Preface [Hot Topic:Inflammatory Markers and Mediators: Emerging Therapeutic Targets in Diabetes, Cardiovascular and Metabolic Disorders (Guest Editor: Samuel Dagogo-Jack, MD)].

The present Hot Topic issue of Current Drug Targets focuses on inflammatory markers and mediators and discusses these in the context of pathophysiology, mechanisms, and management of the cardiovascular dysmetabolic syndrome. Cardiovascular disease is the leading cause of death in people with diabetes. The risk of first myocardial infarction (MI) in diabetes patients is similar to that of recurrent MI in nondiabetic persons who have had a previous MI. Thus, diabetes is not merely a risk factor for cardiovascular disease but a coronary artery disease (CAD) risk-equivalent [1-3]. Although the degree of glycemia (as assessed HbA1c) is an independent predictor of coronary risk [4], hyperglycemia is one of several major etiological factors for macrovascular complications. Thus, whereas a policy of intensive glucose control significantly prevents microvascular complications [5-7], a broader policy involving multiple risk factor reduction must be pursued in order to prevent the macrovascular complications of diabetes [8]. The development of effective interventions for reducing the burden of macrovascular disease can be greatly facilitated by a fuller understanding of the mechanisms that underlie this burden. The insulin resistance syndrome predisposes to macrovascular complications of type 2 diabetes. This condition, also known as the metabolic syndrome, Syndrome X, cardiovascular dysmetabolic syndrome, etc.[3,9], often precedes the diagnosis of type 2 diabetes by several years. Features of the metabolic syndrome include upper body obesity, hyperinsulinemia, hypertriglyceridemia, increased serum LDL-cholesterol and decreased HDL-cholesterol levels, hypertension, hyperuricemia, and a pro-coagulant state, among others. Endothelial dysfunction also tracks the severity of insulin resistance [3,9,10]. The metabolic syndrome affects millions of pre-diabetic persons in the United States, is associated with a two-fold increased risk for CAD, and has recently been allocated the International Classification of Diseases (ICD)-9 code of 277.7. Major criteria for diagnosis include abdominal obesity, hypertriglyceridemia (> 150 mg / dl), hypertension (>130 / 80 mmHg), low HDL-cholesterol (> 40 mg / dl in men; >50 mg / dl in women) and impaired fasting glucose (> 110 mg / dl). The exact mechanisms linking the metabolic syndrome to atherosclerosis are complex and incompletely understood. Recent studies increasing implicate inflammatory and bioactive products of adipocytes in the pathophysiology of insulin resistance and macrovascular disease. The association between insulin resistance and dyslipidemia appears to be triggered by increased free fatty acid (FFA) release from adipose tissue. Central obesity and the resultant increase in portal FFA flux lead to enhanced lipoprotein synthesis, insulin resistance, endothelial dysfunction and increased plasma levels of plasminogen activator inhibitor (PAI)-1. These alterations create a milieu favorable for the development of atherosclerosis and thromboembolic disease [11,12]. Coronary artery disease, the leading macrovascular complication, accounts for most of the diabetes-related mortality. Compared with nondiabetic persons, CAD occurs at a younger age, and is particularly prevalent among diabetic women. Sadly, myocardial infarction carries a worse prognosis, and angioplasty gives less satisfactory results, in diabetic patients compared with nondiabetic individuals. Pro-inflammatory signals and specific cytokines and other products of adipose tissue are emerging as potent mediators of metabolic and vascular processes. The growing evidence suggests that the inflammatory state may constitute a platform for convergence of insulin resistance, atheroclerosis, and macrovascular disorders [11]. Such adverse interactions between pro-inflammatory states and macrovascular disease probably also explain the poor prognosis following coronary events or interventions in the setting of diabetes. Clearly, diabetes mellitus leads to accelerated atherosclerosis through a variety of mutually reinforcing mechanisms, many of which remain to be fully elucidated [1]. A fuller understanding of the mechanisms that underlie the multi-fold increase in the prevalence of