Insulin resistance in ischemic stroke


Insulin resistance often refers to a pathological condition in which cells fail to respond to the normal actions of insulin. Increasing literature has noted a critical role of insulin resistance in the pathogenesis of ischemic stroke. Insulin resistance plays an important role in the pathogenesis of ischemic stroke via enhancing advanced changes of atherosclerosis. A variety of literature indicates that insulin resistance enhances platelet adhesion, activation and aggregation which are conducive to the occurrence of ischemic stroke. Insulin resistance also induces hemodynamic disturbances and contributes to the onset of ischemic stroke. In addition, insulin resistance may augment the role of the modifiable risk factors in ischemic stroke and induce the occurrence of ischemic stroke. Preclinical and clinical studies have supported that improving insulin resistance may be an effective measure to prevent or delay ischemic stroke.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2


  1. Bansilal S, Farkouh ME, Fuster V (2007) Role of insulin resistance and hyperglycemia in the development of atherosclerosis. Am J Cardiol 99:6B–14B

  2. Bas DF, Ozdemir AO, Colak E, Kebapci N (2016) Higher insulin resistance level is associated with worse clinical response in acute ischemic stroke patients treated with intravenous thrombolysis. Transl Stroke Res 7:167–171

  3. Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287:2570–2581

  4. Bellolio MF, Gilmore RM, Stead LG (2011) Insulin for glycaemic control in acute ischaemic stroke Cochrane Database Syst Rev:CD005346

  5. Bevers MB, Vaishnav NH, Pham L, Battey TW, Kimberly WT (2016) Hyperglycemia is associated with more severe cytotoxic injury after stroke. J Cereb blood flow Metab 271678X16671730

  6. Bondarenko IZ, Shirshina IA, Kalashnikov V (2014) Antithrombotic therapy after X-ray endovascular treatment: are there specific features in patients with diabetes mellitus? Ter Arkh 86:103–108

  7. Bornfeldt KE, Tabas I (2011) Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab 14:575–585

  8. Busija DW, Katakam PV (2014) Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res 51:175–189

  9. Cade WT (2008) Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther 88:1322–1335

  10. Calleja AI, Garcia-Bermejo P, Cortijo E, Bustamante R, Rojo Martinez E, Gonzalez Sarmiento E, Fernandez-Herranz R, Arenillas JF (2011) Insulin resistance is associated with a poor response to intravenous thrombolysis in acute ischemic stroke. Diabetes Care 34:2413–2417

  11. Cesaroni G, Agabiti N, Forastiere F, Perucci CA (2009) Socioeconomic differences in stroke incidence and prognosis under a universal healthcare system. Stroke 40:2812–2819

  12. Chantler PD, Shrader CD, Tabone LE, d'Audiffret AC, Huseynova K, Brooks SD, Branyan KW, Grogg KA, Frisbee JC (2015) Cerebral cortical microvascular rarefaction in metabolic syndrome is dependent on insulin resistance and loss of nitric oxide bioavailability. Microcirculation 22:435–445

  13. Chazova IE, Mychka VB, Mamyrbaeva KM, Gornostaev VV, Dvoskina IM, Sergienko VB (2004) Cerebrovascular complications in metabolic syndrome: possible approaches to decrease risk. Ter Arkh 76:74–80

  14. Chazova IE, Mychka VB, Gornostaev VV, Dvoskina IM, Sergienko VB (2005) Cerebral perfusion in patients with metabolic syndrome. Zh Nevrol Psikhiatr Im S S Korsakova:8–13

  15. Chen T, Kusunoki M, Sato D, Tsutsui H, Nakamura T, Miyata T, Oshida Y (2013) Clinical effect of addition of beraprost sodium to pioglitazone treatment on the blood glucose levels in patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 121:624–627

  16. Chiu CC, Wu SS, Lee PY, Huang YC, Tan TY, Chang KC (2008) Control of modifiable risk factors in ischemic stroke outpatients by pharmacist intervention: an equal allocation stratified randomized study. J Clin Pharm Ther 33:529–535

  17. Choi JH, Cha JK, Huh JT (2014) Adenosine diphosphate-induced platelet aggregation might contribute to poor outcomes in atrial fibrillation-related ischemic stroke. J Stroke Cerebrovasc Dis 23:e215–e220

  18. Cosmi F, Cosmi D (2010) Hypoglycemic therapy in heart disease patients with type 2 diabetes mellitus. G Ital Cardiol (Rome) 11:460–466

  19. Coucha M, Li W, Hafez S, Abdelsaid M, Johnson MH, Fagan SC, Ergul A (2015) SOD1 overexpression prevents acute hyperglycemia-induced cerebral myogenic dysfunction: relevance to contralateral hemisphere and stroke outcomes. Am J Physiol Heart Circ Physiol 308:H456–H466

  20. Dali-Youcef N, Mecili M, Ricci R, Andres E (2013) Metabolic inflammation: connecting obesity and insulin resistance. Ann Med 45:242–253

  21. Danaei G, Ding EL, Mozaffarian D, Taylor B, Rehm J, Murray CJ, Ezzati M (2009) The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med 6:e1000058

  22. Dandona P, Aljada A, Dhindsa S, Garg R (2003) Insulin as an anti-inflammatory and antiatherosclerotic hormone. Clin Cornerstone Suppl 4:S13–S20

  23. Das UN (2010) A defect in Delta6 and Delta5 desaturases may be a factor in the initiation and progression of insulin resistance, the metabolic syndrome and ischemic heart disease in South Asians. Lipids Health Dis 9:130

  24. De Vecchis R, Baldi C, Palmisani L (2015) Protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a meta-analysis of the literature data. Anadolu Kardiyol Derg 16:2–9

