European Heart Journal Advance Access originally published online on March 18, 2008
European Heart Journal 2008 29(8):1075-1076; doi:10.1093/eurheartj/ehn116
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Glucose, insulin, and coronary heart disease
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It has been reported that higher plasma glucose levels after acute myocardial infarction (AMI) predict higher mortality in non-diabetic and diabetic patients1 since glucose is pro-inflammatory and insulin has anti-inflammatory actions. The beneficial actions of insulin has been attributed to its inhibitory action on tumour necrosis factor-
(TNF-), macrophage migration inhibitory factor (MIF), and superoxide anion production and increase in the synthesis of eNO, and anti-inflammatory cytokines.2–4 In the light of these observations, it is interesting to note that insulin therapy may relate to a more serious prognosis in patients with coronary artery disease (CAD)5 and the risk of non-fatal myocardial infarction and stroke increased significantly by insulin treatment while metformin was protective.6 These apparently paradoxical and negative results could be due to higher serum glucose levels in the insulin group since glucose has pro-inflammatory actions, whereas insulin is anti-inflammatory in nature.2–4 I suggest that the results could have been more positive had the plasma glucose levels were maintained 
80–100 mg%, such that the production of pro-inflammatory cytokines is suppressed and synthesis and release of anti-inflammatory cytokines is enhanced, and failure to do so would give negative results. Since there could be individual variations in response to the anti-inflammatory actions of insulin, it is important that the plasma levels of pro- and anti-inflammatory cytokines and free radicals should be measured in order to know the adequacy of the dose of insulin instituted. This is supported by the observation that intensive insulin treatment improved survival of the critically ill surgical patients and those without diabetes mellitus who had blood glucose concentrations 110–144 mg% (6.1–8.0 mmol/L) had a 3.9-fold higher risk of death than patients without diabetes who had lower glucose concentrations.7
In this context, it is interesting to note that pyruvate, the intermediate product of glucose metabolism, protects myocardium, intestines, hepatic, and renal tissues from reactive oxygen species and cytokines, and ischaemia/reperfusion-induced injury. Pyruvate inhibited TNF- production, reduced circulating HMGB1 (high-mobility group B1) levels and NF-
B signalling pathways, decreased COX-2 (cyclo-oxygenase-2), iNOS (inducible nitric oxide synthase), and IL-6 (interleukin-6) mRNA expression in animal models with shock, and quenched free radicals.4 Hence, I suggest that plasma levels of TNF-, MIF, HMGB1, IL-6, IL-4, IL-10, pyruvate, and various free radicals need to be measured in addition to plasma glucose concentrations to ensure that insulin regimen adopted is adequate to ensure its beneficial actions. In the absence of such a comprehensive assessment, it is not prudent to conclude that insulin therapy may relate to a more serious prognosis in patients with CAD and the risk of non-fatal myocardial infarction and stroke increased significantly by insulin treatment. This proposal is supported by the recent observation that immunosuppressive therapy is useful in the management of congestive cardiac failure7 that could, in part, be attributed to the fact that CHD is associated with low-grade systemic inflammation.
References
- Goyal A, Mahaffey KW, Garg J, Nicolau JC, Hochman JS, Weaver WD, Theroux P, Oliveira GBF, Todaro TG, Mojcik CF, Armstrong PW, Granger CB. Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study. Eur Heart J (2006) 27:1289–1297.
[Abstract/Free Full Text] - Jeschke MG, Klein D, Bolder U, Einspanier R. Insulin attenuates the systemic inflammatory response in endotoxemic rats. Endocrinology (2004) 145:4084–4093.
[Abstract/Free Full Text] - Das UN. Is insulin an anti-inflammatory molecule? Nutrition (2001) 17:409–413.[CrossRef][Web of Science][Medline]
- Das UN. Glucose, insulin, and acute myocardial infarction. Eur Heart J (2006) 27:21141–2142.
- Anselmino M, Ohrvik J, Malmberg K, Standl E, Ryden L, on behalf of the Euro Heart Survey Investigators. Glucose lowering treatment in patients with coronary artery disease is prognostically important not only in established but also in newly detected diabetes mellitus: a report from the Euro Heart Survey on Diabetes and the Heart. Eur Heart J (2008) 29:177–184.
[Abstract/Free Full Text] - Mellbin LG, Malmberg K, Norhammar A, Wedel H, Ryden L, for the DIGAMI 2 Investigators. The impact of glucose lowering treatment on long-term prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Eur Heart J (2008) 29:166–176.
[Abstract/Free Full Text] - Torre-Amione G, Anker SD, Bourge RC, Colucci WS, Greenberg BH, Hildenbrandt P, Keren A, Motra M, Moye LA, Otterstad JE, Pratt CM, Panikowski P, Rouleau JL, Sestier F, Winkelmann BR, Young JB, for the Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy Investigators. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial. Lancet (2008) 371:228–236.[CrossRef][Medline]
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