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Section II

Diabetes and Hypertension Induced

Atherosclerosis

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Abbreviations: ABC, ATP-binding cassette; ACC, acetyl-CoA carboxylase; apoB, apolipoprotein B; BAT, brown adipose tissue; BMI, body mass index; CHD, coronary heart disease; CPT, carnitine palmitoyl transferase; CR, chylomicron remnants; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; FAS, fatty acid synthase; FFA, free fatty acid; FXR, farnesoid X receptor; GLUT, glucose transporter; HDL, high-density lipoprotein; IDF, International Diabetes Federation; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl coenzyme A reductase; HSL, hormone sensitive lipase; IR, insulin receptor; IRS, insulin receptor substrate; JAK2, Janus kinase 2; JNK, c-jun kinase; KO, knockout; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LXR, liver X receptor; MAP, mitogen-activated protein; MEK, MAPK/ERK kinase; MTP, microsomal triglyceride transfer protein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PGC-1, PPARgamma coactivator-1; PI-3-K, phosphatidylinositol-3-kinase; PKB, protein kinase B; PKC, protein kinase C; PPAR, peroxisome proliferator-activated receptor; PTEN, phosphatase and tensin homolog; PTP-1B, phosphotyrosyl-protein phosphatase 1B; SCAP, SREBP cleavage-activating protein; SCD, stearoyl-CoA desaturase; SH, src homology; SRE, sterol regulatory element; SREBP, sterol regulatory element-binding protein; STZ, streptozotocin; TG, triglyceride; TNF, tumor necrosis factor; VLDL, very low-density lipoprotein; WHHL, Watanabe heritable hyperlipidemic; WHO, World Health Organization

The Rising Global Epidemic of Diabetes and Associated

Dyslipidemic Complications

Social and economic changes within the last century have brought countless advances, and have vastly improved lifestyles in many parts of the world. Paradoxically, the global trend toward a more sedentary lifestyle, associated with a positive energy balance, has also led to an array of increased health risks in an aging population. Numerous sources including the World Health Organization (WHO) and International Diabetes Federation (IDF) report a worldwide diabetes epidemic, with a parallel rise in obesity and insulin resistance [1]. It is estimated that approximately 5% of the global population is diabetic, with 85–95% of this being attributed to noninsulin-dependent diabetes mellitus or type 2 diabetes [2]. The IDF currently estimates the number of individuals with type 2 diabetes at 125 million with a projected rise to between 200 and 300 million within the next decade [2]. In 2002, the American Diabetes Association estimated the total economic cost of diabetes in the United States alone at 132 billion dollars, with 18.2 million individuals (or 6.3% of the U.S. population) being affected [3]. Numerous ethnic populations appear to be particularly predisposed to the development of diabetes. Mexican–Americans have a 21% prevalence compared with 3% among nonHispanic Americans [4]. Native Hawaiians are known to have a prevalence of type 2 diabetes that is four times higher than the general population of the

United States [5]. The potential for increased cases of type 2 diabetes is also very high in developing countries, including China and India [6–8].

Associated with diabetes is a wide array of very severe health risks, and long-term complications including eye, nerve, and kidney disease; as well as diseases of the circulatory system that may lead to amputation. Metabolic dyslipidemia is the most common complication of insulin resistance and type 2 diabetes, and is believed to be exacerbated by obesity, as well as numerous detrimental environmental factors such as a high-fat diet and sedentary lifestyle. The dyslipidemia accompanying insulin resistance is characterized by distinct changes from a normal plasma lipid and lipoprotein profile. Such changes include decreases in plasma levels of HDL with elevated plasma FFA and triglycerides (TG). These lipid changes are commonly associated with elevated VLDL production, a concomitant increase in apoB, an essential structural component of these atherogenic lipoproteins, and increased plasma levels of small dense low-density lipoprotein (LDL) [9, 10]. These parameters constitute a highly atherogenic dyslipidemic profile that significantly contributes to increased risk of cardiovascular disease, the most prevalent cause of death in industrialized countries and one which is rising at an alarming rate in less-developed countries.

Insulin Resistance and Metabolic Dyslipidemia: Components of a Complex Metabolic Syndrome

The current consensus is that obesity and insulin resistance may be part of a common pathologic state termed as “metabolic syndrome.” The metabolic syndrome, formerly referred to as insulin resistance syndrome [11] or syndrome X [12], is characterized by a constellation of pathologies that include glucose intolerance, insulin resistance, obesity, dyslipidemia, and hypertension. Insulin resistance generally develops as the first indicator of type 2 diabetes and manifests as a decreased biological response to normal levels of circulating plasma insulin. Indicators of insulin resistance include impaired glucose tolerance, hyperglycemia, and elevated plasma insulin levels. As long as the pancreas can compensate for the decreased insulin response by increasing insulin secretion, the individual is able to control blood glucose level. Allowed to continue untreated, however, the pancreas eventually fails to produce sufficient insulin, and type 2 diabetes occurs. Although not formerly considered a disease of childhood, type 2 diabetes has begun to present with increasing frequency in the pediatric population [13, 14]. It is feared that the disease progression begins early in life, and persistence from childhood to adulthood produces type 2 diabetes and cardiovascular disease in early adulthood [15, 16].

