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; IB, 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 to produce less anti- Ͻ els 70 mg/dl were associated with better level (44). There is some evidence that atherogenic HDL3. Insulin-resistant per- outcome in those persons with lower CRP interventions influence CAC, with statins sons from a normal population, and levels (29). Thus, there is now evidence appearing to decrease progression (45) similarly (but to a greater extent) persons suggesting that one might follow CRP and with an association of physical activ- with type 2 diabetes, have increased levels to optimize treatment of high-risk ity with reduction in CAC (46). Goldberg VLDL cholesterol, a shift in LDL choles- persons. suggested that CAC measurement is less terol to more dense (hence smaller and costly than stress testing, which only gives more numerous) particles, and a decrease Coronary artery calcification risk information in the presence of ob- in HDL cholesterol. Ronald Goldberg (Miami, FL) reviewed structive CAD, and concluded that the FH is caused, Brunzell stated, by an the use of the coronary artery calcium CAC score predicts risk more accurately interaction between genes for insulin re- (CAC) score (30), a novel risk factor, than and independent of standard risk sistance/metabolic syndrome and a lipid which although very different from CRP, factors, as well as adding to the risk as- disturbance such as increased apoB pro- may also allow one to increase the preci- sessment. duction. In these families there is variabil- sion with which therapy is offered. Coro- ity in lipoprotein phenotype, and lipid nary plaque evolution is associated with Dyslipidemia and insulin resistance levels vary over time in individuals, with calcification, a phenomenon exploited in Assessing LDL size and density in the apoB always elevated although differently measuring CAC. CAC may be measured metabolic syndrome, John D. Brunzell distributed between VLDL and LDL. either with spiral computed tomography (Seattle, WA) noted the association of ApoB measurement may then be particu- or with the more accurate electron beam metabolic syndrome with type 2 diabetes larly helpful in the assessment of FH (49). tomography. The prevalence of CAC in- and with familial combined hyperlipid- FH is a particularly atherogenic dyslipide- creases with age and is greater in males emia (FH), both of which contribute to mia, with risk of myocardial infarction (31), with normative data available from premature coronary disease. The meta- twice that in spouse control subjects and more than 10,000 persons (32). CAC is bolic syndrome is associated with maldis- in persons with familial hypertriglyceri- associated with CVD independent of age, tribution of body fat, increased free fatty demia (50). Seven-year follow-up of the blood pressure, diabetes, cigarette smok- acids (FFAs), and insulin resistance, lead- Quebec cardiovascular study showed that ing, and lipids both in cross-sectional ing to type 2 diabetes, hypertension, dys- LDL size and apoB are independent risk (33,34) and prospective studies (35), sug- lipidemia, and hypercoagulability. There factors, with persons having large LDL gesting, Goldberg stated, that “you are as is a high correlation between insulin sen- manifesting a doubling of in risk with in- old as your arteries.” Indeed, CAC pre- sitivity and intra-abdominal fat (47). The creased apoB, while those with small LDL dicts risk more accurately than traditional effect of insulin resistance may be medi- have a sixfold increase in risk with high risk factors (36). CAC correlates with the ated by increased portal FFAs, by hepatic apoB (51). Framingham risk score and even more or muscle fat, by decreased adiponectin, Small LDL particles are more athero- strongly with family history, obesity, and or by other factors. The National Choles- genic, permeating the arterial wall, bind-
DIABETES CARE, VOLUME 28, NUMBER 9, SEPTEMBER 2005 2313 Perspectives on the News ing proteoglycans, and showing greater ing cleared. Lipoprotein(a) levels are state of chronic macrophage activation, susceptibility to oxidation. Assessment of highly heritable, and there is also lipopro- chronic increase in cytokines, with cen- these particles can be performed directly tein(a) elevation in patients with renal tral obesity, insulin resistance, defective with gradient gel electrophoresis or ultra- disease and in African Americans. In- insulin secretion, and overproduction by centrifugation or indirectly by measuring creased lipoprotein(a) is strongly associ- the liver of the hepatic products of cyto- apoB and simply with calculation of the ated with premature CVD and is present kine activation. non-HDL