Does an Adipokine-Induced Activation of the Immune System Mediate the Effect of Overnutrition on Type 2 Diabetes
http://www.100md.com
糖尿病学杂志 2005年第4期
Obesity and Diabetes Clinical Research Section, Department of Health and Human Services, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
ABSTRACT
There is growing support for the hypothesis that obesity is an inflammatory condition leading to chronic activation of the innate immune system, which ultimately causes progressive impairment of glucose tolerance. Experimental studies in animals and evidence from prospective and longitudinal studies in humans are consistent with an etiologic role of subclinical inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance. However, the exact chain of molecular events linking overnutrition, activation of the innate immune system, and impairment of insulin signaling in peripheral tissues remains incompletely understood. Notwithstanding this limitation, treating the underlying subclinical inflammation may constitute a novel approach to prevention and/or treatment of type 2 diabetes.
Through the story of evolution, animals and humans have developed redundant mechanisms that promote the accumulation of fat tissue during periods of "feast," thus enabling survival during periods of "famine" (1). However, what once was an asset has become a liability in the current "obesigenic" environment of readily available high-energy foods and little need for physical activity. As a consequence, obesity has reached epidemic proportions in both industrialized and developing countries around the world, which is a major public health problem because obesity is associated with significant comorbidities and increased mortality.
Clinicians have long observed that fatter people are more likely to develop type 2 diabetes, and overwhelming scientific evidence has proven this clinical impression to be accurate. The association of obesity with type 2 diabetes has been observed in comparisons of different populations and within populations. Prospective studies of pre-diabetic subjects have conclusively shown that obesity and its duration are major risk factors for type 2 diabetes. Despite the remarkable consistency of the association between the two diseases, obesity is neither sufficient nor necessary for the development of type 2 diabetes. For example, many U.S. whites are overweight or obese, but <10% of this population has type 2 diabetes.
How does obesity cause type 2 diabetes and why in only certain people Experimental weight gain results in hyperinsulinemia and insulin resistance in animals and humans. It is clear how type 2 diabetes develops in the absence of insulin secretion, but how does insulin resistance gradually result in the disease
The concepts of glucotoxicity, lipotoxicity, and cellular nutrient overload to explain the pathogenesis of type 2 diabetes in obese individuals have been advanced previously, but these theories have evidently failed to provide a universally accepted and pathophysiologically conclusive explanation that would link excessive adiposity to insulin resistance and insulin secretory dysfunction. Thus, new theories continue to emerge.
In this review, we will present the growing body of evidence indicating that obesity may be an inflammatory condition leading to chronic activation of the innate immune system, which ultimately causes progressive impairment of glucose tolerance and eventually type 2 diabetes.
ORIGIN OF THE HYPOTHESIS
The theory that inflammation may be involved in the pathogenesis of type 2 diabetes is not new. The first indication of this pathophysiological connection can be traced to Ebstein (2) who, >100 years ago, reported in the German scientific literature that high doses of salycilate improved glycosuria in diabetic patients. This idea was then forgotten until a group of epidemiologists in the mid-1990s discussed the possibility that diabetes and atherosclerosis, an inflammatory condition in its own right, have common antecedents (the "common soil hypothesis" [3]). But it was the 1998 publication "Is Type II Diabetes Mellitus a Disease of the Innate Immune System" by Pickup and Crook (4) that finally laid out a more specific pathophysiological hypothesis. Based on the observation that the dyslipidemia common to people with type 2 diabetes (high triglycerides and low HDL cholesterol) is also a feature of experimental and naturally occurring acute-phase reactions, Pickup and Crook proposed that in individuals with an innately hypersensitive acute-phase response, long-term lifestyle and environmental stressors, such as nutrition, produce disease (type 2 diabetes) instead of repair.
Pickup and Crook explained that the innate immune system, a rapid first-line defense system based on nonlymphoid tissue, is primarily responsible for the acute-phase response, a self-limiting process induced by a variety of stressors (infection, tissue injury, and malignancy) causing a number of cells (macrophages, adipocytes, and endothelial cells) to secrete cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor- [TNF-]), which act on the liver to synthesize acute-phase proteins (fibrinogen, C-reactive protein, serum amyloid A, and others). Due to its self-limiting nature, the acute-phase response is aimed at restoring the homeostasis disturbed by an acute stressor. However, in response to chronic stressors, the system may become allostatic, i.e., the sustained effort to acutely battle challenges may ultimately result in an overload of the system resources. Eventually when the allostatic load exceeds these resources, the system breaks down.
