Hypoglycemia and the predisposition to cardiovascular disease: Is the pro-inflammatory-pro-coagulant diathesis a plausible explanation?

Abstract

Hypoglycemia is a major stress for the body and patients with diabetes are regularly exposed to it. Factors that predispose to hypoglycemia include the use of insulin and sulfonylureas, renal dysfunction, aging, cognitive impairment, and missed meals [[1]Connelly K.A. Yan A.T. Leiter L.A. Bhatt D.L. Verma S. Cardiovascular implications of hypoglycemia in diabetes mellitus.Circulation. 2015; 132: 2345-2350Crossref PubMed Scopus (40) Google Scholar]. While the clinical manifestations of acute state of hypoglycemia are obvious and treatment is straightforward, we have limited understanding of the long term detrimental consequences of repeated hypoglycemic episodes. Studies in various settings have documented that hypoglycemia is a predictor of mortality. Iatrogenic hypoglycemia after insulin infusions in ICU setting led to increased mortality [2Finfer S. Chittock D.R. Su S.Y. Blair D. Foster D. Dhingra V. Bellomo R. Cook D. Dodek P. Henderson W.R. et al.Intensive versus conventional glucose control in critically ill patients.N. Engl. J. Med. 2009; 360: 1283-1297Crossref PubMed Scopus (3749) Google Scholar, 3Griesdale D.E. de Souza R.J. van Dam R.M. Heyland D.K. Cook D.J. Malhotra A. Dhaliwal R. Henderson W.R. Chittock D.R. Finfer S. et al.Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data.CMAJ. 2009; 180: 821-827Crossref PubMed Scopus (860) Google Scholar]. Spontaneous hypoglycemia in patients admitted to hospital also serves as a predictor of mortality [4Kosiborod M. Inzucchi S.E. Goyal A. Krumholz H.M. Masoudi F.A. Xiao L. Spertus J.A. Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction.JAMA. 2009; 301: 1556-1564Crossref PubMed Scopus (282) Google Scholar, 5Boucai L. Southern W.N. Zonszein J. Hypoglycemia-associated mortality is not drug-associated but linked to comorbidities.Am. J. Med. 2011; 124: 1028-1035Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. The association of hypoglycemia with mortality in these settings may be due to the underlying comorbidities. However, the counter-regulatory hormone surge and inflammation/thrombosis initiated by the hypoglycemia probably play a role as well [[6]Hanefeld M. Duetting E. Bramlage P. Cardiac implications of hypoglycaemia in patients with diabetes – a systematic review.Cardiovasc. Diabetol. 2013; 12: 135Crossref PubMed Scopus (56) Google Scholar]. In patients with both type 1 and type 2 diabetes, severe hypoglycemic episodes are associated with at least a doubling of cardiovascular mortality [[7]Khunti K. Davies M. Majeed A. Thorsted B.L. Wolden M.L. Paul S.K. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: a cohort study.Diabetes Care. 2015; 38: 316-322Crossref PubMed Scopus (227) Google Scholar]. The data are consistent in patients with type 2 diabetes [8Goto A. Arah O.A. Goto M. Terauchi Y. Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis.BMJ. 2013; 347: f4533Crossref PubMed Scopus (367) Google Scholar, 9Zoungas S. Patel A. Chalmers J. de Galan B.E. Li Q. Billot L. Woodward M. Ninomiya T. Neal B. MacMahon S. et al.Severe hypoglycemia and risks of vascular events and death.N. Engl. J. Med. 2010; 363: 1410-1418Crossref PubMed Scopus (1172) Google Scholar]. However, some studies on patients with type 1 diabetes have not documented an association [[10]Sejling A.S. Schouwenberg B. Faerch L.H. Thorsteinsson B. de Galan B.E. Pedersen-Bjergaard U. Association between hypoglycaemia and impaired hypoglycaemia awareness and mortality in people with type 1 diabetes mellitus.Diabet. Med. 2016; 33: 77-83Crossref PubMed Scopus (14) Google Scholar], probably reflective of a lower baseline risk of cardiovascular disease in patients with type 1 diabetes. Whether hypoglycemia is causative for cardiovascular disease or an index of vulnerability is still an open question. Nonetheless, in this commentary we will adopt the stance that it is causative and will attempt to substantiate this hypothesis. It appears that at least 3 pathophysiological mechanisms can be advanced to support this hypothesis: hemodynamic and electrophysiological effects, a pro-thrombotic diathesis and a pro-inflammatory phenotype [1Connelly K.A. Yan A.T. Leiter L.A. Bhatt D.L. Verma S. Cardiovascular implications of hypoglycemia in diabetes mellitus.Circulation. 2015; 132: 2345-2350Crossref PubMed Scopus (40) Google Scholar, 6Hanefeld M. Duetting E. Bramlage P. Cardiac implications of hypoglycaemia in patients with diabetes – a systematic review.Cardiovasc. Diabetol. 