Reviews/Commentaries/ADA Statements PERSPECTIVES ON THE NEWS Inflammation, Atherosclerosis, and Aspects of Insulin Action ZACHARY T. BLOOMGARDEN, MD resistance is associated with increased CRP levels, insulin secretion does not it- self increase CRP (15). CRP levels in non- diabetic persons increase with worsening C-reactive protein Chait noted, CVD prevalence is greater in glycemia and particularly with postload At the American Diabetes Association persons with metabolic syndrome with- glycemia (16). Insulin resistance is asso- Postgraduate Course held in New York on out diabetes than in those with diabetes ciated with a number of inflammatory 5 February 2005, Alan Chait (Seattle, who do not have the metabolic syndrome markers in addition to CRP, such as se- WA) discussed C-reactive protein (CRP). (13). Similarly, a study of persons from cretory phospholipase A2, e-selectin, and Although it may not be as predictive of Botnia in Finland showed, that for all lev- ICAM-1 (17). In the context of insulin re- cardiovascular disease (CVD) as choles- els of glycemia, the presence of metabolic sistance, obese persons have improve- terol, hypertension, and cigarette use (1), syndrome is associated with an increase in ment in insulin sensitivity and in CRP CRP appears to be the strongest “novel” CVD prevalence (14). The metabolic syn- with weight loss, while obese persons risk factor thus far identified, showing drome, then, is both associated with in- with normal insulin sensitivity, whose greater predictive power than homocys- flammation and appears to be a CRP level is lower, do not show further teine, interleukin (IL)-6 (2), and other in- particularly important marker of CVD decrease following weight loss, suggest- flammatory markers, such as serum risk. ing improvement in insulin sensitivity amyloid A (SAA), circulating levels of CRP is a member of the pentraxin rather than weight loss to mediate the re- which parallel CRP, and intracellular ad- family, which consists of five nonco- duction in CRP (18). hesion molecule (ICAM)-1. CRP adds valently associated peptides surrounding The adipocyte is another important prognostic information at all levels of risk a central core, binding bacterial and fun- component of inflammation. Adipose tis- based on Framingham score (3). gal polysaccharides. CRP acts as a mem- sue secretes inflammatory cytokines such Chait noted that several studies have ber of the innate immune system, as TNF-␣ and IL-6, and CRP levels in- shown that persons with diabetes without activating the classical pathway of com- crease with increasing weight. A new con- prior myocardial infarction have in- plement fixation and inducing phagocy- cept is that obesity leads to macrophage creased CVD risk, either to the same de- tosis. SAA, another acute-phase protein, infiltration of adipose tissues, perhaps be- gree as persons without diabetes but with is induced by IL-6, IL-1, and tumor ne- cause of the action of factors produced by prior evidence of CVD (4,5) or to a some- crosis factor (TNF)-␣ and is synthesized adipocytes themselves, with macro- what lower level (6). An important poten- by the liver. SAA is an apolipoprotein as- phages rather than adipocytes producing tial linkage between diabetes and sociated primarily with HDL, inducing some of the typically measured inflamma- atherosclerosis may involve inflammatory matrix-degrading enzymes and acting as a tory cytokines (19). In this view, macro- factors. CRP is increased by diabetes, as chemoattractant for monocytes, as well as phages may produce factors such as well as by obesity, estrogen, cigarette mediating lipid delivery to peripheral TNF-␣, causing insulin resistance, while smoking, chronic infections such as gin- cells and removal of cholesterol from both macrophages and adipocytes pro- givitis, and chronic inflammatory diseases damaged tissues. The COOH-terminus of duce factors that increase hepatic CRP such as rheumatoid arthritis, while being SAA leads to its retention in areas of in- synthesis, such as IL-6. decreased by statins (7), fibrates, niacin, flammation, playing a role in the innate Atherosclerosis is accelerated both di- aspirin (8), ␣-tocopherol (in high dose), immune system as well. Thus, inflamma- rectly by effects of cytokines on endothe- thiazolidinediones (TZDs) (9), alcohol, tory stimuli, by eliciting a macrophage re- lial cells and indirectly by cytokine effects and lifestyle factors such as exercise and sponse, promote release of cytokines, on the liver, causing increased production weight loss (10), with weight loss also de- which in turn promote hepatic synthesis of CRP and related factors (20). CRP in- creasing IL-6 levels (11). CRP increases if of inflammatory factors such as CRP and duces