sign in sign up
<<
Home , Inflammation

Reviews/Commentaries/Position Statements REVIEW ARTICLE

Inflammation and Activated Innate in the of

JOHN C. PICKUP, DPHIL, FRCPATH predicting type 2 diabetes and its compli- cations. The purpose of this review is to dis- cuss critically the evidence that now sup- ports a role for inflammation and innate There is increasing evidence that an ongoing -induced -phase response (sometimes immunity in type 2 diabetes and to high- called low-grade inflammation, but part of a widespread activation of the innate ) light the implications of this theory and is closely involved in the pathogenesis of type 2 diabetes and associated complications such as the indications for future research. dyslipidemia and . Elevated circulating inflammatory markers such as C-reactive and -6 predict the development of type 2 diabetes, and several with anti-inflammatory properties lower both acute-phase reactants and glycemia ( and thia- METHODS — The Embase and Med- zolidinediones) and possibly decrease the risk of developing type 2 diabetes (). Among the line electronic databases were searched risk factors for type 2 diabetes, which are also known to be associated with activated innate using the following key words: acute- immunity, are age, inactivity, certain dietary components, smoking, psychological stress, and phase response/reaction, innate/natural low birth weight. Activated immunity may be the common antecedent of both type 2 diabetes immunity/immune system, inflamma- and atherosclerosis, which probably develop in parallel. Other features of type 2 diabetes, such tion, stress, , C-reactive protein as fatigue, sleep disturbance, and , are likely to be at least partly due to hypercytoki- nemia and activated innate immunity. Further research is needed to confirm and clarify the role (CRP), sialic acid, type 2 diabetes melli- of innate immunity in type 2 diabetes, particularly the extent to which inflammation in type 2 tus, and noninsulin-dependent diabetes diabetes is a primary abnormality or partly secondary to hyperglycemia, , atherosclerosis, mellitus. Articles cited in key references, or other common features of the . personal communications, and a personal database of relevant articles were also Diabetes Care 27:813–823, 2004 considered.

INNATE IMMUNITY, here has been a recent explosion of type 2 diabetes, it has been unclear how , AND THE interest in the notion that chronic these abnormalities arise and how they ACUTE-PHASE AND STRESS T low-grade inflammation and activa- are related to the many different clinical RESPONSE: WHAT THEY tion of the are and biochemical features common in type ARE AND HOW THEY ARE closely involved in the pathogenesis of 2 diabetes, including central obesity, hy- RELATED type 2 diabetes. For example, since this pertension, accelerated atherosclerosis, hypothesis was first proposed in 1997 dyslipidemia, depression, disordered he- Innate immunity and 1998 (1,2), at least 12 studies have mostasis, and altered metal ion metabo- The innate or natural immune system is shown that circulating markers of inflam- lism, sleep, and reproductive the body’s rapid first-line defense against mation, acute-phase reactants, or inter- levels. Activation of innate immunity pro- environmental threats such as microbial leukin (IL)-6 (the major cytokine vides a new model for the pathogenesis of and physical or chemical mediator of the acute-phase response) are type 2 diabetes and the metabolic syn- (15). A series of reactions are induced that strong predictors of the development of drome, which may explain some or all of prevent ongoing tissue damage, isolate type 2 diabetes (3–14). these features, and points to research di- and destroy infective agents, and activate Although it is well established that in- repair processes to restore homeostasis sulin resistance and impaired se- rections that might result in new thera- peutic approaches for managing and (Fig. 1). Study of innate immunity has cretion are central to the pathogenesis of been somewhat neglected until recently, ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● overshadowed by the complexities of the From the Metabolic Unit, Guy’s, King’s and St. Thomas’s School of Medicine, Guy’s Hospital, London, U.K. acquired or (i.e., Address correspondence and reprint requests to John Pickup, Metabolic Unit, Thomas Guy House, GKT B- and T-cells) and suffering from the er- School of Medicine, Guy’s Hospital, London SE1 9RT, U.K. E-mail: [email protected]. roneous belief that this evolutionary an- Received for publication 7 April 2003 and accepted in revised form 17 November 2003. Abbreviations: AGE, advanced glycation end product; CRP, C-reactive protein; HPA, hypothalamic- cient system is unsophisticated and now pituitary-adrenal; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IL, interleukin; IRS, obsolescent for vertebrates (16). insulin receptor substrate; LC-NE, locus coeruleus-norepinephrine; LPS, ; NF-␬B, nu- A major component of innate immu- clear factor-␬B; PAI-1, plasminogen activator inhibitor 1; PPAR, peroxisome proliferator–activated receptor; nity is a series of sentinel cells (classically PRR, pattern recognition receptor; TLR, toll-like receptor; TNF, tumor factor. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion , -presenting B-cells, factors for many substances. and dendritic cells, but probably also in- © 2004 by the American Diabetes Association. testinal epithelial cells, ,

DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 813 Inflammation and type 2 diabetes

Inflammation Inflammation is the local protective re- sponse to tissue injury (21). The word in- flammation means “setting on fire” (16th century), and the process has been known since Egyptian times (c. 2500 B.C.). The cardinal signs of redness, swelling, heat, and were described by Celsus (first- century A.D.), and loss of function was added by Galen (130–200 A.D.). Micro- scopically, these features are due to vaso- dilation, accumulation of leukocytes, increased permeability and in- terstitial fluid, and stimulation of nerve endings by mediators such as .

The acute-phase response In addition to local effects in inflamma- tion, there is a systemic reaction known as the acute-phase response, best character- Figure 1—The components of the innate immune system. Sentinel cells such as the ized by pronounced changes in the con- detect potential environmental threats from infection, chemicals, and foods by PRRs that activate centration of certain circulating signaling pathways and release proinflammatory cytokines (IL-6 and TNF-␣). Known PRRs and other substances, called acute-phase include TLR-4, which senses bacterial LPS and the receptor for AGEs. Cytokines stimulate acute- reactants (22–24). Acute-phase proteins phase protein production from the and also act on the brain to release adrenocorticotrophic usually increase in concentration, with hormone (and thereby from the ) and activate the sympathetic nervous examples being CRP, complement, serum system with the release of catecholamines. Psychological stress can an acute-phase response ␣ via innervation of cytokine-producing cells and via activation of the sympathetic nervous system amyloid A, 1-acid , hapto- and adrenergic receptors on macrophages. Central cytokine-induced “sickness behavior” includes globin, and fibrinogen, but some such as lethargy, sleep changes, and depression. The innate immune system also controls the adaptive albumin are negative acute-phase reac- (acquired) immune system via costimulatory molecule expression that is necessary for antigen tants that decrease in concentration. The presentation. SAA, . acute-phase proteins are mostly synthe- sized in the liver, and production is stim- ulated by cytokines of the innate immune Kupffer cells in the liver, adipocytes, and pecially those for inflammatory cyto- response—mainly IL-6 and tumor necro- others) that act as “trouble detectors.” A kines, which are the main mediators of sis factor (TNF)-␣ (Fig. 1). In general, the number of germ line–encoded (i.e., non- inflammation and the acute-phase re- acute-phase proteins limit injury or aid clonal) pattern recognition receptors sponse. Secreted and circulating PRRs . (PRRs) on and in these cells recognize such as CRP and mannan-binding There are many other acute-phase re- conserved molecular structures (patho- function as , binding to micro- sponses induced by inflammatory cyto- gen-associated molecular patterns) that bial cell components and flagging them kines, including , , and are characteristic of a class of harmful for recognition by the complement sys- behavioral changes such as somnolence agents. The most studied PRRs are prob- tem and . and lethargy. Despite the apparent oxy- ably the family of at least 10 toll-like re- An important second function of in- moron, an ongoing “acute”-phase re- ceptors (TLRs) (named after the toll nate immunity, which has only recently sponse is seen in many chronic , receptor, first identified in the fruit fly, been appreciated, is to control the adap- such as and (and, as dis- drosphophila) that are present at the cell cussed below, type 2 diabetes and athero- tive immune response (15,20). T-cells re- surface as transmembrane receptors (17). sclerosis). quire two signals to be activated: the TLR-4, for example, recognizes lipopoly- saccharide (LPS) from Gram-negative complex of presented antigen and the ma- The stress response , in conjunction with associated jor histocompatibility complex class II Innate immunity and the acute-phase re- accessory molecules (CD14, MD-2). molecule on the surface of an antigen- sponse are integrated with the neuroen- Other cell surface PRRs are macrophage presenting cell and costimulatory mole- docrine system, particularly via the scavenger receptors (18), the mannose re- cules (CD80 and CD86), which are hypothalamic-pituitary-adrenal (HPA) ceptor (15), and the receptor for ad- invoked by the innate immune system axis and the locus coeruleus-norepineph- vanced glycation end products (AGEs) and the binding of -associated rine (LC-NE) system of the sympathetic (19). There are also intracellular PRRs, molecular patterns to PRRs. Thus, the in- nervous system (25–27). Cytokines re- e.g., for double-stranded RNA (present in nate immune system ensures that the leased by macrophages at the site of in- ). Binding to PRR activates nuclear adaptive immune system responds only flammation act on the brain to release factor-␬B (NF-␬B) signaling pathways to harmful and that the biologi- corticotrophin-releasing factor from the that induce immune response genes, es- cal context of a threat is recognized. hypothalamus, adrenocorticotrophic

