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(Stroke. 2006;37:944.)
© 2006 American Heart Association, Inc.

Letters to the Editor

Hyperglycemia and Hyperinsulinemia in Circulatory Disorder After Subarachnoid Hemorrhage

Kazushi Tsuda, MD, FAHA

Division of Cardiology, Department of Medicine, Wakayama Medical University, Wakayama, Japan

To the Editor:

We read with great interest the recent article by Dr Frontera and colleagues¹ dealing with the relationship between hyperglycemia and complications after subarachnoid hemorrhage (SAH). The results of their study demonstrated that hyperglycemia (the average peak daily glucose level >105 mg/dL) after SAH was associated with serious hospital complications, such as congestive heart failure, increased intensive care unit length of stay, and an increased risk of death or severe disability. The authors proposed that strict normoglycemic management in patients with SAH might be important.

Numerous studies have shown that hyperglycemia may actively participate in the regulation of cellular functions. Barbagallo et al² showed that hyperglycemia elevated cytosolic free calcium (Ca) both in myocardial and vascular smooth muscle cells, suggesting that glucose-related excess intracellular Ca might be a fundamental lesion in diabetes that contribute to the elevated blood pressure and cardiac mass in this disease. On the other hand, it is well recognized that hyperglycemia may be associated with hyperinsulinemia. Evidence indicates that hyperinsulinemia might actively participate in the regulation of circulatory disorders. Sela et al³ demonstrated that polymorphonuclear leukocytes (PMN) in essential hypertension showed increased level of intracellular Ca content correlating positively with the individulal’s blood pressure and plasma insulin. They proposed that, because PMN priming may lead to oxidative stress and inflammation, intracellular Ca and insulin are involved in the pathogenesis of hypertension-induced vascular injury. In a study we presented earlier, a relationship between membrane fluidity (a reciprocal value of membrane microviscosity) of erythrocytes and insulin was investigated in essential hypertension by means of an electron paramagnetic resonance method.⁴ It was demonstrated that the higher the plasma insulin level, the lower the membrane fluidity of erythrocytes, which might indicate that hyperinsulinemia might be involved in the regulation of membrane fluidity of erythrocytes. In an in vitro study, we showed that insulin alone and in combination with Ca decreased the membrane fluidity of erythrocytes.⁵ The decreased membrane fluidity of erythrocytes might cause a disturbance in the blood rheologic behavior and the microcirculation, which could contribute, at least in part, to the pathophysiology of circulatory disorders. One hypothesis is that insulin might accelerate abnormalities in intracellular Ca-metabolism and membrane function in blood cells, such as PMN and erythrocytes, which could partially explain the cardiovascular complications in subjects with hyperinsulinemia.

In this context, we speculate that abnormal membrane functions associated with hyperglycemia and hyperinsulinemia might partially explain the increased complications in patients with SAH. Therefore, we would like to know whether hyperinsulinemia might be related to the complications after SAH. Further studies should be performed to assess more precisely the mechanisms by which hyperglycemia could induce complications in patients with SAH.

References

1. Frontera JA, Fernandez A, Claassen J, Schmidt M, Schumacher HC, Wartenberg K, Temes R, Parra A, Ostapkovich ND, Mayer SA. Hyperglycemia after SAH: predictors, asscoated complications, and impact on outcome. Stroke. 2006; 37: 199–203.[Abstract/Free Full Text]
2. Barbagallo M, Shan J, Pang PK, Resnick LM. Glucose-induced alterations of cytosolic free calcium in cultured rat tail artery vascular smooth muscle cells. J Clin Invest. 1995; 95: 763–767.[Medline] [Order article via Infotrieve]
3. Sela S, Shurtz-Swirski R, Farah R, Levy R, Shapiro G, Chezar J, Shasha SM, Kristal B. A link between polymorphonuclear leukocyte intracellular calcium, plasma insulin, and essential hypertension. Am J Hypertens. 2002; 15: 291–295.[CrossRef][Medline] [Order article via Infotrieve]
4. Tsuda K, Kinoshita Y, Nishio I, Masuyama Y. Hyperinsulinemia is a dterminant of membrane fluidity of erythrocytes in essential hypertension. Am J Hypertens. 2001; 14: 419–423.[CrossRef][Medline] [Order article via Infotrieve]
5. Tsuda K, Kinoshita Y, Nishio I, Masuyama Y. The role of insulin in the regulation of membrane fluidity of erythrocytes in essential hypertension: an electron paramagnetic resonance investigation. Am J Hypertens. 2000; 13: 376–382.[CrossRef][Medline] [Order article via Infotrieve]