While brilliant, Pickup and Crook’s theory had a few shortcomings. It was based primarily on cross-sectional observations, and, although it predicted that the most likely chronic stressors are nutritional ones, it did not explain how this could result in increased secretion of cytokines by multiple cell types and gave no molecular explanation as to how these cytokines could inhibit insulin action in peripheral tissues and/or glucose-stimulated insulin secretion in the pancreas.
CHRONIC ACTIVATION OF THE IMMUNE SYSTEM AND TYPE 2 DIABETES: CAUSE OR CONSEQUENCE
A number of studies (5,6) have reported increased acute-phase proteins and other nonspecific markers of inflam-mation in type 2 diabetes. This is not particularly surprising, since inflammatory processes in affected tissues accompany some of the chronic complications of type 2 diabetes. However, studies in nondiabetic individuals have challenged this interpretation.
Healthy people who go on to develop diabetes, when compared with those who remain nondiabetic, are more obese (particularly centrally), insulin resistant, and have abnormal insulin secretory function (7). Interestingly, obesity and insulin resistance seem to be positively associated with elevated markers of inflammation in most studies, whereas no convincing evidence of a relationship between insulin secretory dysfunction and inflammation has been reported. Obesity was found to be associated with nonspecific measures of activation of the immune system, such us total -globulin concentration (8), body temperature (9), white blood cell count (10), and C-reactive protein (11). Associations between fibrinogen and clinical features of the metabolic syndrome (12), as well as associations between oral temperature or white blood cell count and insulin sensitivity (10,13,14), have also been reported. Because in most (15eC22) if not all (23,24) cases the association between inflammatory markers and insulin resistance was found to be independent of adiposity, it has been suggested that inflammation is a possible pathophysiological link between obesity and insulin resistance. How-ever, whether or not inflammation is a pre-diabetic abnormality cannot be determined from cross-sectional studies alone. Such conclusions are better drawn from prospective and longitudinal studies.
Many prospective studies (8,20,25eC36), in diverse human populations, have identified proinflammatory cytokines, acute-phase proteins, and several indirect markers of inflammation as predictors of type 2 diabetes. This predictive effect of inflammation on the risk of type 2 diabetes does not seem to depend on subclinical cardiovascular disease (25,30,32,35), undiagnosed diabetes at baseline (8,20,29eC31,33,36), or, surprisingly, initial degree of insulin resistance (20,25,27,29eC32,35,36). Although this association is substantially lessened by obesity, in most of the studies at least one of the inflammatory markers identifies people at risk of diabetes independent of their degree of adiposity or upper body fat distribution (Table 1). Very few longitudinal studies have investigated whether inflammation may cause diabetes by reducing insulin sensitivity and/or insulin secretory function. We addressed this issue in a study (20) of 81 Pima Indians with normal glucose tolerance at baseline, after adjustment for several covariates including concomitant changes in adiposity, and found that white blood cell count was associated with a decline in insulin sensitivity but not insulin secretory function.
Thus, while an inconsistent use of inflammatory markers to biochemically define chronic activation of the immune system makes it very difficult to summarize this body of literature, it seems that the evidence from prospective and longitudinal studies is consistent with an etiologic role of inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance (Fig. 1A). Pickup (37) reached a similar conclusion in a recently published reappraisal of the original 1998 theory.
OVERNUTRITION AND CHRONIC ACTIVATION OF THE INNATE IMMUNE SYSTEM: THE ROLE OF ADIPOKINES
The traditional view of adipose tissue as a passive energy storage depot was challenged when it was identified as a major site for the metabolism of steroid hormones (38), and it is no longer valid after the discovery that adipose tissue secretes a number of bioactive proteins. These proteins, known as adipokines, have local autocrine/paracrine effects as well as systemic hormonal effects and span a vast array of chemical structures and functional classes (Fig. 2), as recently reviewed by Kershaw and Flier (39).
