Skip to main content

Advertisement

SpringerLink
Log in

Pre-diabetes, Diabetes, Hyperglycemia, and Stroke: Bittersweet Therapeutic Opportunities

  • Stroke (B. Ovbiagele, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purposeof Review

Diabetes mellitus (DM) causes systemic vascular complications. Chronic hyperglycemia is a hallmark of DM and appears to be at least partially responsible for the vascular complications. In addition, hyperglycemia during acute tissue injury has been postulated to augment the injury. This review addresses the potential therapeutic benefits related to ischemic stroke from lowering hyperglycemia in two settings, in chronic hyperglycemia and during acute ischemic stroke.

Recent Findings

A recent efficacy trial to lower hyperglycemia during acute ischemic stroke showed no significant benefit overall as well as in patient subgroups. This finding helps to establish good clinical practice protocols for patients with acute ischemic stroke and hyperglycemia.

Summary

Hyperglycemia appears to be a key mediator of the systemic vascular complications of DM. Despite current lack of evidence that lowering hyperglycemia during acute ischemic stroke improves functional outcome, unanswered questions remain in specific acute ischemic stroke settings that warrant additional research.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kitada M, Zhang Z, Mima A, King GL. Molecular mechanisms of diabetic vascular complications. J Diabetes Investig. 2010;1:77–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sarwar N, Gao P, KondapallySeshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–22.

    Article  CAS  PubMed  Google Scholar 

  3. Mitsios JP, Ekinci EI, Mitsios GP, Churilov L, Thijs V. Relationship between glycated hemoglobin and stroke risk: a systematic review and meta-analysis. J Am Heart Assoc. 2018;7(11):007858.

    Article  Google Scholar 

  4. Luitse MJA, Biessels GJ, Rutten GEHM, Kappelle LJ. Diabetes, hyperglycaemia, and acute ischaemic stroke. Lancet Neurol. 2012;11:261–71.

    Article  PubMed  Google Scholar 

  5. Lau LH, Lew J, Borschmann K, Thijs V, Ekinci EI. Prevalence of diabetes and its effects on stroke outcomes: a meta-analysis and literature review. J Diabetes Investig. 2019;10(3):780–92.

    Article  PubMed  Google Scholar 

  6. Ntaios G, Papavasileiou V, Bargiota A, Makaritsis K, Michel P. Intravenous insulin treatment in acute stroke: a systematic review and meta-analysis of randomized controlled trials. Int J Stroke. 2014;9(4):489–93.

    Article  CAS  PubMed  Google Scholar 

  7. • Cai X, Zhang Y, Li M, Wu JHY, Mai L, Li J, et al. Association between prediabetes and risk of all cause mortality and cardiovascular disease: updated meta-analysis. BMJ. 2020;370:848–9. This report summarizes the major vascular complications associated with prediabetes.

    Google Scholar 

  8. Spence JD, Viscoli CM, Inzucchi SE, Dearborn-Tomazos J, Ford GA, Gorman M, et al. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial. JAMA Neurol. 2019;76(5):526–35.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ago T, Matsuo R, Hata J, Wakisaka Y, Kuroda J, Kitazono T, et al. Insulin resistance and clinical outcomes after acute ischemic stroke. Neurology. 2018;90(17):E1470–7.

    Article  CAS  PubMed  Google Scholar 

  10. Zhou M, Pan Y, Jing J, Wang Y, Zhao X, Liu L, et al. Association between β-cell function estimated by HOMA-β and prognosis of non-diabetic patients with ischaemic stroke. Eur J Neurol. 2018;25(3):549–55.

    Article  CAS  PubMed  Google Scholar 

  11. • Pan Y, Chen W, Wang Y. Prediabetes and outcome of ischemic stroke or transient ischemic attack a systematic review and meta-analysis. J Stroke Cerebrovasc Dis. 2019;28(3):683–92. This report summarizes the functional outcomes after cerebral ischemic events associated with prediabetes.

  12. Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention of cardiovascular disease through glycemic control in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2009;19(9):604–12.

    Article  CAS  PubMed  Google Scholar 

  13. Ma J, Yang W, Fang N, Zhu W, Wei M. The association between intensive glycemic control and vascular complications in type 2 diabetes mellitus: a meta-analysis. Nutr Metab Cardiovasc Dis. 2009;19(9):596–603.

