Diabetes mellitus affects approximately 100 million persons worldwide.1 Five to ten percent have type 1 (formerly known as insulin-dependent) and 90% to 95% have type 2 (non–insulin-dependent) diabetes mellitus. It is likely that the incidence of type 2 diabetes will rise as a consequence of lifestyle patterns contributing to obesity.2 Cardiovascular physicians are encountering many of these patients because vascular diseases are the principal causes of death and disability in people with diabetes. The macrovascular manifestations include atherosclerosis and medial calcification. The microvascular consequences, retinopathy and nephropathy, are major causes of blindness and end-stage renal failure. Physicians must be cognizant of the salient features of diabetic vascular disease in order to treat these patients most effectively. The present review will focus on the relationship of diabetes mellitus and atherosclerotic vascular disease, highlighting pathophysiology and molecular mechanisms (Part I) and clinical manifestations and management strategies (Part II).

Abnormalities in endothelial and vascular smooth muscle cell function, as well as a propensity to thrombosis, contribute to atherosclerosis and its complications. Endothelial cells, because of their strategic anatomic position between the circulating blood and the vessel wall, regulate vascular function and structure. In normal endothelial cells, biologically active substances are synthesized and released to maintain vascular homeostasis, ensuring adequate blood flow and nutrient delivery while preventing thrombosis and leukocyte diapedesis.3 Among the important molecules synthesized by the endothelial cell is nitric oxide (NO), which is constitutively produced by endothelial NO synthase (eNOS) through a 5-electron oxidation of the guanidine-nitrogen terminal of l-arginine.4 The bioavailability of NO represents a key marker in vascular health. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells.4 In addition, NO protects the blood vessel from endogenous injury—ie, atherosclerosis—by mediating molecular signals that prevent platelet and leukocyte interaction with …

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Diabetes and Vascular Disease Pathophysiology, Clinical Consequences, and Medical Therapy: Part I

The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-α, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1.

The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described.

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Adipose tissue dysfunction in obesity, diabetes, and vascular diseases

Developmental Origin of Fat: Tracking Obesity to Its Source

In part II of this review, we describe the epidemiology and clinical consequences of vascular disease in patients with diabetes, and discuss the efficacy of risk factor modification and antiplatelet treatment. Specifically, evidence-based cardiovascular therapies are discussed through novel clinical insights on management of hyperglycaemia, hypertension, dyslipidaemia as well as platelet dysfunction. Recent trends in the incidence and outcomes of vascular disease in diabetes suggest that timely and effective implementation of therapies is making a favourable impact.

https://www.zora.uzh.ch/id/eprint/155136/1/ZORA_NL_155136.pdf

Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I

Context: Insulin resistance is an almost universal finding in nonalcoholic fatty liver disease (NAFLD). This review outlines the evidence linking insulin resistance and NAFLD, explores whether liver fat is a cause or consequence of insulin resistance, and reviews the current evidence for treatment of NAFLD. Evidence Acquisition: Evidence from epidemiological, experimental, and clinical research studies investigating NAFLD and insulin resistance was reviewed. Evidence Synthesis: Insulin resistance in NAFLD is characterized by reductions in whole-body, hepatic, and adipose tissue insulin sensitivity. The mechanisms underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation, and increased de novo lipogenesis. Insulin resistance may enhance hepatic fat accumulation by increasing free fatty acid delivery and by the effect of hyperinsulinemia to stimulate anabolic processes. The impact of weight loss, metfo...

Review: The role of insulin resistance in nonalcoholic fatty liver disease.

Obesity and dysfunctional energy partitioning can lead to the development of insulin resistance and type 2 diabetes. The antidiabetic thiazolidinediones shift the energy balance toward storage, leading to an increase in whole-body adiposity. These studies examine the effects of pioglitazone (Pio) on adipose tissue physiology, accumulation, and distribution in female Zucker (fa/fa) rats. Pio treatment (up to 28 days) decreased the insulin-resistant and hyperlipidemic states and increased food consumption and whole-body adiposity. Magnetic resonance imaging (MRI) analysis and weights of fat pads demonstrated that the increase in adiposity was not only limited to the major fat depots but also to fat deposition throughout the body. Adipocyte sizing profiles, fat pad histology, and DNA content show that Pio treatment increased the number of small adipocytes because of both the appearance of new adipocytes and the shrinkage and/or disappearance of existing mature adipocytes. The remodeling was time dependent, with new small adipocytes appearing in clusters throughout the fat pad, and accompanied by a three- to fourfold increase in citrate synthase and fatty acid synthase activity. The appearance of new fat cells and the increase in fat mass were depot specific, with a rank order of responsiveness of ovarian > retroperitoneal > subcutaneous. This differential depot effect resulted in a redistribution of the fat mass in the abdominal region such that there was an increase in the visceral:subcutaneous ratio, as confirmed by MRI analysis. Although the increased adiposity is paradoxical to an improvement in insulin sensitivity, the quantitative increase of adipose mass should be viewed in context of the qualitative changes in adipose tissue, including the remodeling of adipocytes to a smaller size with higher lipid storage potential. This shift in energy balance is likely to result in lower circulating free fatty acid levels, ultimately improving insulin sensitivity and the metabolic state.

https://diabetes.diabetesjournals.org/content/diabetes/50/8/1863.full.pdf

Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance.