Why is obesity associated with inflammation Pickup and Crook’s (4) prediction of nutritional factors as a chronic activator of the innate immune response makes sense if one extends the concept to include overnutrition and the resulting increase in adiposity. Thus, the simplest explanation for why obesity is associated with inflammation is that the hyperplastic/hypertrophic expansion of the adipocyte mass results in altered circulating levels of proinflammatory cytokines. Other hypotheses include elevated local production of TNF-, which is both a local adipostatic signal (inhibitor of lipoprotein lipase) and a trigger of the inflammatory response. Adipose tissue expansion, like tumors, is angiogenesis dependent (40). It has been suggested that adipocytes may become hypoxic during a rapid expansion of adipose tissue and start secreting inflammatory cytokines, which serve to increase blood flow, and some of them (such us leptin and vascular endothelial growth factor) may directly stimulate angiogenic factors (41). Adipose tissue from obese humans has been shown to have increased 11-hydroxysteroid dehydrogenase type 1 activity (42). In rodents, selective overexpression of 11-hydroxysteroid dehydrogenase type 1 in adipose tissue is accompanied by proinflammatory changes in the adipokine expression profile (leptin, resistin, adiponectin, and TNF-) (43). Finally, adipose tissue is now recognized as a complex organ containing adipocytes as well as connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. Lately, the presence of immune cells has received increased attention owing to significant functional and molecular overlap between adipocytes and macrophages, as in the recent discovery that adipocyte precursors can be transformed into macrophage-like cells in response to the appropriate stimuli (44) and that adipose tissue, but not liver or muscle, in obese people is characterized by macrophage infiltration (45,46). Increased levels of monocyte chemotactic protein-1 secreted by adipocyte or preadipocytes in response to TNF- could be one of the chemokines implicated in this recruitment of macrophages, which would perpetuate the inflammatory response.
Interestingly, adipose tissue secretes proteins that have both stimulatory and inhibitory effects on the inflammatory process. Among the proinflammatory adipokines, TNF- and IL-6 have been studied most extensively. The effects of TNF- on glucose metabolism may be mediated in an autocrine/paracrine manner by regulating secretion of other adipokines or by promoting lipolysis and raising serum free fatty acid (FFA) levels. TNF- is overexpressed in different models of murine (47) and in human obesity (48,49), whereas weight reduction decreases its expression and/or plasma concentration (48eC50). In humans, a single bolus intravenous injection of recombinant human TNF- increased plasma glucose concentrations and plasma FFAs (51); TNF- neutralization affects direct measures of whole-body insulin sensitivity in rats (47) but not in humans (52).
While TNF- in human plasma has been found at very low concentrations, adipose tissue accounts for 30% of the circulating IL-6, suggesting an endocrine role for this adipokine (53). In the liver, IL-6 is the primary stimulator for the production of most of the acute-phase proteins (54). IL-6 in vitro reduces insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, as well as IRS-1eCassociated phosphatidylinositol (PI) 3-kinase activity (55), and in mice, IL-6 treatment causes insulin resistance in skeletal muscle and in liver most likely due to defects in IRS-1 (and IRS-2, respectively)-associated PI 3-kinase activity (56). In humans, IL-6 is related to insulin resistance, independent of obesity (57,58). In the Atherosclerosis Risk in Communities study (26) and Nurses Health study (30), IL-6 at baseline was independently associated with future risk of diabetes (Table 1). Similar results were reported in the European Prospective Investigation into Cancer and NutritioneCPotsdam study (33), in which participants with elevated IL-6 and IL-1 had a threefold increase in risk for developing diabetes when compared with the reference group.
Other proinflammatory adipokines have been studied. Leptin, in vitro, has been found to have proinflammatory properties (59) and may promote monocyte diapedesis and the accumulation of macrophages in adipose tissue (60). However, because leptin improved insulin sensitivity in rodents (61) and in humans (62) with lipodystrophy, this makes it an unlikely contributor to the inflammatory response associated with obesity. Resistin was originally reported as an adipose tissueeCspecific hormone that provided a link between obesity and diabetes. Resistin is part of a new class of cysteine-rich secreted proteins that were found, by one of the groups who discovered it, to be induced during lung inflammation (found in inflammatory zone 1 [FIZZ1]). In vitro studies have shown that resistin mRNA expression is increased by proinflammatory cytokines in human mononuclear cells (63) and that resistin has a direct proinflammatory effect, probably mediated through nuclear factor-B (NF-kB) signaling pathway on vascular endothelial human cells (64). In rodents, resistin affects glucose tolerance and is related with whole-body and hepatic insulin resistance (65,66). Differences in resistin gene expression have been observed between human and mice tissues. While in mice adipocytes are the mayor source of circulating resistin, in humans secretion or expression is predominantly found in mononuclear cells, and the release of resistin by explants of adipose tissue in primary culture is largely derived from the nonfat cells present in the explants (67). Resistin is detectable in human serum, and its circulating levels were found to be elevated in proportion to the degree of adiposity (68,69). Although these data might suggest a contribution of resistin to inflammation and insulin resistance, the role of resistin in obesity has not been proven (68,69). Finally, other proinflammatory adipokines, such as complement C3 and macrophage inhibitor factor, were inversely and independently associated with insulin sensitivity (70,71).
