A: Urinary albumin excretion rate and its determinants after 6 years in non-insulin-dependent diabetic patients. Nephrol Dial Transplant 1996;11:449–456.
Spangler JG, Konen JC: Hypertension, hyperlipidemia, and abdominal obesity and the development of microalbuminuria in patients with non-insulin-dependent diabetes mellitus. J Am Board Fam Pract 1996;9:1–6.
Rowley KG, Iser DM, Best JD, O’Dea K, Leonard D, McDermott R: Albuminuria in Australian Aboriginal people: prevalence and associations with components of the metabolic syndrome. Diabetologia 2000;43:1397–1403.
World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Report of a WHO Consultation. 1. Diagnosis and Classification of Diabetes Mellitus. Geneva, World Health Organization, 1999.
Emoto M, Nishizawa Y, Maekawa K, Kawagishi T, Kogawa K, Hiura Y, Mori K, Tanaka S, Ishimura E, Inaba M, Okuno Y, Morii H: Insulin resistance in non-obese, non-insulin-dependent diabetic patients with diabetic nephropathy. Metabolism 1997;46:1013–1018.
Kobayashi S, Maesato K, Moriya H, Ohtake T, Ikeda T: Insulin resistance in patients with chronic kidney disease. Am J Kidney Dis 2005;45:275–280.
Becker B, Kronenberg F, Kielstein JT, Haller H, Morath C, Ritz E, Fliser D: Renal insulin resistance syndrome, adiponectin and cardiovascular events in patients with kidney disease: the Mild and Moderate Kidney Disease Study. J Am Soc Nephrol 2005;16:1091–1098.
Chen J, Muntner P, Hamm LL, Fonseca V, Batuman V, Whelton PK, He J: Insulin resistance and risk of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol 2003;14:469–477.
Chen J, Muntner P, Hamm LL, Jones DW, Batuman V, Fonseca V, Whelton PK, He J: The metabolic syndrome and chronic kidney disease in US adults. Ann Intern Med 2004;140:167–174.
Muntner P, He J, Chen J, Fonseca V, Whelton PK: Prevalence of non-traditional cardiovascular disease risk factors among persons with impaired fasting glucose, impaired glucose tolerance, diabetes, and the metabolic syndrome: analysis of the Third National Health and Nutrition Examination Survey (NHANES III). Ann Epidemiol 2004;14:686–695.
Kurella M, Lo JC, Chertow GM: Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J Am Soc Nephrol 2005;16:2134–2140.
Fox CS, Larson MG, Leip EP, Culleton B, Wilson PW, Levy D: Predictors of new-onset kidney disease in a community-based population. JAMA 2004;291:844–850.
Bakris GL: Protecting renal function in the hypertensive patient: clinical guidelines. Am J Hypertens 2005;18(4 Pt 2):112S–119S.
Beck-Nielsen H, Groop LC: Metabolic and genetic characterization of prediabetic states: sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 1994;94:1714–1721.
Yki-Jarvinen H: Pathogenesis of non-insulin-dependent diabetes mellitus. Lancet 1994;343:91–95.
Turner NC, Clapham JC: Insulin resistance, impaired glucose tolerance and non-insulin-dependent diabetes, pathologic mechanisms and treatment: current status and therapeutic possibilities. Prog Drug Res 1998;51:33–94.
McFarlane SI, Banerji M, Sowers JR: Insulin resistance and cardiovascular disease. J Clin Endocrinol Metab 2001;86:713–718.
Sarafidis PA, Lasaridis AN: Actions of PPARγ agonists explaining a possible blood pressure lowering effect. Am J Hypertens 2006;19:646–653.
Sartori C, Scherrer U: Insulin, nitric oxide and the sympathetic nervous system: at the crossroads of metabolic and cardiovascular regulation. J Hypertens 1999;17:1517–1525.
Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A: Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata Diabetes Study. Diabetes Care 1999;22:920–924.