cholesterol. Therapy to de- in 19% of families with premature coro- Tarantino asked how this hypothe- crease small LDL particle levels in HF can nary heart disease but 10% of control sized mechanism of the metabolic syn- involve weight loss or administration of families (61). In the Lipid Research Clin- drome might come about, with nicotinic acid, with or without a statin. In ics trial, mean lipoprotein(a) levels were overnutrition increasing cytokines, and persons with diabetes, statins and TZDs 23.7 in persons with CVD vs. 19.5 mg/dl what molecular mechanisms exist linking are effective, with some evidence of ben- in control subjects, with persons in the cytokines to insulin resistance and de- efit of nicotinic acid as well (52). Recent upper 40% of lipoprotein(a) having a creased insulin secretion. He described a studies described by Brunzell compared doubling in CVD event rates (62,63). series of studies of Pima Indians related to effects of rosiglitazone and pioglitazone, Similarly, in the Framingham study, there the question of whether inflammation is showing similar effects on A1C, subcuta- was 2.4- and 1.7-fold increase in CVD caused by diabetes or is rather a causal neous fat, insulin resistance, FFAs, adi- risk in women and men, respectively, factor, noting that on average the body ponectin, and hepatic fat, but some with increased lipoprotein(a) levels (64), temperature of this population is ϳ1o differences in lipid effects, with pioglita- and meta-analysis of 18 studies shows a higher and that there is a negative corre- zone but not rosiglitazone decreasing trig- 1.7-fold increase in risk for persons in the lation of body temperature with insulin lycerides and rosiglitazone, leading to a highest tertile of lipoprotein(a) with ad- sensitivity. A number of markers of in- greater increase in LDL cholesterol, al- justment for age, blood pressure, diabe- flammation are associated with insulin re- though both increased LDL size and tes, cigarette use, and LDL and HDL sistance and risk of type 2 diabetes in buoyancy and increased HDL, with ros- cholesterol (65). Treatment approaches Pimas. One of the first such discovered iglitazone having a greater effect in in- that lower lipoprotein(a) include niacin, was ␥ globulin (70). The leukocyte count creasing HDL2. Brunzell noted that TZDs leading to 20–30% reductions, and estro- (white blood cell count [WBC]) correlates decrease CRP and hepatic steatosis, with gen plus progesterone, reducing levels with body fat, insulin sensitivity, and fast- “the crucial thing” the question of 15–25%. Interestingly, in the HERS ing insulin, but not with the acute insulin whether they reduce CVD events. Out- (Heart and Estrogen-Progestin Replace- response to intravenous glucose. Ad- come studies are in progress. He sug- ment Study) there was evidence of reduc- justed for age, sex, and percent body fat, gested particular benefit of niacin, with tion in CVD with hormone replacement the WBC is associated with cumulative doses of Ͻ3 g daily increasing HDL by therapy in women with increased li- incidence of diabetes (71). Longitudinal approximately one-quarter and decreas- poprotein(a) (66). Atorvastatin 40 mg analysis shows that the baseline WBC is ing triglycerides by one-third, and with daily decreases lipoprotein(a) cholesterol associated with the decrease over time in modest effect in reducing LDL levels by 16%, although actually increasing the insulin sensitivity but not with the change (53,54). total lipoprotein(a) level (67). in acute insulin secretion. CRP and ICAM Ernest Schaefer (Boston MA) dis- (72), as well as ALT, which is indicative of cussed lipoprotein(a), diabetic dyslipide- Adipokines and inflammation in steatohepatitis (73), are further inflam- mia, and coronary heart disease. insulin resistance matory markers in the Pimas. Similar Lipoprotein(a) was found to be associated P. Antonio Tataranni (Paris, France) dis- studies have been reported in other pop- with CHD risk over 40 years ago (55). cussed the roles of adipokines and of in- ulations. In the ARIC (Atherosclerosis Niacin was shown to reduce lipopro- flammatory factors in the metabolic Risk in Communities) study, insulin sen- tein(a) in 1989 (56), and the apo(a) gene syndrome, addressing pathophysiological sitivity correlated with WBC, fibrinogen, was cloned and sequenced in 1991, with linkages, including obesity, insulin resis- sialic acid, and orosomucoid, as well as recognition of its similarity to plasmino- tance, glucotoxicity, lipotoxicity, and cell with low serum albumin (74). In the WHI gen (57). Apo(a) is attached to apoB100 nutrient overload (68). High-dose salicy- (Women’s Health Initiative) study, WBC by a disulfide bond (58) and contains a lates have long