Reviews/Commentaries/Position Statements PERSPECTIVES ON THE NEWS

Third Annual World Congress on the Insulin Resistance Syndrome Atherothrombotic disease

ZACHARY T. BLOOMGARDEN, MD thalamic “clock,” which generates protein signals feeding back to create rhythmic behaviors and metabolic changes. Rhyth- his is the second of three articles re- structure, coagulation, and platelets in a mic mRNA expression of clock genes and viewing presentations at the 3rd An- prothrombotic direction (3). adipokines can also be demonstrated in T nual World Congress on the Insulin It is not apparent why insulin resis- mouse visceral adipose tissue, with adi- Resistance Syndrome, San Francisco, Cal- tance should be linked to atherosclerosis. ponectin and resistin responses both at- ifornia, 17–19 November 2005. The thrifty genotype hypothesis suggests tenuated in obese mice. Grant showed an that there is a survival advantage to insu- animal model in which pioglitazone im- proved hepatic rhythmicity. Thus, light, Diabetes and vascular disease lin resistance during periods of feast alter- as well as other stimuli such as ambient At a symposium cosponsored by the In- nating with famine (4), but that chronic ternational Society of Diabetes and Vascu- exposure to high nutrient intake converts temperature, acts via the suprachiasmatic lar Disease (www.dvdres.com), Peter the organism to the phenotype of insulin nucleus to send signals to adipocytes, the Grant (Leeds, U.K.) discussed the role of resistance sydrome and diabetes, with en- endothelium, liver, fibroblasts, cardiac insulin signaling pathways in acute coro- ergy preferentially stored in the liver and myocytes, and multiple other tissues, reg- nary syndrome (ACS), pointing out that in fat and with the clustering of risk mark- ulating reproductive, metabolic, and be- type 2 diabetes is characterized by fasting ers we have come to identify with insulin havioral aspects of life. hyperglycemia, usually with obesity, ac- resistance. The common-soil hypothesis An interesting model of insulin resis- companied by a clustering of CVD risk suggests that diabetes and CVD are the tance that also demonstrates the impor- factors, with 80% of persons with type 2 same condition, underpinned by com- tance of cycles is the hibernating animal. diabetes dying of premature vascular dis- mon genetic and environmental influ- Such animals eat during the summer, ease. In persons with diabetes, glycemic ences (5). gaining weight, becoming hyperinsuline- abnormality is superimposed on the ab- Grant continued that inflammation mic and insulin resistant, with increased normalities of the insulin resistance sy- and thrombosis are related processes that free fatty acid levels and increased inflam- drome, so that similar considerations must have primary protective function, matory response. Adipocyte-derived cy- apply to the larger group of persons with that the adipocyte response to fat loading tokines lead to what is termed endothelial insulin resistance. Indeed, we may under- also must be interpreted as a physiological cell dysfunction, but during hibernation, estimate the importance of glycemic ab- response, and that to understand the in- these factors are reversed over a several- normality in cardiovascular disease flammatory atherothrombotic insulin re- week period, while in humans with insu- (CVD), with recent studies suggesting sistance syndrome, we must unravel its lin resistance sydrome, there is that some 40% of persons with myocar- derivation as a set of normal responses to progressively worsening insulin resis- dial infarction have diabetes, with an ad- an abnormal setting, perhaps with abnor- tance at the heart of a “broken relation- ditional 40% having impaired glucose mal cyclical responses underpinning the ship to the environment,” leading to ever- tolerance (1). The cardiovascular mani- link between diabetes and CVD (6). The growing fat mass. Grant termed festations of insulin resistance sydrome organism exhibits a variety of cycles, melatonin the “forgotten hormone,” reg- constitute a series of inflammatory ranging from the cell cycle to circannual ulating the clock systems, activating the atherothrombotic processes, with rhythms, the menstrual cycle, and diurnal adipocyte phosphatidylinositol 3-kinase atherectomy specimen analysis showing variation. A set of circadian oscillators ex- (PI3K) pathway, increasing insulin sensi- more thrombus, more macrophage infil- ists to keep life functions synchronized tivity, and improving glucose metabolism tration, and a greater area of lipid-rich with the external environment. Light acts in humans. Interestingly, pinealectonized