Jennifer Frontera, MD Stephan Mayer, MD

Division of Stroke and Neuro-Critical Care, Columbia University College of Physicians and Surgeons, New York, NY

Response:

Dr Tsuda postulates that elevated plasma insulin levels lower erythrocyte membrane fluidity leading to adverse rheologic effects and microcirulatory complications. Erythrocyte rigidity and plasma and whole blood viscosities are higher in animal models of non–insulin-dependent diabetes mellitus,¹ but insulin itself may further exacerbate these effects by altering intracellular calcium metabolism. Furthermore, intensive insulin therapy has been shown to have deleterious effects on retinopathy by increasing vascular endothelial growth factor gene expression.²

In contrast, since van den Berghe’s landmark article,³ in which intensive insulin therapy led to substantially reduced mortality and lowered hospital complications in critically ill patients, speculation has arisen over whether glycemic control alone was responsible for these effects or if insulin therapy confers its own protective benefit. Local administration of insulin has been shown to increase the availability of -aminobutyric acid (GABA) and the sensitivity of post-synaptic GABA receptors. Increased GABA-nergic inhibitory effects may be neuroprotective⁴ and indeed, in a separate study, van den Berghe found that intensive insulin therapy reduced the incidence of seizure in patients with isolate brain injury.⁵ Similarly, other nonglycemic effects of insulin include partial correction of abnormal lipid profiles and attenuation of the catabolic state present in critical illness.⁶

In our recent article⁷ we did not find an association between hyperglycemia and vascular complications, such as vasospasm or cerebral infarction, though others have.⁸ We were, however, unable to quantify the amount of insulin our patients received and cannot directly address the effect of insulin on these vascular complications. Thus, though it is clear that hyperglycemia is detrimental in the critically ill, the effects of insulin on endothelial and rheologic function warrant further investigation.

References

1. Kaymaz AA, Tamer S, Albeniz I, Cefle K, Palanduz S, Ozturk S, Salmayenli N. Alterations in rheological properties and erythrocyte membrane proteins in cats with diabetes mellitus. Clin Hemorheol Microcirc. 2005; 33: 81–88.[Medline] [Order article via Infotrieve]
2. Lu M, Amano S, Miyamoto K, Garland R, Keough K, Qin W, Adamis AP. Insulin-induced vascular endothelial growth factor expression in retina. Invest Ophthalmol Vis Sci. 1999; 40: 3281–3286.[Abstract/Free Full Text]
3. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001; 345: 1359–1367.[Abstract/Free Full Text]
4. Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature. 1997; 388: 686–690.[CrossRef][Medline] [Order article via Infotrieve]
5. van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters PJ. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology. 2005; 64 (8): 1348–1353.[Abstract/Free Full Text]
6. Vanhorebeek I, Langouche L, Van den Berghe G. Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness? Curr Opin Crit Care. 2005; 11: 304–311.[CrossRef][Medline] [Order article via Infotrieve]
7. Frontera JA, Fernandez A, Claassen J, Schmidt M, Schumacher HC, Wartenberg K, Temes R, Parra A, Ostapkovich ND, Mayer SA. Hyperglycemia after SAH: predictors, associated complications, and impact on outcome. Stroke. 2006; 37: 199–203.[Abstract/Free Full Text]
8. Charpentier C, Audibert G, Guillemin F, Civit T, Ducrocq X, Bracard S, Hepner H, Picard L, Laxenaire MC. Multivariate analysis of predictors of cerebral vasospasm occurrence after aneurysmal subarachnoid hemorrhage. Stroke. 1999; 30: 1402–1408.[Abstract/Free Full Text]

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