Skip to main content
AAN.com

Abstract

Background and purpose: Resistance to insulin-mediated glucose uptake by peripheral tissues is a cardinal defect in type 2 diabetes mellitus. Insulin resistance is also common among nondiabetic individuals, and may be an important risk factor for stroke in both populations. The authors review the definition, epidemiology, and treatment of insulin resistance.
Methods: The authors searched Medline (1977–2001) and reviewed bibliographies to identify pertinent English-language publications.
Results: Insulin resistance is present in most patients with type 2 diabetes. It is also common among elderly persons, certain ethnic groups, and persons with hypertension, obesity, physical deconditioning, and vascular disease. The principal pathophysiologic defect is impaired intracellular signaling in muscle tissue leading to defective glycogen synthesis. Insulin resistance is associated with numerous metabolic, hematologic, and cellular events that promote atherosclerosis and coagulation. The association between insulin resistance and risk for stroke has been examined in four case-control studies and five prospective observational cohort studies. Six of the nine studies are methodologically sound and provide evidence that insulin resistance is associated with risk for stroke.
Conclusion: Insulin resistance may be a prevalent risk factor for stroke. New drugs can safely reduce insulin resistance and may have a role in stroke prevention.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

File (table_of_studies_for_e_publishing.pdf)

References

1.
Shinozaki K, Naritomi H, Shimizu T, et al. Role of insulin resistance associated with compensatory hyperinsulinemia in ischemic stroke. Stroke . 1996; 27: 37–43.
2.
Gertler MM, Leetma HE, Koutrouby RJ, Johnson ED. The assessment of insulin, glucose and lipids in ischemic thrombotic cerebrovascular disease. Stroke . 1975; 6: 77–84.
3.
Lindberg O, Tilvis RS, Strandberg TE, et al. Elevated fasting plasma insulin in a general aged population: an innocent companion of cardiovascular diseases. J Am Geriatr Soc . 1997; 45: 407–412.
4.
Wannamethee SG, Perry IJ, Shaper AG. Nonfasting serum glucose and insulin concentrations and the risk of stroke. Stroke . 1999; 30: 1780–1786.
5.
Pyorala M, Miettinen H, Laakso M, Pyorala K. Hyperinsulinemia and the risk of stroke in healthy middle-aged men. The 22 year follow-up results of the Helsinki Policemen Study. Stroke . 1998; 29: 1860–1866.
6.
Kuusisto J, Mykkanen L, Pyorala K, Laakso M. Non-insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects. Stroke . 1994; 25: 1157–1164.
7.
Lakka H-M, Lakka TA, Tuomilehto J, Sivenius J, Salonen JT. Hyperinsulinemia and the risk of cardiovascular death and acute coronary and cerebrovascular events in men. Arch Intern Med . 2000; 160: 1160–1168.
8.
Folsom AR, Rasmussen ML, Chambless LE, et al. Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. Diabetes Care . 1999; 22: 1077–1083.
9.
Lindahl B, Dinesen B, Eliasson M, Roder M, Hallmans G, Stegmayr B. High proinsulin levels precede first-ever stroke in a nondiabetic population. Stroke . 2000; 31: 2936–2941.
10.
Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in essential hypertension. N Engl J Med . 1987; 317: 350–357.
11.
Eriksson J, Franssila-Kallunki J, Ekstrand A, et al. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med . 1989; 321: 337–343.
12.
Hollenbeck C, Reaven GM. Variations in insulin-stimulated glucose uptake in healthy individuals with normal glucose tolerance. J Clin Endocrinol Metab . 1987; 64: 1169–1173.
13.
Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest . 1984; 74: 1238–1246.
14.
Kernan WN, Viscoli CM, Inzucchi SE, et al. Insulin resistance among patients with ischemic stroke and TIA. Stroke . 2002; 33: 389.
15.
Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest . 2000; 106: 171–176.
16.
Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic abnormalities—the role of insulin resistance and the sympathoadrenal system. N Engl J Med . 1996; 334: 374–381.
17.
Zavaroni I, Bonora E, Pagliara M, et al. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med . 1989; 320: 702–706.
