Jiwanjeet K. Dhaliwall1, Tony Kim1, Kalam K. Chan1, Michelle Bendeck2,3, and Adria Giacca1,3, Departments of 1Physiology, 2Laboratory Medicine and Pathobiology, and 3Medicine, University of Toronto, Toronto, Canada

Metabolic Syndrome and Insulin Resistance

The metabolic syndrome is a common disorder characterized by the development of a cluster of abnormalities which include abdominal obesity, insulin resistance with or without glucose intolerance, dyslipidemia, hypertension, and a procoagulative inflammatory state [1,2]. The most widely adopted definitions of the metabolic syndrome are those by the National Cholesterol Education Program Adult Treatment Panel III and more recently by the International Diabetes Federation [2,3]. The metabolic syndrome affects at least 25% of the population [4] and is associated with an increased risk of cardiovascular disease (CVD) [1].

The most accepted and unifying hypothesis to describe the pathophysiology of the metabolic syndrome is insulin resistance, mainly due to abdominal obesity [5]. In the insulin resistant state, the ability of insulin to stimulate glucose uptake in peripheral tissues is reduced. Compensatory hyperinsulinemia occurs to maintain normal glucose tolerance. Progressive failure of this compensation leads to impaired glucose tolerance and type 2 diabetes mellitus.

Metabolic Syndrome, Atherosclerosis, and Restenosis

There is an increased risk of CVD associated with the metabolic syndrome [1]. However, the prevalence of CVD depends on which definition of the metabolic syndrome is used. In addition, there is much debate as to whether the metabolic syndrome as a cluster provides a better assessment of CVD risk than the sum of its individual risk factor components [6]. Related to this debate is the question as to whether insulin resistance and/or hyperinsulinemia per se are independent CVD risk factors. Epidemiological studies suggest that this indeed may be the case [7-9]. In the Insulin Resistance and Atherosclerosis Study, an association between insulin resistance and increased carotid intimal medial thickness, an indicator of CVD and a surrogate marker for future cardiovascular events, was established that was partly independent of traditional risk factors and of fasting insulin levels [8].

Pathophysiological studies also suggest the possibility of a causal link between lack of insulin action in the vasculature and key events in the atherogenic process. Insulin resistance is associated with endothelial dysfunction, which is now presumed to presage CVD [10]. Insulin resistance and endothelial dysfunction are also early predictors of restenosis after coronary stenting [11]. Endothelial dysfunction results from decreased nitric oxide (NO) production, and is likely a consequence of insulin resistance at the level of the endothelium [10].

Insulin Actions in the Vasculature

In the vasculature, insulin has both protective and injurious effects. In vitro studies have shown that insulin increases the synthesis of and stimulates eNOS which results in increased NO production by endothelium [12,13]. The NO produced diffuses into the vascular smooth muscle cells (SMCs) to promote vasodilation [13]. NO also inhibits leukocyte adhesion to the endothelium by regulating the expression of adhesion molecules thus promoting an anti-inflammatory response [14]. As well, NO decreases platelet adhesion and aggregation [15]. These protective actions of insulin are mediated through PI3K signaling.

Many in vitro studies have focused on the effects of insulin on the migration of SMCs from media to intima, which plays a role in both atherosclerosis and restenosis. The results are controversial with some studies reporting MAPK-dependent stimulation of SMC migration by insulin at high concentrations [16,17] but NO-cGMP-dependent inhibition of SMC migration at physiological concentrations [18,19]. Furthermore, there have been numerous in vitro studies reporting a MAPK-dependent action of insulin to stimulate SMC proliferation [20-22].

The effects of insulin on vascular growth have not been established in vivo. Our study investigated the effect of insulin on neointimal hyperplasia after balloon catheter injury of the carotid artery. Normal rats were fed a low-fat or high-fat diet and were treated with either subcutaneous blank or insulin implants delivering insulin at a rate of 5U/day [23]. Three days later, rats underwent balloon catheter injury of the carotid artery and after 14 days, the rats were sacrificed to measure neointimal area and proliferation. The rats on chronic insulin treatment and given a low fat control diet had significantly reduced intimal growth after arterial injury. However this effect of insulin was abolished by high fat diet and such diets are known to induce insulin resistance. The decrease in intimal area occurred despite an increase in SMC proliferation [23].