atheroma in persons with diabetes (2). at the suprachiasmatic nucleus to increase animals develop type 2 diabetes, and mice Furthermore, type 2 diabetes alters fibrin levels of melatonin, regulating the hypo- with mutations in circadian clock genes develop insulin resistance (7). In the ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● Leeds family study of 537 persons from Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with 89 families, three common polymor- the Division of Endocrinology, Mount Sinai School of Medicine, New York, New York. phisms have been found in the clock Abbreviations: ACEI, ACE inhibitor; ACS, acute coronary syndrome; ADMA, asymmetric dimethylargi- nine; apo, apolipoprotein; CHF, congestive heart failure; COX, cyclooxygenase; CRP, C-reactive protein; gene, all associated with the insulin resis- CVD, cardiovascular disease; IL, interleukin; MMP, matrix metalloproteinase; NF, nerve factor; NOS, NO tance sydrome. Persons whose cyclic pat- synthase; PAI, plasminogen activator inhibitor; PCI, percutaneous intervention; PGE, prostaglandin E; PI3K, terns are disrupted may have adverse phosphatidylinositol 3-kinase; PPAR, peroxisome proliferator–activated receptor; RAGE, receptor for ad- health outcomes, with shift working asso- vanced glycation end products; SSPG, steady-state plasma glucose; tPA, tissue plasminogen activator; TZD, thiazolidinedione; VTE, venous thromboembolism; vWF, von Willenbrand factor; WBC, white blood cell. ciated with 1.6- and 3-fold increased CVD DOI: 10.2337/dc06-zb08 rates in men and women, respectively. © 2006 by the American Diabetes Association. We are meant, Grant concluded, to expe-

DIABETES CARE, VOLUME 29, NUMBER 8, AUGUST 2006 1973 Perspectives on the News rience short-term periods of weight gain PCI in diabetic persons with multivessel ification reduces the need for blood that are seasonal and beneficial, with our disease. pressure and lipid treatment (15). Cur- “abnormal relationship with our environ- The National Registry of Myocardial rent guidelines for CVD risk reduction in ment” leading us to ignore the adaptations Infarction involves 1.4 million persons. persons with diabetes suggest that aspirin for which certain basic genes have been Registry patients with diabetes tended to and ACEIs should be given to all those developed. use less aspirin, ␤-blockers, heparin, and Ͼ40 years of age or with another CVD Paul Martin (Geneva, Switzerland) IIb/IIIa inhibitors and more ACE inhibi- risk factor; that all persons with diabetes discussed the evidence base of acute man- tors (ACEIs). Similarly, in the CRUSADE should be treated with a statin, regardless agement of ACS in diabetic patients. Dur- registry of 36000 persons, those with di- of their baseline LDL cholesterol, when ing the ACS, there is acute reduction in abetes were less likely to have appropriate Ͼ40 years of age; and that the blood pres- coronary blood flow in the setting of treatment and more likely to have had sure goal should be 130/85 mmHg. Re- thrombosis superimposed on atheroscle- myocardial infarction, CHF, and death. cent studies, however, show that only rosis. The activation of multiple hemo- Adherence to guidelines appeared to im- one-quarter of diabetic persons receive static mechanisms suggests the potential prove mortality in this study, with each aspirin, only half are at lipid treatment for multiple approaches to prevention 10% increase in guideline adherence as- goal, and only one-third are at blood pres- and reversal of pathological thrombosis, sociated with an 11% decrease in mortal- sure goal (16,17). An interesting new con- including aspirin, clopidogrel, heparin, ity. A number of new biomarkers are cept is the potential benefit of combined glycoprotein IIb/IIIa inhibitors, throm- being developed, with C-reactive protein administration of a thiazolidinedione bolysis, and percutaneous intervention (CRP), basic natriutretic peptide, placen- (TZD) with metformin in persons with di- (PCI); the approach of PCI/thrombolysis tal growth factor, ischemia-modified al- abetes and CVD (18). Furthermore, the versus medical management is deter- bumin, fatty acid–binding protein, and risk of metformin-associated lactic acido- mined by clinical findings, such as tropo- soluble CD40 ligand appearing poten- sis may be considerably lower than previ- nin levels and angiographic findings. The tially useful in addition to the electrocar- ously thought, with limited evidence base objective of ACS management is the res- diogram and quantitative troponin. The for recommendations that its use be re- toration of blood flow, myocardial