18.
Corry DB, Tuck MA. Glucose and insulin metabolism in hypertension. Am J Nephrol . 1996; 16: 223–236.
19.
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.
20.
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 production. J Clin Invest . 1994; 94: 1172–1179.
21.
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.
22.
Vollenweider P, Randin D, Tappy L, Jequier E, Nicod P, Scherrer U. Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans. J Clin Invest . 1994; 93: 2365–2371.
23.
Scherrer U, Sartori C. Insulin as a vascular and sympathoexcitatory hormone. Implications for blood pressure regulation, insulin sensitivity, and cardiovascular morbidity. Circulation . 1997; 96: 4104–4113.
24.
Hu R-M, Levin ER, Pedram A, Frank HJL. Insulin stimulates production and secretion of endothelin from bovine endothelial cells. Diabetes . 1993; 42: 351–358.
25.
Reaven GM, Chen Y-DI, Jeppesen J, Maheux P, Krauss RM. Insulin resistance and hyperinsulinemia in individuals with small, dense, low density lipoprotein particles. J Clin Invest . 1993; 92: 141–146.
26.
van Loon BJP. The cardiovascular risk factor plasminogen activator inhibitor type I is related to insulin resistance. Metabolism . 1993; 42: 945–949.
27.
Imperatore G, Riccardi G, Iovine C, Rivellese AA, Vaccaro O. Plasma fibrinogen: a new factor of the metabolic syndrome. Diabetes Care . 1998; 21: 649–654.
28.
Trovati M, Anfossi G. Insulin, insulin resistance and platelet function: similarities with insulin effects on cultured vascular smooth muscle cells. Diabetologia . 1998; 41: 609–622.
29.
Mansfield MW, Heywood DM, Grant PJ. Circulating levels of factor VII, fibrinogen, and von Willebrand factor and features of Insulin resistance in first-degree relatives of patients with NIDDM. Circulation . 1996; 94: 2171–2176.
30.
Meigs JB, Mittleman MA, Nathan DM, et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis. The Framingham Offspring Study. JAMA . 2000; 283: 221–228.
31.
Association AD. Consensus development conference on insulin resistance. Diabetes Care . 1998; 21: 310–314.
32.
Chen W, Srinivasan SR, Elkasabany A, Berenson GS. The association of cardiovascular risk factor clustering related to insulin resistance syndrome (syndrome X) between young parents and their offspring: the Bobalusa Heart Study. Atherosclerosis . 1999; 145: 197–205.
33.
Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP. Clustering of procoagulant, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol . 2000; 152: 897–907.
34.
Hanson RL, Pratley RE, Bogardus C, et al. Evaluation of simple indices of insulin sensitivity and insulin secretion for use in epidemiologic studies. Am J Epidemiol . 2000; 151: 190–198.
35.
Despres J-P, LaMarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med . 1996; 334: 952–957.
36.
Welborn TA, Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care . 1979; 2: 154–160.
37.
Pyorala K. Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: results from two population studies in Finland. Diabetes Care . 1979; 2: 121–141.
38.
Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia . 1980; 19: 205–210.
39.
Perry IJ, Wannamethee G, Whincup PH, Shaper AG, Walker MK, Alberti KGMM. Serum insulin and incident coronary heart disease in middle-aged British men. Am J Epidemiol . 1996; 144: 224–234.
40.
Feskens EJM, Kromhout D. Hyperinsulinemia, risk factors, and coronary heart disease. The Zutphen Elderly Study. Arterioscler Thromb . 1994; 14: 1641–1647.
41.
Kuusisto J, Mykkanen L, Pyorala K, Laakso M. Hyperinsulinemic microalbuminuria. A new risk indicator for coronary heart disease. Circulation . 1995; 91: 831–837.
42.
Welin L, Eriksson H, Larsson B, Ohlson LO, Svardsudd K, Tibblin G. Hyperinsulinaemia is not a major coronary risk factor in elderly men. Diabetologia . 1992; 35: 766–770.
43.
Hargreaves AD, Logan RL, Elton RA, Buchanan KD, Oliver MF, Riemersma RA. Glucose tolerance, plasma insulin, HDL cholesterol and obesity: 12-year follow-up and development of coronary heart disease in Edinburgh men. Atherosclerosis . 1992; 94: 61–69.
44.