endothelial cell adhesion molecules one simply counts the number of positive SAA. Chait noted that insulin has what and increases endothelial cell monocyte metabolic syndrome markers, dyslipide- may be considered an anti-inflammatory chemoattractant protein-1 (21), inhibits mia, upper-body obesity, hypertension, effect in inhibiting the hepatic response to nitric oxide synthesis (22), increases plas- and hyperglycemia (12). Furthermore, cytokine stimulation. Although insulin minogen activator inhibitor (PAI)-1 ex- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● pression (23), and leads to endothelial Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with dysfunction (24), with atherosclerosis- the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. prone mice overexpressing CRP showing Abbreviations: apo, apolipoprotein; CAC, coronary artery calcium; CETP, cholesterol ester transfer evidence of increased atherosclerosis protein; CRP, C-reactive protein; CVD, cardiovascular disease; FFA, free fatty acid; FH, familial combined (25). Similarly, there is evidence that SAA hyperlipidemia; ICAM, intracellular adhesion molecule; I␬B, inhibitor of ␬B; IL, interleukin; NF-␬B, nuclear factor-␬B; PAI, plasminogen activator inhibitor; SAA, serum amyloid A; TNF, tumor necrosis factor; TZD, may be a mediator of atherosclerosis. thiazolidinedione; WBC, white blood cell count. HDL particles containing SAA rather than © 2005 by the American Diabetes Association. apolipoprotein (apo)A1 show adherence 2312 DIABETES CARE, VOLUME 28, NUMBER 9, SEPTEMBER 2005 Bloomgarden to vascular proteoglycans via the tether- sedentary lifestyle (37). Insulin resistance terol Education Program criteria (48) ing region of SAA, suggesting the exis- was associated with increased CAC score have been used to show the high preva- tence of “inflammatory HDL” (26). in the Framingham Offspring Study, with lence of metabolic syndrome in the pop- Chait reviewed current recommenda- a greater effect of glycemic abnormality ulation, with evidence that metabolic tions that CRP is of greatest use in CVD (38). This correlation is somewhat de- syndrome rather than hyperglycemia per risk assessment of persons with interme- bated, however, with there being some se is associated with CVD (13). diate CVD risk (10–20%/10 years), ap- evidence of a stronger correlation with The dyslipidemia of the metabolic pearing not to be useful either in low-risk visceral fat levels (39). Both diabetes and syndrome is associated with increased persons or in those at high risk, who metabolic syndrome are associated with triglycerides, decreased HDL2 choles- would already be given aggressive therapy increasing CAC levels, with evidence of terol, and increased small dense LDL par- (27). He noted that CRP levels are not greater effect of diabetes than metabolic ticles, in the presence of normal LDL very stable, changing with infection and syndrome in men but a greater effect of cholesterol. The liver makes triglyceride- other intercurrent stresses, so that serial metabolic syndrome than diabetes in rich VLDL particles, each containing one CRP measurement has been suggested women (40). As with CRP, the number of apoB molecule, with subsequent process- not to be useful in monitoring therapy. metabolic abnormalities present has been ing by lipoprotein lipase to remnant li- Two recent studies have challenged this associated with higher CAC score (41). poprotein particles containing less paradigm concept; the REVERSAL (Re- In persons with type 2 diabetes, age, triglyceride and further processing by he- versal of Atherosclerosis with Aggressive male sex, diabetes duration, waist-to-hip patic lipase to LDL and then to small Lipid Lowering) study showed CRP to be ratio, blood pressure, and statin therapy dense LDL particles. Thus, hepatic lipase independent of LDL cholesterol in pre- are associated with CAC (42), with Gold- plays a major role in the development of dicting progression of atherosclerosis berg wondering whether CAC can be diabetic dyslipidemia. In addition, trig- (28), and the PROVE-IT (Pravastatin or used in monitoring therapies. In type 1 lyceride-rich VLDL interacts with LDL to Atorvastatin Evaluation and Infection diabetes, CAC is associated with diabetes exchange triglycerides for cholesterol es- Therapy) study demonstrated that CVD duration, HbA1c (A1C), BMI, and insulin ter via cholesterol ester transfer protein events in persons at high risk were asso- dose (43), with baseline CAC correlating (CETP) to produce atherogenic small ciated with both higher LDL and higher with the CAC score at 2-year follow-up, LDL. CETP also mediates an interaction of CRP levels, whereas LDL cholesterol lev- suggesting a relationship to initial plaque VLDL with HDL2