Insulin resistance is defined as a clinical state in which a normal or elevated insulin level produces an attenuated biologic response. Specifically, the biologic response most studied is insulin-stimulated glucose disposal, yet the precise cellular mechanism responsible is not yet known. However, the presence of insulin resistance is observed many years before the onset of clinical hyperglycemia and the diagnosis of Type 2 diabetes. Insulin resistance at this stage appears to be significantly associated with a clustering of cardiovascular risk factors predisposing the individual to accelerated cardiovascular disease. An overview of insulin resistance and the associated clinical insulin resistant state will be discussed.
ReavenGM. Bantin lecture 1988: Role of insulin resistance in human disease. Diabetes37:1595–1607, 1988.
2.
HaffnerSM. The prediabetic problem: Development of non-insulin-dependent diabetes mellitus and related abnormalities. J Diabetes Complications11:69–76, 1997.
3.
LilliojaS, MottDM, SpraulM, FerraroR, FoleyJE, RavussinE, KnowlerWC, BennettPH, BogardusC.Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: Prospective studies of Pima Indians. N Engl J Med329:1988–1992, 1993.
4.
MartinBC, WarramJH, KrolewskiAS, BergmanRN, SoeldnerJS, KahnCR. Role of glucose and insulin resistance in development of type II diabetes mellitus: Results of a 25-year follow-up study. Lancet340:925–929, 1992.
5.
American Diabetes Association.Consensus Development Conference on Insulin Resistance1, 5–6 November 1997. Diabetes Care 21:310–314, 1998.
6.
HunterSJ, GarveyWT. Insulin action and insulin resistance: Diseases involving defects in insulin receptors, signal transduction, and the glucose transport effector system. Am J Med105:331–345, 1998.
7.
DeedwaniaPC. The deadly quartet revisited. Am J Med105:1S–3S, 1998.
8.
DeFronzoRA. Insulin resistance, hyperinsulinemia, and coronary artery disease: A complex metabolic web. J Cardiovasc Pharmacol20(Suppl 11):S1–S16, 1992.
9.
HaffnerSM, ValdezRA, HazudaHP, MitchellBD, MoralesPA, SternMP. Prospective analysis of the insulin-resistance syndrome (syndrome X). Diabetes41:715–722, 1992.
10.
OparaJU, LevineJH. The deadly quartet: The insulin resistance syndrome. South Med J90:1162–1168, 1997.
11.
The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type II diabetes. Diabetes Care 22:623–634, 1999.
12.
HaffnerSM, MiettinenH.Insulin resistance implications for type II diabetes mellitus and coronary heart disease. Am J Med103:152–162, 1997.
13.
EschwegeE, RichardJL, ThibultN, DucimetiereP, WarnetJM, ClaudeJR, RosselinGE. Coronary heart disease mortality in relation with diabetes, blood glucose, and plasma insulin levels: The Paris Prospective Study, 10 years later. Horm Metab Res Suppl15:41–46, 1985.
14.
FontbonneAM, EschwegeEM. Insulin and cardiovascular disease. Paris Prospective Study. Diabetes Care14:461–469, 1991.
15.
DesprésJP, LamarcheB, MauriègeP, CantinB, DagenaisGR, MoorjaniS, LupienPJ. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med334:952–957, 1996.
16.
DucimetiereP, EschwegeE, PapozL, RichardJL, ClaudeJR, RosselinG.Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia19:205–210, 1980.
17.
WelbornTA, WearneK.Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care2:154–160, 1979.
18.
PyöräläK.Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: Results from two population studies in Finland. Diabetes Care2:131–141, 1979.
19.
WhiteMF, KahnCR. The insulin signaling system. J Biol Chem269:1–4, 1994.
20.
CheathamB, KahnCR. Insulin action and the insulin signaling network. Endocr Rev16:117–142, 1995.
21.
EbinaY, ArakiE, TairaM, ShimadaF, MoriM, CraikCS, SiddleK, PierceSB, RothRA, RutterWJ. Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin- and antibody-stimulated glucose uptake and receptor kinase activity. Proc Natl Acad Sci U S A84:704–708, 1987.
22.
ChouCK, DullTJ, RussellDS, GherziR, LebwohlD, UllrichA, RosenOM. Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin. J Biol Chem262:1842–1847, 1987.
23.
KimYB, NikoulinaSE, CiaraldiTP, HenryRR, KahnBB. Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type II diabetes. J Clin Invest104:733–741, 1999.
WhiteMF. The insulin signalling system and the IRS proteins. Diabetologia40(Suppl 2):S2–S17, 1997.