sal- ideal cardiac biomarker will be specific stricted in persons with mild renal insuf- vage, and maintenance of left ventricular and sensitive when used early in myocar- ficiency, CHF, and liver disease, so that function. Studies comparing PCI with dial infarction, will have therapeutic im- this agent might be appropriate for many persons with these conditions. Similarly, thrombolysis suggest that diabetic pa- plications if positive, and should be precise, reliable, and cost-effective. In a TZD-related peripheral edema may be tients with ACS have better outcome with study of the use of multiple markers, a less of a risk than generally considered, angioplasty (8,9). Martin pointed out that combination of troponin I, CRP, and with the suggestion that TZDs increase fibrinolysis leads to increased thrombin brain natriuretic peptide allowed im- CHF hospitalization but decrease mortal- release, potentially further activating proved prediction (11). Martin con- ity (19). McGuire noted that peroxisome platelet aggregation and contributing to cluded by reminding the audience of the proliferator–activated receptor (PPAR)␥ undesirable outcome. Further studies of important new understanding of the use is expressed in the inner medullary col- ACS without electrocardiographic ST ele- of primary angioplasty and drug-eluting lecting duct, with a mouse model not ex- vation suggest that invasive approaches stents for ST elevation myocardial infarc- pressing this gene at this location are optimal. Persons with diabetes have tion, as well as of aspirin, low–molecular preventing TZD-induced edema. Spi- twice the early mortality in ACS, more weight heparin, ␤-blockers, ACEIs, clopi- ronolactone and the aldosterone receptor periprocedural complications, a higher dogrel, IIb/IIIa, and insulin-glucose infu- antagonist eplerenone may allow optimal rate of early reinfarction after PCI, and a sion with subsequent targeting of HbA1c treatment of TZD-induced edema, al- higher restenosis rate, despite similar pro- (A1C) to a goal Ͻ7% (12,13). though caution is required in avoiding cedural outcome, with greater risk for Darren McGuire (Dallas, TX) re- hyperkalemia. While hydrochlorothia- early and late congestive heart failure viewed the epidemiology of CVD in dia- zide is somewhat effective, furosemide is (CHF) after myocardial infarction and betes, noting that the number of persons not effective for this condition. longer intensive care unit and hospital with diagnosed diabetes in the U.S. is es- Francesco Cipollone (Chieti, Italy) stays. This leads to the question of timated at 21 million, driven by obesity discussed the vulnerable plaque in insulin whether coronary artery bypass grafting is and visceral adiposity, which may be seen resistance and type 2 diabetes, noting that better for persons with diabetes (10). as behavioral and social as well as envi- most myocardial infarctions are caused by With drug-eluting stents, restenosis rates ronmental disorders. “We have become small nonobstructive lesions. The stable have decreased dramatically, suggesting obese and inactive, overconsuming calo- plaque is characterized by a thick fibrous that surgery and PCI may now have com- ries,” he stated, with the diabetes preva- plaque, small lipid core, and little inflam- parable outcome. PCI may, however, lence approaching 10% of the adult matory infiltrate, with the vulnerable have prothrombotic effects, leading to tis- population. Among persons referred for plaque having opposite characteristics of sue factor and adhesion molecule genera- cardiac evaluation and treatment, some a large macrophage infiltrate, potentially tion. PCI with IIb/IIIa inhibitor treatment 30–50% have diabetes, many of whom producing proteolytic factors leading to is recommended for single-vessel disease, have not been diagnosed. Persons with plaque rupture. Beyond the concept of but American College of Cardiology/ diagnosed and undiagnosed diabetes and, the vulnerable plaque is that of the vul- American Heart Association guidelines to a lesser extent, those with impaired glu- nerable patient. Multiple plaques with the currently recommend that coronary ar- cose tolerance have increased mortality potential to thrombose are typically tery bypass grafting using an internal risk when compared with those with nor- present in persons who have a myocardial mammary artery graft is preferred over mal glucose tolerance (14). Lifestyle mod- infarction, and 80% of persons with ACS

