Insulin resistance and cardiovascular disease

Various studies have shown that hyperinsulinaemia is a predictor of cardiovascular disease. The Quebec Study showed that fasting insulin concentrations are independent predictors of CHD. Haffner and colleagues found that people who developed diabetes had higher fasting glucose and insulin concentrations along with elevated blood pressure, lower HDLc and higher TG than in those whose glucose metabolism remained normal. Thus, for the macrovascular complications of type 2 diabetes like stroke or myocardial infarction, the period of increased risk begins or 'the clock starts ticking' even before the onset of hyperglycaemia (Haffner et al., 1990).

Evidence is emerging that inflammation and endothelial dysfunction are likely to be the important contributors to the accelerated atherosclerosis seen in people with insulin resistance, obesity and type 2 diabetes. Atherosclerosis precedes the development of type 2 diabetes and the inflammation may be involved in the underlying process (Pradhan and Ridker, 2002).

Yudkin et al. (1999) showed that inflammatory markers like C-reactive protein (CRP), pro-inflammatory cytokines, IL-6 and TNF-a correlate with obesity and IR. In a prospective study, Pradhan et al. (2001) followed 27 628 women free of diagnosis of diabetes and cardiovascular disease for 4 years and found that baseline elevated markers of systemic inflammation like CRP and IL-6 powerfully predict the development of type 2 diabetes. Ridker et al. found that elevated level of CRP in the previously healthy women predicted the development of type 2 diabetes as well as likelihood of developing myocardial infarction (Pradhan and Ridker, 2002).

Increased levels of circulating inflammatory markers are also found in groups at risk of developing type 2 diabetes such as obese children, women with poly-cystic ovary syndrome, women with a family history of type 2 diabetes and people of South Asian origin and Pima Indians, independently of total BMI (Cook et al., 2000; Forouhi et al., 2001; Kelly et al., 2001; Pannacciulli et al., 2002). These studies showed that inflammatory markers which are related to atherosclerosis also predicted the onset of cardiovascular disease and type 2 diabetes ('common soil hypothesis') (Stern, 1995; Pradhan and Ridker, 2002).

Loss of normal endothelial cell (EC) function is thought to be an early marker of development of atherosclerosis. In type 2 diabetes, there is early endothelial injury probably as a result of hyperglycaemia, hypertension, dyslipidaemia and insulin resistance. Impaired EC dysfunction is also seen in the early stages of diabetes, IGT and in first degree relatives of type 2 diabetes (Figures 9.2 and 9.3).

EC serve as a metabolically active barrier between the lumen and the vessel wall and play a pivotal role in vascular homeostasis. Normal endothelial function includes regulation of vasomotor tone, homeostasis, leucocyte trafficking and vascular smooth muscle cell proliferation and migration. Endothelial cells elaborates Nitric oxide (NO) which mediates vasodilation, antagonizes thrombosis, and has anti-inflammatory properties and inhibits growth of vascular smooth muscle cells (VSMC) (McVeigh et al., 1992; Williams et al., 1996; Stehouwer et al., 1997; Loscalzo, 2001; Storey et al., 2001). In a dysfunctional state, apart from the loss of NO secretion, EC release substances such as AII and endothelin. They mediate vasoconstriction, aggravate thrombosis and activate platelets. These substances are proinflammatory and in the absence of NO, promote growth of VSMC and stimulate adhesion molecules like ICAM and VCAM (intracellular and vascular cell adhesion molecules) (Lim et al., 1999; Figure 9.3).

The mechanisms of EC dysfunction are secondary to hyperglycaemia and resistance to insulin. Hyperglycaemia contributes to EC dysfunction in several ways (glucose hypothesis). Exposure to a high glucose level results in intra-cellular hyperglycaemia that damages the cells by several mechanisms. These


Advanced glycation end products

Diacylglycerol generation

Oxidative stress

PKC activation

Endothelial dysfunction

Figure 9.2 Mechanisms of hyperglycaemia - induced endothelial dysfunction. PKC, protein kinase C.


Dyslipidaemia (LDLc) ,


Dyslipidaemia (LDLc) ,

i NO Î

Local mediators

Growth factors


î Tissue



Î Endothelin/ET-1



î PAI -1






Vasoconstriction Inflammation Vascular Thrombosis Plaque lesion and rupture remodelling

Vasoconstriction Inflammation Vascular Thrombosis Plaque lesion and rupture remodelling

Figure 9.3 Endothelial dysfunction and mediators of vascular injury. NO, nitric oxide; VCAM, vascular cell adhesion molecule; ICAM intracellular adhesion molecule; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; AII, angiotensin II; PAI-1, plasminogen activator inhibitor-1.

include increased activity of the aldose reductase/sorbitol pathway, increased formation of advanced glycation end products (AGE) and increased synthesis of diacylglycerol (DAG) with generation of protein kinase C (PKC). All these mechanisms reflect a single upstream process which is the overproduction of superoxide by the mitochondrial electron transport chain. Generation of superoxide O2 reduces the availability of NO (Hawthorne et al., 1989; Bucala et al., 1991; Wolf et al., 1991; Tesfamariam et al., 1993; Figure 9.2).

Insulin resistance has shown to be associated with EC dysfunction even in the absence of hyperglycaemia (insulin hypothesis). Insulin resistance is implicated in the development of cardiovascular disease. Postreceptor pathway involving phosphatidylinositol-3 (PI-3) kinase activity is implicated in insulin resistance. Insulin normally binds to its receptors and phosphorylates IRS-1, which in turn activates the PI-3 kinase. PI-3 kinase plays a major role in both insulin mediated glucose disposal in adipose tissue and also in NO production by the EC.

The insulin stimulation of PI-3 kinase is reduced in obese subjects and almost absent in type 2 diabetes (Nolan et al., 1997), whereas, insulin action on the mitogen-activated protein kinase (MAPK) is unaffected. This 'selective insulin resistance' results in enhancement of the mitogenic pathway with increased VSMC growth and migration and increase in plasminogen activator inhibitor-1 (PAI-1) and endothelin. This pathway is present in vasculature, heart and kidneys (Begum et al., 1998).

Adipocytes also contribute towards endothelial dysfunction. Adipocyte releases IL-6 and TNF-a. IL-6 is one of the key promoter of hepatic CRP synthesis. CRP in turn has been shown to down-regulates ENOS in vitro and also regulates PAI-1 synthesis and secretion. TNF-a may have a direct effect on EC (Hotamisligil et al. (1993).

Endothelial dysfunction predisposes to atherosclerosis in the presence of increased prothrombotic factors like coagulation abnormalities, increased platelet activation, inflammatory mediators and the presence of oxidized lipoproteins.

Visceral obesity and insulin resistance are associated with an increased level of PAI-1, increased plasma level of fibrinogen, factor VII, and factor VIII C coagulant activities. High levels of PAI-1 predisposes to CHD. Hyperinsuli-naemia, hyperglycaemia and A II are all important simulators of PAI-1 gene expression and PAI-1 production (Meigs et al., 1997; McFarlane et al., 2001). Elevated PAI-1 levels have been found in non-diabetic first degree relatives of type 2 diabetic probands and in patients with established cardiovascular disease. Hyperfibrinogenaemia is a strong independent risk factor for CHD and acts synergistically with dyslipidaemia and hypertension to promote atherosclerosis (Thompson et al., 1995).

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