814 DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 Pickup hormone from the pituitary gland, and tants, e.g., fibrinogen, von Willebrand and IL-6 levels in type 2 diabetes may not cortisol from the adrenal cortex, which factor, plasminogen activator inhibitor 1 reach statistical significance—the con- acts as an anti-inflammatory negative (PAI-1), ferritin, complement, lipopro- centrations of both analytes, although feedback by suppressing cytokine release tein(a), cortisol, (lowered), higher than in nondiabetic subjects, are and stimulating liver synthesis of acute- and (lowered) (2). low in comparison to other acute-phase phase proteins. Psychological stress Because there are many plausible conditions such as cancer and acute infec- causes an acute-phase response by acti- mechanisms by which cytokines can lead tions and require ultrasensitive assays to vating the HPA axis and the LC-NE sys- to , impaired insulin se- demonstrate accurately the circulating tem and by inducing IL-6, TNF-␣, and cretion, dyslipidemia, and accelerated concentrations in diabetes. other cytokine secretion from macro- atherosclerosis, this led us to hypothesize In apparent contrast to IGT/IFG phages (via several mechanisms, includ- that in type 2 diabetes, there is an ongoing (where TNF-␣ levels are reportedly nor- ing catecholamines acting on the cytokine-mediated acute-phase response mal [41]), circulating TNF-␣ is usually macrophage ␤-adrenergic receptor, and (part of a wide-ranging activation of in- elevated in established type 2 diabetes corticotrophin-releasing factor and sub- nate immunity), and this is closely in- (49–51). stance P release from local nerve endings volved in the pathogenesis of the disease acting on macrophages [27]). Thus, the (1,2). 2) Markers of inflammation predict brain can both produce and modulate How have recent studies provided ev- type 2 diabetes inflammation. idence to support this theory? Schmidt and colleagues (3,4), using data from the Atherosclerosis Risk in Commu- THE ORIGINS OF THE 1) Markers of inflammation are nities study, were the first to show that a ACTIVATED INNATE associated with type 2 diabetes and variety of inflammatory markers, includ- IMMUNITY PARADIGM — A features of the ing count, low serum al- decade ago, we showed that, in compari- in cross-sectional studies bumin, ␣1-acid glycoprotein, fibrinogen, son with nondiabetic subjects, circulating Several cross-sectional studies in nondia- and sialic acid, predict the development concentrations of commonly recognized betic subjects or the general population of type 2 diabetes in a middle-aged pop- acute-phase reactants were increased in (32–40), or in individuals with impaired ulation. This has been confirmed over type 2 but not type 1 diabetic patients glucose tolerance (IGT)/impaired fasting mean follow-up times from 2 to 20 years who were matched for age, sex, glycemic glucose (IFG) (41–44), have confirmed for women in the U.S. Women’s Health control, and the absence of tissue compli- that acute-phase reactants such as CRP Study (CRP and IL-6) (5), for elderly sub- cations (28). These acute-phase reactants (and sometimes the cytokines IL-6 and jects in the U.S. Cardiovascular Health included CRP, serum amyloid A, ␣1-acid TNF-␣) are positively correlated with Study (CRP) (6), in Pima Indians (white glycoprotein, and sialic acid (the latter is measures of insulin resistance/plasma in- blood count) (7), for multiethnic subjects an integrated measure of the acute-phase sulin concentration, BMI/waist circum- in the U.S. Insulin Resistance and Athero- response because many of the acute- ference, and circulating triglyceride and sclerosis Study (CRP, fibrinogen, and phase proteins are with negatively correlated with HDL choles- PAI-1) (8), in Scottish men in the West of sialic acid as the terminal sugar of the oli- terol concentration. In general, increasing Scotland Coronary Prevention Study gosaccharide chain). Serum levels of components of the metabolic syndrome (CRP) (9), in the U.S. National Health and acute-phase reactants (including cortisol) in individuals are associated with higher Nutrition Examination Survey (white and the cytokine mediator of the acute- levels of inflammatory markers. In sub- blood count) (10), for Japanese men phase response, IL-6, showed a graded jects with IGT or IFG, IL-6 but not TNF-␣ (white blood count) (11), for participants increase with increasing features of the appears to be elevated compared with in- in the Hoorn Study in the Netherlands metabolic syndrome in type 2 diabetic dividuals with normal glucose tolerance (CRP) (12), for participants in the Euro- and nondiabetic subjects, i.e., obesity, (41), and in one study, inflammatory pean Prospective Investigation into Can- coronary heart disease, , hy- markers were related to insulin resistance cer and Nutrition (EPIC)-Postdam Study pertriglyceridemia, and low levels of HDL but not to insulin secretion (42). in Germany (IL-6, with additional risk of (1). Additional cross-sectional studies in IL-6 and IL-1␤ combined) (13), and in We also noted that others had found newly diagnosed (43) or established type middle-aged men in the MONICA Augs- that after experimental induction of the 2 diabetic patients (45– 48) have con- burg Study in Germany (CRP) (14). Inter- acute-phase response in animals (29) and firmed that acute-phase markers such as estingly, CRP was a significant predictor in illnesses in humans likely to be associ- CRP and IL-6 are elevated in these sub- of diabetes in women but not in men in ated with an acute-phase response such as jects compared with nondiabetic control the Mexico City Diabetes Study (52), in- (30) and infection (31), there subjects. In the study by Leinonen et al. dicating that the differential role of in- are elevated serum concentrations of total (47), all markers of inflammation, includ- flammation in men and women needs cholesterol and VLDL triglyceride and ing CRP, serum amyloid A, secretory further elucidation. lowered HDL cholesterol—typical fea- , and IL-6, and endo- In addition, low circulating levels of tures (“dyslipidemia”) of type 2 diabetes thelial dysfunction (soluble cell the recently identified anti-inflammatory and the metabolic syndrome. Also, many molecules) correlated with the homeosta- – derived cytokine, adi- circulating analytes, which are known to sis model–measured insulin resistance. In ponectin, predict type 2 diabetes in Pima have altered concentrations in type 2 dia- studies with a small number of subjects Indians (53). Although slightly weakened betes, are established acute-phase reac- (48), the elevated mean or median CRP by adjusting for obesity, the association of

DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 815 Inflammation and type 2 diabetes altered levels of acute-phase reactants and later diabetes in these studies is generally independent of age, sex, blood glucose concentration, family history of diabetes, physical activity, smoking, and baseline atherosclerosis. In the Pima Indian study (7), elevated white blood cell count was associated with a decline in insulin sensi- tivity but not insulin secretion, echoing the cross-sectional relationship in IGT be- tween inflammatory markers and insulin resistance but not insulin secretion (42).