Qiao Q, Jousilahti P, Eriksson J, Tuomilehto J: Predictive properties of impaired glucose tolerance for cardiovascular risk are not explained by the development of overt diabetes during follow-up. Diabetes Care 2003;26:2910–2914.
Cusumano AM, Bodkin NL, Hansen BC, Iotti R, Owens J, Klotman PE, Kopp JB: Glomerular hypertrophy is associated with hyperinsulinemia and precedes overt diabetes in aging rhesus monkeys. Am J Kidney Dis 2002;40:1075–1085.
Butlen D, Vadrot S, Roseau S, Morel F: Insulin receptors along the rat nephron: [125I] insulin binding in microdissected glomeruli and tubules. Pflügers Arch 1988;412:604–612.
Miller JH, Bogdonoff MD: Antidiuresis associated with administration of insulin. J Appl Physiol 1954;6:509–512.
Nizet A, Lefebvre P, Crabbe J: Control by insulin of sodium, potassium and water excretion by the isolated dog kidney. Pflügers Arch 1971;323:11–20.
DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ: The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest 1975;55:845–855.
Skott P, Hother-Nielsen O, Bruun NE, Giese J, Nielsen MD, Beck-Nielsen H, Parving HH: Effects of insulin on kidney function and sodium excretion in healthy subjects. Diabetologia 1989;32:694–699.
DeFronzo RA, Goldberg M, Agus ZS: The effects of glucose and insulin on renal electrolyte transport. J Clin Invest 1976;58:83–90.
Baum M: Insulin stimulates volume absorption in the rabbit proximal convoluted tubule. J Clin Invest 1987;79:1104–1109.
Kirchner K: Insulin increases loop segment chloride reabsorption in the euglycemic rat. Am J Physiol 1988;255(6 Pt 2):F1206–F1213.
Finch D, Davis G, Bower J, Kirchner K: Effect of insulin on renal sodium handling in hypertensive rats. Hypertension 1990;15:514–518.
Rocchini AP, Katch V, Kveselis D, Moorehead C, Martin M, Lampman R, Gregory M: Insulin and renal sodium retention in obese adolescents. Hypertension 1989;14:367–374.
Natali A, Quinones Galvan A, Santoro D, Pecori N, Taddei S, Salvetti A, Ferrannini E: Relationship between insulin release, antinatriuresis and hypokalaemia after glucose ingestion in normal and hypertensive man. Clin Sci (Lond) 1993;85:327–335.
Muscelli E, Natali A, Bianchi S, Bigazzi R, Galvan AQ, Sironi AM, Frascerra S, Ciociaro D, Ferrannini E: Effect of insulin on renal sodium and uric acid handling in essential hypertension. Am J Hypertens 1996;9:746–752.
Sharma AM, Schorr U: Salt sensitivity and insulin resistance: is there a link? Blood Press Suppl 1996;1:59–63.
Fuenmayor N, Moreira E, Cubeddu LX: Salt sensitivity is associated with insulin resistance in essential hypertension. Am J Hypertens 1998;11:397–402.
Galletti F, Strazzullo P, Ferrara I, Annuzzi G, Rivellese AA, Gatto S, Mancini M: NaCl sensitivity of essential hypertensive patients is related to insulin resistance. J Hypertens 1997;15:1485–1491.
Trevisan R, Bruttomesso D, Vedovato M, Brocco S, Pianta A, Mazzon C, Girardi C, Jori E, Semplicini A, Tiengo A, Del Prato S: Enhanced responsiveness of blood pressure to sodium intake and to angiotensin II is associated with insulin resistance in IDDM patients with microalbuminuria. Diabetes 1998;47:1347–1353.
Imanishi M, Yoshioka K, Okumura M, Konishi Y, Okada N, Morikawa T, Sato T, Tanaka S, Fujii S: Sodium sensitivity related to albuminuria appearing before hypertension in type 2 diabetic patients. Diabetes Care 2001;24:111–116.