Our results suggest an inhibitory effect of insulin on neointimal hyperplasia; however the mechanism of this effect is unknown. We are currently investigating whether the effect of insulin in vivo is due to decreased migration of SMCs from media to intima, and/or reduced deposition of extracellular matrix by the SMCs, and whether these effects are related to the inhibition of SMC dedifferentiation by insulin. Future studies will focus on the signaling mechanism by which insulin is able to reduce neointimal area after arterial injury in rats.

In summary, we have demonstrated a protective effect of insulin following vascular injury in vivo which was abolished by high fat diet, a well-known means to induce insulin resistance. Thus, our studies support the hypothesis that insulin resistance per se adversely affect the vascular response to injury, and that other risk factors (high-fat diet) act through induction of insulin resistance in the vascular tissue. This would imply that metabolic syndrome, which is characterized by insulin resistance, may by itself provide an intrinsic risk of CVD and thus be different from the sum of its individual risk factor components.

References

1. Grundy SM, Brewer HB, Jr, Cleeman JI, Smith SC, Jr, Lenfant C. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004;109:433-38.
2. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 200623:469-80.
3. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.
4. Groop L, Orho-Melander M. The dysmetabolic syndrome. J Intern Med 2001;250:105-20.
5. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415-28.
6. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005;28:2289-2304.
7. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-57.
8. Howard G, O'Leary DH, Zaccaro D, et al. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation 1996;93:1809-17.
9. Pyorala M, Miettinen H, Halonen P, Laakso M, Pyorala K. Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Arterioscler Thromb Vasc Biol 2000;20:538-44.
10. Hsueh WA, Lyon CJ, Quinones MJ: Insulin resistance and the endothelium. Am J Med 2004;117:109-17.
11. Piatti P, Di Mario C, Monti LD, et al. Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting. Circulation 2003;108:2074-81.
12. Hartell NA, Archer HE, Bailey CJ. Insulin-stimulated endothelial nitric oxide release is calcium independent and mediated via protein kinase B. Biochem Pharmacol 2005;69:781-90.
13. Montagnani M, Chen H, Barr VA, Quon MJ. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem 2001;276:30392-98.
14. Aljada A, Saadeh R, Assian E, Ghanim H, Dandona P. Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide. J Clin Endocrinol Metab 2000;85:2572-75.
15. Trovati M, Massucco P, Mattiello L, et al. The insulin-induced increase of guanosine-3',5'-cyclic monophosphate in human platelets is mediated by nitric oxide. Diabetes 1996;45:768-70
16. Gockerman A, Prevette T, Jones JI, Clemmons DR. Insulin-like growth factor (IGF)-binding proteins inhibit the smooth muscle cell migration responses to IGF-I and IGF-II. Endocrinology 1995;136:4168-73.
17. Grotendorst GR, Chang T, Seppa HE, Kleinman HK, Martin GR. Platelet-derived growth factor is a chemoattractant for vascular smooth muscle cells. J Cell Physiol 1982;113:261-66.
18. Zhang S, Yang Y, Kone BC, Allen JC, Kahn AM. Insulin-stimulated cyclic guanosine monophosphate inhibits vascular smooth muscle cell migration by inhibiting Ca/calmodulin-dependent protein kinase II. Circulation 2003;107:1539-44.
19. Jacob A, Molkentin JD, Smolenski A, Lohmann SM, Begum N. Insulin inhibits PDGF-directed VSMC migration via NO/ cGMP increase of MKP-1 and its inactivation of MAPKs. Am J Physiol Cell Physiol 2002;283:C704-C713.
20. Cruzado M, Risler N, Castro C, Ortiz A, Ruttler ME. Proliferative effect of insulin on cultured smooth muscle cells from rat mesenteric resistance vessels. Am J Hypertens 1998;11:54-58.
21. Xi XP, Graf K, Goetze S, Hsueh WA, Law RE. Inhibition of MAP kinase blocks insulin-mediated DNA synthesis and transcriptional activation of c-fos by Elk-1 in vascular smooth muscle cells. FEBS Lett 1997;417:283-86.
22. Stout RW, Bierman EL, Ross R. Effect of insulin on the proliferation of cultured primate arterial smooth muscle cells. Circ Res 1975;36:319-27.
23. Kim T, Chan KK, Dhaliwall JK, et al. Anti-atherogenic effect of insulin in vivo. J Vasc Res 2005;42:455-62.

Please address correspondence to:
Dr. Adria Giacca
Department of Physiology
University of Toronto
Medical Sciences Building
1 King's College Circle, Room 3336
Toronto, ON M5S 1A8, Canada
Te: +1 416 978 0167
Fax: +1 416 978 4940
E-mail: adria.giacca@utoronto.ca