3)Inflammation is involved in the pathogenesis of atherosclerosis, a common feature of type 2 diabetes Inflammation is now known to be in- volved in the pathogenesis of all stages of atherosclerosis (54,55). Numerous stud- Figure 2—Several factors such as altered nutrition, inactivity, age, fetal metabolic programming, ies (e.g., 56–59) in the general population and genetic propensity are known activators of the innate immune system. Cytokine production have shown that low-grade elevation of leads to insulin resistance (possibly impaired insulin secretion), type 2 diabetes, and other com- circulating markers of inflammation ponents of the metabolic syndrome, such as dyslipidemia. Activated innate immunity is a possible (CRP, sialic acid, and proinflammatory common antecedent of both type 2 diabetes and atherosclerosis. cytokines) is associated with the future development of myocardial infarction, , and peripheral perimental coronary artery ligation (67). causes a 25% reduction in fasting plasma and with cardiovascular mortality. The Cytokines such as IL-6 and TNF-␣ have glucose, a 50% reduction in triglyceride, inflammatory marker, serum sialic acid, is many pro-atherosclerotic actions, includ- and a 15% reduction in CRP concentra- cross-sectionally related to coronary heart ing promoting leukocyte recruitment to tion, independently of changes in plasma disease in type 2 diabetes (60) and also the endothelium by inducing adhesion insulin concentration (70). predicts future cardiovascular mortality molecule and chemoattractant synthesis Statins. Assignment to pravastatin ther- in type 2 diabetes, independently of base- and increasing capillary permeability apy in the West of Scotland Coronary Pre- line atherosclerosis (61). Taken together (54). Such cytokines may be produced by vention Study resulted in a 30% with the evidence that inflammation also the endothelium, smooth muscle cells, reduction in the risk of developing type 2 predicts type 2 diabetes independently of and macrophages at the site of atheroscle- diabetes (71), perhaps related to the atherosclerosis (above), these studies sug- rosis and contribute to a systemic acute- ’s anti-inflammatory properties. Al- gest that activation of the innate immune phase response, and/or cytokinemia and though the beneficial effects of statins system is likely to be at least one of the augmented acute-phase reactants inher- (HMG-CoA reductase inhibitors) on car- long-postulated (62) common anteced- ent to type 2 diabetes may promote arte- diovascular disease have been generally ents of both atherosclerosis and type 2 rial disease. attributed to cholesterol lowering, there is diabetes (61) (Fig. 2). considerable in vitro and in vivo evidence The acute-phase responses associated 4) Anti-inflammatory agents that statins have a cholesterol- with type 2 diabetes thus offer plausible decrease the acute-phase response, independent anti-inflammatory effect mechanisms that would explain why ath- may reduce the risk of developing (72–74), for example, lowering CRP in erosclerosis is accelerated in type 2 diabe- type 2 diabetes, and improve control post–myocardial infarction patients (in- tes, including mediation by acute-phase in established diabetes dependently of cholesterol levels) (75) proteins themselves. For example, in ad- Aspirin. High doses of salicylates such and in subjects with type 2 diabetes (76). dition to pro-coagulant acute-phase pro- as aspirin have been known since the 19th Statins can act through both HMG-CoA teins such as fibrinogen and PAI-1, serum century to lower glycosuria in diabetic pa- reductase– dependent mechanisms (in- amyloid A displaces apolipoprotein A1 tients (68), but only recently has the hibiting release of cytokines by upregulat- from HDL3, redirecting HDL cholesterol mechanism been shown as inhibition of ing peroxisome proliferator–activated from the liver to tissues, and increases NF-␬B and its upstream activator, I␬B ki- receptor [PPAR]-␣ and -␥ and inhibiting binding to macrophages (23,29). CRP nase ␤, rather than via the classic cyclo- the NF-␬B pathway) and HMG-CoA re- causes expression of endothelial adhesion oxygenase targets of nonsteroidal anti- ductase–independent means (inhibiting molecules (63) and chemoattractants (64) inflammatory drugs (69). Insulin the adhesion cascade by binding to the and mediates LDL uptake by macro- resistance in genetically obese fa/fa rats function–associated phages (65). Bound CRP activates com- and ob/ob mice is reversed by salicylates antigen-1 and thus inhibiting leukocyte plement, colocalizes with it in human via an I␬B ␤–dependent mecha- adhesion to intercellular adhesion mole- hearts during acute myocardial infraction nism (69). Two weeks’ treatment of type 2 cule-1) (72). (66), and increases infarct size after ex- diabetic patients with high-dose aspirin However, the West of Scotland Coro-

816 DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 Pickup nary Prevention Study results should be POSSIBLE MECHANISMS OF degree of hepatic insulin resistance in this interpreted with caution for several rea- ACTIVATED INNATE type of diabetes is sufficient to restrain sons: the study was not designed to exam- IMMUNITY IN TYPE 2 acute-phase protein production. ine the effects of this on diabetes DIABETES: CYTOKINES, development, it studied only men, and FETAL PROGRAMMING, Fetal and neonatal programming the multivariate hazard ratio for the pre- GENETICS, NUTRITION, In the short-term, innate immunity has diction of diabetes by baseline pravastatin INACTIVITY, STRESS, AND survival value and restores homeostasis therapy was of only borderline signifi- AGE — What are the factors that might after an environmental stress, but in type cance (0.7 [0.50–0.99, 95% CI], P ϭ cause activated innate immunity in type 2 2 diabetes and IGT, it may be that pro- 0.042). Also, any effect of pravastatin may diabetic patients or in patients destined to longed lifestyle or environmental stimu- include noninflammatory mechanisms develop the disease? lants cause maladaptation to the normal such as reduction in the use of hypergly- physiological responses to stress, causing cemia-inducing cardiovascular drugs as Insulin resistance disease instead of repair; a genetic or in- the result of improved cardiovascular sta- We previously indicated how activated born propensity to a hyper-responsive in- tus or a secondary reduction in triglycer- innate immunity may give rise to the fea- nate immune system might exist in ide and thus insulin resistance. tures of type 2 diabetes, including cyto- certain individuals (Fig. 2). This notion is Glitazones. The recently introduced kine-induced insulin resistance and supported by recent evidence that low oral hypoglycemic agents thiazo- impaired insulin secretion, increased cap- birth weight or disproportionate size at lidinediones (“glitazones”) are PPAR-␥ illary permeability and microalbumin- birth is associated with elevated levels of agonists that have been regarded as insu- uria, dyslipidemia, hypercortisolemia, acute-phase reactants such as cortisol and lin-sensitizing through mechanisms such hypertension, central obesity, and a hy- fibrinogen in adult life (94,95). as altered transcription of insulin- percoagulant state (1,2). Mechanisms by sensitive genes controlling lipogenesis, which cytokines such as TNF-␣ can cause Genetics and race adipocyte differentiation and fatty acid insulin resistance have been further clar- Specific polymorphisms in the TNF-␣ uptake, and GLUT4 expression. But glita- ified recently and include activation of the gene (96,97), TNF-␣ receptor zones are also anti-inflammatory (77), in- prototype stress-induced kinase, c-Jun gene (98), and IL-6 gene (99) are vari- hibiting cytokine production and NH2-terminal kinase, which serine phos- ously associated with insulin sensitivity or macrophage activation (78–80) and re- phorylates many signaling proteins in- resistance. Nondiabetic subjects with a ducing (to a varying extent depending on cluding insulin receptor substrate (IRS)-1 family history of type 2 diabetes have the study and the marker) circulating in- and IRS-2, thereby inhibiting insulin sig- higher circulating CRP levels than age- flammatory markers such as CRP and naling and stimulation of expression of and BMI-matched control subjects with- white blood cell count in type 2 diabetic SOCS [suppressor of cytokine signaling] out a family history (100). The influence subjects (81–85). A failure to find a re- proteins, which bind IRS-1 and -2 and of race on the acute-phase response is not duction of IL-6 accompanying the CRP mediate their degradation (88). Inflam- well studied, but serum sialic acid con- reduction with glitazone treatment in matory cytokines such as TNF-␣, IL-1␤, centrations are higher in Asian type 2 di- some of these studies (81,84) is interest- and IL-6 also downregulate PPAR-␥ ex- abetic subjects living in London but ing and might indicate that statins alter pression (89). originating from the Indian subcontinent the production of other cytokines in- It should be pointed out, however, (who have a high frequency of type 2 di- volved in CRP synthesis (IL-1␤ and that the exact effect of inflammatory cyto- abetes) than in Caucasian type 2 diabetic TNF-␣) or inhibit the action of IL-6 at the kines on glucose metabolism in humans is subjects matched for age, sex, diabetes liver or act through some other mecha- still unclear. For example, Steensberg et duration, and glycemic control (101). nism. al. (90) recently showed that acute (3-h) femoral arterial infusion of IL-6 in healthy Nutrition men did not result in changes in glucose Many dietary factors may contribute to 5) Gestational diabetes, a risk factor production or disposal or leg uptake. The activation of innate immunity in the ge- for type 2 diabetes, is associated presumably chronic elevated IL-6 levels netically or metabolically programmed with an inflammatory response in type 2 diabetes may or may not have individual, including the effect of There is considerable evidence that non- different effects. (102) and the n3:n6 fatty acid ratio (103) diabetic pregnancy is a state of activated Interestingly, insulin is itself an inhib- on cytokine production. Meal intake in- innate immunity, with increased acute- itor of acute-phase protein synthesis creases adipose tissue IL-6 production by phase proteins and proinflammatory cy- (91,92), and in animal models of diabe- some fivefold when measured by subcu- tokines (86). First-trimester CRP levels tes, the acute-phase response is increased taneous microperfusion (104), offering a are significantly higher in women who by insulin deficiency (93). This indicates mechanism by which repeated dietary ex- subsequently develop gestational diabe- that there could be a positive feedback in cess might favor hypercytokinemia. tes later in their pregnancy than in women type 2 diabetes whereby cytokine- Plasma CRP is reduced by dietary vitamin who remain euglycemic (87). Moreover, induced insulin resistance further aug- E supplementation, known to inhibit se- sialic acid, another inflammatory marker, ments the acute-phase response. The cretion of proinflammatory cytokines, is higher in women with previous gesta- relatively normal levels of acute-phase re- probably independent of its antioxidant tional diabetes than in women without actants in type 1 diabetes (28) suggest that (105). (44). insulin replacement and the much lesser Although AGEs are best known as en-

DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 817 Inflammation and type 2 diabetes dogenous products of glycation of body But two less obvious observations are of Several cross-sectional studies of type 2 proteins in diabetes, they are also present particular note. First, stress decreases diabetes show that CRP and IL-6 are in food—the result of heat-generated re- splanchnic blood flow, increases intesti- significantly correlated with blood glu- actions between sugars and proteins or nal permeability, and results in increased cose concentration or glycated hemoglo- . Vlassara et al. (106) recently absorption of LPS from the gut (the great- bin percentage (45,47), although we showed that administration of a high- est source of LPS). Elevated portal blood- found no relationship between serum AGE diet to diabetic subjects (type 1 and stream LPS levels stimulate sialic acid concentration and glycemia 2) caused plasma CRP and mononuclear receptors and cytokine release (27). Pre- (60). Because the acute-phase response cell TNF-␣ to increase, whereas a low- sumably, the absorption of other intesti- and cytokinemia are so closely related to AGE diet caused CRP and TNF-␣ to nal activators of innate immunity might insulin resistance, the relationship with decrease. also be augmented by stress, including hyperglycemia is not unexpected. Lower- AGEs present in food (see above). ing of blood glucose levels in type 2 dia- Age Second, repeated stress with the re- betic patients is accompanied by reduced The production of cytokines from mono- peated induction of can levels of inflammation markers (46,123). cytes and macrophages (107) and circu- result in hippocampal damage, causing a In blood samples from nondiabetic sub- lating acute-phase proteins (108) IL-6 failure in the downregulation of cortico- jects, high glucose levels stimulated IL-6 and TNF-␣ (109) increase with age, as of steroid production by the feedback mech- production from in vitro course does the propensity to develop anism and thus persisting elevated (124). AGEs are known to have a similar type 2 diabetes. Indeed, it has been ar- circulating cortisol levels (118,119). This cytokine-stimulating effect on macro- gued that a major characteristic of aging is encourages the idea that resetting the con- phages (125). And particularly cogent is the a global reduction in the capacity to cope trol point of innate immunity at a higher recent finding that acute hyperglycemia in with a variety of stressors and a concom- level of activation might be caused by nondiabetic and IGT subjects elevates itant increase in proinflammatory status multiple stimuli over time— either a plasma IL-6 and TNF-␣ concentrations, (110). range of different stressors or repeated ep- higher and longer in individuals with IGT isodes of the same type. and when the glucose was given as pulses Smoking and inactivity (126). The effect was abolished by infu- Similarly, the risk factors for type 2 dia- PROBLEMS AND sion of the antioxidant glutathione, sug- betes of smoking and lack of physical ex- UNCERTAINTIES gesting that hyperglycemia-induced ercise are both associated with an increase cytokine production is mediated by reac- in circulating acute-phase reactants (111– A role also for adaptive immunity? tive oxygen species. 113). Lindsay et al. (120) reported that elevated On the other hand, acute-phase serum total ␥-globulin levels, a nonspe- markers are not elevated in type 1 diabetic Stress and multiple “hits” cific measure of the adaptive immune sys- subjects who have the same degree and There is a long history of largely inconclu- tem, predict the development of type 2 duration of hyperglycemia as type 2 dia- sive speculation about the relationship of diabetes in Pima Indians. Cseh et al. (121) betic patients (28). In the large number of psychological stress and the onset of type have also questioned whether both innate prospective studies mentioned above (3– 2 diabetes (114,115). Thomas Willis and adaptive immunity have a role in 14), the prediction of type 2 diabetes de- (17th century) and Henry Maudsley metabolic regulation and type 2 diabetes. velopment in initially nondiabetic (19th century) both believed that diabetes It is unclear why ␥-globulin is increased subjects by elevated inflammatory mark- often follows nervous trauma or anxiety, in type 2 diabetes, and further study in ers is generally independent of baseline and William Osler in his famous Textbook this area is needed. The observation may glycemia. Thus, it seems that chronic hy- of Medicine actually comments that, of the represent the interplay between innate perglycemia is not sufficient to induce in- two types of diabetes, it is the less severe and acquired immunity (see above); for flammation, although it may contribute obese (what we now call) type 2 diabetes example, a single injection of LPS in the to it, and improving glycemic control that is associated with “mental ” mouse mobilizes up to 10% of the pro- may therefore reduce the inflammatory (116). To give some modern perspective tein-encoded genome and some 60 (at response. to this notion, in the Hoorn Study of a city least) genes involved in both innate and population in the Netherlands aged adaptive host defense (122). The role of obesity and 50–74 years and without a history of di- atherosclerosis abetes, the number of stressful life events The inflammatory response: primary Obesity was strongly related to elevated in the previous 5 years was positively re- or secondary? The role of circulating levels of inflammatory mark- lated to the prevalence of newly detected hyperglycemia. ers (mainly CRP) in several cross- diabetes (117). Does a cytokine-induced inflammatory sectional studies in the general There are many ways in which psy- response cause type 2 diabetes or is it just population (32,34,37,39) and type 2 dia- chological stress might increase the like- secondary to one or more biochemical betes (47). Subcutaneous and intra- lihood of developing type 2 diabetes, for and pathophysiological disturbances of abdominal adipose tissue is a major example, relating to central activation of the disease? A major uncertainty is source of TNF-␣ and IL-6 production the HPA axis and the LC-NE system with whether hyperglycemia is a main deter- (127–129). This raises the question of counterregulatory hormone release, and minant of the inflammation in type 2 di- whether the acute-phase reaction of type cytokine-induced insulin resistance (27). abetes—there is evidence for and against. 2 diabetes is mainly secondary to obesity.