26.
LavanBE, FantinVR, ChangET, LaneWS, KellerSR, LienhardGE. A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. J Biol Chem272:21403–21407, 1997.
27.
LavanBE, LaneWS, LienhardGE. The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family. J Biol Chem272:11439–11443, 1997.
28.
SunXJ, RothenbergP, KahnCR, BackerJM, ArakiE, WildenPA, CahillDA, GoldsteinBJ, WhiteMF. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature352:73–77, 1991.
29.
WhiteMF. The IRS-signaling system in insulin and cytokine action. Philos Trans R Soc Lond B Biol Sci351:181–189, 1996.
30.
KahnCR. Diabetes: Causes of insulin resistance. Nature373:384–385, 1995.
31.
CheathamB, VlahosCJ, CheathamL, WangL, BlenisJ, KahnCR. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol14:4902–4911, 1994.
32.
OkadaT, KawanoY, SakakibaraT, HazekiO, UiM.Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes: Studies with a selective inhibitor wortmannin. J Biol Chem269:3568–3573, 1994.
33.
Le Marchand-BrustelY, GautierN, CormontM, Van ObberghenE.Wortmannin inhibits the action of insulin but not that of okadaic acid in skeletal muscle: Comparison with fat cells. Endocrinology136:3564–3570, 1995.
34.
HaraK, YonezawaK, SakaueH, AndoA, KotaniK, KitamuraT, KitamuraY, UedaH, StephensL, JacksonTR. 1-Phosphatidylinositol 3-kinase activity is required for insulin-stimulated glucose transport but not for RAS activation in CHO cells. Proc Natl Acad Sci USA91:7415–7419, 1994.
35.
ShepherdPR, NaveBT, SiddleK.Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: Evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase. Biochem J305:25–28, 1995.
36.
MendezR, MyersMGJ, WhiteMF, RhoadsRE. Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation, and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidylinositol 3-kinase. Mol Cell Biol16:2857–2864, 1996.
37.
SutherlandC, Waltner-LawM, GnudiL, KahnBB, GrannerDK. Activation of the ras mitogen-activated protein kinase-ribosomal protein kinase pathway is not required for the repression of phosphoenolpyruvate carboxykinase gene transcription by insulin. J Biol Chem273:3198–3204, 1998.
38.
FrevertEU, KahnBB. Differential effects of constitutively active phosphatidylinositol 3-kinase on glucose transport, glycogen synthase activity, and DNA synthesis in 3T3-L1 adipocytes. Mol Cell Biol17:190–198, 1997.
39.
TantiJF, GremeauxT, GrilloS, CallejaV, KlippelA, WilliamsLT, Van ObberghenE, Le Marchand-BrustelY.Overexpression of a constitutively active form of phosphatidylinositol 3-kinase is sufficient to promote Glut-4 translocation in adipocytes. J Biol Chem271:25227–25232, 1996.
40.
ShepherdPR, KahnBB. Glucose transporters and insulin action: Implications for insulin resistance and diabetes mellitus. N Engl J Med341:248–257, 1999.
41.
ShulmanGI. Cellular mechanisms of insulin resistance in humans. Am J Cardiol84:3J–10J, 1999.
42.
ClineGW, PetersenKF, KrssakM, ShenJ, HundalRS, TrajanoskiZ, InzucchiS, DresnerA, RothmanDL, ShulmanGI. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type II diabetes. N Engl J Med341:240–246, 1999.
43.
Beck-NielsenH.Mechanisms of insulin resistance in non-oxidative glucose metabolism: The role of glycogen synthase. J Basic Clin Physiol Pharmacol9:255–279, 1998.
44.
QuonMJ, ChenH, IngBL, LiuML, ZarnowskiMJ, YonezawaK, KasugaM, CushmanSW, TaylorSI. Roles of 1-phosphatidylinositol 3-kinase and ras in regulating translocation of Glut-4 in transfected rat adipose cells. Mol Cell Biol15:5403–5411, 1995.
45.
ClarkeJF, YoungPW, YonezawaK, KasugaM, HolmanGD. Inhibition of the translocation of Glut-1 and Glut-4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. Biochem J300:631–635, 1994.
46.
HerbstJJ, AndrewsGC, ContilloLG, SingletonDH, GenereuxPE, GibbsEM, LienhardGE. Effect of the activation of phosphatidylinositol 3-kinase by a thiophosphotyrosine peptide on glucose transport in 3T3-L1 adipocytes. J Biol Chem270:26000–26005, 1995.