  25. De Vecchis R, Baldi C, Palmisani L (2016) Protective effects of methotrexate against ischemic cardiovascular disorders in patients treated for rheumatoid arthritis or psoriasis: novel therapeutic insights coming from a meta-analysis of the literature data. Anatol J Cardiol 16:2–9

  26. Dearborn JL, Schneider AL, Sharrett AR, Mosley TH, Bezerra DC, Knopman DS, Selvin E, Jack CR, Coker LH, Alonso A, Wagenknecht LE, Windham BG, Gottesman RF (2015) Obesity, insulin resistance, and incident small vessel disease on magnetic resonance imaging: atherosclerosis risk in communities study. Stroke 46:3131–3136

  27. Dentali F, Squizzato A, Ageno W (2009) The metabolic syndrome as a risk factor for venous and arterial thrombosis. Semin Thromb Hemost 35:451–457

  28. Dorrance AM, Matin N, Pires PW (2014) The effects of obesity on the cerebral vasculature. Curr Vasc Pharmacol 12:462–472

  29. Ebron K, Andersen CJ, Aguilar D, Blesso CN, Barona J, Dugan CE, Jones JL, Al-Sarraj T, Fernandez ML (2015) A larger body mass index is associated with increased Atherogenic dyslipidemia, insulin resistance, and low-grade inflammation in individuals with metabolic syndrome. Metab Syndr Relat Disord 13:458–464

  30. Efstathiou SP, Tsiakou AG, Tsioulos DI, Panagiotou TN, Pefanis AV, Achimastos AD, Mountokalakis TD (2007) Prognostic significance of plasma resistin levels in patients with atherothrombotic ischemic stroke. Clin Chim Acta 378:78–85

  31. El-Gendy AA, Abbas AM (2014) Effect of omega-3 fatty acids on haemostatic functions in urocortin-treated obese rats. J Physiol Biochem 70:809–820

  32. Elkind MS, Ramakrishnan P, Moon YP, Boden-Albala B, Liu KM, Spitalnik SL, Rundek T, Sacco RL, Paik MC (2010) Infectious burden and risk of stroke: the northern Manhattan study. Arch Neurol 67:33–38

  33. Els T, Rother J, Beaulieu C, de Crespigny A, Moseley M (1997) Hyperglycemia delays terminal depolarization and enhances repolarization after peri-infarct spreading depression as measured by serial diffusion MR mapping. J Cereb Blood Flow Metab 17:591–595

  34. Fava C, Montagnana M, Favaloro EJ, Guidi GC, Lippi G (2011) Obstructive sleep apnea syndrome and cardiovascular diseases. Semin Thromb Hemost 37:280–297

  35. Fedorova EL, Ruiatkina LA, Bondareva ZG, Nesterenko EV, Ruiatkin DS, Vas'kina EA (2007) Insulin-glucose parameters in healthy women and patients with arterial hypertension and ischemic heart disease in dependence on age and follicle-stimulating hormone levels. Kardiologiia 47:9–14

  36. Ferreiro JL, Angiolillo DJ (2012) Challenges and perspectives of antiplatelet therapy in patients with diabetes mellitus and coronary artery disease. Curr Pharm Des 18:5273–5293

  37. Ferreiro JL, Gomez-Hospital JA, Angiolillo DJ (2010) Platelet abnormalities in diabetes mellitus. Diab Vasc Dis Res 7:251–259

  38. Ferri C, Desideri G, Ferri L, Proietti I, Di Agostino S, Martella L, Mai F, Di Giosia P, Grassi D (2015) Cocoa, blood pressure, and cardiovascular health. J Agric Food Chem 63:9901–9909

  39. Fitzgibbons TP, Czech MP (2016) Emerging evidence for beneficial macrophage functions in atherosclerosis and obesity-induced insulin resistance. J Mol Med (Berl) 94:267–275

  40. Flemming KD, Brown RD Jr (2004) Secondary prevention strategies in ischemic stroke: identification and optimal management of modifiable risk factors. Mayo Clin Proc 79:1330–1340

  41. Floyd JS, Wiggins KL, Christiansen M, Dublin S, Longstreth WT, Smith NL, McKnight B, Heckbert SR, Weiss NS, Psaty BM (2016) Case-control study of oral glucose-lowering drugs in combination with long-acting insulin and the risks of incident myocardial infarction and incident stroke. Pharmacoepidemiol Drug Saf 25:151–160

  42. Fonville S, Zandbergen AA, Koudstaal PJ, den Hertog HM (2014) Prediabetes in patients with stroke or transient ischemic attack: prevalence, risk and clinical management. Cerebrovasc Dis 37:393–400

  43. Fujiwara T, Saitoh S, Takagi S, Takeuchi H, Isobe T, Chiba Y, Miura T, Shimamoto K (2005) Development and progression of atherosclerotic disease in relation to insulin resistance and hyperinsulinemia. Hypertens Res 28:665–670

  44. Gaggini M, Morelli M, Buzzigoli E, DeFronzo RA, Bugianesi E, Gastaldelli A (2013) Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 5:1544–1560

  45. Gast KB, Smit JW, den Heijer M, Middeldorp S, Rippe RC, le Cessie S, de Koning EJ, Jukema JW, Rabelink TJ, de Roos A, Rosendaal FR, de Mutsert R (2013) Abdominal adiposity largely explains associations between insulin resistance, hyperglycemia and subclinical atherosclerosis: the NEO study. Atherosclerosis 229:423–429

  46. Gebel E (2011) The key to glucose: a guide to the hormone (and protein) insulin. Diabetes Forecast 64(32):35

  47. Gentile NT, Vaidyula VR, Kanamalla U, DeAngelis M, Gaughan J, Rao AK (2007) Factor VIIa and tissue factor procoagulant activity in diabetes mellitus after acute ischemic stroke: impact of hyperglycemia. Thromb Haemost 98:1007–1013

