Diabetes, BMI, Belly Fat & Heart Disease
"Obesity and diabetes as risk factors for coronary artery disease: from the epidemiological aspect to the initial vascular mechanisms"
Diabetes, Obesity and Metabolism
Turku PET Centre and Department of Medicine, Turku University, Turku, Finland
"...Chronic hyperglycaemia increases the risk of coronary artery disease via multiple mechanisms...
... In addition to hyperglycaemia, diabetic long-term complications have been found to contribute to the increased occurrence of coronary artery disease. Associations between nephropathy, retinopathy, neuropathy and coronary artery disease have been demonstrated in diabetic patients...
... A BMI greater than 28 kg/m2 is associated with three to four times higher risk of morbidity from coronary artery disease or stroke than the risk in the general population...
...Abdominal obesity, also known as central or visceral obesity, exists when the waist to hip ratio is > 0.90 in males and > 0.85 in females. Abdominal obesity has been demonstrated to be an independent predictor of silent myocardial ischaemia in otherwise healthy asymptomatic subjects...
... cardiovascular disease is the leading cause of death in diabetic patients...
... Diabetes independently affects coronary endothelial function...
... Diabetic long-term complications such as autonomic neuropathy  and nephropathy seem to have a role in the development of endothelial dysfunction..."
Coronary artery disease, the principal cause of death in developed countries, is a multifactorial disease because approximately 250 risk factors have been suggested . The major risk factors for coronary artery disease are diabetes mellitus, hypertension, dyslipidaemias and smoking. Recently, the American Heart Association (AHA) has classified obesity as a major risk factor for coronary artery disease .
The alarming increase in diabetes is mainly a consequence of the rapid rise in the prevalence of obesity . Eighty per cent of people with type 2 diabetes are overweight or obese, and 10% of subjects with obesity have type 2 diabetes [4,5]. The prevalence of type 2 diabetes is increasing even in children and is reaching epidemic proportions in some western countries . This serious public health problem has been the subject of intensive studies which could help contain the problem before it is beyond the capacity of health care system. The prevention and treatment of coronary artery disease in obese and diabetic subjects require a thorough understanding of cardiovascular pathophysiology.
Endothelial dysfunction appears to be one of the earliest abnormalities in the development of coronary artery disease . Sympathetic activity may also have a role in the pathophysiology of coronary artery disease in obesity and diabetes . The potential initial mechanisms for impaired endothelial function in obese and diabetic subjects are hyperinsulinaemia , hyperglycaemia , free fatty acid metabolism  and diabetic complications . Moreover, in these subjects, leptin [13,14] and C-peptide [15,16] might provide novel mechanisms for coronary artery disease progression.
This article first reviews the role of obesity and diabetes as risk factors for coronary artery disease from the epidemiological aspect to demonstrate clear association with the findings in vascular studies. Second, this article shortly reviews the regulation of coronary arteries and endothelial dysfunction. Finally, the article reviews the initial vascular mechanisms in obesity and diabetes, which are the main focuses of this article.
Obesity is an important risk factor for coronary artery disease [2,17-19]. The World Health Organization  has defined a body mass index (BMI) of 25-30 kg/m2 as overweight and a BMI of over 30 kg/m2 as obesity. In 2000, there were more than 300 million obese adults in the world, and in industrialized countries, the prevalence of obesity is 20% of the adult population . In addition, the prevalence of obesity is rapidly increasing even in children . About one-third of obese people will develop diabetes . A BMI greater than 28 kg/m2 is associated with three to four times higher risk of morbidity from coronary artery disease or stroke than the risk in the general population . Recently, obesity has been found to be associated with the early development of coronary atherosclerosis in adolescent and young adult men . The risk of coronary artery disease increases with the severity of obesity especially for those with abdominal obesity . Abdominal obesity, also known as central or visceral obesity, exists when the waist to hip ratio is > 0.90 in males and > 0.85 in females. Abdominal obesity has been demonstrated to be an independent predictor of silent myocardial ischaemia in otherwise healthy asymptomatic subjects . Men with a waist circumference of > 93 cm have a 31% greater increase in the mean intima media thickness in the common carotid artery when compared with men with a waist circumference of < 85 cm, indicating that abdominal obesity is associated with accelerated progression of atherosclerosis .