47.
KatagiriH, AsanoT, IshiharaH, InukaiK, ShibasakiY, KikuchiM, YazakiY, OkaY.Overexpression of catalytic subunit p110α of phosphatidylinositol 3-kinase increases glucose transport activity with translocation of glucose transporters in 3T3-L1 adipocytes. J Biol Chem271:16987–16990, 1996.
48.
TsakiridisT, McDowellHE, WalkerT, DownesCP, HundalHS, VranicM, KlipA.Multiple roles of phosphatidylinositol 3-kinase in regulation of glucose transport, amino acid transport, and glucose transporters in L6 skeletal muscle cells. Endocrinology136:4315–4322, 1995.
49.
YehJI, GulveEA, RamehL, BirnbaumMJ. The effects of wortmannin on rat skeletal muscle: Dissociation of signaling pathways for insulin- and contraction-activated hexose transport. J Biol Chem270:2107–2111, 1995.
50.
CofferPJ, JinJ, WoodgettJR. Protein kinase B (c-Akt): A multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J335:1–13, 1998.
51.
BurgeringBM, CofferPJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature376:599–602, 1995.
52.
FrankeTF, YangSI, ChanTO, DattaK, KazlauskasA, MorrisonDK, KaplanDR, TsichlisPN. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell81:727–736, 1995.
53.
KohnAD, KovacinaKS, RothRA. Insulin stimulates the kinase activity of RAC-PK, a pleckstrin homology domain containing ser/thr kinase. EMBO J14:4288–4295, 1995.
54.
DidichenkoSA, TiltonB, HemmingsBA, Ballmer-HoferK, ThelenM.Constitutive activation of protein kinase B and phosphorylation of p47phox by a membrane-targeted phosphoinositide 3-kinase. Curr Biol6:1271–1278, 1996.
55.
KlippelA, ReinhardC, KavanaughWM, ApellG, EscobedoMA, WilliamsLT. Membrane localization of phosphatidylinositol 3-kinase is sufficient to activate multiple signal-transducing kinase pathways. Mol Cell Biol16:4117–4127, 1996.
56.
MarkunsJF, WojtaszewskiJF, GoodyearLI. Insulin and exercise decrease glycogen synthase kinase-3 activity by different mechanisms in rat skeletal muscle. J Biol Chem274:24896–24900, 1999.
57.
LawrenceJCJ, RoachPJ. New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes46:541–547, 1997.
58.
VestergaardH.Studies of gene expression and activity of hexokinase, phosphofruclokinase and glycogen synthase in human skeletal muscle in states of altered insulin-stimulated glucose metabolism. Dan Med Bull46:13–34, 1999.
59.
AlessiDR, AndjelkovicM, CaudwellB, CronP, MorriceN, CohenP, HemmingsBA. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J15:6541–6551, 1996.
KitamuraT, OgawaW, SakaueH, HinoY, KurodaS, TakataM, MatsumotoM, MaedaT, KonishiH, KikkawaU, KasugaM.Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport. Mol Cell Biol18:3708–3717, 1998.
62.
HajduchE, AlessiDR, HemmingsBA, HundalHS. Constitutive activation of protein kinase B-α by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells. Diabetes47:1006–1013, 1998.
63.
CrossDA, AlessiDR, CohenP, AndjelkovichM, HemmingsBA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature378:785–789, 1995.
64.
CrossDA, AlessiDR, VandenheedeJR, McDowellHE, HundalHS, CohenP.The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: Evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. Biochem J303:21–26, 1994.
65.
FerranniniE, MariA.How to measure insulin sensitivity. J Hypertens16:895–906, 1998.
66.
Del PratoS.Measurement of insulin resistance in vivo. Drugs58 (Suppl 1):3–6, 1999.
67.
BonoraE, TargherG, AlbericheM, BonadonnaRC, SaggianiF, ZenereMB, MonauniT, MuggeoM.Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity. Diabetes Care23:57–63, 2000.
68.
MatthewsDR, HoskerJP, RudenskiAS, NaylorBA, TreacherDF, TurnerRC. Homeostasis model assessment: Insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia28:412–419, 1985.
69.
Yeni-KomshianH, CarantoniM, AbbasiF, ReavenGM. Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers. Diabetes Care23:171–175, 2000.
70.
AbateN.Insulin resistance and obesity: The role of fat distribution pattern. Diabetes Care19:292–294, 1996.
71.