been recognized to im- (75), CRP, and IL-6 (76) correlated with variable number of kringle protein repeat prove diabetes, and there is increasingly risk of type 2 diabetes. An association of sequences, so termed because of the their the concept that diabetes is a disease of CRP with development of diabetes was shape resembling that of a type of Danish the innate immune system (69). Macro- also reported in an elderly population, al- pastry. The lower–molecular weight iso- phages stimulated by injury or infection though this population failed to show in- forms are less rapidly cleared and associ- secrete cytokines such as IL-6, IL-1, and creased risk with WBC, albumin, ated with higher lipoprotein(a) levels TNF-␣, leading to hepatic production of fibrinogen, platelet count, or factor VIIc (59,60). The apo(a) secretion rate is ap- acute-phase reactants including fibrino- (77). proximately one-third that of apoB100, gen, SAA, CRP, lipoprotein(a), and PAI-1, These and many other studies suggest but apo(a) has twice the residence time of with there also being a feedback system that obesity indeed is associated with sub- apoB100 in circulation, suggesting that whereby cytokines act in the central ner- clinical inflammation and with insulin re- apo(a) attaches to an apoB100 in VLDL vous system to decrease the hepatic ef- sistance. Tarantino discussed the many and may then associate with another fects. Chronic hyperstimulation by cytokines originating in adipose tissue apoB100 particle in circulation before be- overnutrition may, however, lead to a (adipokines). Adipocytes produce com-
2314 DIABETES CARE, VOLUME 28, NUMBER 9, SEPTEMBER 2005 Bloomgarden plement factor B; the serine protease ad- insulin resistance are improved by inhibi- family of 10 peptides present in the hu- ipsin; acylation-stimulating protein, a tion of NF-B by salicylates or by genetic man genome, IGF-1 and -2, and the seven paracrine signal increasing adipocyte tri- deletion. Interestingly, activation or inhi- relaxin-related peptides. The latter group glyceride synthesis; TNF-␣; IL-6, -8, and bition of muscle NF-B in mice does not of hormones have a G-coupled receptor -10; monocyte chemoattractant pro- change their phenotype, while activation system that is completely different from tein-1; PAI-1; lipoprotein lipase; CETP; in either liver or fat produces systemic in- the tyrosine kinase receptors for insulin ACE; the prostacyclin prostaglandine E2; sulin resistance. Specific inhibitors of and IGF-1 and -2. Insulin-like molecules vascular endothelial growth factor; hor- NF-B are being developed as pharmaco- are found throughout the vertebrate and mones such as leptin, resistin, adiponec- logical approaches to breaking the chain invertebrate kingdoms, with Bombyxin tin, and angiotensinogen; and the of events that leads from overnutrition to an insulin-related neurosecretory peptide enzymes 17-hydroxysteroid dehydroge- insulin resistance and decreased insulin present in invertebrates such as the silk- nase and 11--hydroxysteroid dehydro- secretion, although there is as yet no evi- moth, Bombyx mori. genase. Adiponectin is a specific white dence of a relationship between inflam- There are a total of 19 different hu- adipose tissue–derived protein, with anti- mation and insulin secretory dysfunction, man tyrosine kinase receptors identified inflammatory/antiatherogenic properties and the precise molecular mechanism at present, all of which have the property such as decreasing the expression of ad- linking inflammation to impairment of in- of manifesting biologic activity upon the hesion molecules, decreasing monocyte sulin action remains uncertain. interaction of two activated receptors, al- adhesion to endothelial cells, decreasing There is no consensus as to the exis- though only the insulin receptor, IGF-1R, uptake of oxidized LDL, decreasing foam tence of a “unique defect at the molecular and insulin receptor–related receptor ex- cell formation, and decreasing prolifera- level” in the metabolic syndrome, with isting in the nonactivated state are identi- tion and migration of vascular smooth Tarantino pointing out that it may be sim- fied as dimers. The insulin receptor has A muscle cells. Adiponectin increases insu- ply “an epidemiological construct,” with and B isoforms; the former plays a role in lin sensitivity, increases smooth muscle increased waist circumference and dyslip- embryogenesis and oncogenesis. The in- glucose uptake and FFA oxidation, de- idemia the major constituents. Visceral sulin receptor A and B isoforms and creases hepatic glucose production, and and subcutaneous fat differ in lipolytic re- IGF-1R exist on a variety of cells, with decreases intracellular triglycerides. Adi- sponse to