1974 DIABETES CARE, VOLUME 29, NUMBER 8, AUGUST 2006 Bloomgarden have at least one additional ruptured portance of monocytes and CD4-positive courses of inflammation may be relevant plaque, which is clinically asymptomatic lymphocytes that differentiate into the ac- to the atherosclerotic process: 1) chronic (20). In human atherosclerosis specimens tivated, mediator-releasing Th1 cells. inflammation associated with slow pro- obtained during carotid endarterectomy, These steps are increased in persons with gression and 2) acute inflammatory pro- plaques from persons with diabetes have type 2 diabetes who exhibit multiple and cesses leading to acute CVD events. more pronounced inflammatory infil- diffuse angiographic lesions. Given the el- Vallance reviewed evidence that acute in- trate, as shown by the presence of CD68 evated C-peptide seen in early type 2 di- fections are associated with increased (a macrophage marker), CD3 (T-cell), abetes, he asked whether there might be a CVD event rates. In a study of patients and HLA-DR (activated macrophage) causal role of this peptide in early athero- with bacteremia, 4% had a myocardial in- (21). The interstitial collagen content in genesis. Increased endothelial permeabil- farction within the following month (26). plaques from patients with diabetes is less ity is seen in early atherosclerosis, and Similarly, as many as 10% of all strokes than half of that in plaques from nondia- C-peptide but not insulin or proinsulin may be preceded by bacteremia (27), betic persons, while oxidized LDL stain- immunostaining was seen in early athero- there is a several-week period of increased ing more than doubles in the plaque of the sclerotic lesions of persons with diabetes myocardial infarction and stroke risk fol- person with diabetes. Similar assessment but not in nondiabetic persons. The C- lowing abdominal surgery (28), and a of plaque from metabolic syndrome pa- peptide colocalized with monocyte/ 2-week period of increased myocardial tients shows increased CD68 and CD3 macrophages, although macrophages infarction and stroke risk follows respira- staining. were only present in 75%, whereas C- tory and urinary infections (29). In vivo, Cyclooxygenase (COX)-2 does not peptide was present in 100%, of speci- endotoxin and proinflammatory cyto- appear to play a role in plaque growth, mens from persons with diabetes, kines induce endothelial dysfunction with COX-2 polymorphisms not associ- suggesting C-peptide to be a macrophage (30). In six men before and after admin- ated with different size of atherotic lesions chemoattractant, with confirmatory stud- istration of typhoid vaccine, which (22), but COX-2 overexpression does ap- ies suggesting that C-peptide, but not in- caused an inflammatory response over 8 h pear to increase the likelihood of plaque sulin, acts as a chemoattractant for with mild leukocytosis, levels of interleu- rupture (23). COX-2 may be involved in macrophages in vitro to the same degree kin (IL)-6 and IL-1 receptor antagonist expression of the receptor for advanced as macrophage chemoattractant protein 1 increased, with evidence of decreased en- glycation end products (RAGE), with ev- (25). Furthermore, studies with CD4- dothelial function, as shown by decreased idence of increased RAGE expression in positive lymphocytes show these cell bradykinin response in flow-mediated va- diabetic plaque (24). RAGE may induce types also colocalize with C-peptide, with sodilation. High-dose aspirin blocked the nerve factor (NF)-␬B expression, with the evidence that C-peptide acts as chemoat- effect on IL-1 receptor antagonist and on p50 and p65 NF-␬B subunits more tractant for T-cells. C-peptide is not, how- endothelial function. Vallance suggested strongly present in diabetic plaque, as ever, a chemoattractant for neutrophils. that CRP is not involved, as the decrease well as in COX-2 and matrix metallopro- C-peptide induces T-cell migration, in flow-mediated vasodilation paralleled teinase (MMP)-9 and MMP-2, the prosta- which is inhibited by pertussis-toxin, sug- that in IL-6, during a time period without Ϫ Ϫ glandin E (PGE)2-dependent MMPs. gesting that a G-protein–coupled recep- an increase in CRP (31). In the apoE / Isolated monocytes from diabetic patients tor is involved, and by wortmanin, mouse following ␥-herpes virus infection, show advanced glycation end product– suggesting a role of PI3K. Furthermore, aortic atherogenesis is markedly in- induced expression of COX-2, with both C-peptide stimulation leads to transloca- creased, but this is blocked by antiviral suppressed by antibody to RAGE. Regu- tion of PI3K-␥ but not class IA PI3K, sug- treatment, suggesting either effects of sys- lation of RAGE in diabetic plaque shows gesting a specific isoenzyme to be temic or local inflammatory