Orchard TJ, Eichner J, Kuller LH, Becker DJ, McCallum LM, Grandits GA. Insulin as a predictor of coronary heart disease: interaction with apolipoprotein E phenotype. A report from the Multiple Risk Factor Intervention Trial. Ann Epidemiol . 1994; 4: 40–45.
45.
Ferrara A, Barrett-Connor EL, Edelstein SL. Hyperinsulinemia does not increase the risk of fatal cardiovascular disease in elderly men or women without diabetes: The Rancho Bernardo Study, 1984–1991. Am J Epidemiol . 1994; 140: 857–869.
46.
Welborn TA, Knuiman MW, Ward N, Whittall DE. Serum insulin is a risk marker for coronary heart disease mortality in men but not in women. Diabetes Res Clin Pract . 1994; 26: 51–59.
47.
Ronnemaa T, Laakso M, Pyorala K, Kallio V, Puuka P. High fasting plasma insulin is an indicator of coronary heart disease in non-insulin-dependent diabetic patients and nondiabetic subjects. Arterioscler Thromb . 1991; 11: 80–90.
48.
Mykkanen L, Laakso M, Pyorala K. High plasma insulin level associated with coronary heart disease in the elderly. Am J Epidemiol . 1993; 137: 1190–1202.
49.
Folsom AR, Szklo M, Stevens J, Liao F, Smith R, Eckfeldt JH. A prospective study of coronary heart disease in relation to fasting insulin, glucose, and diabetes. The Atherosclerosis Risk in communities (ARIC) Study. Diabetes Care . 1997; 20: 935–942.
50.
Ruige JB, Assendelft WJJ, Dekker JM, Kostense PJ, Heine RJ, Bouter LM. Insulin and risk of cardiovascular disease. A meta-analysis. Circulation . 1998; 97: 996–1001.
51.
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med . 1998; 339: 229–234.
52.
Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA . 1990; 263: 2893–2898.
53.
Laakso ML, Sarlund H, Salonen R, et al. Asymptomatic atherosclerosis and insulin resistance. Arterioscler Thromb . 1991; 11: 1068–1076.
54.
Agewall S, Fagerberg B, Attvall S, Wendelhag I, Urbanavicius V, Wikstrand J. Carotid artery wall intima-media thickness is associated with insulin-mediated glucose disposal in men at high and low coronary risk. Stroke . 1995; 26: 956–960.
55.
Howard G, O’Leary DH, Zaccaro D, et al. Insulin sensitivity and atherosclerosis. Circulation . 1996; 93: 1809–1817.
56.
Suzuki M, Shinozaki K, Kanazawa A, et al. Insulin resistance as an independent risk factor for carotid wall thickening. Hypertension . 1996; 28: 593–598.
57.
Bonora E, Tessari R, Micciolo R, et al. Intimal-medial thickness of the carotid artery in nondiabetic and NIDDM patients. Diabetes Care . 1997; 20: 627–631.
58.
Tonino RF. Effect of physical training on the insulin resistance of aging. Am J Physiol . 1989; 256: E352–E356.
59.
Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med . 1998; 338: 867–872.
60.
Nolan J, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med . 1994; 331: 1188–1193.
61.
Wee CC. Physical activity counseling in primary care. The challenge of effecting behavioral change. JAMA . 2001; 286: 717–719.
62.
Schwartz A, Raskin P, Fonseca V, Graveline JF, for the Troglitazone and Exogenous Insulin Study Group. Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. N Engl J Med . 1998; 338: 861–866.
63.
Maggs DG, Buchanan TA, Burant CF, et al. Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. Ann Intern Med . 1998; 128: 176–185.
64.
Buchanan TA, Meehan WP, Jeng YY, et al. Blood pressure lowering by pioglitazone. Evidence for a direct vascular effect. J Clin Invest . 1995; 96: 354–360.
65.
Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab . 1997; 82: 2108–2116.
66.
Villa E, Rabano A, Albarran OG, Ruilope LM, Garcia-Robles R. Effects of chronic combined treatment with captopril and pravastatin on the progression of insulin resistance and cardiovascular alterations in an experimental model of obesity in dogs. Am J Hypertens . 1998; 11: 844–851.
67.
Minamikawa J, Tanaka S, Yamauchi M, Inoue D, Koshiyama H. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab . 1998; 83: 1818–1820.
68.
Koshiyama H, Shimono D, Kuwamura N, Minamikawa J, Nakamura Y. Inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab . 2001; 86: 3452–3456.
69.
Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke. A statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke . 2001; 32: 280–299.