  48. Gofir A, Mulyono B, Sutarni S (2017) Hyperglycemia as a prognosis predictor of length of stay and functional outcomes in patients with acute ischemic stroke. Int J Neurosci:1–7

  49. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, Degraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL (2006) Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association stroke Council: cosponsored by the atherosclerotic peripheral vascular disease interdisciplinary working Group; cardiovascular nursing Council; clinical cardiology Council; nutrition, physical activity, and metabolism Council; and the quality of care and outcomes research interdisciplinary working Group: the American Academy of Neurology affirms the value of this guideline. Stroke 37:1583–1633

  50. Grzelkowska-Kowalczyk K, Wieteska W (2005) The impairment of IGF-I-stimulated protein synthesis and activation of protein kinase B, p70(S6k), MAP kinase, and p90(rsk) in mouse C2C12 myogenic cells exposed to high glucose and high insulin. Pol J Vet Sci 8:241–250

  51. Hadjiev DI, Mineva PP, Vukov MI (2003) Multiple modifiable risk factors for first ischemic stroke: a population-based epidemiological study. Eur J Neurol 10:577–582

  52. Hagg S, Thorn LM, Forsblom CM, Gordin D, Saraheimo M, Tolonen N, Waden J, Liebkind R, Putaala J, Tatlisumak T, Groop PH (2014) Different risk factor profiles for ischemic and hemorrhagic stroke in type 1 diabetes mellitus. Stroke 45:2558–2562

  53. Hankey GJ, Feng TZ (2010) Insulin resistance a possible causal and treatable risk factor for ischemic stroke. Arch Neurol 67:1177–1178

  54. Haratz S, Tanne D (2011) Diabetes, hyperglycemia and the management of cerebrovascular disease. Curr Opin Neurol 24:81–88

  55. Hidasi E, Kaplar M, Dioszeghy P, Bereczki D, Csiba L, Limburg M, Fulesdi B (2002) No correlation between impairment of cerebrovascular reserve capacity and electrophysiologically assessed severity of neuropathy in noninsulin-dependent diabetes mellitus. J Diabetes Complicat 16:228–234

  56. Hillegass WB, Brott BC, Dobbs JC, Papapietro SE, Misra VK, Zoghbi GJ (2011) Oral antiplatelet therapy in diabetes mellitus and the role of prasugrel: an overview. Vasc Health Risk Manag 7:445–459

  57. Hilsted J, Bonde-Petersen F, Norgaard MB, Greniman M, Christensen NJ, Parving HH, Suzuki M (1984) Haemodynamic changes in insulin-induced hypoglycaemia in normal man. Diabetologia 26:328–332

  58. Hishinuma A, Majima M, Kurabayashi H (2009) Is insulin resistance related to recurrence of stroke or incident of ischemic heart disease in patients with stroke? A preliminary report J Stroke Cerebrovasc Dis 18:294–297

  59. Ince H, Tasdemir HA, Aydin M, Ozyurek H, Tilki HE (2015) Evaluation of nerve conduction studies in obese children with insulin resistance or impaired glucose tolerance. J Child Neurol 30:989–999

  60. Jimenez-Caballero PE, Lopez-Espuela F, Portilla-Cuenca JC, Jimenez-Gracia MA, Casado-Naranjo I (2013) Detection of vascular risk factors and unknown atrial fibrillation in patients hospitalised in the stroke unit. Rev Neurol 56:464–470

  61. Johnson LA, Zuloaga KL, Kugelman TL, Mader KS, Morre JT, Zuloaga DG, Weber S, Marzulla T, Mulford A, Button D, Lindner JR, Alkayed NJ, Stevens JF, Raber J (2016) Amelioration of metabolic syndrome-associated cognitive impairments in mice via a reduction in dietary fat content or infusion of non-diabetic plasma. EBioMedicine 3:26–42

  62. Jotic A, Milicic T, Covickovic Sternic N, Kostic VS, Lalic K, Jeremic V, Mijajlovic M, Lukic L, Rajkovic N, Civcic M, Macesic M, Seferovic JP, Stanarcic J, Aleksic S, Lalic NM (2015) Decreased insulin sensitivity and impaired fibrinolytic activity in type 2 diabetes patients and nondiabetics with ischemic stroke. Int J Endocrinol 2015:934791

  63. Kain K, Catto AJ, Young J, Bamford J, Bavington J, Grant PJ (2001) Insulin resistance and elevated levels of tissue plasminogen activator in first-degree relatives of South Asian patients with ischemic cerebrovascular disease. Stroke 32:1069–1073

  64. Kain K, Catto AJ, Grant PJ (2003) Associations between insulin resistance and thrombotic risk factors in high-risk South Asian subjects. Diabet Med 20:651–655

  65. Kang BT, Leoni RF, Silva AC (2014) Impaired CBF regulation and high CBF threshold contribute to the increased sensitivity of spontaneously hypertensive rats to cerebral ischemia. Neuroscience 269:223–231

  66. Kaplon-Cieslicka A, Rosiak M, Postula M, Serafin A, Kondracka A, Opolski G, Filipiak KJ (2013) Predictors of high platelet reactivity during aspirin treatment in patients with type 2 diabetes. Kardiol Pol 71:893–902

  67. Katakam PV, Snipes JA, Steed MM, Busija DW (2012) Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J Cereb Blood Flow Metab 32:792–804

  68. Katsumata T, Otori T, Nishiyama Y, Okubo S, Nagayama H, Ueda M, Utsumi K, Yamazaki M, Komaba Y, Katsura K, Katayama Y (2010) Correlation between insulin resistance and white matter lesions among non-diabetic patients with ischemic stroke. Neurol Res 32:743–747