The potential links between obesity and increased risk for atherosclerosis are glucose intolerance, hyperinsulinaemia, hyperleptinaemia, free fatty acid metabolism, lipid disorders [reduction of high-density lipoprotein (HDL) and elevation of triglycerides] and hypertension. Hyperinsulinaemia and hyperleptinaemia characterize obese subjects already at the early phase of obesity. Hyperinsulinaemia has been identified by epidemiological studies as an independent risk factor for the development of coronary artery disease, and a link between hyperinsulinaemia and cardiovascular mortality has been suggested [26-28]. Hyperleptinaemia, which has been demonstrated to be associated with increased intima media thickness of common carotid artery , has been also found to be an independent risk factor for coronary artery disease [30,31].
Type 1 and 2 diabetes are important risk factors for the development of coronary artery disease, and cardiovascular disease is the leading cause of death in diabetic patients [32-34]. The incidence of cardiovascular disease among diabetic men is twice and among diabetic women three times that of non-diabetic subjects . Furthermore, type 1 diabetic patients have more severe, extensive and distal coronary artery disease than non-diabetic subjects . Type 1 diabetes is an autoimmune disease triggered by genetic and environmental factors in which progressive destruction of pancreatic beta-cells leads to permanent insulin deficiency and hyperglycaemia. In contrast, type 2 diabetes is one component of the metabolic syndrome and is strongly associated with obesity and physical inactivity. Although type 2 diabetes is frequently associated with hypertension and dyslipidaemia, the other classical risk factors for coronary artery disease do not explain all the increased atherosclerotic burden seen in the diabetic subjects .
Poor glycaemic control is associated with microvascular complications (retinopathy, nephropathy and neuropathy) in type 1 diabetic patients [36-38]. In addition, poor glycaemic control seems to act as an independent risk factor for coronary artery disease in diabetic patients [39-42]. In the Diabetes Control and Complications Trial (1993), intensive therapy reduced the risk of coronary artery disease by 41% in patients with type 1 diabetes. On the other hand, the UK Prospective Diabetes Study (UKPDS) showed that treatment of other cardiovascular risk factors in type 2 diabetic patients appears to be more effective at preventing macrovascular disease than treatment of hyperglycaemia. Thus, in type 2 diabetic patients, treatment of multiple cardiovascular risk factors is required to reduce the risk of coronary artery disease . An increased risk of coronary artery disease is already present in subjects with impaired glucose tolerance, the precursor of type 2 diabetes . In addition, increased risk of coronary artery disease has been demonstrated in subjects with impaired fasting glycaemia, a state in which fasting plasma glucose values are above normal (6.1 mmol/l) but below the diagnostic cut-off for diabetes (< 7.0 mmol/l) . Recently, it has been found that postprandial glucose value is a better risk predictor for incident coronary artery disease and cardiovascular mortality than fasting glucose value .
In addition to hyperglycaemia, diabetic long-term complications have been found to contribute to the increased occurrence of coronary artery disease. Associations between nephropathy, retinopathy, neuropathy and coronary artery disease have been demonstrated in diabetic patients [47-49].