    Article  CAS  PubMed  Google Scholar 

  14. Despa F, Goldstein LB. Amylin dyshomeostasis hypothesis: small vessel-type ischemic stroke in the setting of type-2 diabetes. Stroke. 2021;52:E244–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Desilles JP, Meseguer E, Labreuche J, Lapergue B, Sirimarco G, Gonzalez-Valcarcel J, et al. Diabetes mellitus, admission glucose, and outcomes after stroke thrombolysis: a registry and systematic review. Stroke. 2013;44:1915–23.

    Article  CAS  PubMed  Google Scholar 

  16. Baird TA, Parsons MW, Phanh T, Butcher KS, Desmond PM, Tress BM, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke. 2003;34(9):2208–14.

    Article  CAS  PubMed  Google Scholar 

  17. Kruyt ND, Biessels GJ, Devries JH, Roos YB. Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management. Nat Rev Neurol Nat Pub Group. 2010;6:145–55.

    Article  CAS  Google Scholar 

  18. Garg R, Chaudhuri A, Munschauer F, Dandona P. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke. 2006;37:267–73.

    Article  CAS  PubMed  Google Scholar 

  19. Suh SW, Shin BS, Ma H, Van Hoecke M, Brennan AM, Yenari MA, et al. Glucose and NADPH oxidase drive neuronal superoxide formation in stroke. Ann Neurol. 2008;64(6):654–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rosso C, Pires C, Corvol JC, Baronnet F, Crozier S, Leger A, et al. Hyperglycaemia, insulin therapy and critical penumbral regions for prognosis in acute stroke: further insights from the INSULINFARCT trial. PLoS ONE. 2015;10(3): e0120230.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ribo M, Molina C, Montaner J, Rubiera M, Delgado-Mederos R, Arenillas JF, et al. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke. 2005;36(8):1705–9.

    Article  CAS  PubMed  Google Scholar 

  22. Saqqur M, Shuaib A, Alexandrov AV, Sebastian J, Khan K, Uchino K. The correlation between admission blood glucose and intravenous rt-PA-induced arterial recanalization in acute ischemic stroke: a multi-centre TCD study. Int J Stroke. 2015;10(7):1087–92.

    Article  PubMed  Google Scholar 

  23. Ahmed N, Dávalos A, Eriksson N, Ford GA, Glahn J, Hennerici M, et al. Association of admission blood glucose and outcome in patients treated with intravenous thrombolysis: results from the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Register (SITS-ISTR). Arch Neurol. 2010;67(9):1123–30.

    Article  PubMed  Google Scholar 

  24. Masrur S, Cox M, Bhatt DL, Smith EE, Ellrodt G, Fonarow GC, et al. Association of acute and chronic hyperglycemia with acute ischemic stroke outcomes post-thrombolysis: findings from get with the guidelines-stroke. J Am Heart Assoc. 2015;4(10):e002193.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Rocco A, Heuschmann PU, Schellinger PD, Köhrmann M, Diedler J, Sykora M, et al. Glycosylated hemoglobin a1 predicts risk for symptomatic hemorrhage after thrombolysis for acute stroke. Stroke. 2013;44(8):2134–8.

    Article  CAS  PubMed  Google Scholar 

  26. Bruno A, Biller J, Adams HP Jr, Clarke WR, Woolson RF, Williams LS, et al. Acute blood glucose level and outcome from ischemic stroke. Neurology. 1999;52(2):280–4.

  27. • Zang L, Zhang D, Yao Y, Wang Y. Symptomatic intracranial hemorrhage in patients with admission hyperglycemia and diabetes after mechanical thrombectomy: a systematic review and meta-analysis. Am J Emerg Med WB Saunders. 2021;45:23–8. This report summarizes the risk of symptomatic hemorrhagic transformation of acute brain infarcts after mechanical thrombectomy in relation to hyperglycemia.