  69. Kaundal RK, Sharma SS (2010) Peroxisome proliferator-activated receptor gamma agonists as neuroprotective agents. Drug News Perspect 23:241–256

  70. Kernan WN, Inzucchi SE (2004) Type 2 diabetes mellitus and insulin resistance: stroke prevention and management. Curr Treat Options Neurol 6:443–450

  71. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Shulman GI, McVeety JC, Horwitz RI (2003) Pioglitazone improves insulin sensitivity among nondiabetic patients with a recent transient ischemic attack or ischemic stroke. Stroke 34:1431–1436

  72. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP Jr, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O'Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR (2016) Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 374:1321–1331

  73. Khan NI, Naz L, Mushtaq S, Rukh L, Ali S, Hussain Z (2009) Ischemic stroke: prevalence of modifiable risk factors in male and female patients in Pakistan. Pak J Pharm Sci 22:62–67

  74. Khan MA, Schultz S, Othman A, Fleming T, Lebron-Galan R, Rades D, Clemente D, Nawroth PP, Schwaninger M (2016) Hyperglycemia in stroke impairs polarization of monocytes/macrophages to a protective Noninflammatory cell type. J Neurosci 36:9313–9325

  75. Kintscher U, Law RE (2005) PPARgamma-mediated insulin sensitization: the importance of fat versus muscle. Am J Physiol Endocrinol Metab 288:E287–E291

  76. Kishida T, Ejima A, Yamamoto K, Tanaka S, Yamamoto T, Mazda O (2015) Reprogrammed functional Brown adipocytes ameliorate insulin resistance and dyslipidemia in diet-induced obesity and type 2 diabetes. Stem Cell Reports 5:569–581

  77. Kitta Y, Nakamura T, Uematsu M, Sugamata W, Deyama J, Fujioka D, Saito Y, Kawabata K, Obata JE, Kugiyama K (2013) Insulin resistance negatively affects long-term outcome in non-diabetic patients with coronary artery disease after therapies to reduce atherosclerotic risk factors. J Cardiol 62:348–353

  78. Kolbitsch C, Lorenz IH, Hormann C, Hinteregger M, Lockinger A, Moser PL, Kremser C, Schocke M, Felber S, Pfeiffer KP, Benzer A (2002) The influence of hyperoxia on regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV) and cerebral blood flow velocity in the middle cerebral artery (CBFVMCA) in human volunteers. Magn Reson Imaging 20:535–541

  79. Kostiuk E, Zubkova ST (1993) Pathogenesis of atherosclerosis in diabetes mellitus. The role of insulin resistance and hyperinsulinemia. Fiziol Zh 39:93–98

  80. Kwon Y, Norby FL, Jensen PN, Agarwal SK, Soliman EZ, Lip GY, Longstreth WT Jr, Alonso A, Heckbert SR, Chen LY (2016) Association of Smoking, alcohol, and obesity with cardiovascular death and ischemic stroke in atrial fibrillation: the atherosclerosis risk in communities (ARIC) study and cardiovascular health study (CHS). PLoS One 11:e0147065

  81. Laakso M (1992) Dyslipidaemias, insulin resistance and atherosclerosis. Ann Med 24:505–509

  82. Laakso M, Sarlund H, Salonen R, Suhonen M, Pyorala K, Salonen JT, Karhapaa P (1991) Asymptomatic atherosclerosis and insulin resistance. Arterioscler Thromb 11:1068–1076

  83. Lagaud GJ, Masih-Khan E, Kai S, van Breemen C, Dube GP (2001) Influence of type II diabetes on arterial tone and endothelial function in murine mesenteric resistance arteries. J Vasc Res 38:578–589

  84. Lebovitz HE, Banerji MA (2001) Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res 56:265–294

  85. Lee KO, Nam JS, Ahn CW, Hong JM, Kim SM, Sunwoo IN, Moon JS, Na SJ, Choi YC (2012) Insulin resistance is independently associated with peripheral and autonomic neuropathy in Korean type 2 diabetic patients. Acta Diabetol 49:97–103

  86. Lesniewski LA, Donato AJ, Behnke BJ, Woodman CR, Laughlin MH, Ray CA, Delp MD (2008) Decreased NO signaling leads to enhanced vasoconstrictor responsiveness in skeletal muscle arterioles of the ZDF rat prior to overt diabetes and hypertension. Am J Physiol Heart Circ Physiol 294:H1840–H1850

  87. Li J, Benashski SE, Siegel C, Liu F, McCullough LD (2010) Adenosine monophosphate activated protein kinase inhibition is protective in both sexes after experimental stroke. Neurosci Lett 482:62–65

  88. Lioutas VA, Alfaro-Martinez F, Bedoya F, Chung CC, Pimentel DA, Novak V (2015) Intranasal insulin and insulin-like growth factor 1 as Neuroprotectants in acute ischemic stroke. Transl Stroke Res 6:264–275

  89. Lu H, Lei S, Zhao J, Chen N (2014) Platelet activity in Chinese obese adolescents with and without insulin resistance. J Thromb Thrombolysis 37:165–170

  90. Luchsinger JA (2010) Insulin resistance, type 2 diabetes, and AD: cerebrovascular disease or neurodegeneration? Neurology 75:758–759

  91. Luitse MJ, Velthuis BK, Kappelle LJ, van der Graaf Y, Biessels GJ (2017) Chronic hyperglycemia is related to poor functional outcome after acute ischemic stroke. Int J Stroke 12:180–186

  92. Lukasik M, Kozubski W (2012) Metabolic syndrome as the risk factor for ischaemic stroke. Neurol Neurochir Pol 46:271–278