cardiovascular, cerebrovascular, and peripheral vascular diseases in patients with diabetes is of utmost priority. In this issue of Hot Topics, Dr. Pierre Theuma and Dr. Vivian Fonseca from Tulane University discuss Novel Cardiovascular Risk Factors and Macrovascular and Microvascular Complications of Diabetes, highlighting the possible roles of endothelial dysfunction, subclinical inflammation, impaired fibrinolysis, microbial infection, and hyperhomocysteinemia, among others. The discussion by Drs. Theuma and Fonseca is followed by a discussion of Insulin resistance as a Proinflammatory State: Mechanisms, Mediators, and Therapeutic Interventions by researchers from the Dandona Laboratory at State University of New York at Buffalo. In their article, Drs. Garg, Tripathy, and Dandona review current understanding of insulin resistance as an inflammatory disease and discuss their recent work on the effect of therapeutic interventions. In the next article titled “Activated T Lymphocytes in Type 2 diabetes: implications from in vitro studies”, Dr. Frankie Stentz and Dr. Abbas Kitabchi from the University of Tennessee, Memphis discuss novel and intriguing ideas that extend immunopathologic frontiers from the classical area of type 1 diabetes to insulin resistance and type diabetes phenotypes. The authors reason that activation of T-lymphocytes shares some similarities with oxidative stress, both conditions being associated with a proinflammatory state. This notion also extends to the growing understanding that metabolic and vascular disease states, such as insulin resistance, type 2 diabetes, and atherosclerosis, may themselves share proinflammatory etiologies. Finally, a state-of-the-art review on the emerging role of aldosterone as a proinflammatory / fibrogenic mediator in cardiac disease is by Drs. Karl Weber, Ivan Gerling, Mohammad Kiani and their multidisciplinary research team from the University of Tennessee, Memphis. The neurohumeral activation that accompanies congestive heart failure is discussed in the context of concomitant induction of oxidative / nitrosative stress, adverse vascular remodeling, and immunomodulation. Unravelling the ramifications of the athero-inflammatory cascade in human metabolic and cardiovascular disorders is an ongoing effort in numerous laboratories and clinical research centers. It is hoped that these vigorous efforts will uncover novel and compelling targets for the development of rational and effective interventions for the prevention and treatment of macrovascular complications of diabetes and prediabetes. References [1] Beckman, J.A., Creager, M.A., Peter Libby, P. (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287, 2570-2581. [2] Haffner, S.M., Lehto, S., Ronnemaa, T., et al. (1998) Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N. Engl. J. Med. 339, 229-234. [3] De Fronzo, R.A., Ferrannini, F. (1991) Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14, 173-194. [4] Singer, D.E., Nathan, D.M., Anderson, K.M., Wilson, P.W.F., Evans, J.C. (1992) Association of HbA1c with prevalent cardiovascular disease in the original cohort of the Framingham Heart Study. Diabetes 41, 202-208. [5] The Diabetes Control and Complications Trial Research Group. (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N. Engl. J. Med. 329, 978-986. [6] Ohkubo, Y., Kishikawa, H., Araki, E., et al. (1995) Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res. Clin. Pract. 28, 103-117. [7] Stratton, I.M., Adler, A.I., Neil, H.A., Matthews, D.R., Manley, S.E., Cull, C.A., Hadden, D., Turner, R.C., Holman, R.R. (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321, 405-412. [8] Moneva, M., Dagogo-Jack, S. (2002) Multiple drug targets in the management of type 2 diabetes. Curr. Drug. Targets. 3, 203-221. [9] Stuhlinger, M.C., Abbasi, F., Chu, J.W., Lamendola, C., McLaughlin, T.L., Cooke, J.P., Reaven, G.M., Tsao, P.S. (2002) Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287, 1420-1426. [10] Taniguchi, A., Nakai, Y., Fukushima, M., et al. (2002) Ultrasonographically assessed carotid atherosclerosis in Japanese type 2 diabetic patients: Role of nonesterified fatty acids. Metabolism 5, 539-543. [11] Moller, D.E. (2002) Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol. Metab. 11, 212-217. [12] Dagogo-Jack, S. (2002) Management of diabetes and prevention of heart disease. Cardiology Special Edition 8, 11-14.