818 DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 Pickup

The power of inflammatory markers to supportive research includes the associa- 1998 predict type 2 diabetes, although often tion of with features 3. Schmidt MI, Duncan BB, Sharrett AR, markedly reduced, remains after adjust- of the metabolic syndrome, including an Lindberg G, Savage PJ, Offenbacher S, ment for BMI (3,5–8,12,13), but the role increased frequency of cardiovascular Azambuja MI, Tracey RP, Heiss G: Mark- of obesity in the activated innate immu- disease and type 2 diabetes not related to ers of inflammation and prediction of di- abetes mellitus in adults (Atherosclerosis nity of diabetes needs more investigation. use (132). Risk in Communities study): a cohort In a recent study in which case and study. Lancet 353:1649–1652, 1999 control subjects were matched by BMI 4. Duncan BB, Schmidt MI, Offenbacher S, and waist circumference, neither CRP nor IMPLICATIONS AND Wu KK, Savage PJ, Heiss G: Factor VIII IL-6 predicted the development of type 2 FUTURE RESEARCH — We need to and other variables are re- diabetes, although lowered levels of adi- know the temporal relationship of lated to incident diabetes in adults: The ponectin did (130). These authors sug- changes in circulating proinflammatory Atherosclerosis Risk in Communities gest, as an alternative hypothesis, that cytokines, acute-phase markers, insulin (ARIC) study. Diabetes Care 22:767– because inflammatory markers are associ- resistance, and glycemia during the devel- 772, 1999 ated with obesity, they only indirectly opment of IGT and type 2 diabetes. An 5. Pradhan AD, Manson JE, Rifai N, Buring interesting example might be a prospec- JE, Ridker PM: C-reactive protein, inter- predict diabetes and act as surrogate leukin 6, and risk of developing type 2 markers of hypoadiponectinemia. tive study of children, many of whom are diabetes mellitus. JAMA 286:327–334, Atherosclerosis is another cosegre- now developing type 2 diabetes in associ- 2001 gate of type 2 diabetes that is strongly as- ation with obesity. Also, there is still little 6. Barzilay JI, Abraham L, Heckbert SR, sociated with an acute-phase response in information on inflammatory markers in Cushman M, Kuller LH, Resnick HE, its own right (131). However, elevated in- ethnic groups at high risk of developing Tracey RP: The relation of markers of flammatory markers are also a feature of type 2 diabetes. The power of elevated inflammation to the development of type 2 diabetic subjects without vascular acute-phase markers and IL-6 to predict glucose disorders in the elderly: the complications (28) and, when studied, type 2 diabetes development raises the Cardiovascular Health Study. Diabetes inflammatory markers were predictive of question of whether these would be help- 50:2384–2389, 2001 ful in screening programs identifying in- 7. Vozarova B, Weyer C, Lindsay RS, Prat- diabetes independently of baseline ath- ley RE, Bogardus C, Tataranni PA: High erosclerosis (3). Present evidence sup- dividuals at risk of diabetes. And if type 2 white blood cell count is associated with ports the notion that atherosclerosis diabetes is an inflammatory disease, can a worsening of insulin sensitivity and develops in parallel with type 2 diabetes anti-inflammatory drugs, such as those predicts the development of type 2 dia- (61), with both conditions sharing the targeted at the NF-␬B signaling pathway, betes. Diabetes 51:455–461, 2002 common antecedent of activated innate contribute to the management of the 8. Festa A, D’Agostino R, Tracey RP, Haff- immunity (Fig. 2), but like hyperglycemia disease? ner SM: Elevated levels of acute-phase and possibly some other manifestations of The realization that type 2 diabetes is proteins and plasminogen activator in- type 2 diabetes such obesity, macroangi- a proinflammatory cytokine-associated hibitor-1 predict the development of type opathy, once present, would presumably disease leads us to question what other 2 diabetes: the Insulin Resistance Ath- manifestations of type 2 diabetes are cy- erosclerosis Study. Diabetes 51:1131– further enhance inflammation. 1137, 2002 A particular puzzle is that type 1 dia- tokine-induced and should join the usual 9. Freeman DJ, Norrie J, Caslake MJ, Gaw betic patients without tissue complica- features of the metabolic syndrome. For A, Ford I, Lowe GDO, O’Reilly DSJ, tions do not have elevated acute-phase example, depression is common in type 2 Packard CJ, Sattar N: C-reactive protein reactants (28) but remain at risk of accel- diabetes (133), and many of the behav- is an independent predictor of risk for erated atherosclerosis in the same way as ioral changes seen in depression are stim- the development of diabetes in the West type 2 diabetic patients. If the above ulated by IL-6 and TNF-␣ (134). of Scotland Coronary Prevention Study. model is correct, at least in part, one may Similarly, fatigue and alterations in sleep Diabetes 51:1596–1600, 2002 speculate that specifically diabetes- patterns, which are symptoms well 10. Ford ES: Leukocyte count, erythrocyte related factors (possibly glucose) would known in the diabetic clinic, are linked sedimentation rate, and diabetes inci- dence in a national sample of US adults. need to additionally sensitize the arteries with insulin resistance and elevated blood ␣ Am J Epidemiol 155:57–64, 2002 to cytokines and other atherogenic factors IL-6 and TNF- (independently of obe- 11. Nakanishi N, Yoshida H, Matsuo Y, Su- such as hypercholesterolemia, but little is sity) (1,135,136). What else in type 2 di- zuki K, Tatara K: White blood-cell count known about this. abetes is related to innate immunity? and the risk of impaired fasting glucose or type II diabetes in middle-aged Japa- nese men. Diabetologia 45:42–48, 2002 Glucose intolerance in other References 12. Snijder MB, Dekker JM, Visser M, Ste- inflammatory diseases 1. Pickup JC, Mattock MB, Chusney GD, houwer CDA, van Hinsberg VWM, One would predict that chronic inflam- Burt D: NIDDM as a disease of the innate Bouter LM, Heine RJ: C-reactive protein matory illnesses would be associated with immune system: association of acute and diabetes mellitus type 2. Diabetolo- phase reactants and interleukin-6 with gia 44 (Suppl. 1):115A, 2001 either type 2 diabetes or the metabolic metabolic syndrome X. Diabetologia 40: 13. Spranger J, Kroke A, Mo¨hlig M, Hoffman syndrome, unless the trigger is not con- 1286–1292, 1997 K, Bergman MM, Ristow M, Boeing H, stant hypercytokinemia but repeated 2. Pickup JC, Crook MA: Is type II diabetes Pfeiffer AFH: Inflammatory cytokines bursts. There is too little information on mellitus a disease of the innate immune and the risk to develop type 2 diabetes: glucose tolerance in chronic disease, but system? Diabetologia 41:1241–1248, results of the prospective population-

DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 819 Inflammation and type 2 diabetes