  93. Lundstrom A, Laska AC, Von Arbin M, Jorneskog G, Wallen H (2014) Glucose intolerance and insulin resistance as predictors of low platelet response to clopidogrel in patients with minor ischemic stroke or TIA. Platelets 25:102–110

  94. Lv Y, Fang X, Asmaro K, Liu H, Zhang X, Zhang H, Qin X, Ji X (2013) Five-year prognosis after mild to moderate ischemic stroke by stroke subtype: a multi-clinic registry study. PLoS One 8:e75019

  95. Ma L, Feng M, Qian Y, Yang W, Liu J, Han R, Zhu H, Li Y (2015) Insulin resistance is an important risk factor for cognitive impairment in elderly patients with primary hypertension. Yonsei Med J 56:89–94

  96. Mandic M, Rancic N (2011) Risk factors for stroke. Med Pregl 64:600–605

  97. Manucha W, Ritchie B, Ferder L (2015) Hypertension and insulin resistance: implications of mitochondrial dysfunction. Curr Hypertens Rep 17:504

  98. Mayanagi K, Katakam PV, Gaspar T, Domoki F, Busija DW (2008) Acute treatment with rosuvastatin protects insulin resistant (C57BL/6J ob/ob) mice against transient cerebral ischemia. J Cereb Blood Flow Metab 28:1927–1935

  99. Michael KM, Shaughnessy M (2006) Stroke prevention and management in older adults. J Cardiovasc Nurs 21:S21–S26

  100. Moore SF, Williams CM, Brown E, Blair TA, Harper MT, Coward RJ, Poole AW, Hers I (2015) Loss of the insulin receptor in murine megakaryocytes/platelets causes thrombocytosis and alterations in IGF signalling. Cardiovasc Res 107:9–19

  101. Morris JK, Vidoni ED, Perea RD, Rada R, Johnson DK, Lyons K, Pahwa R, Burns JM, Honea RA (2014) Insulin resistance and gray matter volume in neurodegenerative disease. Neuroscience 270:139–147

  102. Muniyappa R, Quon MJ (2007) Insulin action and insulin resistance in vascular endothelium. Curr Opin Clin Nutr Metab Care 10:523–530

  103. Newman JM, Dwyer RM, St-Pierre P, Richards SM, Clark MG, Rattigan S (2009) Decreased microvascular vasomotion and myogenic response in rat skeletal muscle in association with acute insulin resistance. J Physiol 587:2579–2588

  104. Ning, B., X. Wang, Y. Yu, A.B. Waqar, Q. Yu, T. Koike, M. Shiomi, E. Liu, Y. Wang, and J. Fan. 2015. High-fructose and high-fat diet-induced insulin resistance enhances atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Nutr Metab (Lond). 12:30.

  105. Ntaios G, Abatzi C, Alexandrou M, Lambrou D, Chatzopoulos S, Egli M, Ruiz J, Bornstein N, Michel P (2011) Persistent hyperglycemia at 24-48 h in acute hyperglycemic stroke patients is not associated with a worse functional outcome. Cerebrovasc Dis 32:561–566

  106. Ntaios, G., M. Egli, A. Arsovska, D. Joye, Y. Bettex, E. Lauber, A. Eskandari, D.A. S, B. Richoz, J. Ruiz, and P. Michel. 2012. An intravenous insulin protocol for strict glycemic control in acute ischaemic stroke. Eur J Neurol 19:443–451.

  107. Oh J, Riek AE, Darwech I, Funai K, Shao J, Chin K, Sierra OL, Carmeliet G, Ostlund RE Jr, Bernal-Mizrachi C (2015) Deletion of macrophage vitamin D receptor promotes insulin resistance and monocyte cholesterol transport to accelerate atherosclerosis in mice. Cell Rep 10:1872–1886

  108. Ohashi M, Tsuji A, Kaneko M, Matsuda M (2005) Threshold of regional cerebral blood flow for infarction in patients with acute cerebral ischemia. J Neuroradiol 32:337–341

  109. Paillard F (2014) Effects of chocolate consumption on physiology and cardiovascular diseases. Presse Med 43:848–851

  110. Paneni F, Beckman JA, Creager MA, Cosentino F (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 34:2436–2443

  111. Park HY, Kyeong H, Park DS, Lee HS, Chang H, Kim YS, Cho KH (2008) Correlation between insulin resistance and intracranial atherosclerosis in patients with ischemic stroke without diabetes. J Stroke Cerebrovasc Dis 17:401–405

  112. Perez PM, Moore-Carrasco R, Gonzalez DR, Fuentes EQ, Palomo IG (2012) Gene expression of adipose tissue, endothelial cells and platelets in subjects with metabolic syndrome (review). Mol Med Rep 5:1135–1140

  113. Perez-Campos-Mayoral L, Perez-Campos E, Zenteno E, Majluf-Cruz A, Perez-Ortega E, Matias-Perez D, Rodal-Canales FJ, Martinez-Cruz R, Pina-Canseco S, Reyes Franco MA, Mayoral Andrade G, Hernandez P, Gallegos B (2014) Better detection of platelet aggregation in patients with metabolic syndrome using epinephrine and ADP. Diabetol Metab Syndr 6:93

  114. Perez-Jimenez J, Saura-Calixto F (2008) Grape products and cardiovascular disease risk factors. Nutr Res Rev 21:158–173

  115. Pham N, Dhar A, Khalaj S, Desai K, Taghibiglou C (2014) Down regulation of brain cellular prion protein in an animal model of insulin resistance: possible implication in increased prevalence of stroke in pre-diabetics/diabetics. Biochem Biophys Res Commun 448:151–156

  116. Pikija S, Trkulja V, Malojcic B, Mutzenbach JS, Sellner J (2015) A high burden of ischemic stroke in regions of eastern/Central Europe is largely due to modifiable risk factors. Curr Neurovasc Res 12:341–352

  117. Pires, A., P. Martins, A.M. Pereira, P.V. Silva, J. Marinho, M. Marques, E. Castela, C. Sena, and R. Seica. 2015. Insulin resistance, dyslipidemia and cardiovascular changes in a Group of Obese Children. Arq Bras Cardiol 0:0.