catecholamines, with visceral there also being hybrid receptors with ponectin exists in low –and high– fat having increased adrenergic receptors, dimers of two of the three peptides. Mice molecular weight forms, with the latter lower insulin sensitivity, and altered adi- not expressing the insulin receptor de- having a biological effect. Despite being pokines. Obesity with excess visceral fat is velop severe hyperglycemia with ketoaci- expressed exclusively by adipocytes, its associated with reduced adiponectin, dosis, while those lacking the IGF-1R levels are lower in obese individuals. At whereas obese persons with normal vis- have severe growth retardation (86). An any level of adiposity, however, persons ceral fat have normal adiponectin levels, important question, which can be ad- with higher levels of adiponectin have and low adiponectin and high visceral fat dressed by analysis of the molecular con- greater insulin sensitivity (77). Low adi- are independently associated with low figuration of insulin and IGF-1, is why ponectin is a characteristic of persons HDL cholesterol (84). In the HPFS IGF-1 does not bind strongly to the insu- having increased risk of diabetes, with (Health Professionals Follow-up Study), lin receptor. multivariate analysis showing it to explain low adiponectin predicted elevated Demeyts addressed the relationship the effect of CRP, IL-6, TNF-␣, secretory 6-year risk of myocardial infarction, con- between insulin action and aging. Death phospholipase A2, e-selectin, ICAM-1, trolling for age, exercise, cigarettes, CRP, results from an increase in systemic mo- and VCAM-1 (78–82). BMI, A1C, blood pressure, alcohol, and lecular disorder, which to this point has Tarantino suggested that adiponectin diabetes, with the relationship between appeared to be inevitable. Conceptually, “is a key piece of the puzzle,” potentially adiponectin and HDL cholesterol ex- this process may be regulated by two sets offering a link between overnutrition and plaining part of the association (85). A of genes, those controlling DNA repair insulin resistance, further implying that crucial question, based on these consid- and antioxidant defenses, and deleterious cytokines are side players rather than di- erations, is whether greater understand- genes promoting DNA damage and oxi- rect mediators. He turned to the question ing of the interrelationship between dant stress; from an evolutionary perspec- of a molecular link between activation of adiponectin and inflammation will lead to tive, the latter must have had benefit in the innate immune system and impair- better understanding and treatment of the early life to be commonly present, despite ment of insulin action and insulin secre- metabolic syndrome. their propensity to cause harm in older tion, discussing studies showing that the age. inhibitor of B(IB)- is inactivated by New concepts of the insulin (and The insulin receptor is also an ancient adipokines and bacterial lipopolysaccha- related) receptors molecule, with related receptors found in rides but activated by insulin. Breakage of At a meeting of the Metropolitan Diabetes coelenterates, insects, gastropods, and the nuclear factor-B (NF-B)/IB dimer Society, New York, New York, 5 April prochordates (87). An invertebrate insu- leads to release of NF-B, leading to in- 2005, Pierre Demeyts (Gentofte, Den- lin receptor that has been the subject of a flammatory effects via actions in the cyto- mark) discussed aspects of insulin action great deal of interest is that of the nema- plasm and cell nucleus. Mice based on current understanding of the ex- tode Caenorhabditis elegans, which has heterozygous for an inactivating mutation panding physiological role of insulin and been widely used in biological, biochem- of IB have decreased insulin response the insulin receptor. Insulin is composed ical, and genetic studies. C. elegans is (83). High-fat diet– and obesity-related of an A- and B-chain and belongs to a ϳ1.5 mm in length, with 20,000 genes
DIABETES CARE, VOLUME 28, NUMBER 9, SEPTEMBER 2005 2315 Perspectives on the News found on six chromosomes. In this spe- liver responding to both direct insulin ef- Stefanadis C, Toutouzas P, Nihoyanno- cies, the insulin–IGF-1 system regulates fects and indirect actions via vagal signals poulos P: Increased proinflammatory cy- longevity, as manifested by two forms, the originating in the arcuate nucleus of the tokines in patients with chronic stable short-lived adult reproductive form and hypothalamus. -Cell dysfunction leads angina and their reduction by aspirin. Cir- the long-lived dauer form. Under envi- to islet hypertrophy and hyperplasia, ul- culation 100:793–798, 1999 9. 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