based European Prospective Investiga- 30. Spiegel R, Schaffer EJ, Magrath IT, Ed- and co-regulated acute- tion into Cancer and Nutrition (EPIC)- wards BK: Plasma alterations in phase proteins but not TNF-␣ or its re- Potsdam study. Diabetes 52:812–817, leukemia and lymphoma. Am J Med 72: ceptors. Diabetologia 45:805–812, 2002 2003 775–782, 1982 42. Temelkova-Kurktschiev T, Siegert G, 14. Thorand B, Lowel H, Schneider A, Kolb 31. Olsson AG: Non-atherosclerotic disease Bergmann S, Henkel E, Koehler C, Jaross H, Frohlich M, Koenig W: C-reactive and . Curr Opin Lipidol 2: W, Hanefield M: Subclinical inflamma- protein as a predictor for incident diabe- 206–210, 1991 tion is strongly related to insulin resis- tes mellitus among middle-aged men: 32. Yudkin JS, Stehouwer CDA, Emeis JJ, tance but not insulin secretion in a high results from the MONICA Augsburg co- Coppack SW: C-reactive protein in risk population for diabetes. Metabolism hort study. Arch Intern Med 163:93–99, healthy subjects: association with obe- 51:743–749, 2002 2003 sity, insulin resistance, and endothelial 43. Temelkova-Kurktschiev T, Henkel E, 15. Medzhitov R, Janeway C: Innate immu- dysfunction: a potential role for cyto- Koehler C, Karrei K, Hanefield M: Sub- nity. N Engl J Med 343:338–344, 2000 kines originating from the adipose tis- clinical inflammation in newly detected 16. Fearon DT: Seeking wisdom in innate sue? Arterioscler Thromb Vasc Biol 19: type II diabetes and impaired glucose immunity. Nature 388:323–324, 1997 972–978, 1999 tolerance. Diabetologia 45:151, 2002 17. Medzhitov R: Toll-like receptors and in- 33. Fro¨hlich M, Imhof A, Berg G, Hutchin- 44. Sriharan M, Reichelt AJ, Opperman ML, nate immunity. Nat Rev Immunol 1:135– son WL, Pepys MB, Boeing H, Muche R, Duncan BB, Mengue SS, Crook MA, 145, 2001 Brenner H, Koenig W: Association be- Schmidt MI: Total sialic acid and associ- 18. Pearson AM: Scavenger receptors in in- tween C-reactive protein and features of ated elements of the metabolic syn- nateimmunity.CurrOpinImmunol8:20– the metabolic syndrome: a population- drome in women with and without 28, 1996 based study. Diabetes Care 23:1835– previous gestational diabetes. Diabetes 19. Li YM, Mitsuhashi T, Wojciechowicz D, 1839, 2000 Care 25:1331–1335, 2002 Shimizu N, Li J, Stitt A, He C, Banerjee 34. Festa A, D’Agostino R, Howard G, 45. Rodrı´guez-Mora´n M, Guerrero-Romero D, Vlassara H: Molecular identity and Mykka¨nen L, Tracey RP, Haffner SM: F: Increased levels of C-reactive protein cellular distribution of advanced glyca- Chronic subclinical inflammation as in noncontrolled type II diabetic sub- tion endproduct receptors: relationship part of the insulin resistance syndrome: jects. J Diabetes Complications 13:211– of p60 to OST-48 and p90–80K-H the Insulin Resistance Atherosclerosis 215, 1999 membrane proteins. Proc Natl Acad Sci U Study (IRAS). Circulation 101:42–47, 46. Arnalich F, Hernanz A, Lopez-Made- SA93:11047–11052, 1996 2000 ruelo D, Camacho J, Madero R, Vazquez 20. Medzhitov R, Janeway CA: Decoding the 35. Sakkinen PA, Wahl P, Cushman M, JJ, Montiel C: Enhanced acute-phase re- patterns of self and nonself by the innate Lewis MR, Tracey RP: Clustering of pro- sponse and oxidative stress in older immune system. Science 296:298–300, , inflammation and fibrino- adults with type II diabetes. Horm Metab 2002 lysis variables with metabolic factors in Res 32:407–412, 2000 21. Cone JB: Inflammation. Am J Surg 182: insulin resistance syndrome. Am J Epide- 47. Leinonen E, Hurt-Camejo E, Wiklund 558–562, 2001 miol 152:897–907, 2000 O, Hulte´n LM, Hiukka A, Taskinen M-R: 22. Baumann H, Gauldie J: The acute phase 36. Weyer C, Yudkin JS, Stehouwer CD, Insulin resistance and adiposity corre- response. Immunol Today 15:74–80, Schalkwijk CG, Pratley RE, Tataranni late with acute-phase reaction and solu- 1994 PA: Humoral markers of inflammation ble molecules in type 2 23. Steel DM, Whitehead AS: The major and endothelial dysfunction in relation diabetes. Atherosclerosis 166:387–394, acute phase reactants: C-reactive pro- to adiposity and in vivo insulin action in 2003 tein, serum amyloid P component and Pima Indians. Atherosclerosis 161:233– 48. Richardson AP, Tayek JA: Type 2 dia- serum amyloid A protein. Immunol To- 242, 2002 betic patients may have a mild form of day 15:81–87, 1994 37. Ford ES: Body mass index, diabetes, and an injury response: a clinical research 24. Gabay C, Kushner I: Acute-phase pro- C-reactive protein among US adults. Di- center study. Am J Physiol 282:E1286– teins and other systemic responses to in- abetes 22:1971–1977, 1999 E1290, 2002 flammation. N Engl J Med 340:448–454, 38. Ford ES: Diabetes and serum ferritin 49. Katsuki A, Sumida Y, Murashima S, Mu- 1999 concentration among US adults. Diabe- rata K, Takarada Y, Ito K, Fujii M, 25. Sternberg EM: The stress response and tes Care 22:1978–1983, 1999 Tsuchihashi K, Goto H, Nakatani K, the regulation of inflammatory disease. 39. Visser M, Bouter LM, McQuillan GM, Yano Y: Serum levels of tumor necrosis Ann Intern Med 117:854–866, 1992 Wener MH, Harris TB: Elevated C-reac- factor-␣ are increased in obese patients 26. Chrousos GP, Gold PW: The concepts of tive protein levels in overweight and with noninsulin-dependent diabetes stress and stress system disorders. JAMA obese adults. JAMA 282:2131–2135, mellitus. J Clin Endocrinol Metab 83: 267:1244–1252, 1992 1999 859–862, 1998 27. Black PH: Stress and the inflammatory 40. Hak EA, Pols HA, Stehouwer CDA, Mei- 50. Winkler G, Salamon F, Salamon D, response: a review of neurogenic inflam- jer J, Kiliaan AJ, Hofman A, Breteler Speer G, Simon K, Cseh K: Elevated tu- mation. Brain Behav Immun 16:622–653, MMB, Witteman JCM: Markers of in- mour necrosis factor alpha levels can 2002 flammation and cellular adhesion mo- contribute to the insulin resistance in 28. Crook MA, Tutt P, Simpson H, Pickup lecules in relation to insulin resistance type II (non-insulin-dependent) diabe- JC: Serum sialic acid and acute phase in nondiabetic elderly: the Rotterdam tes and obesity. Diabetologia 41:860– proteins in type 1 and 2 diabetes. Clin Study. J Clin Endocr Metab 86:4398– 862, 1998 Chim Acta 219:131–138, 1993 4405, 2001 51. Pickup JC, Chusney GC, Thomas SM, 29. Cabana VG, Siegel JN, Sabesin SM: Ef- 41. Mu¨ ller S, Martin S, Koenig W, Hanifi- Burt D: Plasma interleukin-6, tumor ne- fects of the acute phase response on the Moghaddam P, Rathmann W, Haastert crosis factor alpha and blood cytokine concentration and density distribution B, Giani G, Illig T, Thorand B, Kolb H: production in types 2 diabetes. Life Sci of plasma lipids and apolipoproteins. J Impaired glucose tolerance is associated 67:291–300, 2000 Lipid Res 30:39–49, 1989 with increased serum concentrations of 52. Han TS, Sattar N, Williams K, Gonzalez-