2013; 12: 135Crossref PubMed Scopus (56) Google Scholar, 11Dandona P. Chaudhuri A. Dhindsa S. Proinflammatory and prothrombotic effects of hypoglycemia.Diabetes Care. 2010; 33: 1686-1687Crossref PubMed Scopus (62) Google Scholar]. Since hypoglycemia is a life threatening event, the human body responds dramatically by releasing a surge of stress hormones, which are vasoconstrictive and likely responsible (at least in part) for the acute cardiovascular events. In one study of patients with type 2 diabetes and coronary heart disease, whose blood glucose concentrations were continuously monitored, 20% of the episodes of spontaneous hypoglycemia were associated with chest pain [[12]Desouza C. Salazar H. Cheong B. Murgo J. Fonseca V. Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring.Diabetes Care. 2003; 26: 1485-1489Crossref PubMed Scopus (317) Google Scholar]. 40% of these episodes of angina associated with hypoglycemia also had concomitant electrocardiogram changes consistent with ischemia. The activation of sympathoadrenal system (mainly epinephrine), hemodynamic changes, prolongation of the QT interval and the induction of catastrophic cardiac arrhythmias and sudden death after hypoglycemia is well known [[6]Hanefeld M. Duetting E. Bramlage P. Cardiac implications of hypoglycaemia in patients with diabetes – a systematic review.Cardiovasc. Diabetol. 2013; 12: 135Crossref PubMed Scopus (56) Google Scholar]. Based on the constraints of space and the focus of this commentary, we will discuss the other two i.e., pro-thrombotic-pro-inflammatory diathesis to explain the increased CVD risk with hypoglycemia. Hypoglycemia induces platelet hyperaggregability and induces a pro-thrombotic state [13Hutton R.A. Mikhailidis D. Dormandy K.M. Ginsburg J. Platelet aggregation studies during transient hypoglycaemia: a potential method for evaluating platelet function.J. Clin. Pathol. 1979; 32: 434-438Crossref PubMed Scopus (70) Google Scholar, 14Dalsgaard-Nielsen J. Madsbad S. Hilsted J. Changes in platelet function, blood coagulation and fibrinolysis during insulin-induced hypoglycaemia in juvenile diabetics and normal subjects.Thromb. Haemost. 1982; 47: 254-258Crossref PubMed Scopus (71) Google Scholar]. Studies have reported an increase in platelet monocyte aggregates, increase in soluble P-selectin, increase in PAI-1, increased fibrinogen and factor VIII [6Hanefeld M. Duetting E. Bramlage P. Cardiac implications of hypoglycaemia in patients with diabetes – a systematic review.Cardiovasc. Diabetol. 2013; 12: 135Crossref PubMed Scopus (56) Google Scholar, 15Razavi Nematollahi L. Kitabchi A.E. Stentz F.B. Wan J.Y. Larijani B.A. Tehrani M.M. Gozashti M.H. Omidfar K. Taheri E. Proinflammatory cytokines in response to insulin-induced hypoglycemic stress in healthy subjects.Metabolism. 2009; 58: 443-448Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 16Gogitidze Joy N. Hedrington M.S. Briscoe V.J. Tate D.B. Ertl A.C. Davis S.N. Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals.Diabetes Care. 2010; 33: 1529-1535Crossref PubMed Scopus (173) Google Scholar]. Most recently, Joy et al. showed that hypoglycemia and repeated hypoglycemia also prompted increased biomarkers of thrombosis including PAI-1, P-selectin, thrombin-antithrombin complex [[17]Joy N.G. Tate D.B. Younk L.M. Davis S.N. Effects of acute and antecedent hypoglycemia on endothelial function and markers of atherothrombotic balance in healthy humans.Diabetes. 2015; 64: 2571-2580Crossref PubMed Scopus (72) Google Scholar]. However, in the report by Wright et al. showing increase in platelet monocyte aggregates, they failed to show any changes in P-selectin, von Willebrand factor and TPA in patients with type 1 diabetes during hypoglycemia [[18]Wright R.J. Newby D.E. Stirling D. Ludlam C.A. Macdonald I.A. Frier B.M. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes.Diabetes Care. 2010; 33: 1591-1597Crossref PubMed Scopus (147) Google Scholar]. Joy et al. also failed to see an effect of hypoglycemia on PAI-1 and TPA [[16]Gogitidze Joy N. Hedrington M.S. Briscoe V.J. Tate D.B. Ertl A.C. Davis S.N. Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals.Diabetes Care. 2010; 33: 1529-1535Crossref PubMed Scopus (173) Google Scholar]. However, collectively we can conclude that the totality of evidence suggests that hypoglycemia increases the propensity to increased pro-coagulation and hence thrombosis. The other important area is the role of hypoglycemia on inflammation and endothelial dysfunction since this has implications for atherosclerosis the major cause of mortality. Work from several groups has confirmed that hypoglycemia induces both a pro-inflammatory phenotype and endothelial dysfunction. Studies have shown an increased CD40 expression on monocytes, increase in soluble CD40 ligand, and increased pro-inflammatory cytokines such as IL-1, IL-6, IL-8 and TNF-alpha [17Joy N.G. Tate D.B. Younk L.M. Davis S.N. Effects of acute and antecedent hypoglycemia on endothelial function and markers of atherothrombotic balance in healthy humans.Diabetes. 2015; 64: 2571-2580Crossref PubMed Scopus (72) Google Scholar, 18Wright R.J. Newby D.E. Stirling D. Ludlam C.A. Macdonald I.A. Frier B.M. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes.Diabetes Care. 2010; 33: 1591-1597Crossref PubMed Scopus (147) Google Scholar]. Whilst CD40L is largely considered a biomarker of inflammation, it needs to be appreciated that it derives from activated platelets and also denotes increase platelet activity [[19]Pamukcu B. Lip G.Y. Snezhitskiy V. Shantsila E. The CD40-CD40L system in cardiovascular disease.Ann. Med. 2011; 43: 331-340Crossref PubMed Scopus (105) Google Scholar]. A finding that needs to be studied further is the increase in adiponectin levels reported by Joy et al. with hypoglycemia [[16]Gogitidze Joy N. Hedrington M.S. Briscoe V.J. Tate D.B. Ertl A.C. Davis S.N. Effects of acute hypoglycemia on inflammatory and pro-atherothrombotic biomarkers in individuals with type 1 diabetes and healthy individuals.Diabetes Care. 2010; 33: 1529-1535Crossref PubMed Scopus (173) Google Scholar]. In this vein, investigators should also report on anti-inflammatory cytokines such as IL-10, IL-1 receptor antagonist, etc. With respect to endothelial dysfunction, increased levels of soluble ICAM-1, VCAM-1, E-selectin have been reported. Furthermore, the recent study by Joy et al. using Doppler ultrasound showed that there was a significant impairment in flow mediated dilation, mediated by both endogenous and exogenous nitric oxide [[17]Joy N.G. Tate D.B. Younk L.M. Davis S.N. Effects of acute and antecedent hypoglycemia on endothelial function and markers of atherothrombotic balance in healthy humans.Diabetes. 2015; 64: 2571-2580Crossref PubMed Scopus (72) Google Scholar]. As stated above, these effects of hypoglycemia persisted following repeated episode and the investigators should be lauded for this excellent study. Repeated episodes of hypoglycemia further impaired endothelial vasodilation while the rise in epinephrine and cortisol concentrations was slightly blunted after repeated hypoglycemia as compared to a single episode of hypoglycemia. The rise in inflammatory mediators was higher after repeated hypoglycemia as compared to a single hypoglycemic episode. Thus there are convincing data that hypoglycemia induces inflammation, pro-coagulation and endothelial dysfunction and at least some of these effects are enhanced after repeated episodes of hypoglycemia. Repeated hypoglycemic episodes therefore likely have cumulative effects that are detrimental to inflammation-based processes such as atherogenesis and its thrombotic complications. Hence it is possible that hypoglycemia is not only detrimental to the cardiovascular system by inducing sudden events, but also contributes to long term atherosclerosis and hence could be considered as an evolving risk marker. However, the induction of such mechanistic processes has not yet been demonstrated in patients with diabetes. Sadly, the diabetic patient is not spared during hyperglycemia since it also promotes a pro-inflammatory phenotype [[20]Devaraj S. Dasu M.R. Jialal I. Diabetes is a proinflammatory state: a translational perspective.Expert Rev. Endocrinol. Metab. 2010; 5: 19-28Crossref PubMed Scopus (96) Google Scholar], which predisposes to cardiovascular disease. It is, therefore, of interest that a recent study published in this issue of Atherosclerosis measured circulating concentrations of inflammatory mediators in patients with type 1 diabetes in relation to hypoglycemia [[21]Kiec-Wilk B. Matejko B. Razny U. et al.Hypoglycemic episodes are associated with inflammatory status in patients with T1DM.Atherosclerosis. 