  118. Popovic B, Carillo S, Agrinier N, Christophe C, Selton-Suty C, Juilliere Y, Aliot E (2013) Ischemic stroke associated with left cardiac catheterization: the importance of modifiable and non-modifiable risk factors. Am Heart J 165:421–426

  119. Posadas-Romero C, Jorge-Galarza E, Posadas-Sanchez R, Acuna-Valerio J, Juarez-Rojas JG, Kimura-Hayama E, Medina-Urrutia A, Cardoso-Saldana GC (2014) Fatty liver largely explains associations of subclinical hypothyroidism with insulin resistance, metabolic syndrome, and subclinical coronary atherosclerosis. Eur J Endocrinol 171:319–325

  120. Prakash P, Singh V, Jain M, Rana M, Khanna V, Barthwal MK, Dikshit M (2014) Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat. Eur J Pharmacol 727:15–28

  121. Prakash K, Chandran DS, Khadgawat R, Jaryal AK, Deepak KK (2016) Correlations between endothelial function in the systemic and cerebral circulation and insulin resistance in type 2 diabetes mellitus. Diab Vasc Dis Res 13:49–55

  122. Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, Nishigaki I (2013) The vascular endothelium and human diseases. Int J Biol Sci 9:1057–1069

  123. Randriamboavonjy V, Fleming I (2009) Insulin, insulin resistance, and platelet signaling in diabetes. Diabetes Care 32:528–530

  124. Randriamboavonjy V, Mann WA, Elgheznawy A, Popp R, Rogowski P, Dornauf I, Drose S, Fleming I (2015) Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity. Thromb Haemost 114:569–578

  125. Rao GH (2011) Management of type-2 diabetes with anti-platelet therapies: special reference to aspirin. Front Biosci (Schol Ed) 3:1–15

  126. Reikeras O, Gunnes P (1986) Effects of high doses of insulin on systemic haemodynamics and regional blood flows in dogs. Clin Physiol 6:129–138

  127. Rendschmidt T, Luddeke HJ, Renner R, Hepp KD (2000) Insulin resistance. Frequently administration errors are the source MMW Fortschr Med 142:38–41

  128. Rodriguez-Flores M, Garcia-Garcia E, Cano-Nigenda CV, Cantu-Brito C (2014) Relationship of obesity and insulin resistance with the cerebrovascular reactivity: a case control study. Cardiovasc Diabetol 13:2

  129. Roitberg GE, Artamonova EA, Ushakova TI (2005) Predictive significance of insulin resistance and metabolic syndrome for assessment of the degree of endothelium disfunction and early signs of atherosclerotic lesion. Angiol Sosud Khir 11:15–19

  130. Rosso C, Pires C, Corvol JC, Baronnet F, Crozier S, Leger A, Deltour S, Valabregue R, Amor-Sahli M, Lehericy S, Dormont D, Samson Y (2015) Hyperglycaemia, insulin therapy and critical penumbral regions for prognosis in acute stroke: further insights from the INSULINFARCT trial. PLoS One 10:e0120230

  131. Rundek T, Gardener H, Xu Q, Goldberg RB, Wright CB, Boden-Albala B, Disla N, Paik MC, Elkind MS, Sacco RL (2010) Insulin resistance and risk of ischemic stroke among nondiabetic individuals from the northern Manhattan study. Arch Neurol 67:1195–1200

  132. Rusinek H, Ha J, Yau PL, Storey P, Tirsi A, Tsui WH, Frosch O, Azova S, Convit A (2015) Cerebral perfusion in insulin resistance and type 2 diabetes. J Cereb Blood Flow Metab 35:95–102

  133. Russell JC, Ahuja SK, Manickavel V, Rajotte RV, Amy RM (1987) Insulin resistance and impaired glucose tolerance in the atherosclerosis-prone LA/N corpulent rat. Arteriosclerosis 7:620–626

  134. Ryan JP, Sheu LK, Verstynen TD, Onyewuenyi IC, Gianaros PJ (2013) Cerebral blood flow links insulin resistance and baroreflex sensitivity. PLoS One 8:e83288

  135. Saboor M, Moinuddin MA, Ilyas S (2014) Functional status of vascular endothelium in diabetes mellitus. J Ayub Med Coll Abbottabad 26:239–243

  136. Sacco RL (2001) Newer risk factors for stroke. Neurology 57:S31–S34

  137. Saitoh S (2006) Risk of cardiovascular diseases in relation to insulin resistance: the Tanno-Sobetsu study. Nihon Rinsho 64(Suppl 9):59–63

  138. Saltiel AR, Olefsky JM (1996) Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45:1661–1669

  139. Santilli F, Vazzana N, Liani R, Guagnano MT, Davi G (2012) Platelet activation in obesity and metabolic syndrome. Obes Rev 13:27–42

  140. Sarfo FS, Acheampong JW, Appiah LT, Oparebea E, Akpalu A, Bedu-Addo G (2014) The profile of risk factors and in-patient outcomes of stroke in Kumasi. Ghana Ghana Med J 48:127–134

  141. von Sarnowski B, Putaala J, Grittner U, Gaertner B, Schminke U, Curtze S, Huber R, Tanislav C, Lichy C, Demarin V, Basic-Kes V, Ringelstein EB, Neumann-Haefelin T, Enzinger C, Fazekas F, Rothwell PM, Dichgans M, Jungehulsing GJ, Heuschmann PU, Kaps M, Norrving B, Rolfs A, Kessler C, Tatlisumak T (2013) Lifestyle risk factors for ischemic stroke and transient ischemic attack in young adults in the stroke in young Fabry patients study. Stroke 44:119–125