820 DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 Pickup

Villapando C, Lean MEJ, Haffner SM: Jaspars LH, Visser CA, Verheugt FW, 391:79–82, 1998 Prospective study of C-reactive protein Meijer CJ, Hack CE: C-reactive protein 79. Jiang C, Ting AT, Seed B: PPAR-␥ ago- in relation to the development of diabe- colocalizes with complement in human nists inhibit production of in- tes and metabolic syndrome in the Mex- hearts during acute myocardial infarc- flammatory cytokines. Nature 391:82– ico City Diabetes Study. Diabetes Care tion. Circulation 95:97–103, 1997 85, 1998 25:2016–2021, 2002 67. Griselli M, Herbert J, Hutchinson WL, 80. Rosenson RS, Tangney CC, Casey LC: 53. Lindsay RS, Funahashi T, Hanson RL, Taylor KM, Sohail M, Krausz T, Pepys Inhibition of proinflammatory cytokine Matsuzawa Y, Tanaka S, Tatarranni PA, MB: C-reactive protein and complement production by pravastatin. Lancet 353: Knowler WC, Krakoff J: Adiponectin are important mediators of tissue dam- 983–984, 1999 and development of type 2 diabetes in age in acute myocardial infarction. J Exp 81. Haffner SM, Greenberg AS, Weston the Pima Indian population. Lancet 360: Med 190:1733–1740, 1999 WM, Chen H, Williams K, Freed MI: Ef- 57–58, 2002 68. Ebstein W: Zur therapie des diabetes fect of treatment on non- 54. Libby P, Ridker PM, Maseri A: Inflam- mellitus insbesondere uber die an- traditional markers of cardiovascular mation and atherosclerosis. Circulation wedung des salicylsauren natron bei disease in patients with type 2 diabetes 105:1135–1143, 2002 demselben. Berl Klin Wochenschr 13: mellitus. Circulation 106:679–684, 2002 55. Binder CJ, Chang M-K, Shaw PX, Miller 337–340, 1877 82. Chu NV, Kong APS, Kim DD, Armstrong YI, Hartvigsen K, Dewan A, Witztum JL: 69. Yuan M, Konstanopoulos N, Lee J, Han- D, Baxi S, Deutsch R, Caulfield M, Mu- Innate and acquired immunity in ath- sen L, Li Z-W, Karin M, Shoelson SE: daliar SR, Reitz R, Henry RR, Reaven PD: erosclerosis. Nat Med 8:1218–1226, Reversal of obesity- and diet-induced in- Differential effects of metformin and tro- 2002 sulin resistance with salicylates or tar- glitazone on cardiovascular risk factors 56. Ridker PM, Cushman M, Stamfer MJ, geted disruption of ikk␤. Science 293: with type 2 diabetes. Diabetes Care 25: Tracy RP, Hennekens CH: Inflamma- 1673–1677, 2001 542–549, 2002 tion, aspirin, and the risk of cardiovas- 70. Hundal RS, Petersen KF, Mayerson AB, 83. Ebeling P, Teppo A-M, Koistinen HA, cular disease in apparently healthy men. Randhawa PS, Inzucchi S, Shoelsen SE, Viikari J, Ro¨nnemaa T, Nisse´nM, N Engl J Med 336:973–979, 1997 Shulman GI: Mechanism by which high- Bergkulla, Salmela P, Saltevo J, Koivisto 57. Ridker PM, Hennekens CH, Buring JE, dose aspirin improves glucose metabo- VA: reduces hyperglycae- Rifai N: C-reactive protein and other lism in type 2 diabetes. J Clin Invest 109: mia and selectively acute-phase proteins markers of inflammation in the predic- 1321–1326, 2002 in patients with type II diabetes. Diabe- tion of in women. 71. Freeman DJ, Norrie J, Naveed S, Neely tologia 42:1433–1438, 1999 N Engl J Med 342:836–843, 2000 DG, Cobbe SM, Ford I, Isles C, Lorimer 84. Van de Ree MA, Huisman MV, Princen 58. Lindberg G, Eklund G, Gullberg B, Ras- AR, Macfarlane PW, McKillop JH, Pack- HMG, Meinders AE, Kluft C: Strong de- tam L: Serum sialic acid concentration ard CJ, Shepherd J, Gaw A: Pravastatin crease of high sensitivity C-reactive pro- and cardiovascular mortality. BMJ 302: and the development of diabetes melli- tein with high-dose atorvastatin in 143–146, 1991 tus: evidence for a protective treatment patients with type 2 diabetes mellitus. 59. Blake GJ, Ridker PM: Inflammatory bio- effect in the West of Scotland Coronary Atherosclerosis 166:129–135, 2003 markers and cardiovascular risk predic- Prevention Study. Circulation 103:357– 85. Dandona P, Aljada A: A rational ap- tion. J Intern Med 252:283–294, 2002 362, 2001 proach to pathogenesis and treatment of 60. Pickup JC, Mattock MB, Crook MA, 72. Weitz-Schmidt G: Statins as anti-inflam- type 2 diabetes mellitus, insulin resis- Chusney GD, Burt D, Fitzgerald AP: Se- matory agents. Trends Pharmacol Sci 23: tance, and atherosclerosis. Am J Cardiol rum sialic acid concentration and coro- 482–486, 2002 90:27G–33G, 2002 nary heart disease in NIDDM. Diabetes 73. Munford RS: Statins and the acute-phase 86. Sacks G, Sargent I, Redman C: An innate Care 18:1100–1103, 1995 response. N Engl J Med 344:2016–2018, view of human pregnancy. Immunol To- 61. Pickup JC, Mattock MB: Activation of 2001 day 20:114–118, 1999 the innate immune system as a predictor 74. McFarlane SI, Muniyappa R, Fransisco 87. Wolf M, Sandler L, Hsu K, Vossen- of cardiovascular mortality in type 2 di- R, Stowers JR: Pleiotropic effects of st- Smirnakis K, Ecker JL, Thadhani R: abetes mellitus. Diabet Med 20:723–726, atins: lipid reduction and beyond. J Clin First-trimester C-reactive protein and 2003 Endocrinol Metab 87:1451–1458, 2002 subsequent gestational diabetes. Diabe- 62. Jarrett RJ: Type 2 (non-insulin-depen- 75. Ridker PM, Rifai N, Pfeiffer MA, Sacks F, tes Care 26:819–825, 2003 dent) diabetes mellitus and coronary Braunwald E: Long-term effects of prav- 88. Morris MF: Insulin receptor signalling heart disease: chicken, egg or neither? astatin on plasma concentration of C- and regulation. In Textbook of Diabetes. Diabetologia 26:99–102, 1984 reactive protein. Circulation 100:230– 3rd ed. Pickup JC, Williams G, Eds. 63. Pasceri V, Willerson JT, Yeh ET: Direct 235, 1999 Oxford, U.K., Blackwell, 2003, p. 14.1– proinflammatory effect of C-reactive 76. Tan KCB, Chow WS, Tam SCF, Ai VHG, 14.17 protein on human endothelial cells. Cir- Lam CHL, Lam KSL: Atorvastatin lowers 89. Tanaka T, Itoh H, Doi K, Fukunaga K, culation 102:2165–2168, 2000 C-reactive protein and improves endo- Shintani M, Yamashita J, Chun T-H, In- 64. Pasceri V, Cheng JS, Willerson JT, Yeh thelium-dependent vasodilatation in oue M, Masatsugu K, Sawada N, Saito T, ET, Chang J: Modulation of C-reactive type 2 diabetes mellitus. J Clin Endocrinol Nishimura H, Yoshimasa Y, Nakao K: protein mediated monocyte chemoat- Metab 87:563–568, 2002 Down regulation of peroxisome prolif- tractant protein-1 induction by anti-ath- 77. Murphy GJ, Holder JC: PPAR-␥ agonists: erator-activated receptor ␥ expression eroscleroticdrugs.Circulation103:2531– therapeutic role in diabetes, inflamma- by inflammatory cytokines and its rever- 2534, 2001 tion and cancer. Trends Pharmacol Sci 21: sal by thiazolidinediones. Diabetologia 65. Zwaka TP, Hombach V, Torzewski J: 469–474, 2000 42:702–710, 1999 C-reactive protein-mediated low density 78. Ricote M, Li AC, Willson TM, Kelly CJ, 90. Steensberg A, Fischer CP, Sacchetti M, lipoprotein uptake by macrophages. Cir- Glass CK: The peroxisome proliferator- Keller C, Osada T, Schjerling P, van Hall culation 103:1194–1197, 2001 activated receptor-␥ is a negative regula- G, Febbraio MA, Klarlund Pedersen B: 66. Lagrand WK, Niessen HW, Wolbink GJ, tor of macrophage activation. Nature Acute interleukin-6 administration does

DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 821 Inflammation and type 2 diabetes