Adiponectin is the anti-inflammatory adipokine that has been studied most extensively. It is produced exclusively by white adipocytes but is paradoxically lower in obese versus lean individuals (72). Adiponectin has been related to insulin resistance and diabetes not only because of its AMP-activated protein kinase effects on FFA metabolism and glucose uptake but also because of its anti-inflammatory properties. Inhibition of phagocyte activity and TNF- production by macrophages and inhibition of the TNF-eCinduced expression of adhesion molecules (through NF-B signaling pathways) are some of the known mechanisms by which adiponectin mediate its anti-inflammatory effects (73). Many studies have now suggested that in humans adiponectin is more closely related to insulin resistance than to obesity (73). Prospective and longitudinal studies (74eC78) have found a correlation between low adiponectin levels and a higher risk of diabetes, independent of many confounders including obesity and other inflammatory markers (75,79). Krakoff et al. (79) hypothesized that in studies in which substantial baseline differences in the degree of adiposity exist, the predictive value of inflammatory markers may be a result of their association with obesity, i.e., they may be acting as surrogate markers of hypoadiponectinemia and may be only indirectly associated with the development of diabetes (Fig. 1B) (Table 2).
Adipose tissue is also a source of other anti-inflammatory cytokines whose roles are mostly unknown. IL-10 is an anti-inflammatory cytokine produced by immune cells (T-helper, B-cells, and macrophages). In mice, IL-10 treatment prevented IL-6eCinduced defects in both hepatic and skeletal insulin action (56). Circulating IL-10 is elevated in human obesity (80); in adipose tissue, IL-10 is primarily produced by nonfat cells (81). In humans, lower serum concentrations of IL-10 were associated with the metabolic syndrome (80) and with diabetes (82).
CHRONIC ACTIVATION OF THE INNATE IMMUNE SYSTEM AND IMPAIRMENT OF INSULIN SIGNALING AND/OR INSULIN SECRETION: PUTATIVE MOLECULAR MECHANISMS
Since it was first proposed that chronic activation of the innate immune system could be a possible pathogenic factor in the development of obesity-associated type 2 diabetes, the challenge has been to identify the molecular link between these two entities. The innate immune response and the process of inflammation are inextricably interwoven. Signaling receptors of the immune system (such as the mammalian toll-like receptors) induce signal transduction pathways that lead to the activation of transcription factors (83) that are also activated in response to proinflammatory cytokines. At this point, the leading theory is that activation of some inflammatory pathways, by some of the adipokines previously discussed, ultimately results in suppression of the insulin signal transduction by serine/threonine (Ser/Thr) phosphorylation (inactivation) of the IRS. Two major inflammatory transcription factors, NF-B and activating protein (AP)-1, and their key enzymes IB kinase (IKK) and c-Jun NH2-terminal kinase (JNK), respectively, have been studied more extensively. However, obesity may cause activation of the innate immune/inflammatory system not only by its secreted adipokines. Hyper-lipidemia in mice seems to mediate an inflammatory response by the same signaling cascade (engaged by a receptor complex comprising mammalian toll-like receptor 4, CD14, and MD-2) through which lipopolysaccharide activates the innate immune system (84). FFAs, probably through protein kinase C, can activate IKK and JNK (85). Furthermore, oxidative stress (closely associated with obesity, hyperglycemia, and elevation of FFAs) not only leads to mitochondrial dysfunction but can also induce key redox-sensitive transcription factors (NF-B and AP-1) involved in the innate immune response.