Initial Vascular Mechanisms
Regulation of Coronary Arteries
The resistance of the coronary arterial tree is regulated by endothelial, neural and metabolic control, autoregulation (myogenic control) and extravascular compressive forces. The endothelium plays an important role in the regulation of myocardial blood flow. By releasing vasodilator and vasoconstrictive factors in response to physiological or pathological stimuli, endothelial cells modulate the tone of the underlying vascular smooth muscle cells. The most important vasodilator released from endothelial cells is nitric oxide (NO), which is the principal mediator of normal endothelial function. NO is generated in the endothelium by endothelial NO synthase (eNOS) which can be blocked by arginine analogues such as NG-monomethyl-l-arginine (L-NMMA) . Endothelium-dependent NO production can be stimulated by receptor-dependent pathways by substances such as acetylcholine and bradykinin and by receptor-independent mechanism such as the mechanical force of flow (shear stress) [51,52] (figure 2). Endothelin-1 (ET-1), the most potent endothelium-derived vasoconstrictor, is released by many stimuli such as adrenaline, thrombin and hypoxia. ET-1 may also increase sympathetic activity and the vasoconstrictive effects of norepinephrine [53,54]. The major effect of sympathetic activation in the cardiac vasculature is alpha-adrenoreceptor-mediated vasoconstriction, which is overridden by endothelial and metabolic control, and beta-receptor-mediated vasodilation in healthy subjects .
Atherosclerosis is a progressive disease. It often begins in adolescence and accelerates in young adulthood. In contrast, advanced lesions, fibrous plaques, generally appear during adulthood and progress with age. Atherosclerosis becomes a clinical disease when symptoms of reduced flow occur. Endothelial dysfunction and atherosclerosis have the same risk factors, and endothelial dysfunction appears to affect all arteries. Patients with coronary artery disease are characterized by endothelial dysfunction . In addition, even healthy subjects with risk factors for coronary artery disease have been found to have impaired endothelial function . Thus, reduced coronary endothelium-dependent vasodilation seems to be one of the earliest abnormalities in the development of coronary artery disease .
The endothelial cells line all vessels of the body in a continuous monolayer, with a surface area of approximately 1000 m2 and weight of about 1 kg. Because this huge surface is the first barrier between blood and vessel, the endothelium appears to be also very vulnerable. It has been hypothesized that risk factors for coronary artery disease somehow damage endothelial cells [58,59], leading to increased permeability of endothelium and intimal oedema [60,61]. These changes might impair normal endothelial function, and the imbalance between endothelium-derived relaxing (NO) and contracting (ET-1) factors decreases the vasodilatory properties of the artery . Moreover, because endothelium-dependent relaxation competes with alpha-mediated adrenergic constriction , subjects with coronary endothelial dysfunction have increased sensitivity to the constrictive effects of catecholamines . Impaired endothelial function may also promote adherence of leucocytes to the vessel wall and induce an inflammatory response . In addition, endothelial dysfunction has effects on lipid accumulation, several adhesion molecules and growth factors and haemostasis . Moreover, atherosclerotic lesions result from series of cellular interactions in the vascular endothelial and smooth muscle cells [58,59,65,66].
The Initial Vascular Mechanisms in Obesity
Basal myocardial blood flow has been demonstrated to be normal in obese subjects, although coronary endothelial function appears to be impaired in obesity . In subjects with cardiovascular risk factors or coronary artery disease, exercise, together with a low-lipid diet, increased coronary flow reserve . Recently, Al Suwaidi et al.  studied 397 patients with normal or mildly diseased coronary arteries with quantitative angiography. After multivariate analysis, they reported that coronary flow reserve, measured using intracoronary acetylcholine infusion, was significantly reduced in obese subjects when compared with non-obese subjects, whereas the response to endothelium-independent vasodilators was unaltered. We have recently demonstrated that otherwise healthy obese subjects are characterized by reduced myocardial vasoreactivity, indicating that obesity per se impairs myocardial blood supply .
It has been suggested that endothelial dysfunction originates from impaired production or release of NO in obese subjects . Consistent with that, eNOS activity seems to be reduced in obese subjects . Hyperinsulinaemia and hyperleptinaemia which are often associated with obesity might partly explain the endothelial dysfunction observed in obese subjects. In addition, obese subjects are characterized by elevated circulating free fatty acid concentrations which have been found to impair endothelial function in lean insulin-sensitive subjects . C-reactive protein (CRP), an inflammatory response protein, is positively associated with BMI . Recently, in obese subjects, endothelial function has been found to correlate with visceral body fat, a key regulator site for the process of inflammation . In these subjects, weight reduction was associated with reduction of cytokine and adhesin concentrations and with improvement of endothelial function . Thus, inflammatory response might also be important in the development of atherosclerosis in obese subjects.
