Cardiovascular Risk Factors

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As waist circumference increases, visceral adiposity increases. Visceral adipose tissue is metabolically highly active. An important conceptual shift has occurred in recent years with respect to how adipose tissue is viewed. It is no longer seen as a passive storage site for excess caloric ingestion. Instead, it is clear that visceral adipose tissue displays many features of an endocrine organ (Bradley et al., 2001; Toth, 2005a) (Fig. 27-3). Visceral adipose tissue produces a variety of inflammatory cytokines (tumor necrosis factor, transforming growth factor-p), interleukins (IL-1, IL-6), and effector molecules that regulate appetite (leptin) as well as insulin sensitivity and resistance (e.g., adiponectin, resistin). As the mass of visceral adipose tissue increases, adiponectin production decreases, which is associated with increased insulin resistance in adipose tissue, skeletal muscle, and the hepatic parenchyma (see Fig. 27-3). As adipose tissue becomes more insulin resistant, the capacity to regulate the catabolism of stored TGs becomes progressively more dysregulated and unresponsive to systemic tissue

Fat area (cm2)

Figure 27-3 Insulin sensitivity and degree of adiposity. (From Fujimoto WY, Abbate SL, Kahn SE, et al. The visceral adiposity syndrome in Japanese-American men. Obes Res 1994;2:364-371)

Fat area (cm2)

Figure 27-3 Insulin sensitivity and degree of adiposity. (From Fujimoto WY, Abbate SL, Kahn SE, et al. The visceral adiposity syndrome in Japanese-American men. Obes Res 1994;2:364-371)

Visceral Adiposity

Visceral/total adipose tissue ratio

Figure 27-5 Severity of hepatic fat deposition as visceral adiposity worsens.

(From Banerji MA, Buckley MC, Chaiken RL, et al. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NDDM. Int J Obes 1995;19:846-850)

Visceral/total adipose tissue ratio

Figure 27-5 Severity of hepatic fat deposition as visceral adiposity worsens.

(From Banerji MA, Buckley MC, Chaiken RL, et al. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NDDM. Int J Obes 1995;19:846-850)

KAPLAN-MEIER SURVIVAL CURVE

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KAPLAN-MEIER SURVIVAL CURVE

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Figure 27-4 Risk of a major coronary heart disease (CHD)-related event associated with quintile of insulin levels in nondiabetic men enrolled in the Helsinki Policemen Study. (From PyoralaM, Miettinen H, LaaksoM, Pyorala K. Hyper-insulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Circulation 1998;98:398-404.)

needs. Serum levels of free fatty acids (FFAs) rise. The portal circulation becomes flooded with FFAs, resulting in both increased TG deposition within the liver (nonalcoholic ste-atohepatitis [NASH] or fatty liver) (Banerji et al., 1995) and increased VLDL secretion resulting in hypertriglyceridemia. A fatty liver in the absence of excessive alcohol intake is an important marker for insulin resistance and is highly correlated with the magnitude and severity of adiposity (Fig. 27-4). Elevation in FFAs induces progressive deterioration in glycemic control by (1) interfering with normal phosphory-lation of the insulin receptor, resulting in less expression of a glucose transporter (GLUT 4) necessary for the internalization and oxidation of serum glucose (Dresner et al., 1999), and (2) the induction of "lipotoxicity," the process by which FFAs induce premature apoptosis and dropout of pancreatic p-islet cells. Patients experiencing concomitant worsening insulin resistance and progressive loss of insulin-producing capacity experience a continuum of glycemic disturbance, beginning with impaired fasting glucose, then impaired glucose tolerance, and ultimately diabetes mel-litus. As serum levels of insulin rise, risk for CAD-related events increases precipitously (Pyorala et al., 1996) (Fig. 27-5). Patients with metabolic syndrome have a threefold to fivefold increased risk for developing diabetes compared to patients without metabolic syndrome.