  142. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, Kondo T, Alber J, Galldiks N, Kustermann E, Arndt S, Jacobs AH, Krone W, Kahn CR, Bruning JC (2004) Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A 101:3100–3105

  143. Shinozaki K, Naritomi H, Shimizu T, Suzuki M, Ikebuchi M, Sawada T, Harano Y (1996) Role of insulin resistance associated with compensatory hyperinsulinemia in ischemic stroke. Stroke 27:37–43

  144. Sieber FE, Koehler RC, Derrer SA, Saudek CD, Traystman RJ (1990) Hypoglycemia and cerebral autoregulation in anesthetized dogs. Am J Phys 258:H1714–H1721

  145. Siegler JE, Boehme AK, Kumar AD, Gillette MA, Albright KC, Beasley TM, Martin-Schild S (2013) Identification of modifiable and nonmodifiable risk factors for neurologic deterioration after acute ischemic stroke. J Stroke Cerebrovasc Dis 22:e207–e213

  146. Singh V, Jain M, Misra A, Khanna V, Prakash P, Malasoni R, Dwivedi AK, Dikshit M, Barthwal MK (2015) Curcuma oil ameliorates insulin resistance & associated thrombotic complications in hamster & rat. Indian J Med Res 141:823–832

  147. Slyper AH, Rosenberg H, Kabra A, Weiss MJ, Blech B, Gensler S, Matsumura M (2014) Early atherogenesis and visceral fat in obese adolescents. Int J Obes 38:954–958

  148. Snarska KK, Bachorzewska-Gajewska H, Kapica-Topczewska K, Drozdowski W, Chorazy M, Kulakowska A, Malyszko J (2017) Hyperglycemia and diabetes have different impacts on outcome of ischemic and hemorrhagic stroke. Arch Med Sci 13:100–108

  149. Soleimani M (2015) Insulin resistance and hypertension: new insights. Kidney Int 87:497–499

  150. Sourij H, Schmoelzer I, Dittrich P, Paulweber B, Iglseder B, Wascher TC (2008) Insulin resistance as a risk factor for carotid atherosclerosis: a comparison of the homeostasis model assessment and the short insulin tolerance test. Stroke 39:1349–1351

  151. Sowers JR (1992) Insulin resistance, hyperinsulinemia, dyslipidemia, hypertension, and accelerated atherosclerosis. J Clin Pharmacol 32:529–535

  152. Sowers JR, Standley PR, Ram JL, Jacober S, Simpson L, Rose K (1993) Hyperinsulinemia, insulin resistance, and hyperglycemia: contributing factors in the pathogenesis of hypertension and atherosclerosis. Am J Hypertens 6:260S–270S

  153. Spustova V (1992) Insulin resistance as a risk factor in atherosclerosis. Vnitr Lek 38:1105–1110

  154. Staszewski J, Brodacki B, Kotowicz J, Stepien A (2011) Intravenous insulin therapy in the maintenance of strict glycemic control in nondiabetic acute stroke patients with mild hyperglycemia. J Stroke Cerebrovasc Dis 20:150–154

  155. Stohr R, Federici M (2013) Insulin resistance and atherosclerosis: convergence between metabolic pathways and inflammatory nodes. Biochem J 454:1–11

  156. Suslova TE, Sitozhevskii AV, Ogurkova ON, Kravchenko ES, Kologrivova IV, Anfinogenova Y, Karpov RS (2014) Platelet hemostasis in patients with metabolic syndrome and type 2 diabetes mellitus: cGMP- and NO-dependent mechanisms in the insulin-mediated platelet aggregation. Front Physiol 5:501

  157. Tack CJ, Smits P, Lutterman JA (1992) Role of insulin resistance in diabetes mellitus and other risk factors for cardiovascular diseases. Ned Tijdschr Geneeskd 136:1697–1701

  158. Tangvarasittichai S (2015) Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 6:456–480

  159. Tanne D, Tenenbaum A, Boyko V, Benderly M, Fisman EZ, Matas Z, Adler Y, Behar S (2009) Increased insulin resistance and risk of incident cerebrovascular events in patients with pre-existing atherothrombotic disease. Eur J Neurol 16:1217–1223

  160. Teesalu RV, Keis UE, Kallikorm AP, Tsil'mer K, Kuusk AE (1981) Dynamics of the insulin, somatotropic hormone, glucose and free fatty acid content in the blood during a direct myocardial revascularization operation under neuroleptanalgesia. Kardiologiia 21:97–100

  161. Thacker EL, Psaty BM, McKnight B, Heckbert SR, Longstreth WT Jr, Mukamal KJ, Meigs JB, de Boer IH, Boyko EJ, Carnethon MR, Kizer JR, Tracy RP, Smith NL, Siscovick DS (2011) Fasting and post-glucose load measures of insulin resistance and risk of ischemic stroke in older adults. Stroke 42:3347–3351

  162. Tian XY, Ganeshan K, Hong C, Nguyen KD, Qiu Y, Kim J, Tangirala RK, Tonotonoz P, Chawla A (2016) Thermoneutral housing accelerates metabolic inflammation to potentiate atherosclerosis but not insulin resistance. Cell Metab 23:165–178

  163. Toth PP (2014) Insulin resistance, small LDL particles, and risk for atherosclerotic disease. Curr Vasc Pharmacol 12:653–657

  164. Ueno M, Fujita K, Yamamoto H, Ikeda T, Suga T, Yamaji K, Ikuta S, Kobuke K, Iwanaga Y, Angiolillo DJ, Miyazaki S (2015) Impact of impaired glucose tolerance on clopidogrel response in patients with coronary artery disease. J Thromb Thrombolysis 40:174–181