The concept of the metabolic syndrome emerged progressively from clinical observations over many decades. The clustering of metabolic perturbations was first recognized in the early 1920s by the Swedish physician Eskil

208 Rita Kohen Avramoglu et al.

Kylin who defined this multifactorial disease as including hypertension, gout, and hyperglycemia [17]. A quarter century later, Jean Vague a professor at the Université de Marseille, established a correlation between body fat distribution, in particular abdominal or android obesity, with the risk of diabetes and cardiovascular disease [18]. In 1965, Pietro Avogaro and Gaetano Crepaldi described the metabolic syndrome as being accompanied by hyperlipidemia due to elevated plasma TG levels, obesity, diabetes, hypertension, and a high risk of coronary artery disease [19]. In 1988, Gerald Reaven went on to further characterize the lipoprotein abnormalities associated with metabolic syndrome, and coined a new term, “syndrome X.” This was followed by the terms “deadly quartet” [20] and “insulin resistance syndrome” [21]. In 1998, the WHO coined the term “metabolic syndrome” [22], which has since become the more popular designation of this metabolic disorder. The most current definition of metabolic syndrome according to the WHO includes insulin resistance as defined by glucose intolerance, impaired fasting glucose or type 2 diabetes accompanied by at least two of the following states; hypertension, elevated plasma TG, decreased plasma HDL, high body mass index (BMI), or elevated urinary albumin. Currently this definition is again shifting and the trend has been to diagnose metabolic syndrome based on individual clinical judgment, taking into account these previously described metabolic perturbations.

Link between Insulin Resistance, Metabolic Dyslipidemia, and Cardiovascular Disease

The single most common complication and the leading cause of mortality of the metabolic syndrome remains diabetic/metabolic dyslipidemia. The diabetic dyslipidemia that accompanies the metabolic syndrome is generally characterized by increased plasma TG, increased small dense LDL, and decreased HDL each of which is believed to be an independent risk factor for cardiovascular disease [23, 24]. Numerous clinical studies, as well as observations in animal models, have led to metabolic models of the possible causes of this common diabetic complication.

Although the molecular mechanisms underlying diabetic dyslipidemia are far from being completely understood, it is now generally believed that the elevation in plasma TG accompanying the disorder is central to development of this complex phenotype. Over the last several decades, a number of largescale, long-term clinical studies testing several classes of lipid-lowering drugs have been conducted, and several have included diabetic individuals among their experimental subgroups. The general consensus among these studies has been that an increased risk of developing coronary heart disease (CHD) is associated with increased plasma lipids in insulin-resistant states. The larger of these studies include the Scandinavian Simvastatin Survival Study Group (4S), the Long-Term Intervention with Pravastatin in Ischemic Disease Study Group (LIPID), and the Cholesterol and Recurrent Events study (CARE)

[25–29]. Although these studies have focused on the cholesterol-lowering 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor drugs also known as statins, a general trend was found in lowering of CHD risk, both overall, as well as in a diabetes subgroup in the study. The Helsinki Heart Study was the first pioneering study that showed a small trend towards improvement of CHD risk in diabetic individuals using fibrates, a peroxisome proliferator-activated receptor (PPAR) alpha agonist class of compounds that reduce production and enhance clearance of VLDL [30]. These findings were reinforced recently with evidence from the Veterans Administration HighDensity Lipoprotein Intervention Trial (VA-HIT) [31, 32] and the Diabetes Atherosclerosis Intervention Study (DAIS) [33–35], the latter showing a decrease in progression of atherosclerosis following 3 years of fenofibrate treatment. Numerous other studies such as the Lipids in Diabetes Study (LDS) are currently underway to evaluate the efficacy of fibrates or combination therapies in the treatment of diabetes-related CHD. The Fenofibrate Intervention and Event Lowering in Diabetes Study (FIELD) once completed will compile data from 12,000 individuals and will be one of the largest clinical trial studies performed to date. A newer class of compounds, the thiazolidinediones or glitazones, are PPAR gamma agonists that exert an insulin-sensitizing effect and improve glucose tolerance. As the thiazolidinediones have only been available for a few years, large-scale comparative clinical trials currently need to be undertaken in order to fully understand the effects of this class of drugs. In a smaller-scale clinical setting however, it has been repeatedly shown that use of these compounds result in normalization of glucose liver homeostasis accompanied by a decrease in plasma FFA, an increase in HDL, a decrease in small dense LDL, and a decrease in vascular inflammation [36–38].

Insulin Resistance and Metabolic Dyslipidemia: Lessons from Animal Models

In animal models, alterations in lipid and glucose metabolism may be induced through genetic manipulation, drug administration, or even relatively simple changes in diet. To date, a wide variety of models have been developed for the study of metabolic defects of insulin resistance or lipid metabolism [39, 40]. Use of animal models of insulin resistance has provided strong evidence for a link between insulin resistance and metabolic dyslipidemia (reviewed in Refs. [40, 41]). Genetic models such as the ob/ob mouse, the db/db mouse, the Zucker fa/fa (fatty) rat, and the ZDF/Drt-fa (diabetic/fatty) rat exhibit phenotypes of insulin resistance or diabetes, obesity, and dyslipidemia [39, 40-44]. The most widely recognized of these is perhaps the ob/ob mouse, which lacks the satiety factor leptin, a gene implicated in the development of obesity. The dramatic phenotype of the ob/ob mice includes morbid obesity, diabetes, infertility, as well as reduced activity, metabolism, and body temperature. The genetically diabetic or db/db mouse,