response or both glucose-dependent and -indepen- involved in the effect. Thus, C-peptide direct arterial wall infection, with strong dent components. Comparing persons appears to phosphorylate a number of correlation between the T-cell response treated with 40 mg simvastatin versus diet steps involved in macrophage motility, and increased atherosclerosis. alone for 4 months before carotid endar- perhaps binding to a G-protein–coupled Gerald Reaven (Stanford, CA) re- terectomy, staining for myeloperoxidase, receptor and leading to activation of Rho- flected on hypertension as a disease of MMP-2 and -9, RAGE, NF-␬B, COX-2, GTPase and subsequently to cell adhesion carbohydrate and lipid metabolism. He and PGE synthase-1, the enzyme involved and contraction, with a potential role in noted the six- to eightfold variation in in- in PGE2 synthesis, were markedly de- the early phases of atherogenesis. sulin sensitivity among persons with nor- creased by the statin, while collagen stain- mal glucose homeostasis. Approximately ing was increased following simvastatin Insulin resistance and CVD one-quarter of this variation may be ex- treatment. Thus, Cipollone suggested Patrick Vallance (London, U.K.) dis- plained by obesity, measured either with that focal intervention to stabilize the rup- cussed studies of the relationship between BMI or waist circumference, another one- tured plaque, followed by systemic med- inflammation and CVD. In a mouse quarter is related to physical fitness, and ical therapy with agents including aspirin, model expressing neither apolipoprotein ethnic/genetic factors appear to explain Ϫ Ϫ clopidogrel, statins, and ACEIs, will be (apo)E (apoE / ) nor endothelial nitric approximately half of the variation in in- appropriate, with the additional mecha- oxide (NO) synthase, atherogenesis is en- sulin sensitivity. Essential hypertension is nisms of plaque abnormality suggesting hanced with the development of aneu- associated with mild glucose intolerance the potential for development of new ap- risms. There is decreased NO-mediated and marked hyperinsulinemia, with in- proaches. dilation in hypertension, diabetes, hyper- creased steady-state plasma glucose Nikolaus Marx (Ulm, German) dis- cholesterolemia, smoking, and renal dis- (SSPG). Similar evidence of insulin resis- cussed the role of C-peptide in diabetes ease. Inflammation may underlie some of tance is seen in normotensive first-degree and in atherogenesis, reviewing the im- these relationships. Two distinct time relatives of hypertensive persons, with

DIABETES CARE, VOLUME 29, NUMBER 8, AUGUST 2006 1975 Perspectives on the News fasting insulin a predictor of risk of hyper- thrombotic events, and persons with a present in atheromata and in adipose tis- tension (32,33). Half of newly diagnosed new event are often found to have either sue, with IL-6 a key component of these hypertensive persons are insulin resistant, or both conditions. Pathologic examina- inflammatory processes (46). Diabetes, and it is this subset that is associated with tion of atheromas from persons with dia- insulin resistance, and the components of the greatest degree of dyslipidemia, par- betes show increased lipid area, the insulin resistance sydrome are associ- ticularly in triglyceride elevation, and macrophage infiltration, and thrombosis ated with CRP, plasma viscosity, the leu- with the greatest likelihood of CVD. In the (36). Similar abnormalities are seen in kocyte count (white blood cells [WBCs]), Copenhagen male study, hypertensive persons with IGT or hyperinsulinemic eu- fibrinogen, and a variety of clotting fac- persons with a normal lipid pattern had glycemia, with 85% of persons develop- tors (47). In a study comparing 325 men no increase in CVD risk, while low HDL ing diabetes having preexisting insulin with and 2,899 without diabetes between cholesterol and high triglyceride levels resistance (37), constituting a large group 60 and 79 years of age, the diabetic pa- had additive effects on risk (34). Mono- of individuals with increased athero- tients had 20% higher levels of CRP and nuclear cell binding to endothelium cor- thrombotic risk. Inflammatory mediators ϳ10% higher WBCs, viscosity, fibrino- relates with blood pressure and with the such as CRP are involved in the athero- gen, clotting factors, and tissue plasmin- SSPG. A mediator of hypertension may be sclerotic process, with increased coagula- ogen activator (tPA) (48). Among the endogenous endothelial NO synthase tion, increased platelet activation and nondiabetic men, BMI and, even more (NOS) inhibitor asymmetric dimethyl- adhesion, and inhibition of