  165. Urabe T, Watada H, Okuma Y, Tanaka R, Ueno Y, Miyamoto N, Tanaka Y, Hattori N, Kawamori R (2009) Prevalence of abnormal glucose metabolism and insulin resistance among subtypes of ischemic stroke in Japanese patients. Stroke 40:1289–1295

  166. Vazzana N, Ranalli P, Cuccurullo C, Davi G (2012) Diabetes mellitus and thrombosis. Thromb Res 129:371–377

  167. Victor VM (2013) New insights into insulin resistance, cardiovascular diseases and oxidative stress: pathophysiological and clinical consequences. Curr Pharm Des 19:5661–5662

  168. Vignini A, Nanetti L, Moroni C, Testa R, Sirolla C, Marra M, Cenerelli S, Gregori A, Fumelli D, Olivieri F, Mazzanti L, Rabini RA (2008) Platelet nitric oxide production and IR: relation with obesity and hypertriglyceridemia. Nutr Metab Cardiovasc Dis 18:553–558

  169. Viscoli CM, Brass LM, Carolei A, Conwit R, Ford GA, Furie KL, Gorman M, Guarino PD, Inzucchi SE, Lovejoy AM, Parsons MW, Peduzzi PN, Ringleb PA, Schwartz GG, Spence JD, Tanne D, Young LH, Kernan WN (2014) Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the insulin resistance intervention after stroke trial. Am Heart J 168(823–829):e826

  170. Wadley VG, McClure LA, Howard VJ, Unverzagt FW, Go RC, Moy CS, Crowther MR, Gomez CR, Howard G (2007) Cognitive status, stroke symptom reports, and modifiable risk factors among individuals with no diagnosis of stroke or transient ischemic attack in the REasons for geographic and racial differences in stroke (REGARDS) study. Stroke 38:1143–1147

  171. Wannamethee SG, Lowe GD, Shaper AG, Rumley A, Lennon L, Whincup PH (2005) The metabolic syndrome and insulin resistance: relationship to haemostatic and inflammatory markers in older non-diabetic men. Atherosclerosis 181:101–108

  172. Wiernsperger NF (2001) In defense of microvascular constriction in diabetes. Clin Hemorheol Microcirc 25:55–62

  173. Xu G, Liu X, Wu W, Zhang R, Yin Q (2007) Recurrence after ischemic stroke in chinese patients: impact of uncontrolled modifiable risk factors. Cerebrovasc Dis 23:117–120

  174. Yang B, Li TD, Wang JS, Zhi G, Jin WS, Xu Y (2005) Insulin resistance and carotid atherosclerosis in 221 patients with potential hyperglycemia. Chin Med Sci J 20:108–111

  175. Yang SJ, Hwang SY, Choi HY, Yoo HJ, Seo JA, Kim SG, Kim NH, Baik SH, Choi DS, Choi KM (2011) Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: implications for insulin resistance, inflammation, and atherosclerosis. J Clin Endocrinol Metab 96:E1325–E1329

  176. Zethelius B, Cederholm J (2015) Comparison between indexes of insulin resistance for risk prediction of cardiovascular diseases or development of diabetes. Diabetes Res Clin Pract 110:183–192

  177. Zhang Z, Yan J, Shi H (2013) Hyperglycemia as a risk factor of ischemic stroke. J Drug Metab Toxicol 4:153

  178. Zhang CR, Cloonan L, Fitzpatrick KM, Kanakis AS, Ayres AM, Furie KL, Rosand J, Rost NS (2015) Determinants of white matter hyperintensity burden differ at the extremes of ages of ischemic stroke onset. J Stroke Cerebrovasc Dis 24:649–654

  179. Zhang Z, Yan J, Shi H (2016) Role of hypoxia inducible factor 1 in hyperglycemia-exacerbated blood-brain barrier disruption in ischemic stroke. Neurobiol Dis 95:82–92

  180. Zhi H, Wang H, Li T, Pin F (2015) Correlated analysis and pathological study on insulin resistance and cardiovascular endocrine hormone in elderly hypertension patients. Diabetes Metab Syndr 9:67–70

  181. Zhou J, Wu J, Zhang J, Xu T, Zhang H, Zhang Y, Zhang S (2015) Association of stroke clinical outcomes with coexistence of hyperglycemia and biomarkers of inflammation. J Stroke Cerebrovasc Dis 24:1250–1255

  182. Zonneveld TP, Nederkoorn PJ, Westendorp WF, Brouwer MC, van de Beek D, Kruyt ND (2017) Hyperglycemia predicts poststroke infections in acute ischemic stroke. Neurology 88:1415–1421

Download references


This work was supported by grants from the Natural Science Foundation of Hubei Province (2015CFB260), and the Hubei Province Health and Family Planning Scientific Research Project (WJ2015MB219) and the Shiyan Natural Science Foundation (15 K70) and Renmin Hospital, Hubei University of Medicine to Dr. Zhiyou Cai.

Author information

Xiao-Ling Deng and Zhou Liu wrote the preliminary draft and revised details of the manuscript. Chuanling Wang contributed to the collection and sorting of the data and documents. Yanfeng Li and Zhiyou Cai revised all manuscript in detail and modified the manuscript.

Correspondence to Yanfeng Li or Zhiyou Cai.

Ethics declarations

Conflict of interest

None declared.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Deng, X., Liu, Z., Wang, C. et al. Insulin resistance in ischemic stroke. Metab Brain Dis 32, 1323–1334 (2017).

Download citation


  • Ischemic stroke
  • Insulin resistance
  • Atherosclerosis
  • Risk factor