  28. • Perez-Vega C, Domingo RA, Tripathi S, Ramos-Fresnedo A, Kashyap S, Quinones-Hinojosa A, et al. Influence of glucose levels on clinical outcome after mechanical thrombectomy for large-vessel occlusion: a systematic review and meta-analysis. J Neurointerv Surg. 2022;14:17–21. This report sumamrizes the functional outcomes after mechanical thrombectomy for acute stroke in relation to hyperglycemia.

    Google Scholar 

  29. Wu MY, Yiang GT, Liao WT, Tsai APY, Cheng YL, Cheng PW, et al. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem. 2018;46:1650–67.

    Article  CAS  PubMed  Google Scholar 

  30. Bruno A, Kent TA, Coull BM, Shankar RR, Saha C, Becker KJ, et al. Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial. Stroke. 2008;39(2):384–9.

    Article  CAS  PubMed  Google Scholar 

  31. Johnston KC, Hall CE, Kissela BM, Bleck TP, Conaway MR. Glucose regulation in acute stroke patients (GRASP) trial: a randomized pilot trial. Stroke. 2009;40(12):3804–9.

  32. Gray CS, Hildreth AJ, Sandercock PA, O’Connell JE, Johnston DE, Cartlidge NE, et al. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK glucose insulin in stroke trial (GIST-UK). Lancet Neurol. 2007;6(5):397–406.

    Article  CAS  PubMed  Google Scholar 

  33. •• Johnston KC, Bruno A, Pauls Q, Hall CE, Barrett KM, Barsan W, et al. Intensive vs standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke: the SHINE randomized clinical trial. JAMA - J Am Med Assoc. 2019;322(4):326–35. This is the latest efficacy trial of intensive hyperglycemia lowering during acute ischemic stroke.

  34. • Torbey MT, Pauls Q, Gentile N, Falciglia M, Meurer W, Pettigrew CL, et al. Intensive versus standard treatment of hyperglycemia in acute ischemic stroke patient: a randomized clinical trial subgroups analysis. Stroke. 2022;53(5):1510–5. This post hoc analysis of the SHINE efficacy trial focuses on patient subgroups with glycemic parameters of special interest.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Quast MJ, Wei J, Huang NC, Brunder DG, Sell SL, Gonzalez JM, et al. Perfusion deficit parallels exacerbation of cerebral ischemia/reperfusion injury in hyperglycemic rats. J Cereb Blood Flow Metab. 1997;17(5):553–9.

    Article  CAS  PubMed  Google Scholar 

  36. Liu L, Wang Z, Wang X, Song L, Chen H, Bémeur C, et al. Comparison of two rat models of cerebral ischemia under hyperglycemic conditions. Microsurg Wiley-Liss, Inc Microsurg. 2007;27(4):258–62.

    Google Scholar 

  37. Kim JT, Jahan R, Saver JL. Impact of glucose on outcomes in patients treated with mechanical thrombectomy: a post hoc analysis of the solitaire flow restoration with the intention for thrombectomy study. Stroke. 2016;47(1):120–7.

    Article  CAS  PubMed  Google Scholar 

  38. Lee SJ, Hwang YH, Hong JM, Choi JW, Yoon BS, Kang DH, et al. Impact of varying levels of hyperglycemia on clinicoradiographic outcomes after endovascular reperfusion treatment. Sci Rep. 2018;8(1):1–9.

    Google Scholar 

  39. Rinkel LA, Nguyen TTM, Guglielmi V, Groot AE, Posthuma L, Roos YBWEM, et al. High admission glucose is associated with poor outcome after endovascular treatment for ischemic stroke. Stroke. 2020;51:3215–23.

    Article  CAS  PubMed  Google Scholar 

  40. Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007;38(3):967–73.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Medical College of Georgia at Augusta University, Augusta, GA, USA

    Askiel Bruno

Authors
  1. Askiel Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Askiel Bruno.

Ethics declarations

Conflict of Interest

The author declares no competing interests.

Human and Animal Rights and Informed Consent

This article does not involve studies with human or animal subjects.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Stroke.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bruno, A. Pre-diabetes, Diabetes, Hyperglycemia, and Stroke: Bittersweet Therapeutic Opportunities. Curr Neurol Neurosci Rep 22, 781–787 (2022). https://doi.org/10.1007/s11910-022-01236-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-022-01236-0

Keywords

Search

Navigation