2016; (in press)PubMed Google Scholar]. In this “real life setting”, blood sugar data were collected on 101 type 1 diabetes patients on insulin pump therapy (mean HbA1c 7.1%) who were self-monitoring their blood sugars around 7–9 times a day (fasting, before meals, 2 hours after meals, bedtime and during special situations such as hypoglycemic episodes, exercise etc) for a 7-day period. Following this period, they provided a fasting blood sample to measure concentrations of IL-6, s-VCAM-1, s-ICAM-1 and s-E-selectin. Based on a HbAIC of 7%, the patients were divided into 2 groups; <7% and >7%. There were more hypoglycemic episodes in the better controlled group (3.2 versus 2.1, p = 0.04). Each patient suffered from a mean of 2.6 episodes of hypoglycemia (defined as blood sugar <55 mg/dl) during the observation week. Using multiple regression analyses, the number of hypoglycemic episodes was the only significant predictor of the levels of sICAM-1, sVCAM-1, E-selectin and IL-6. There was no significant relationship with glucose variability. There was also no significant relationship between inflammatory mediators and number of hypoglycemic episodes. Some limitations of the study need to be mentioned. The patients were not using continuous glucose monitoring devices. Although authors excluded patients who had hypoglycemia unawareness, it is likely that the frequency of hypoglycemic episodes was underestimated [[22]Bay C. Kristensen P.L. Pedersen-Bjergaard U. Tarnow L. Thorsteinsson B. Nocturnal continuous glucose monitoring: accuracy and reliability of hypoglycemia detection in patients with type 1 diabetes at high risk of severe hypoglycemia.Diabetes Technol. Ther. 2013; 15: 371-377Crossref PubMed Scopus (38) Google Scholar]. Whether an accurate estimation of hypoglycemia would have made the associations stronger or diluted the results is not known. Nonetheless the practical study by Kiec-Wilk et al. [[21]Kiec-Wilk B. Matejko B. Razny U. et al.Hypoglycemic episodes are associated with inflammatory status in patients with T1DM.Atherosclerosis. 2016; (in press)PubMed Google Scholar] raises the possibility that type 1 diabetes patients, who suffer from repeated episodes of hypoglycemia, also live in a constant state of generalized inflammation. They would thus be at risk of endothelial dysfunction and accelerated atherosclerosis. The effects of hypoglycemia on inflammation cannot be blamed on higher insulin concentrations because hyperinsulinemia in the presence of euglycemia actually causes a decrease in inflammatory mediators [17Joy N.G. Tate D.B. Younk L.M. Davis S.N. Effects of acute and antecedent hypoglycemia on endothelial function and markers of atherothrombotic balance in healthy humans.Diabetes. 2015; 64: 2571-2580Crossref PubMed Scopus (72) Google Scholar, 23Dandona P. Aljada A. Mohanty P. Ghanim H. Hamouda W. Assian E. Ahmad S. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?.J. Clin. Endocrinol. Metab. 2001; 86: 3257-3265Crossref PubMed Scopus (649) Google Scholar]. Insulin is now well accepted to have anti-inflammatory and antithrombogenic properties. However, hypoglycemia leads to an increase in inflammation in spite of higher circulating insulin concentrations in hyperinsulinemic-hypoglycemic experiments as well as in patients with diabetes. In conclusion, hypoglycemia is linked to increased cardiovascular events and mortality. The surge in catecholamines induces hemodynamic changes and electrophysiological changes that can result in acute events. The thrombogenic phenotype also can predispose and contribute to acute events. Finally the role of increased inflammation both in the acute phase and chronically cannot be underestimated. Clearly, much further research is needed to elucidate the link with atherosclerosis. Since the metabolic milieu is substantially different between non-diabetic controls and patients with diabetes further studies need to focus on patients with diabetes, in the main, and will hence be more relevant to the clinical problem. For the present, therapeutic strategies avoiding hypoglycemia will go a long way in preventing these unwanted and deadly sequelae and the ushering in of newer therapies such as the incretin-based therapies and SGLT-2 inhibitors are a welcome advance for the betterment of diabetes management [[24]Swislocki A. Jialal I. Diabetes management abd cardiovascular risk :are SGLT-2 inhibitors are safest.Metab. Syndr. Relat. Disord. 2016; 14: 3-6Crossref PubMed Scopus (2) Google Scholar]. Hypoglycemic episodes are associated with inflammatory status in patients with type 1 diabetes mellitusAtherosclerosisVol. 251PreviewGlycemic control may be associated with inflammatory status in type 1 diabetes (T1DM). We examined the association between glucose control parameters and circulating inflammation markers in T1DM. Full-Text PDF