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Third Annual World Congress on the Insulin Resistance Syndrome Atherothrombotic Disease

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Third Annual World Congress on the Insulin Resistance Syndrome Atherothrombotic Disease 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,
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