Vedovato M, Lepore G, Coracina A, Dodesini AR, Jori E, Tiengo A, Del Prato S, Trevisan R: Effect of sodium intake on blood pressure and albuminuria in type 2 diabetic patients: the role of insulin resistance. Diabetologia 2004;47:300–303.
Cohen AJ, McCarthy DM, Stoff JS: Direct hemodynamic effect of insulin in the isolated perfused kidney. Am J Physiol 1989;257(4 Pt 2):F580–F585.
Hall JE, Brands MW, Mizelle HL, Gaillard CA, Hildebrandt DA: Chronic intrarenal hyperinsulinemia does not cause hypertension. Am J Physiol 1991;260(5 Pt 2):F663–F669.
Briggs JP, Schnermann J: The tubuloglomerular feedback mechanism: functional and biochemical aspects. Annu Rev Physiol 1987;49:251–273.
Mogensen CE, Christensen NJ, Gundersen HJ: The acute effect of insulin on heart rate, blood pressure, plasma noradrenaline and urinary albumin excretion: the role of changes in blood glucose. Diabetologia 1980;18:453–457.
Christiansen JS, Frandsen M, Parving HH: The effect of intravenous insulin infusion on kidney function in insulin-dependent diabetes mellitus. Diabetologia 1981;20:199–204.
Christensen NJ, Gundersen HJ, Mogensen CE, Vittinghus E: Intravenous insulin decreases urinary albumin excretion in long-term diabetics with nephropathy. Diabetologia 1980;18:285–288.
Quinones-Galvan A, Ferrannini E: Renal effects of insulin in man. J Nephrol 1997;10:188–191.
Catalano C, Muscelli E, Quinones Galvan A, Baldi S, Masoni A, Gibb I, Torffvit O, Seghieri G, Ferrannini E: Effect of insulin on systemic and renal handling of albumin in nondiabetic and NIDDM subjects. Diabetes 1997;46:868–875.
Stout RW, Bierman EL, Ross R: Effect of insulin on the proliferation of cultured primate arterial smooth muscle cells. Circ Res 1975;36:319–327.
Capron L, Jarnet J, Kazandjian S, Housset E: Growth-promoting effects of diabetes and insulin on arteries: an in vivo study of rat aorta. Diabetes 1986;35:973–978.
Delafontaine P: Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res 1995;30:825–834.
Sowers JR, Draznin B: Insulin, cation metabolism and insulin resistance. J Basic Clin Physiol Pharmacol 1998;9:223–233.
Murphy LJ, Ghahary A, Chakrabarti S: Insulin regulation of IGF-I expression in rat aorta. Diabetes 1990;39:657–662.
Bornfeldt KE, Skottner A, Arnqvist HJ: In vivo regulation of messenger RNA encoding insulin-like growth factor-I (IGF-I) and its receptor by diabetes, insulin and IGF-I in rat muscle. J Endocrinol 1992;135:203–211.
King GL, Goodman AD, Buzney S, Moses A, Kahn CR: Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest 1985;75:1028–1036.
LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr: Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995;16:143–163.
Banskota NK, Taub R, Zellner K, Olsen P, King GL: Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I. Diabetes 1989;38:123–129.
Avena R, Mitchell ME, Carmody B, Arora S, Neville RF, Sidaway AN: Insulin-like growth factor-1 receptors mediate infragenicular vascular smooth muscle cell proliferation in response to glucose and insulin not by insulin receptors. Am J Surg 1999;178:156–161.
Aron DC, Rosenzweig JL, Abboud HE: Synthesis and binding of insulin-like growth factor I by human glomerular mesangial cells. J Clin Endocrinol Metab 1989;68:585–591.
Weiss O, Anner H, Nephesh I, Alayoff A, Bursztyn M, Raz I: Insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in the kidney of the chronically hypoinsulinemic rat and hyperinsulinemic rat. Metabolism 1995;44:982–986.
