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The Relationship Between Hyperinsulinemia, Hypertension and Progressive Renal Disease

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The Relationship Between Hyperinsulinemia, Hypertension and Progressive Renal Disease J Am Soc Nephrol 15: 2816–2827, 2004 The Relationship between Hyperinsulinemia, Hypertension and Progressive Renal Disease FADI A. EL-ATAT, SAMEER N. STAS, SAMY I. MCFARLANE, and JAMES R. SOWERS Department of Internal Medicine, University of Missouri-Columbia and H. S. Truman VAMC, Columbia, Missouri; Divisions of Cardiovascular Medicine and Endocrinology, Diabetes and Hypertension, Department of Medicine, State University of New York-Downstate Medical Center, Brooklyn, New York; USA and VA Medical Center, Brooklyn, New York. Abstract. The incidence of end-stage renal disease (ESRD) has increase the risk of renal disease, cardiovascular disease risen dramatically in the past decade, mainly due to the in- (CVD) and mortality. Similar findings and cardiorenal risk creasing prevalence of diabetes mellitus, and both impaired factors can occur in subjects with android obesity without glucose tolerance and hypertension are important contributors excess body weight. to rising rates of ESRD. Obesity, especially the visceral type, Recently, microalbuminuria has been gaining momentum as is associated with peripheral resistance to insulin actions and a component and marker for the cardiometabolic syndrome, in hyperinsulinemia, which predisposes to development of diabe- addition to being an early marker for progressive renal disease tes. A common genetic predisposition to insulin resistance and in patients with this syndrome or in those with diabetes. Fur- hypertension and the coexistence of these two disorders pre- thermore, it is now established as an independent predictor of disposes to premature atherosclerosis. A constellation of met- CVD and CVD mortality. This review examines the relation- abolic and cardiovascular derangements, which also includes ship between insulin resistance/hyperinsulinemia and hyper- dyslipidemia, dysglycemia, endothelial dysfunction, fibrino- tension in the context of cardiometabolic syndrome, progres- lytic and inflammatory abnormalities, left ventricular hypertro- sive renal disease and accelerated CVD. The importance of phy, microalbuminuria, and increased oxidative stress, is re- microalbuminuria as an early marker for the cardiometabolic ferred to as the cardiometabolic syndrome. The components of syndrome is also discussed in this review. this syndrome, individually and interdependently, substantially The cardiometabolic syndrome is currently estimated to 14). Other mechanisms include enhanced sympathetic nervous affect 24% of the adult population (1). In addition to diabetes, system (SNS) activity, dyslipidemia, atherosclerosis, enhanced which is the leading cause of end-stage renal disease (ESRD) oxidative stress, hypercoagulability, left ventricular hypertro- in westernized societies, other metabolic and cardiovascular phy (LVH), renal functional and structural changes and glo- abnormalities associated with the cardiometabolic syndrome merulosclerosis, progressive renal disease, and eventually contribute to progressive renal disease, cardiovascular disease ESRD (3–5, 15–21) (Figure 2). Microalbuminuria, in addition (CVD), and CVD mortality (Table 1) (2). Of particular impor- to being an early marker for nephropathy, is an established tance are hypertension and insulin resistance/hyperinsulinemia, marker for increased CVD morbidity and mortality in patients which frequently coexist and contribute substantially to CVD with hyperinsulinemia and hypertension (22). Furthermore, it and ESRD (3–10). There appears to be a common genetic is increasingly recognized as a marker for the cardiometabolic predisposition to both insulin resistance and hypertension. Fur- syndrome (23–26). thermore, insulin resistance/hyperinsulinemia contributes to the elevated BP through several mechanisms, one of which is tissue angiotensin II (AngII) and aldosterone actions, leading Epidemiology of Insulin Resistance, Associated to vascular resistance to the effects of insulin (Figure 1) (6,7,9– Cardiometabolic Derangements and Progressive Renal Disease There has been an alarming growth of the prevalence of Correspondence to Dr. James R. Sowers, Professor of Medicine and Physiology, chronic kidney disease (CKD) (Figure 3) and ESRD (Figures University of Missouri-Columbia, Department of Internal Medicine, MA410 Health Science Center, One Hospital Drive, Columbia, MO 65212. Phone: 573– 4, 5, and 6) over the last decade, in concert with a striking 884–2013; Fax: 573–884–1996; E-mail: [email protected] increase in the burden of diabetes, the leading cause of ESRD 1046-6673/1511-2816 (Figures 5 and 6). Additionally, increasing rates of obesity (Figure Journal of the American Society of Nephrology 