not impair muscle glucose uptake or 103. Endres S, Ghorbani R, Kelley VE, Geor- 115. Surwit RS, Schneider MS, Feinglos MN: whole-body glucose disposal in healthy gilis K, Lonnemann G, van der Meer JW, Stress and diabetes mellitus. Diabetes humans. J Physiol 548:631–638, 2003 Cannon JG, Rogers TS, Klempner MS, Care 15:1413–1422, 1992 91. Thompson D, Harrison SP, Evans SW, Weber PC, et al.: The effect of dietary 116. Osler W: The Principles and Practice of Whicher JT: Insulin modulation of acute supplementation with n-3 polyunsatu- Medicine. New York, Appleton, 1892 phase protein production in a human rated fatty acids on the synthesis of in- 117. Mooy JM, de Vries H, Grootenhuis PA, hepatoma cell line. Cytokine 3:619–626, terleukin-1 and by Bouter LM, Heine RJ: Major stressful life 1991 mononuclear cells. N Engl J Med 320: events in relation to prevalence of unde- 92. Campos SP, Baumann H: Insulin is a 265–271, 1989 tected type 2 diabetes: the Hoorn Study. prominent modulator of the cytokine- 104. Orban Z, Remaley AT, Sampson M, Tra- Diabetes Care 23:197–201, 2000 stimulated expression of acute-phase janoski Z, Chrousas GP: The differential 118. Sapolsky RM, Krey LC, McEwen BS: The plasma protein genes. Mol Cell Biol 12: effect of food intake and beta-adrenergic neuroendocrinology of aging: the glu- 1789–1797, 1992 stimulation on adipose-derived hor- cocorticoid cascade hypothesis. Endocr 93. Pickup JC, Day C, Bailey CJ, Samuel A, mones and cytokines in man. J Clin En- Rev 7:284–301, 1986 Chusney GD, Garland HO, Hamilton K, docrinol Metab 84:2126–2133, 1999 119. McEwen BS, Seeman T: Protective and Balment RJ: Plasma sialic acid in animal 105. Upritchard JE, Sutherland WHF, Mann damaging effects of mediators of stress: models of diabetes mellitus: evidence for JI: Effect of supplementation with to- elaborating and testing the concepts of modulation of sialic acid concentrations mato juice, vitamin E, and vitamin C on allostasis and allostatic load. AnnNY by insulin deficiency. Life Sci 57:1383– LDL oxidation and products of inflam- Acad Sci 896:30–47, 1999 1391, 1995 matory activity in type 2 diabetes. Dia- 120. Lindsay S, Krakoff J, Hanson RL, Bennett 94. Phillips DI, Walker BR, Reynolds RM, betes Care 23:733–738, 2000 PH, Knowler WC: Gamma globulin lev- Flanagan DE, Wood PJ, Osmond C, 106. Vlassara H, Cai W, Crandall J, Goldberg els predict type 2 diabetes in the Pima Barker DJ: Low birth weight predicts el- T, Oberstein R, Dardaine V, Peppa M, Indian population. Diabetes 50:1598– evated plasma cortisol concentrations in Rayfield EJ: Inflammatory mediators are 1603, 2001 adults from 3 populations. Hypertension induced by dietary glycotoxins, a major 121. Cseh K, Baranyi E, Winkler G: The role 35:1301–1306, 2000 risk factor for diabetic . Proc of the innate and adaptive immune sys- 95. Barker DJP: Fetal origins of coronary Natl Acad SciUSA99:15596–15601, tem in the regulation of insulin resis- heart disease. BMJ 311:171–174, 1995 2002 tance. Diabetologia 42:497–498, 1999 96. Fernandez-Real JM, Gutierrez C, Ricart 107. Fagiolo U, Cossarizza A, Scala E, Fa- 122. Yoo JY, Desiderio S: Innate and acquired W, Casamitjana R, Fernandez-Castaner nales-Belasio E, Ortolani C, Cozzi E, immunity intersect in a global view of M, Vendrell J, Richart C, Soler JL: The Monti D, Franceschi C, Paganelli R: In- the acute-phase response. Proc Natl Acad TNF-alpha gene Nco I polymorphism creased cytokine production in mono- SciUSA100:1157–1162, 2003 influences the relationship among insu- nuclear cells of healthy elderly people. 123. Ceriello A, Mercuri F, Fabbro D, Giaco- lin resistance, percent body fat, and in- Eur J Immunol 23:2375–2378, 1993 mello R, Stel G, Taboga C, Tonutti L, creased serum levels. Diabetes 46: 108. Caswell M, Pike LA, Bull BS, Stuart J: Motz E, Damante G: Effect of intensive 1468–1472, 1997 Effect of age on tests of the acute-phase glycaemic control on fibrinogen plasma 97. Day CP, Grove J, Daly AK, Stewart MW, response. Arch Pathol Lab Med 117:906– concentrations in patients with type II Avery PJ, Walker M: Tumour necrosis 910, 1993 diabetes mellitus: relation with ␤-fibrin- factor alpha gene promoter polymor- 109. Bruunsgaard H, Pedersen M, Klarland ogen genotype. Diabetologia 41:1270– phism and decreased insulin resistance. Pedersen B: Aging and proinflammatory 1273, 1998 Diabetologia 41:430–434, 1998 cytokines. Curr Opin Hematol 8:131– 124. Morohoshi M, Fujisawa K, Uchimura I, 98. Ferna´ndez-Real J-M, Vendrell J, Ricart 136, 2001 Numano F: Glucose-dependent inter- W, Broach M, Gutie´rrez C, Casamitjana 110. Francesci C, Bonafe M, Valensin S, leukin-6 and tumor necrosis factor pro- R, Oriola J, Richart C: Polymorphism of Olivieri F, De Luca M, Ottaviani E, duction by human peripheral blood the tumor necrosis factor-a receptor 2 DeBenedictis G: Inflamm-aging: an evo- monocytes in vitro. Diabetes 45:954– gene is associated with obesity, leptin lutionary perspective on immunosenes- 959, 1996 levels, and insulin resistance in young cence. Ann N Y Acad Sci 908:244–254, 125. Vlassara H, Brownlee M, Montague KR, subjects and diet-treated type 2 diabetic 2000 Dinarello C, Pasagian A: Cachectin/TNF patients. Diabetes Care 23:831–837, 2000 111. Lindberg G, Råstam L, Gullberg B, Ek- and IL-1 induced by glucose modified 99. Ferna´ndez-Real J-M, Broch M, Vendrell lund GA, To¨rnberg S: Serum sialic acid proteins: role in normal tissue modeling. J, Gutie´rrez C, Casamitjana R, Pugeat M, concentration and smoking: a popula- Science 240:1546–1548, 1988 Richart C, Ricart W: Interleukin-6 gene tion based study. BMJ 303:1306–1307, 126. Esposito K, Nappo F, Marfella R, Giu- polymorphism and insulin sensitivity. 1991 gliano G, Giugliano F, Ciotola M, Diabetes 49:517–520, 2000 112. Abramson JL, Vaccarino V: Relationship Qaugliaro L, Ceriello A, Guigliano D: 100. Pannacciulli N, De Pergola G, Giorgino between physical activity and inflamma- Inflammatory cytokine concentrations F, Giogino R: A family history of type 2 tion among apparently healthy middle- are acutely increased by hyperglycemia diabetes is associated with increased aged and older US adults. Arch Intern in humans: role of oxidative stress. Cir- plasma levels of C-reactive protein in Med 162:1286–1292, 2002 culation 106:2067–2072, 2002 non-smoking healthy women. Diabet 113. Wannamethee SG, Lowe GD, Whincup 127. Hotamisligil GS, Arner P, Caro JF, At- Med 19:689–692, 2002 PH, Rumley A, Walker M, Lennon L: kinson RL, Spiegelman BM: Increased 101. Pickup JC, Chana T, Mattock MB, Sam- Physical activity and hemostatic and in- adipose tissue expression of tumor ne- uel A, Mather HM: Serum sialic acid flammatory variables in elderly men. crosis factor-alpha in human obesity and concentrations in Asian diabetic patients Circulation 105:1758–1790, 2002 insulin resistance. J Clin Invest 95:2409– in the UK. Diabet Med 13:284–285, 1996 114. Wales JK: Does psychological stress 2415, 1995 102. Grimble RF: Nutrition and cytokine ac- cause diabetes? Diabet Med 12:109–112, 128. Mohamed-Ali V, Goodrick S, Rawesh A, tion. Nutr Res Rev 3:193–210, 1990 1995 Mile JM, Katz DR, Yudkin JS, Coppack

822 DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 Pickup

SW: Human subcutaneous adipose tis- Care 26:1745–1751, 2003 Care 26:744–749, 2003 sue releases IL6 but not TNF-alpha in 131. Stuart J, George AG, Davies AJ, Auklund 134. Leonard BE: Changes in the immune vivo. J Clin Endocrinol Metab 82:4196– A, Hurlow RA: Haematological stress system in depression and : 4200, 1997 syndrome in atherosclerosis. J Clin causal or co-incidental effects? Int J Dev 129. Fried SK, Bunkin DA, Greenberg AS: Pathol 34:464–467, 1981 Neurosci 19:305–312, 2001 Omental and subcutaneous adipose 132. Dessein PH, Stanwix AE, Joffe BI: Car- 135. Vgontzas AN, Papanicolaou DA, Bixler tissues of obese subjects release inter- diovascular risk in rheumatoid arthri- EO, Hopper K, Lotsikas A, Lin H-M, leukin-6: adipose tissue difference and tis versus : acute phase Kales A, Chrousas GP: Sleep apnea and regulation by glucocorticoid. J Clin En- response related to decreased insulin daytime sleepiness and fatigue: relation docrinol Metab 83:847–850, 1998 sensitivity and high-density lipoprotein to visceral obesity, insulin resistance and 130. Krakoff J, Funahashi T, Stehouwer CD, cholesterol, as well as clustering of met- hypercytokinemia. J Clin Endocrinol Schalkwijk CG, Tanaka S, Matsuzawa Y, abolic syndrome features in rheumatoid Metab 85:1151–1158, 2000 Kobes S, Tataranni PA, Hanson RL, arthritis. Arthritis Res 4:R5, 2002 136. Inui A: Cytokines and sickness behav- Knowler WC, Lindsay RS: Inflammatory 133. Nichols GA, Brown JB: Unadjusted and iour: implications from knockout ani- markers, adiponectin, and risk of type 2 adjusted prevalence of diagnosed de- mal models. Trends Immunol 22:469– diabetes in the Pima Indian. Diabetes pression in type 2 diabetes. Diabetes 473, 2001

DIABETES CARE, VOLUME 27, NUMBER 3, MARCH 2004 823