Information & Authors

Information

Published In

Neurology®
Volume 59Number 6September 24, 2002
Pages: 809-815
PubMed: 12349850

Publication History

Received: December 19, 2001
Accepted: May 17, 2002
Published online: September 24, 2002
Published in print: September 24, 2002

Permissions

Request permissions for this article.

Authors

Affiliations & Disclosures

W. N. Kernan, MD
From the Departments of Internal Medicine (Drs. Kernan, Inzucchi, Viscoli, Bravata, and Horwitz), Neurology (Dr. Brass), and Epidemiology & Public Health (Drs. Brass and Horwitz), Yale University School of Medicine; and Veterans Affairs Connecticut Healthcare System (Drs. Brass and Bravata), New Haven, CT.
S. E. Inzucchi, MD
From the Departments of Internal Medicine (Drs. Kernan, Inzucchi, Viscoli, Bravata, and Horwitz), Neurology (Dr. Brass), and Epidemiology & Public Health (Drs. Brass and Horwitz), Yale University School of Medicine; and Veterans Affairs Connecticut Healthcare System (Drs. Brass and Bravata), New Haven, CT.
C. M. Viscoli, PhD
From the Departments of Internal Medicine (Drs. Kernan, Inzucchi, Viscoli, Bravata, and Horwitz), Neurology (Dr. Brass), and Epidemiology & Public Health (Drs. Brass and Horwitz), Yale University School of Medicine; and Veterans Affairs Connecticut Healthcare System (Drs. Brass and Bravata), New Haven, CT.
L. M. Brass, MD
From the Departments of Internal Medicine (Drs. Kernan, Inzucchi, Viscoli, Bravata, and Horwitz), Neurology (Dr. Brass), and Epidemiology & Public Health (Drs. Brass and Horwitz), Yale University School of Medicine; and Veterans Affairs Connecticut Healthcare System (Drs. Brass and Bravata), New Haven, CT.
D. M. Bravata, MD
From the Departments of Internal Medicine (Drs. Kernan, Inzucchi, Viscoli, Bravata, and Horwitz), Neurology (Dr. Brass), and Epidemiology & Public Health (Drs. Brass and Horwitz), Yale University School of Medicine; and Veterans Affairs Connecticut Healthcare System (Drs. Brass and Bravata), New Haven, CT.
R. I. Horwitz, MD
From the Departments of Internal Medicine (Drs. Kernan, Inzucchi, Viscoli, Bravata, and Horwitz), Neurology (Dr. Brass), and Epidemiology & Public Health (Drs. Brass and Horwitz), Yale University School of Medicine; and Veterans Affairs Connecticut Healthcare System (Drs. Brass and Bravata), New Haven, CT.

Notes

Address correspondence and reprint requests to Dr. Walter N. Kernan, Department of Medicine, Yale University School of Medicine, P.O. Box 208025, New Haven, CT 06520-8025; e-mail: [email protected]

Metrics & Citations

Metrics

Citation information is sourced from Crossref Cited-by service.

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

Cited By
  1. Exploring Factors Influencing Stroke Risk: Insights From a Predictive Analysis, Cureus, (2024).https://doi.org/10.7759/cureus.67976
    Crossref
  2. Evaluation of Triglyceride Glucose Index in Patients with Patent Foramen Ovale Who Experienced Cryptogenic Stroke, Journal of Clinical Medicine, 13, 23, (7271), (2024).https://doi.org/10.3390/jcm13237271
    Crossref
  3. Spatial Similarity of MRI-Visible Perivascular Spaces in Healthy Young Adult Twins, Yonsei Medical Journal, 65, 11, (661), (2024).https://doi.org/10.3349/ymj.2023.0581
    Crossref
  4. Insulin resistance and stroke: mechanisms and therapeutic approaches, INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (Ukraine), 20, 1, (80-86), (2024).https://doi.org/10.22141/2224-0721.20.1.2024.1367
    Crossref
  5. Association between the triglyceride-glucose (TyG) index and stroke risk in Chinese normal-weight adults: a population-based study, Diabetology & Metabolic Syndrome, 16, 1, (2024).https://doi.org/10.1186/s13098-024-01421-w
    Crossref
  6. Prognostic significance of the stress hyperglycemia ratio and admission blood glucose in diabetic and nondiabetic patients with spontaneous intracerebral hemorrhage, Diabetology & Metabolic Syndrome, 16, 1, (2024).https://doi.org/10.1186/s13098-024-01293-0
    Crossref
  7. Association between stroke and relative fat mass: a cross-sectional study based on NHANES, Lipids in Health and Disease, 23, 1, (2024).https://doi.org/10.1186/s12944-024-02351-2
    Crossref
  8. Interacting and joint effects of triglyceride-glucose index (TyG) and body mass index on stroke risk and the mediating role of TyG in middle-aged and older Chinese adults: a nationwide prospective cohort study, Cardiovascular Diabetology, 23, 1, (2024).https://doi.org/10.1186/s12933-024-02122-4
    Crossref
  9. Insulin resistance and sarcopenia: a prognostic longitudinal link to stroke risk in middle-aged and elderly Chinese population, BMC Public Health, 24, 1, (2024).https://doi.org/10.1186/s12889-024-20214-4
    Crossref
  10. The role of triglyceride-glucose index in the differential diagnosis of atherosclerotic stroke and cardiogenic stroke, BMC Cardiovascular Disorders, 24, 1, (2024).https://doi.org/10.1186/s12872-024-03857-4
    Crossref
  11. See more
Loading...

View Options

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.

If you need immediate support or to place an order, please call or email customer service:

  • 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
  • 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
  • [email protected]

We appreciate your patience during this time and apologize for any inconvenience.

View options

PDF and All Supplements

Download PDF and Supplementary Material

Full Text

View Full Text

Full Text HTML

View Full Text HTML

Media

Figures

Other

Tables

Share

Share

Share article link

Share