fibrinolysis, strongly, waist circumference and plasma arginine (ADMA), produced by adipose leading Grant to suggest that we need an insulin are associated with CRP, viscosity, tissue, with levels associated with the de- extended concept of the insulin resistance clotting factors, and tPA, with a particular gree of obesity and with a strong correla- syndrome that includes inflammatory relationship of waist circumference with tion between the SSPG and ADMA levels atherothrombotic disease. Management, tPA and of insulin with factor VII/von in insulin-resistant versus insulin- then, must include not only glucose- Willenbrand factor (vWF) and tPA, while sensitive persons with versus without hy- lowering treatment but also the use of there is little association of HDL with pertension. ADMA is a CVD risk marker agents to affect the cluster of additional these inflammatory/thrombotic measures (35). In obesity, ADMA levels are higher CVD risk factors. (49). The triglyceride level, however, is only in the insulin-resistant subgroup and Gordon Lowe (Glasgow, U.K.) dis- strongly associated with viscosity, factors decrease in this group with weight loss. cussed the epidemiology of diabetes, in- VII and IX, and tPA; the blood pressure Similarly, rosiglitazone decreases ADMA. sulin resistance, and cardiovascular shows modest association with CRP, vis- Reaven reviewed several additional thrombosis, addressing the mechanisms cosity, and factor VII; and blood glucose potential links between insulin resistance of the association of the former two ab- is particularly associated with factor VII/ and hypertension. Hyperinsulinemia normalities with thrombosis and whether vWF (36). Thus, inflammation and the causes increased sympathetic nervous abnormality of inflammation, hemostasis, prothrombotic state are associated with system activity even with insulin resis- and fibrinolysis might in some fashion diabetes and insulin resistance, clustering tance, with there being an association be- promote diabetes. It is now well estab- with metabolic factors (50), and therefore tween heart rate and the insulin response lished that diabetes and insulin resistance potentially contributing to the risk of to a meal and between heart rate and are related to increased risk of CVD and thrombosis. There are potential genetic SSPG. Another link may be related to so- stroke, as well to venous thromboembo- associations, with first-degree relatives of dium retention, with hypertensive per- lism (VTE). Persons with diabetes have a persons with type 2 diabetes having in- sons who are “salt sensitive” the insulin- tripling of CVD rates (38), leading to the creased thrombotic factors (51). Insulin resistant subset. The predictor of weight concept of diabetes as a CHD equivalent and triglyceride may have direct effects on gain on a high-salt diet is the lack of na- (39), with the diagnosis of diabetes at age plasminogen activator inhibitor (PAI)-1 triuresis and the degree of insulin resis- 40 years associated with an 8-year reduc- (52). Exercise may have a therapeutic ef- tance. Similarly, lower sodium excretion tion in life expectancy (40). There is also fect, with levels of CRP, fibrinogen, predicts increases in blood pressure. an association of the insulin resistance sy- WBCs, and platelets lower in persons Thus, insulin resistance and associated drome with CVD (41), perhaps underly- with greater degrees of physical activity, metabolic abnormalities are increased in ing the relationship between A1C well with or without a history of CVD (53). hypertension and predicts risk of hyper- below the diabetic range with adverse Lowe noted that a number of meta- tension, defining the subgroup at greatest outcome (42). Underscoring the associa- analyses suggest that CRP is as strong a CVD risk, with multiple potential mech- tion between VTE and atherosclerosis is marker of CHD risk as fibrinogen, IL-6, anisms of causation of these processes. evidence that persons with a history of the vWF, D-dimer, and other hemostatic fac- former have a likelihood of plaques on tors (54–56). Furthermore, persons ex- Coagulation carotid ultrasound ϳ50% greater than pressing the 1444C allele have higher Peter Grant discussed the link among in- that in control subjects that is not cor- CRP levels than those with the 1444TT sulin resistance, inflammation, and rected by multivariate analysis including genotype (57), but they fail to show evi- thrombosis, reviewing the processes of CVD risk factors (43). Furthermore, per- dence of increased CVD risk or of hyper- adhesion and migration of leukocytes in- sons who have had pulmonary emboli tension