Recent advances in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) include the use of thiazolidinediones (TZDs), agents that enhance insulin action, in part, through an activation of adipose tissue peroxisome proliferator-activated receptor gamma. Current evidence also indicates that these agents upregulate uncoupling protein 1 (UCP1) gene expression in brown adipocytes and increase interscapular brown adipose tissue (IBAT) mass in rodents, suggestive of a thermogenic component to their mechanism of action. In the present study, the TZD pioglitazone (PIO) and the beta3-adrenoceptor agonist CL 316,243 (CL), were used to determine whether the antidiabetic effects of PIO, like those of CL, may, in part, be mediated by an increase in either IBAT thermogenesis or whole-body energy expenditure. Treatment of obese, insulin resistant fa/fa Zucker rats with PIO for 10 days resulted in a 2- to 3-fold increase in IBAT mass, due largely to an increase in adipocyte size and number, and increased fatty acid biosynthesis. However, unlike the effects of CL, the PIO-induced IBAT changes were not associated with an increase in UCP1 expression or whole-body energy expenditure. In contrast to CL, PIO substantially increased body weight gains over the 10-day treatment period by increasing feeding efficiency. These data suggest that, unlike CL, the actions of PIO in the obese Zucker rat does not include increased energy expenditure, but rather strengthens its role as an adipogenic and lipogenic agent, which promotes energy storage.

Effects of pioglitazone on promoting energy storage, not expenditure, in brown adipose tissue of obese fa/fa zucker rats: comparison to cl 316,243

The discovery of a third p-adrenergic receptor (β 3 -AR) in the early 1980s and the finding that stimulation of this receptor by selective agonists leads to marked weight loss and glycemic improvements in rodent models of obesity and diabetes, respectively, has led to intensive research efforts to develop β 3 -AR agonists for the treatment of obesity and Type 2 diabetes in humans. Indeed, the ability of β 3 -AR agonists to simultaneously increase lipolysis, fat oxidation, energy expenditure, and insulin sensitivity suggests that this class of agents may have promising potential as both antiobesity and antidiabetic agents. Unfortunately, several pharmaceutical problems have hampered their development as therapeutic agents in humans over the past 15 years. Major obstacles have been the pharmacological differences between the rodent and human β 3 -AR, the lack of selectivity of previous compounds for the β 3 - over β 1 / β 2 -ARs, and unsatisfactory pharmacokinetic properties. More recently, clinical studies with a highly (rodent-) selective β 3 -AR agonist have provided unequivocal evidence that selective β 3 -AR stimulation can increase lipolysis, fat oxidation, and insulin sensitivity in humans. Meanwhile, cloning of the human β 3 -AR has allowed the development of novel compounds that are specifically targeted at the human receptor. This new generation of compounds has shown promising results in nonhuman primates and in Phase 1 studies in humans. Once human β 3 -AR selective compounds with satisfactory pharmacokinetic properties become available, clinical testing will reveal whether their effects are sufficient and safe in the long term to allow the use of these agonists for the treatment of obesity and diabetes in humans.

Development of β3‐adrenoceptor agonists as antiobesity and antidiabetes drugs in humans: Current status and future prospects

The chronic elevation of circulating free fatty acid (FFA) levels is associated with insulin resistance.’ In normal individuals, excess energy is converted to FFAs by the liver and stored as triglyceride in adipocytes. The stored energy can be mobilized as needed via an increase in the rate of FFA release from the adipocytes. However, if the balance between storage and release is disturbed such that the FFAs become chronically elevated, insulin resistance is usually manifest. Elevated FFA levels have been implicated in inducing metabolic derangements. For example, over 30 years ago, Randle demonstrated that FFAs have an impact on peripheral glucose utilization in muscle, principally via a FFA-induced suppression of pyruvate dehydrogenase (PDH).* Felber has recently shown that FFAs may be playing a role in glycogen storage3 and Grill has suggested that they have an important role in regulating beta-cell function and thereby altering insulin secretion profile^.^ Furthermore, recent studies by Bergman demonstrate that lowering of circulating FFAs is required for suppression of hepatic glucose production following a meal.5 The causative role of FFAs in the development or maintenance of insulin resistance has been difficult to assess. One reason for this could be that measurement of circulating FFA levels may be an inadequate measure of the role of FFAs since stored triglycerides and local fluxes may be major factors as well. In a normal individual, the stored triglyceride in tissues such as the liver, the muscle, and even the islet is relatively low. However, with chronic elevation of circulating FFA, as occurs in obesity, the triglyceride content of all of these tissues is predicted to be higher than normal, so local storage and release of FFAs may become important. One may ask the following question: “If the circulating FFAs were reduced, would insulin sensitivity improve?” Acute experiments in humans suggest that the answer is no. However, such conclusions may be flawed because the locally stored triglyc-

Christopher J. de Souza

Papers

Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance.

Effects of pioglitazone on promoting energy storage, not expenditure, in brown adipose tissue of obese fa/fa zucker rats: comparison to cl 316,243

Development of β3‐adrenoceptor agonists as antiobesity and antidiabetes drugs in humans: Current status and future prospects

Pharmacological Strategies for Reduction of Lipid Availability