Insulin resistance increases in a linear fashion with BMI at an age- and sex-adjusted rate . In subjects with a BMI of 30-35 kg/m2, the prevalence of insulin resistance is 34% and in subjects with a BMI > 35 kg/m2 it is 41%. Subjects with insulin resistance are characterized by reduced insulin-mediated glucose uptake  and increased serum insulin concentration . Insulin resistance is associated with a postbinding defect in insulin action in body tissue. Recently, it has been found that insulin-stimulated insulin receptor substrate-1 association with phosphatidylinositol 3-kinase seems to define a key step in insulin resistance to glucose uptake . Hyperinsulinaemia, caused by over-secretion of insulin by pancreas, is a compensatory mechanism for this.
Besides its metabolic actions, insulin has vascular effects. Insulin not only has an important role in the normal functioning of the vasculature but also has an important role in vascular pathophysiology . Insulin induces a time- and dose-dependent vasodilation mainly via the endothelium-dependent mechanism including the l-arginine NO pathway [78,79]. In contrast to these acute beneficial effects of insulin, chronically high serum insulin concentrations appear to have a harmful effect on endothelial function. Chronic exposure to hyperinsulinaemia increases the release of ET-1 [9,80], whereas short-term hyperinsulinaemia mimicking postprandial conditions appears not to stimulate ET-1 production in healthy subjects [81,82]. Therefore, the imbalance between the release of ET-1 and NO may blunt the insulin-induced vasodilation in subjects with insulin resistance. At least in theory, this vascular insulin resistance provides one mechanism in the progression towards coronary artery disease in these patients. In addition, insulin may also promote smooth muscle cell proliferation and cause cholesteryl ester accumulation in the arterial wall .
Insulin increases sympathetic activity in a dose-dependent manner via the central nervous system [84,85]. Insulin-induced sympathetic activity might lead to augmented coronary vasoconstriction in subjects with endothelial dysfunction . It may also predispose endothelial cells to high-shear-stress-induced damage . Thus, hyperinsulinaemia in obese subjects has been suggested to be the link between obesity, hypertension and cardiovascular complications [87,88]. It has been hypothesized that a failure to inhibit cardiac sympathetic tone in response to increased sympathetic activity might lead to obesity-related hypertension [89,90]. On the other hand, increase in sympathetic activity should lead to increased energy expenditure and reduction of weight. Thus, insulin-induced sympathetic activity might be heterogenous and organ specific in obese subjects. However, the exact role of the sympathetic nervous system in obesity is unknown .
Obese subjects are characterized by leptin resistance and hyperleptinaemia. In addition to its effects on energy balance, leptin has, consistent with insulin, effects on vascular function and sympathetic nervous system [92-95]. Leptin has both vasodilatory and vasoconstrictory effects via the endothelium-dependent mechanism. Leptin induces vasodilation mainly via the NO pathway  as the vasodilation can be abolished by removal of endothelium or suppression of NO synthesis by N-nitro-l-arginine methyl ester (L-NAME) . On the other hand, leptin releases also ET-1 . Moreover, leptin infusion elevates arterial blood pressure, heart rate and renal vascular resistance when NO synthesis is blocked by concomitant infusion of L-NAME . Thus, in subjects with endothelial dysfunction such as obese patients, leptin-induced vasodilation might be blunted . It has been demonstrated that high leptin concentrations are predictive of poor vascular compliance in adolescents . Concordantly, we have recently shown that hyperleptinaemia and reduced coronary vasoreactivity occur concomitantly in young obese but otherwise healthy subjects . At least in theory, hyperleptinaemia might provide one novel mechanism for the development of coronary artery disease at the early phase of obesity. In addition, leptin has prothrombotic effects, indicating that elevated plasma concentrations of leptin may contribute to the risk of atherothrombotic complications in human obesity . However, more studies addressing leptin's effects on myocardial perfusion are needed to clarify its specific role in the development of coronary artery disease.