4) and associated insulin resistance and hypertension (Figures 5 Copyright © 2004 by the American Society of Nephrology and 6) are major contributors to ESRD (2). The costs attributed to DOI: 10.1097/01.ASN.0000133698.80390.37 ESRD have risen from 4.8% a decade ago to 6.3% of all Medicare J Am Soc Nephrol 15: 2816–2827, 2004 Hyperinsulinemia, Hypertension and Progressive Renal Disease 2817 Table 1. Cardiovascular and renal risk factors associated with the cardiometabolic syndrome 1. Hypertension 2. Central obesity 3. Hyperinsulinemia/insulin resistance 4. Endothelial dysfunction 5. Microalbuminuria 6. Low HDL-cholesterol levels 7. High triglycerides levels 8. Small, dense LDL cholesterol particles 9. Increased Apo-lipoprotein B particles 10. Increased fibrinogen levels 11. Increased plasma activator inhibitor Ϫ1 levels 12. Increased C-reactive protein and other inflammatory markers 13. Reduced vascular compliance 14. Absent nocturnal dipping of BP and pulse 15. Salt sensitivity 16. Left ventricular hypertrophy 17. Hyperuricemia 18. Increased reactive oxygen species expenditures, consuming a total of $22.83 billion currently (2). ESRD treatment is initiated earlier, reflecting in part, an increas- ing burden of associated comorbidities, including diabetes and other cardiometabolic abnormalities (2), with increasing levels of inflammatory markers, correlating with a decline in kidney func- tion (2). Furthermore, the USRDS 15th annual report projects that by the year 2030, the ESRD population will increase by 460,000 new cases annually and the prevalent population will reach 2.24 million, with two thirds of these numbers having diabetes as the Figure 1. Inhibitory effects of AngII on insulin signaling contributing primary cause of renal disease (2). to the cardiometabolic syndrome. In parallel with the growth in kidney disease, the prevalence of obesity/insulin resistance and impaired glucose metabolism has been increasing rapidly, currently meeting epidemic pro- (Table1; Figure 2) (3–5,14). These responses, including hyper- portions (1,27). The prevalence of diagnosed and undiagnosed insulinemia/insulin resistance, dysglycemia, dyslipidemia, hy- diabetes combined, which constitute a major portion of the perleptinemia, hypercortisolemia, altered vascular structure insulin-resistant population is estimated at 8% of adult popu- and function, enhanced SNS and renin-angiotensin-aldosterone lation (21,27). An even greater number of patients have the system (RAAS) activities, hypercoagulability, and an altered cardiometabolic syndrome (24%) (1). Furthermore, obesity Kallikrein-Kinin system, individually and interdependently, appears to be one of the most important risk factors for ESRD contribute to progressive renal disease/ESRD, hypertension, and is of increasing significance as its prevalence rises in this and other CVD morbidity and mortality (Figure 7) (3–5,16). In country. fact, the parallel increase in the prevalence of obesity and This alarming growth of cardiometabolic abnormalities ESRD suggests that obesity is one of the most important and resultant renal disease emphasizes the importance of precursors of ESRD (4) (Figure 4). prevention and control of these derangements (2,9). Indeed, Insulin resistance and hyperinsulinemia in those with vis- the increasing awareness and improvement of control of ceral obesity relate to the metabolic characteristics of the fat these risk factors, although still suboptimal, may be the that is present in the omental and para-intestinal regions reason behind the slowing trend of ESRD incident rates (13,14). Compared with peripheral fat cells, visceral fat is more between 1998 and 2001 (2). resistant to the metabolic effects of insulin and more sensitive to lipolytic hormones (13). Consequently, increased release of Visceral Obesity free fatty acids (FFA) into the portal system provides increased Visceral obesity triggers a litany of maladaptive cardiovas- substrate for hepatic triglyceride synthesis and may impair first cular, renal, metabolic, prothrombotic and inflammatory re- pass metabolism of INS (13,14). sponses, some of which form the “cardio-metabolic syndrome” Furthermore, data from the NHANES survey show a re- 2818 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 2816–2827, 2004 low-grade inflammatory condition increasingly important in the causation and progression of hypertension and endothelial dysfunction (3,4,13). A direct cause-and-effect relationship, however, has not been clearly established. It is not known, for example, whether long-term treatment with nonsteroidal anti- inflammatory drugs reduces the level of inflammatory cyto- kines or alleviates hypertensive and vascular disease in obese patients (3). Moreover, there are accumulating data to indicate that vis- ceral obesity and attendant risk factors are associated with increased risk for CVD. In the
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