or the insulin resistance sydrome; volved in the development of the athero- have a doubled risk of subsequent cardio- therefore, although diabetes and insulin sclerotic plaque. Plaque rupture leads to vascular events (44), and diabetes is asso- resistance are certainly associated with in- formation of a thrombus with a highly or- ciated with a 50% increase in VTE risk creased risk of CVD and thrombosis, the ganized fibrin mesh causing arterial oc- (45). The effect of diabetes and insulin activation markers are not proven as clusion. Persons with diabetes and the resistance on thrombosis may be medi- causes of either thrombosis or diabetes. metabolic syndrome are at high risk of ated by proinflammatory cytokines Grant discussed insulin resistance

1976 DIABETES CARE, VOLUME 29, NUMBER 8, AUGUST 2006 Bloomgarden and CVD, addressing the regulation of fi- when infused in vivo and modulates reduction in events in persons with versus brin structure and function. Venous platelet calcium flux, a basic regulatory without diabetes treated with aspirin, thromboses are typically platelet poor, process for platelet aggregation. Insulin suggesting the potential for this to be an while arterial thromboses contain a plate- also increases platelet NOS via a PI3K important area for additional intervention let-rich fibrin mesh. The coagulation cas- pathway, with NO showing effects in- (62). Of further note, postprandial plate- cade ultimately results in the generation cluding vasodilation and inhibition of let activation appears to occur, and may of thrombin from prothrombin, leading platelet aggregation. Insulin stimulates be related to, oxidative stress or to to activation of factor XIII (XIIIa), as well platelet phosphorylation of Akt, of changes in both lipid and glucose levels. as leading fibrinogen to change to a solu- AMPK, and of NOS and increases platelet Nikolaus Marx discussed the emerg- ble form, which, under the influence of cGMP and cAMP generation, all causing ing role of PPAR␥ activators in insulin re- factor XIIIa, forms cross-linked fibrin. its antiaggregating effect, with the NOS sistance, diabetes, and atherothrombotic Cross-linked fibrin breakdown by tPA is inhibitor L-NMMA preventing these ef- disorders. PPAR␥ is a nuclear receptor limited by PAI-1. With increasing insulin fects. Prostacyclin has antiaggregatory ef- that heterodimerizes with the retinoid X resistance, factor XIIIa levels rise. Scan- fects mediated by activation of adenylate receptor, binding to promoter regions on ning electron microscopy may be used to cyclase, with insulin increasing these ef- genes leading to adipocyte protein syn- distinguish looser versus more tightly fects and upregulating prostacyclin recep- thesis, resulting in changes in cytokine linked fibrin strands, the latter seen in the tors, again blunted by L-NMMA. Thus, production and fatty acid metabolism prothrombotic state. Permeation and tur- insulin acts via the NOS/cyclic nucleotide (63). There is evidence of PPAR␥ expres- bidity studies and measures of visco- pathways to inhibit platelet function. sion in endothelial cells, macrophages, elastic properties of clots are alternative In insulin-resistant states, all of these smooth muscle cells, and CD4-positive approaches to distinguishing these two processes are impaired, with defective an- lymphocytes (63,64). Atherogenesis is an types of fibrin. Polymorphisms in factors tiaggregating effect of insulin in obese inflammatory process occurring in the XIII and fibrinogen as well as changes in persons. Interestingly, lean persons with vascular wall, with evidence that TZDs insulin sensitivity may further alter fibrin- type 2 diabetes do not demonstrate the decrease vascular monocyte and T-cell re- ogen. The insulin resistance sydrome is abnormality seen in obese persons with or cruitment, decrease T-cell activation and associated with multiple aspects of the without diabetes. Obesity is associated vascular smooth muscle cell migration in prothrombotic state, principally by affect- with decreases in both cGMP and cAMP fatty streak formation, and reduce inflam- ing fibrin and PAI-1. Posttranslational production and action, and states of insu- matory biomarkers in the atherosclerotic modifications in fibrin and fibrinogen lin resistance are associated with in- plaque. PPAR␥ activators have anti- may be important, as glycation, sialyca- creased platelet cytosolic calcium levels. atherogenic effects. In a comparison of tion, oxidation, and acetylation act partic- F2-isoprostane levels are increased in pioglitazone with glimepiride in persons ularly at the lysine residues involved in obesity