Insulin resistance and increased visceral adiposity in the setting of metabolic syndrome are associated with changes in multiple risk factors (Lamon-Fava et al., 1996) (Fig. 27-6). Insulin-resistant adipose tissue is a potent source of angio-tensinogen, the precursor to vasoconstrictor angiotensin II. The BP in these patients also increases because (1) insulin stimulates increased sodium reabsorption at the level of the proximal tubular epithelium, which increases intravascular volume; (2) there is reduced endothelial nitric oxide production (Caballero, 2003); and (3) there is increased vascular sympathetic tone. In the face of insulin resistance, obesity can steadily worsen as a result of dysregulation of central centers transducing the signals for appetite and satiety. Serum HDL levels decrease for three principal reasons (Fig. 27-7). First, as the liver becomes insulin resistant, the capacity for insulin to stimulate the hepatic production of apo AI and AII is compromised, resulting in less HDL secretion. Second, in patients with insulin resistance, lipoprotein lipase is relatively inhibited. This reduces the hydrolysis of triglycerides in VLDL and chylomicrons. These large lipoproteins remain incompletely catabolized and form atherogenic remnant particles. Unless broken down further, they cannot release many of the surface-coat constituents used to assimilate HDL in serum. Third, as HDL particles become more enriched with TGs, they become a better substrate for hepatic lipase, an enzyme that catabolizes HDL and promotes its clearance from serum (Toth, 2005b). Patients with metabolic syndrome also tend to have smaller, denser LDL particles. These small LDL particles are believed to be more atherogenic than the larger, more buoyant variety because they are more easily oxidized, have reduced affinity for the hepatic LDL receptor resulting in less systemic clearance, and appear to more easily access the subendothe-lial space because of their smaller volume (St. Pierre et al., 2001). Visceral adipose tissue promotes increased systemic inflammation by secreting inflammatory mediators and by stimulating hepatic production of C-reactive protein (CRP) through IL-6. As serum levels of such acute-phase reactants as fibrinogen, CRP, and plasminogen activator inhibitor-1

METABOLIC SYNDROME

Insulin Risk Factors

Figure 27-6 Complex interactions among genetic, environmental, and socioeconomic factors increase risk of developing visceral adiposity, insulin resistance with risk factor generation and clustering, and ultimately, diabetes mellitus with atherosclerotic disease. CVD, Cardiovascular disease; LDL, low-density lipoprotein; TG, triglyceride.

Figure 27-6 Complex interactions among genetic, environmental, and socioeconomic factors increase risk of developing visceral adiposity, insulin resistance with risk factor generation and clustering, and ultimately, diabetes mellitus with atherosclerotic disease. CVD, Cardiovascular disease; LDL, low-density lipoprotein; TG, triglyceride.

Diabetes Mellitus Triad

Figure 27-7 Molecular mechanisms that cause the atherogenic lipid triad in patients with insulin resistance. As a patient becomes insulin resistant, the activity of lipoprotein lipase (LL) decreases. This can occur secondary to reduced apoprotein CII and/or increased apoprotein CIII production. With reduced capacity to hydrolyze the triglycerides in such large lipoproteins as very-low-density lipoprotein (VLDL, derived from liver) and chylomicrons (derived from gut), triglycerides and large remnant particles accumulate in serum. In this scenario, low-density lipoprotein (LDL) levels in serum tend to be relatively low because less VLDL is being converted to LDL. As high-density lipoprotein (HDL) and LDL particles become progressively more enriched with triglycerides, these lipoproteins become better substrates for the enzyme hepatic lipase (HL). HL catabolizes these lipoproteins to form small, dense LDL and HDL. The small HDL particles can be further degraded to their phospholipid and apoprotein constituents, thereby reducing circulating levels of this beneficial lipoprotein. (Basedon Toth PP, Davidson MH. Comparative effects of lipid-lowering therapies. Prog Cardiovasc Dis 2004;47:73-i04.)

(PAI-1) rise, the risk for metabolic syndrome and diabetes increases (Dandona et al., 2005; Festa et al., 2002). As shown in the Women's Health Study, as serum CRP levels increase in women with metabolic syndrome but no prior history of CAD, the risk for an acute cardiovascular event increases significantly (Ridker et al., 2003). As insulin resistance worsens, risk for nonalcoholic hepatic steatosis increases steadily (see Fig. 27-6).

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