Miyatake N, Shikata K, Wada J, Sugimoto H, Takahashi S, Makino H: Differential distribution of insulin-like growth factor-1 and insulin-like growth factor binding proteins in experimental diabetic rat kidney. Nephron 1999;81:317–323.
Segev Y, Landau D, Rasch R, Flyvbjerg A, Phillip M: Growth hormone receptor antagonism prevents early renal changes in nonobese diabetic mice. J Am Soc Nephrol 1999;10:2374–2381.
Abrass CK, Raugi GJ, Gabourel LS, Lovett DH: Insulin and insulin-like growth factor I binding to cultured rat glomerular mesangial cells. Endocrinology 1988;123:2432–2439.
Conti FG, Striker LJ, Lesniak MA, MacKay K, Roth J, Striker GE: Studies on binding and mitogenic effect of insulin and insulin-like growth factor I in glomerular mesangial cells. Endocrinology 1988;122:2788–2795.
Abrass CK, Spicer D, Raugi GJ: Insulin induces a change in extracellular matrix glycoproteins synthesized by rat mesangial cells in culture. Kidney Int 1994;46:613–620.
Abrass CK, Spicer D, Raugi GJ: Induction of nodular sclerosis by insulin in rat mesangial cells in vitro: studies of collagen. Kidney Int 1995;47:25–37.
Mooney A, Jobson T, Bacon R, Kitamura M, Savill J: Cytokines promote glomerular mesangial cell survival in vitro by stimulus-dependent inhibition of apoptosis. J Immunol 1997;159:3949–3960.
Lupia E, Elliot SJ, Lenz O, Zheng F, Hattori M, Striker GE, Striker LJ: IGF-1 decreases collagen degradation in diabetic NOD mesangial cells: implications for diabetic nephropathy. Diabetes 1999;48:1638–1644.
Baricos WH: Chronic renal disease: do metalloproteinase inhibitors have a demonstrable role in extracellular matrix accumulation? Curr Opin Nephrol Hypertens 1995;4:365–368.
Baumann U, Eisenhauer T, Hartmann H: Increase of glomerular filtration rate and renal plasma flow by insulin-like growth factor-I during euglycaemic clamping in anaesthetized rats. Eur J Clin Invest 1992;22:204–209.
Guler HP, Eckardt KU, Zapf J, Bauer C, Froesch ER: Insulin-like growth factor I increases glomerular filtration rate and renal plasma flow in man. Acta Endocrinol (Copenh) 1989;121:101–106.
Nicholas SB: Advances in pathogenetic mechanisms of diabetic nephropathy. Cell Mol Biol (Noisy-le-Grand) 2003;49:1319–1325.
Anderson PW, Zhang XY, Tian J, Correale JD, Xi XP, Yang D, Graf K, Law RE, Hsueh WA: Insulin and angiotensin II are additive in stimulating TGF-beta 1 and matrix mRNAs in mesangial cells. Kidney Int 1996;50:745–753.
Morrisey K, Evans RA, Wakefield L, Phillips AO: Translational regulation of renal proximal tubular epithelial cell transforming growth factor-beta1 generation by insulin. Am J Pathol 2001;159:1905–1915.
Wang S, Denichilo M, Brubaker C, Hirschberg R: Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy. Kidney Int 2001;60:96–105.
Rocchini AP, Moorehead C, DeRemer S, Goodfriend TL, Ball DL: Hyperinsulinemia and the aldosterone and pressor responses to angiotensin II. Hypertension 1990;15:861–866.
Engeli S, Negrel R, Sharma AM: Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 2000;35:1270–1277.
Zhang SL, Chen X, Filep JG, Tang SS, Ingelfinger JR, Chan JS: Insulin inhibits angiotensinogen gene expression via the mitogen-activated protein kinase pathway in rat kidney proximal tubular cells. Endocrinology 1999;140:5285–5292.