The Initial Vascular Mechanisms in Diabetes
Basal myocardial blood flow has been found to be usually normal in diabetic subjects [100,101]. Most studies have found decreased coronary vasoreactivity and coronary endothelial dysfunction in diabetic patients [100-103]. The previous studies have included potentially confounding factors such as smoking, hypertension, obesity and lipid abnormalities in the studied groups. Our research group have recently demonstrated that coronary vasoreactivity is already reduced in young otherwise healthy patients with uncomplicated type 1 diabetes and good glycaemic control . This indicates that type 1 diabetes independently affects coronary vasoreactivity.
The potential pathophysiological mechanisms for coronary artery disease in diabetic patients are hyperglycaemia, hyperinsulinaemia and long-term diabetic complications. Recently, it has been demonstrated that monocytes have an attenuated cellular response to vascular endothelial growth factor A in diabetic patients. This may indicate a novel mechanism for the impaired collateral formation observed in diabetes .
Chronic hyperglycaemia increases the risk of coronary artery disease via multiple mechanisms. Endothelial function is related to glycaemic control . Coronary flow reserve has been demonstrated to be inversely related to average glycosylated haemoglobin A1c (HbA1c) in type 2 diabetic patients . Chronic hyperglycaemia induces non-enzymatic glycosylation of molecules and irreversible formation of advanced glycosylation end products (AGEs). AGEs accumulate in the vessel wall and, via free radicals , quench NO activity and induce endothelial dysfunction [108,109]. In addition, glycated collagens might induce smooth muscle cell proliferation, increase arterial wall thickness and reduce arterial elasticity . Glycation of lipoproteins may influence their recognition and binding by receptors . Glycation of low-density lipoprotein (LDL) causes its accumulation in the circulation and may increase cholesteryl ester accumulation in macrophages . Glycation of HDL may also promote cholesteryl ester accumulation in the arterial wall . In addition, in diabetic patients, oxidation of LDL may be augmented, which in turn damages endothelium by apoptosis or NO suppression [114,115].
Chronic hyperglycaemia by stimulating both the polyol pathway and protein kinase C appears to have inhibitory effects on NO synthesis . Oxidative stress also seems to be one mediator of endothelial dysfunction in diabetes . Oxygen-derived free radicals, formed under hyperglycaemic conditions, inactivate NO. Recently, it has been found that chronic hyperglycaemia activates endothelial cells' metalloproteinases and thus increases the risk of atherosclerotic complications . However, short-term hyperglycaemia (24 h) was not able to induce the same alteration .
In contrast to chronic hyperglycaemia, the studies addressing the effect of short-term hyperglycaemia on myocardial perfusion are controversial. Acute hyperglycaemia during somatostatin infusion has been found to have no effect on coronary blood flow in dogs , while in another dog study, 2 h of hyperglycaemia was found to prevent normal vasodilatory responses to graded coronary occlusion . In one case report, hyperglycaemia induced angina pectoris in a patient with complicated type 1 diabetes, hypertension and hyperlipidaemia . In our recent positron emission tomography (PET) study, short-term hyperglycaemia (2 days) did not alter basal myocardial blood flow or coronary vasoreactivity in otherwise healthy type 1 diabetic subjects .
Many similarities of the cardiovascular effects in obesity and diabetes relate to insulin resistance. Hyperglycaemia in type 1 diabetic patients is associated with insulin resistance . Insulin resistance to glucose uptake characterizes type 2 diabetic patients and also many patients with type 1 diabetes. The underlying pathophysiological mechanisms of hyperinsulinaemia might relate to its effects on endothelial function and sympathetic nervous system, as previously discussed. However, reduced coronary vasoreactivity relates to hyperglycaemia rather than insulin resistance in type 2 diabetic patients .