HowardG, O'LearyDH, ZaccaroD, HaffnerS, RewersM, HammanR, SelbyJV, SaadMF, SavageP, BergmanR.Insulin sensitivity and atherosclerosis: The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation93:1809–1817, 1996.
72.
KaplanNM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med149:1514–1520, 1989.
73.
YamashitaS, NakamuraT, ShimomuraI, NishidaM, YoshidaS, KotaniK, Kameda-TakemuaraK, TokunagaK, MatsuzawaY.Insulin resistance and body fat distribution. Diabetes Care19:287–291, 1996.
74.
VagueJ.La différenciation sexuelle facteur déterminant des formes de l'obésité. Presse Med55:339–340, 1947.
75.
Rebuffe-ScriveM, AnderssonB, OlbeL, BjorntorpP.Metabolism of adipose tissue in intra-abdominal depots of non-obese men and women. Metabolism38:453–458, 1989.
76.
Rebuffe-ScriveM, LonnrothP, MarinP, WesslauC, BjorntorpP, SmithU.Regional adipose tissue metabolism in men and postmenopausal women. Int J Obes11:347–355, 1987.
77.
Rebuffe-ScriveM, AndersonB, OlbeL, BjorntorpP.Metabolism of adipose tissue in intra-abdominal depots in severely obese men and women. Metabolism39:1021–1025, 1990.
78.
ArmelliniF, ZamboniM, RigoL, Bergamo-AndreisIA, RobbiR, De MarchiM, BoselloO.Sonography detection of small intra-abdominal fat variations. Int J Obes15:847–852, 1991.
79.
ArmelliniF, ZamboniM, RigoL, TodescoT, Bergamo-AndreisIA, ProcacciC, BoselloO.The contribution of sonography to the measurement of intra-abdominal fat. J Clin Ultrasound18:563–567, 1990.
80.
OhsuzuF, KosudaS, TakayamaE, YanagidaS, NomiM, KasamatsuH, KusanoS, NakamuraH.Imaging techniques for measuring adipose-tissue distribution in the abdomen: A comparison between computed tomography and 1.5-tesla magnetic resonance spin-echo imaging. Radiat Med16:99–107, 1998.
81.
SitesCK, Calles-EscandonJ, BrochuM, ButterfieldM, AshikagaT, PoehlmanET. Relation of regional fat distribution to insulin sensitivity in postmenopausal women. Fertil Steril73:61–65, 2000.
82.
CefaluWT, WangZQ, WerbelS, Bell-FarrowA, CrouseJR, HinsonWH, TerryJG, AndersonR.Contribution of visceral fat mass to the insulin resistance of aging. Metabolism44:954–959, 1995.
83.
GoodpasterBH, ThaeteFL, KelleyDE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type II diabetes mellitus. Am J Clin Nutr71:885–892, 2000.
84.
GrundySM. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation95:1–4, 1997.
85.
FaganTC, DeedwaniaPC. The cardiovascular dysmetabolic syndrome. Am J Med105:77S–82S, 1998.
86.
GrundySM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol83:25F–29F, 1999.
87.
LamarcheB, LemieuxI, DespresJP. The small, dense LDL phenotype and the risk of coronary heart disease: Epidemiology, pathophysiology, and therapeutic aspects. Diabetes Metab25:199–211, 1999.
88.
SheuWH, JengCY, YoungMS, LeWJ, ChenYT. Coronary artery disease risk predicted by insulin resistance, plasma lipids, and hypertension in people without diabetes. Am J Med Sci319:84–88, 2000.
89.
MacLeanPS, VadlamudiS, MacDonaldKG, PoriesWJ, HoumardJA, BarakatHA. Impact of insulin resistance on lipoprotein subpopulation distribution in lean and morbidly obese nondiabetic women. Metabolism49:285–292, 2000.
90.
CefaluWT. Insulin Resistance. In: LeahyJL, ClarkNG, CefaluWT, Eds. Medical Management of Diabetes Mellitus. New York: Marcel Dekker, Inc., pp57–76, 2000.
91.
TackCJ, SmitsP, DemackerPN, StalenhoefAF. Troglitazone decreases the proportion of small, dense LDL and increases the resistance of LDL to oxidation in obese subjects. Diabetes Care21:796–799, 1998.
92.
HsuehWA, QuinonesMJ, CreagerMA. Endothelium in insulin resistance and diabetes. Diabetes Rev5:343–352, 1997.
93.
HsuehWA, LawRE. Cardiovascular risk continuum: Implications of insulin resistance and diabetes. Am J Med105:4S–14S, 1998.