and decreased by weight loss, with type 2 diabetes attaining similar de- the coagulation process. Clot permeabil- with evidence of reduced aspirin sensitiv- grees of glycemic control, CRP levels de- ity decreases as A1C levels rise (50), and ity of the proaggregatory pathway (60). In creased with the TZD (65). Similarly, glycation is associated with decreased a study of 20 persons following a weight- rosiglitazone decreases serum amyloid A generation of plasmin, the critical enzyme loss program for 6 months, 10 subjects within 2 weeks after administration, sug- that breaks down fibrin, so that fibrin ly- lost weight and demonstrated decreased gesting that the anti-inflammatory effects ses more slowly in persons with diabetes. waist circumference, BMI, fasting insulin, of these agents may be independent of Grant speculated that diabetes and insu- triglyceride, and CRP levels and increased their metabolic effects (66). The normal lin resistance may mediate the moderate HDL cholesterol levels. Weight loss re- endothelium generates NO with shear heritability of thrombotic risk (58,59), as stored platelet sensitivity to the antiaggre- stress, leading to 5–10% vasodilation in specific genes coding for variants of clot- gating effects of insulin and of NO, while healthy persons. Endothelial dysfunction ting factors such as fibrinogen, factor VII, no changes occurred in persons not losing can be demonstrated in persons with di- and PAI-1 have not been demonstrated in weight. Travati noted that obesity induces abetes, who fail to show this phenome- association with thrombosis. He sug- inflammatory changes in adipose tissue non. Following TZD treatment, gested that genetic influences on insulin (61) and that the change in platelet NO endothelium-dependent vasodilation is resistance, hypertension, and dyslipide- response after weight loss correlates with restored, with improvement seen as early mia interact as environmental influences the improvement in insulin sensitivity but as the 1st day of treatment (67). on thrombotic processes, and reminded not with changes in a variety of adipo- Restenosis is an important pathologic the audience of the importance of treat- kines. Thus, platelets are targets of insulin process seen following vascular interven- ments such as aspirin, clopidogrel, and action and are affected by insulin resis- tion and resembles atherosclerosis, with the IIb/IIIa inhibitors. tance. She addressed the question of several studies examining the effect of Mariella Travati (Turin, Italy) pre- whether aspirin resistance is seen in indi- TZD treatment. In persons with type 2 sented a fascinating review of the effects of viduals with insulin resistance, noting diabetes treated with rosiglitazone (68) insulin resistance on platelet function. that this does occur and is related to in- and in nondiabetic persons with coronary Platelets exhibit complex interactions creased isoprostane levels and perhaps artery disease treated with pioglitazone with other vascular cells and are them- also to glycation, with high fibrinogen (69), restenosis rates have been reduced. selves targets of insulin action, expressing and vWF markers of aspirin resistance. It In the latter study, there was no effect on insulin receptors, with insulin reducing is not clear, however, whether a clinically glucose, insulin, A1C, or lipids but signif- platelet aggregation in response to factors relevant degree of aspirin resistance oc- icant reduction in neointimal volume. In such as ADP and arachidonic acid. Insulin curs in diabetes. The Antithrombotic Tri- studies of plaque morphology and plaque decreases platelet-collagen interactions alists’ Collaboration showed 8 vs. 22% stability, 24 nondiabetic patients under-

DIABETES CARE, VOLUME 29, NUMBER 8, AUGUST 2006 1977 Perspectives on the News going carotid endarterectomy were ran- Dissait F, Vanzetto G, Leizorowicz A, culation 111:583–590, 2005 domized to pretreatment with 4 mg Touboul P: Is primary angioplasty more 20. Goldstein JA, Demetriou D, Grines CL, rosiglitazone twice daily or placebo, effective than prehospital fibrinolysis in Pica M, Shoukfeh M, O’Neill WW: Multi- showing histologic evidence of decreased diabetics with acute myocardial infarc- ple complex coronary plaques in patients CD4-positive lymphocytes, without tion? Data from the CAPTIM randomized with acute myocardial infarction. N Engl clinical trial. Eur Heart J 26:1712–1718, J Med 343:915–922, 2000 change in macrophage content but with 2005 21. Cipollone F, Rocca B, Patrono C: Cyclo- decreased macrophage HLA-DR staining, 10. 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