Insulin resistance is a common finding in hypertensive humans and animal models. The Dahl salt-sensitive (S) rat is an ideal model of genetically predetermined insulin resistance and salt-sensitive hypertension. Along the insulin signaling pathway, the insulin receptor substrates 1 and 2 (IRS-1 and -2) are important mediators of insulin signaling. IRS-1 and/or IRS-2 genetic variant(s) and/or enhanced serine phosphorylation correlate with insulin resistance. The present commentary was designed to highlight the significance of IRS-1 and/or -2 in the pathogenesis of insulin resistance. An emphasis will be given to the putative role of IRS-1 and/or -2 genetic variant(s) and serine phosphorylation in precipitating insulin resistance.
FerranniniE.Metabolic abnormalities of hypertension. A lesson in complexity.Hypertension1991; 18: 636–9.
9.
FerranniniE., HaffnerS.M., SternM P.Insulin sensitivity and hypertension.J Hypertens1990; 8: S169–74.
10.
DeFronzoR.A., FerranniniE.Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.Diabetes Care1991; 14: 173–94.
11.
ReavenG.M., TwerskyJ., ChangH.Abnormalities of carbohydrate and lipid metabolism in Dahl rats.Hypertension1991; 18: 630–5.
12.
ShehataM.F.Genetic and dietary salt contributors to insulin resistance in Dahl salt-sensitive (S) rats.Cardiovasc Diabetol2008; 7: 7.
13.
KotchenT.A., ZhangH.Y., CovelliM.Insulin resistance and blood pressure in Dahl rats and in one-kidney, one-clip hypertensive rats.Am J Physiol1991; 261: E692–7.
14.
OgiharaT., AsanoT., AndoK.High-salt diet enhances insulin signaling and induces insulin resistance in Dahl salt-sensitive rats.Hypertension2002; 40: 83–9.
15.
SechiL.A., GriffinC.A., ZingaroL.Glucose metabolism and insulin receptor binding and mRNA levels in tissues of Dahl hypertensive rats.Am J Hypertens1997; 10: 1223–30.
16.
TomiyamaH., KushiroT., AbetaH.Blood pressure response to hyperinsulinemia in salt-sensitive and salt-resistant rats.Hypertension1992; 20: 596–600.
17.
ShehataM.F.Important genetic check-points for insulin resistance in salt-sensitive (S) Dahl rats.Cardiovasc Diabetol2008; 7: 19.
18.
CheathamB., KahnC.R.Insulin action and the insulin signaling network.Endocr Rev1995; 16: 117–42.
SunX.J., CrimminsD.L., MyersM.G.Jr.. Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1.Mol Cell Biol1993; 13: 7418–28.
21.
SunX.J., RothenbergP., KahnC.R.Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein.Nature1991; 352: 73–7.
22.
SunX.J., WangL.M., ZhangY.Role of IRS-2 in insulin and cytokine signalling.Nature1995; 377: 173–7.
23.
AlessiD.R., CohenP.Mechanism of activation and function of protein kinase B.Curr Opin Genet Dev1998; 8: 55–62.
24.
TiroshA., PotashnikR., BashanN.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 Chem1999; 274: 10595–602.
25.
AlmindK., InoueG., PedersenO.A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies.J Clin Invest1996; 97: 2569–75.
26.
BergerD., BarrosoI., SoosM.Genetic variants of insulin receptor substrate-1 (IRS-1) in syndromes of severe insulin resistance. Functional analysis of Ala513Pro and Gly1158Glu IRS-1.Diabet Med2002; 19: 804–9.
27.
CeliF.S., NegriC., TannerK.Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with Type 2 diabetes mellitus.Diabetes Metab Res Rev2000; 16: 370–7.
28.
ClausenJ.O., HansenT., BjorbaekC.Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1.Lancet1995; 346: 397–402.
29.
ImaiY., FuscoA., SuzukiY.Variant sequences of insulin receptor substrate-1 in patients with noninsulin-dependent diabetes mellitus.J Clin Endocrinol Metab1994; 79: 1655–8.
30.
Le FurS., Le StunffC., BougneresP.Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms.Diabetes2002; 51: S304–7.
31.
LeiH.H., CoreshJ., ShuldinerA.R.Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the risk of type 2 diabetes, obesity, and hyperinsulinemia in African-Americans: the Atherosclerosis Risk in Communities Study.Diabetes1999; 48: 1868–72.
32.
MammarellaS., CreatiB., EspositoD.L.Novel allele of the insulin receptor substrate-1 bearing two non-conservative amino acid substitutions in a patient with noninsulin-dependent diabetes mellitus. Mutations in brief no. 130. Online.Hum Mutat1998; 11: 411.
33.
‘t HartL.M., NijpelsG., DekkerJ.M.Variations in insulin secretion in carriers of gene variants in IRS-1 and -2.Diabetes2002; 51: 884–7.
34.
SestiG., FedericiM., HribalM.L.Defects of the insulin receptor substrate (IRS) system in human metabolic disorders.FASEB J2001; 15: 2099–111.
35.
QiaoL.Y., ZhandeR., JettonT.L.In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a novel serine kinase in insulin-resistant rodents.J Biol Chem2002; 277: 26530–9.
36.
LiuY.F., HerschkovitzA., Boura-HalfonS.Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance.Mol Cell Biol2004; 24: 9668–81.
37.
DrazninB.: Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85·: the two sides of a coin.Diabetes2006; 55: 2392–7.
38.
GreeneM.W., SakaueH., WangL.Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation.J Biol Chem2003; 278: 8199–211.
39.
PazK., HemiR., LeRoithD.A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation.J Biol Chem1997; 272: 29911–8.