94.
QuyyumiAA. Endothelial function in health and disease: New insights into the genesis of cardiovascular disease. Am J Med105:32S–39S, 1998.
95.
AvenaR, MitchellME, NylenES, CurryKM, SidawyAN. Insulin action enhancement normalizes brachial artery vasoactivity in patients with peripheral vascular disease and occult diabetes. J Vase Surg28:1024–1031, 1998.
96.
OrchardTJ, EichnerJ, KullerLH, BeckerDJ, McCallumLM, GranditsGA. Insulin as a predictor of coronary heart disease: Interaction with apolipoprotein E phenotype. A report from the Multiple Risk Factor Intervention Trial. Ann Epidemiol4:40–45, 1994.
97.
YarnellJW, SweetnamPM, MarksV, TealeJD, BoltonCH. Insulin in ischaemic heart disease: Are associations explained by triglyceride concentrations? The Caerphilly prospective study. Br Heart J71:293–296, 1994.
98.
RewersM, D'AgostinoRJ, BurkeGL. Coronary artery disease is associated with low insulin sensitivity independent of insulin levels and cardiovascular risk factors. Diabetes45 (Suppl 2):52A, 1996.
99.
HallJE, BrandsMW, HenegarJR. Mechanisms of hypertension and kidney disease in obesity. Ann N Y Acad Sci892:91–107, 1999.
100.
HallJE, BrandsMW, ZappeDH, Alonso-GaliciaM.Cardiovascular actions of insulin: Are they important in long-term blood pressure regulation?Clin Exp Pharmacol Physiol22:689–700, 1995.
101.
HallJE. Hyperinsulinemia: A link between obesity and hypertension?Kidney Int43:1402–1417, 1993.
102.
HallJE, BrandsMW, ZappeDH, DixonWN, MizelleHL, ReinhartGA, HildebrandtDA. Hemodynamic and renal responses to chronic hyperinsulinemia in obese, insulin-resistant dogs. Hypertension25:994–1002, 1995.
103.
KeenHL, BrandsMW, SmithMM, ShekEW, HallJE. Inhibition of thromboxane synthesis attenuates insulin hypertension in rats. Am J Hypertens10:1125–1131, 1997.
104.
BrandsMW, HarrisonDL, KeenHL, GardnerA, ShekEW, HallJE. Insulin-induced hypertension in rats depends on an intact renin-angiotensin system. Hypertension29:1014–1019, 1997.
105.
ShekEW, KeenHL, BrandsMW. Inhibition of nitric oxide synthesis enhances insulin-hypertension in rats. FASEB J10:A556, 1996.
106.
Juhan-VagueI, AlessiMC, VagueP.Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus. Ann Med28:371–380, 1996.
107.
PanahlooA, YudkinJS. Diminished fibrinolysis in diabetes mellitus and its implication for diabetic vascular disease. Coron Artery Dis7:723–731, 1996.
108.
SchneiderDJ, NordtTK, SobelBE. Attenuated fibrinolysis and accelerated atherogenesis in type II diabetic patients. Diabetes42:1–7, 1993.
109.
SobelBE, Woodcock-MitchellJ, SchneiderDJ, HoltRE, MarutsukaK, GoldH.Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type II diabetic compared with nondiabetic patients: A potential factor predisposing to thrombosis and its persistence. Circulation97:2213–2221, 1998.
110.
SobelBE. The potential influence of insulin and plasminogen activator inhibitor type 1 on the formation of vulnerable atherosclerotic plaques associated with type II diabetes. Proc Assoc Am Physicians111:313–318, 1999.
111.
SobelBE. Insulin resistance and thrombosis: A cardiologist's view. Am J Cardiol84:37J–41J, 1999.
112.
Juhan-VagueI, AlessiMC, VagueP.Increased plasma plasminogen activator inhibitor 1 levels: A possible link between insulin resistance and atherothrombosis. Diabetologia34:457–462, 1991.
113.
FestaA, D'AgostinoRJ, MykkanenL, TracyRP, ZaccaroDJ, HalesCN, HaffnerSM. Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance: The Insulin Resistance Atherosclerosis Study (IRAS). Arterioscler Thromb Vase Biol19:562–568, 1999.
114.
MeigsJB, MittlemanMA, NathanDM, ToflerGH, SingerDE, Murphy-SheehyPM, LipinskaI, D'AgostinoRB, WilsonPW. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: The Framing-ham Offspring Study. JAMA283:221–228, 2000.