Diabetic long-term complications appear to have a role in the development of coronary artery disease. It has been recently demonstrated in type 1 diabetic patients that cardiac autonomic neuropathy impairs the vasodilatory capacity of coronary arteries . In addition, microalbuminuria has been found to be a marker of endothelial dysfunction . Type 1 diabetic patients with microalbuminuria or macroalbuminuria have changes in lipid profile  and excess generation of endothelium-derived free radicals which can augment the oxidation of LDL and vascular smooth muscle proliferation and may generate an inflammatory response and, thus, accelerate atherosclerosis [122,123].
Endothelium-dependent vasodilation has been found to increase after 3 months of additional insulin therapy in type 2 diabetic patients, indicating that insulin might improve endothelial function . Insulin infusion has been found to normalize reduced coronary vasoreactivity in type 1 diabetes patients . Glucose-insulin-potassium (GIK) therapy has beneficial effect on patients with acute myocardial infarction [125-127]. It has been demonstrated that GIK therapy improves regional myocardial perfusion and function mainly in segments adjacent to the recently infarcted area . Because already very small increase in myocardial blood flow can reduce significantly myocardial ischaemia , the vasodilatory effect of insulin may partly explain the beneficial effect of GIK therapy on myocardial ischaemia in non-diabetic [125,126] and diabetic subjects .
Besides lack of insulin, type 1 diabetic patients are also characterized by lack of C-peptide. C-Peptide has been previously considered to be biologically inert. However, it has been found to have beneficial effects on renal and nerve function in type 1 diabetes [130,131]. Moreover, C-peptide within physiological concentration range has been reported to enhance skeletal muscle [132,133], skin  and renal blood flow  in these patients. Recently, it has been demonstrated that type 1 diabetic patients' impaired myocardial perfusion can be improved by replacement of C-peptide [15,16]. C-Peptide induces vasodilation mainly via the endothelium-dependent mechanism. C-Peptide has been found to increase NO concentrations in a dose-dependent manner, and eNOS inhibitor has been reported to abolish C-peptide-induced NO release and vasodilation . Thus, C-peptide can be classified as a true vasodilatory hormone. At least in theory, C-peptide deficiency can partly explain why young patients with type 1 diabetes show reduced coronary vasodilation despite intensive insulin therapy and good glycaemic control . Therefore, vasodilatory effects of C-peptide might be clinically significant and warrant further studies in type 1 diabetic patients. It might be hypothesized that C-peptide replacement, along with intensive insulin therapy, may prevent the progression of long-term complications such as angiopathy in patients with type 1 diabetes.
Diabetes and obesity are risk factors for the development of coronary artery disease [2,32-34]. The patient population with these diseases is rapidly growing. Endothelial dysfunction, the imbalance between endothelium-derived relaxing and contracting factors and sympathetic activity appear to have an important role in the pathophysiology of coronary artery disease in obese and diabetic subjects.
Obese subjects are characterized by coronary endothelial dysfunction [67,69]. Chronic hyperinsulinaemia, a hallmark of obesity, increases the release of the most potent endothelium-derived vasoconstrictor ET-1 [9,80]. Moreover, insulin enhances sympathetic activity [84,85], which might lead to the augmented alpha-adrenoreceptor-mediated coronary vasoconstriction . High free fatty acid concentrations in obese subjects may also induce endothelial dysfunction . Obese subjects are hyperleptinaemic. Leptin has, consistent with insulin, effects on vascular endothelial function and sympathetic nervous system [92-97]. In obese subjects, leptin-induced vasodilation might be blunted , providing a novel mechanism in the progression towards coronary artery disease [13,14]. However, this hypothesis requires further studies.
Diabetes independently affects coronary endothelial function [102,104]. Hyperglycaemia impairs endothelial function . In addition, diabetic patients are often hyperinsulinaemic, which have an effect on endothelial function and sympathetic nervous system. Diabetic long-term complications such as autonomic neuropathy  and nephropathy  seem to have a role in the development of endothelial dysfunction. Type 1 diabetic patients are also characterized by lack of C-peptide that appears to have endothelial vasodilatory effect in cardiac vasculature [15,16]. Thus, the role of C-peptide deficiency as a risk factor for coronary artery disease needs further studies.