Chen X, Zhang SL, Pang L, Filep JG, Tang SS, Ingelfinger JR, Chan JS: Characterization of a putative insulin-responsive element and its binding protein(s) in rat angiotensinogen gene promoter: regulation by glucose and insulin. Endocrinology 2001;142:2577–2585.
Zhang L, Chen X, Hsieh TJ, Leclerc M, Henley N, Allidina A, Halle JP, Brunette MG, Filep JG, Tang SS, Ingelfinger JR, Chan JS: Hyperglycemia induces insulin resistance on angiotensinogen gene expression in diabetic rat kidney proximal tubular cells. J Endocrinol 2002;172:333–344.
Kreisberg JI: Insulin requirement for contraction of cultured rat glomerular mesangial cells in response to angiotensin II: possible role for insulin in modulating glomerular hemodynamics. Proc Natl Acad Sci USA 1982;79:4190–4192.
Dunlop ME, Larkins RG: Insulin-dependent contractility of glomerular mesangial cells in response to angiotensin II, platelet-activating factor and endothelin is attenuated by prostaglandin E2. Biochem J 1990;272:561–568.
Nickenig G, Roling J, Strehlow K, Schnabel P, Böhm M: Insulin induces upregulation of vascular AT1 receptor gene expression by posttranscriptional mechanisms. Circulation 1998;98:2453–2460.
Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P: Nitric oxide release accounts for insulin’s vascular effects in humans. J Clin Invest 1994;94:2511–2515.
Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD: Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 1994;94:1172–1179.
Sobrevia L, Nadal A, Yudilevich DL, Mann GE: Activation of L-arginine transport (system y+) and nitric oxide synthase by elevated glucose and insulin in human endothelial cells. J Physiol 1996;490(Pt 3):775–781.
Zeng G, Quon MJ: Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells. J Clin Invest 1996;98:894–898.
Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD: Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest 1996;97:2601–2610.
Steinberg HO, Paradisi G, Cronin J, Crowde K, Hempfling A, Hook G, Baron AD: Type II diabetes abrogates sex differences in endothelial function in premenopausal women. Circulation 2000;101:2040–2046.
Laine H, Knuuti MJ, Ruotsalainen U, Raitakari M, Iida H, Kapanen J, Kirvela O, Haaparanta M, Yki-Jarvinen H, Nuutila P: Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle. J Hypertens 1998;16:211–219.
Steinberg HO, Baron AD: Vascular function, insulin resistance and fatty acids. Diabetologia 2002;45:623–634.
Fang TC, Wu CC, Huang WC: Inhibition of nitric oxide synthesis accentuates blood pressure elevation in hyperinsulinemic rats. J Hypertens 2001;19:1255–1262.
Komers R, Anderson S: Paradoxes of nitric oxide in the diabetic kidney. Am J Physiol Renal Physiol 2003;284:F1121–F1137.
Prabhakar SS: Role of nitric oxide in diabetic nephropathy. Semin Nephrol 2004;24:333–344.
Petrie JR, Ueda S, Webb DJ, Elliott HL, Connell JM: Endothelial nitric oxide production and insulin sensitivity: a physiological link with implications for pathogenesis of cardiovascular disease. Circulation 1996;93:1331–1333.
Leslie RD, Taylor R, Pozzilli P: The role of insulin resistance in the natural history of type 1 diabetes. Diabet Med 1997;14:327–331.
Kohan DE: Endothelins in the kidney: physiology and pathophysiology. Am J Kidney Dis 1993;22:493–510.
Marsen TA, Schramek H, Dunn MJ: Renal actions of endothelin: linking cellular signaling pathways to kidney disease. Kidney Int 1994;45:336–344.
Fukui M, Nakamura T, Ebihara I, Osada S, Tomino Y, Masaki T, Goto K, Furuichi Y, Koide H: Gene expression for endothelins and their receptors in glomeruli of diabetic rats. J Lab Clin Med 1993;122:149–156.
Morabito E, Corsico N, Serafini S, Martelli EA: Elevated urinary excretion of endothelins in streptozotocin diabetic rats. Life Sci 1994;54:PL197–PL200.
Lee YJ, Shin SJ, Tsai JH: Increased urinary endothelin-1-like immunoreactivity excretion in NIDDM patients with albuminuria. Diabetes Care 1994;17:263–266.
De Mattia G, Cassone-Faldetta M, Bellini C, Bravi MC, Laurenti O, Baldoncini R, Santucci A, Ferri C: Role of plasma and urinary endothelin-1 in early diabetic and hypertensive nephropathy. Am J Hypertens 1998;11:983–988.
Simonson MS, Herman WH: Protein kinase C and protein tyrosine kinase activity contribute to mitogenic signaling by endothelin-1: cross-talk between G protein-coupled receptors and pp60c-src. J Biol Chem 1993;268:9347–9357.
Nakamura T, Ebihara I, Fukui M, Tomino Y, Koide H: Effect of a specific endothelin receptor A antagonist on mRNA levels for extracellular matrix components and growth factors in diabetic glomeruli. Diabetes 1995;44:895–899.
Hu RM, Levin ER, Pedram A, Frank HJ: Insulin stimulates production and secretion of endothelin from bovine endothelial cells. Diabetes 1993;42:351–358.
Ferri C, Pittoni V, Piccoli A, Laurenti O, Cassone MR, Bellini C, Properzi G, Valesini G, De Mattia G, Santucci A: Insulin stimulates endothelin-1 secretion from human endothelial cells and modulates its circulating levels in vivo. J Clin Endocrinol Metab 1995;80:829–835.
Anfossi G, Cavalot F, Massucco P, Mattiello L, Mularoni E, Hahn A, Trovati M: Insulin influences immunoreactive endothelin release by human vascular smooth muscle cells. Metabolism 1993;42:1081–1083.
Frank HJ, Levin ER, Hu RM, Pedram A: Insulin stimulates endothelin binding and action on cultured vascular smooth muscle cells. Endocrinology 1993;133:1092–1097.
Hopfner RL, Hasnadka RV, Wilson TW, McNeill JR, Gopalakrishnan V: Insulin increases endothelin-1-evoked intracellular free calcium responses by increased ETA receptor expression in rat aortic smooth muscle cells. Diabetes 1998;47:937–944.
Piatti PM, Monti LD, Conti M, Baruffaldi L, Galli L, Phan CV, Guazzini B, Pontiroli AE, Pozza G: Hypertriglyceridemia and hyperinsulinemia are potent inducers of endothelin-1 release in humans. Diabetes 1996;45:316–321.
Ferri C, Bellini C, Desideri G, De Mattia G, Santucci A: Endogenous insulin modulates circulating endothelin-1 concentrations in humans. Diabetes Care 1996;19:504–506.
Ferri C, Bellini C, Desideri G, Baldoncini R, Properzi G, Santucci A, De Mattia G: Circulating endothelin-1 levels in obese patients with the metabolic syndrome. Exp Clin Endocrinol Diabetes 1997;105(Suppl 2):38–40.
Piatti PM, Monti LD, Galli L, Fragasso G, Valsecchi G, Conti M, Gernone F, Pontiroli AE: Relationship between endothelin-1 concentration and metabolic alterations typical of the insulin resistance syndrome. Metabolism 2000;49:748–752.
Irving RJ, Noon JP, Watt GC, Webb DJ, Walker BR: Activation of the endothelin system in insulin resistance. QJM 2001;94:321–326.
Bonnefont-Rousselot D, Bastard JP, Jaudon MC, Delattre J: Consequences of the diabetic status on the oxidant/antioxidant balance. Diabetes Metab 2000;26:163–176.
Laight DW, Desai KM, Gopaul NK, Anggard EE, Carrier MJ: F2-isoprostane evidence of oxidant stress in the insulin resistant, obese Zucker rat: effects of vitamin E. Eur J Pharmacol 1999;377:89–92.
Rudich A, Tirosh A, Potashnik R, Hemi R, Kanety H, Bashan N: Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes 1998;47:1562–1569.
Tirosh A, Potashnik R, Bashan N, Rudich A: Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes: a putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation. J Biol Chem 1999;274:10595–10602.
Hansen LL, Ikeda Y, Olsen GS, Busch AK, Mosthaf L: Insulin signaling is inhibited by micromolar concentrations of H2O2: evidence for a role of H2O2 in tumor necrosis factor alpha-mediated insulin resistance. J Biol Chem 1999;274:25078–25084.
Facchini FS, Humphreys MH, DoNascimento CA, Abbasi F, Reaven GM: Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols. Am J Clin Nutr 2000;72:776–779.
Ceriello A: Oxidative stress and glycemic regulation. Metabolism 2000;49:27–29.
Facchini FS, Hua NW, Reaven GM, Stoohs RA: Hyperinsulinemia: the missing link among oxidative stress and age-related diseases? Free Radic Biol Med 2000;29:1302–1306.
Yaqoob M, McClelland P, Patrick AW, Stevenson A, Mason H, White MC, Bell GM: Evidence of oxidant injury and tubular damage in early diabetic nephropathy. QJM 1994;87:601–607.
Oberg BP, McMenamin E, Lucas FL, McMonagle E, Morrow J, Ikizler TA, Himmelfarb J: Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int 2004;65:1009–1016.
Horie K, Miyata T, Maeda K, Miyata S, Sugiyama S, Sakai H, van Ypersole de Strihou C, Monnier VM, Witztum JL, Kurokawa K: Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions: implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest 1997;100:2995–3004.
Suzuki D, Miyata T, Saotome N, Horie K, Inagi R, Yasuda Y, Uchida K, Izuhara Y, Yagame M, Sakai H, Kurokawa K: Immunohistochemical evidence for an increased oxidative stress and carbonyl modification of proteins in diabetic glomerular lesions. J Am Soc Nephrol 1999;10:822–832.
Suzuki D, Miyata T: Carbonyl stress in the pathogenesis of diabetic nephropathy. Intern Med 1999;38:309–314.
Miyata T, Sugiyama S, Suzuki D, Inagi R, Kurokawa K: Increased carbonyl modification by lipids and carbohydrates in diabetic nephropathy. Kidney Int Suppl 1999;71:S54–S56.
Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y: Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996;2:800–803.
Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I: Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997;46:860–867.
Juhan-Vague I, Thompson SG, Jespersen J: Involvement of the hemostatic system in the insulin resistance syndrome: a study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb 1993;13:1865–1873.
Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer DE, Murphy-Sheehy PM, Lipinska I, D’Agostino RB, Wilson PW: Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA 2000;283:221–228.
Juhan-Vague I, Alessi MC: PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost 1997;78:656–660.
Bastard JP, Pieroni L, Hainque B: Relationship between plasma plasminogen activator inhibitor 1 and insulin resistance. Diabetes Metab Res Rev 2000;16:192–201.
Hirano T, Kashiwazaki K, Moritomo Y, Nagano S, Adachi M: Albuminuria is directly associated with increased plasma PAI-1 and factor VII levels in NIDDM patients. Diabetes Res Clin Pract 1997;36:11–18.
Rerolle JP, Hertig A, Nguyen G, Sraer JD, Rondeau EP: Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. Kidney Int 2000;58:1841–1850.
Hagiwara H, Kaizu K, Uriu K, Noguchi T, Takagi I, Qie YL, Seki T, Ariga T: Expression of type-1 plasminogen activator inhibitor in the kidney of diabetic rat models. Thromb Res 2003;111:301–309.
Sarafidis PA, Bakris GL: Protection of the kidney by thiazolidinediones: an assessment from bench to bedside. Kidney Int 2006, in press.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.