Genetic disruption of these pathways improves insulin resistance (86,87). Heterozygous IKK+/eC mice, fed with a high-fat diet or crossed with obese ob/ob mice, showed a significant decrease in blood glucose levels and improved insulin resistance (87). Furthermore, lipid infusioneCinduced decreases in insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-1eCassociated PI 3-kinase activity in skeletal muscle were prevented in the IKK+/eC mice (88). Recently, this same laboratory has found that selective IKK activation (transgenic mice) in fat or liver but not muscle causes systemic insulin resistance. In agreement with these results, selective inhibition of NF-B (by expressing IB super-repressor) in fat (FISR) and liver, but not in muscle, showed protection against the development of insulin resistance in diet-induced and genetically obese mice, with the additional benefit of preventing weight gain in FISR mice (89)
Total JNK activity, predominantly JNK1, is increased in obese mice (86); JNK1 knockout mice gain less weight and are protected against diet-induced insulin resistance or insulin resistance associated with a genetic model of obesity (ob/ob) (86). It appears that in these mice, serine-307 phosphorylation of IRS-1 was reduced (86). Moreover, suppression of the JNK pathway in liver decreases whole-body insulin resistance and improves glucose tolerance in diabetic animal models (90). Furthermore, loss-of-function mutations in JNK-interacting protein 1, a negative and essential modulator of JNK (91), causes type 2 diabetes in humans (92).
Additional evidence of the involvement of these inflammatory pathways is supported by the protective effect of some anti-inflammatory drugs against obesity-induced insulin resistance. Aspirin may inhibit not only IKK and JNK (93,94) but other Ser/Thr kinases (mamalian target of rapamycin and protein kinase B/Akt) related to TNF- insulin resistance by phosphorylation of IRS-1 at serine residues (94). Furthermore, through its antioxidant properties, aspirin has been shown to reduce the activation of NF-B or AP-1 associated with reactive oxygen species (95). Yuan et al. (87) first hypothesized and then demonstrated that salicylate treatment improves the severe insulin resistance seen in genetically obese rodents. Furthermore, pretreatment in rats with salicylates prevented lipid-induced skeletal insulin resistance by inhibiting lipid-induced decreases in insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1eCassociated PI 3-kinase activation (88). In humans, treatment with high doses of aspirin (7 g/day) or salsalate (3 g/day) improved peripheral insulin sensitivity in subjects with type 2 diabetes (96,97). Although these results are intriguing, randomized controlled trials are needed to clarify the role of these drugs on glucose metabolism and insulin resistance.
Other drugs with documented anti-inflammatory effects, such as thiazolidinediones (TZDs) and statins, have shown antidiabetic effects. TZDs are potent insulin sensitizers, and TZD treatment has been associated with suppression of local TNF- production by adipocytes and reduction of TNF- action in adipose and other tissues (98). TZDs can also act by increasing plasma levels of adiponectin, and some studies have suggested that peroxisome proliferatoreCactivated receptor (like peroxisome proliferatoreCactivated receptor ) activation in selected cell types can repress NF-B and, therefore, cytokine-mediated signaling (98). Statins are potent cholesterol-lowering drugs. Statin treatment has been associated with modulation in the endothelial adhesion and transendothelial migration of leukocytes, inhibition of the release of cytokines, and chemokines and direct interference with the NF-B pathway (99). Interestingly, the use of statins has also been associated with a decrease in the risk of developing type 2 diabetes (100).
We have discussed how activation of protein kinases and transcription factors, such as AP-1 and NF-B, are possible mediators of insulin resistance in peripheral tissues. Because the same molecules are directly involved in -cell apoptosis (101), it is possible that an adipokine-induced activation of the immune system associated with overnutrition and obesity may also explain the -cell failure that precedes the development of type 2 diabetes. Here, data from the literature do not paint a very clear picture. For example, adiponectin has been shown in vitro to have protective effects against both cytokine- and FFA-induced impairment of the -cell (102), an effect that would be lost in obese individuals with hypoadiponectinemia. Leptin, which is very high in obese individuals, has been shown in vitro to have both stimulatory and inhibitory effects on -cell apoptosis (103). More important, thus far there are no reports in the literature from in vivo animal or human studies of an independent association between (markers of) inflammation and -cell dysfunction.
IS EXCESSIVE FATNESS AN OBLIGATORY PATHOPHYSIOLOGICAL FACTOR
While we have developed this review around the pathophysiological construct that overnutrition leads to obesity which in turn is associated with a chronic activation of the immune system, we would like to acknowledge experimental and circumstantial evidence that challenges this course of events.
The postprandial period following a single meal is associated with an increase in plasma levels of proinflammatory cytokines, recruitment of neutrophils, and oxidative stress (104eC106). The quality, intensity, and duration of this inflammatory response may not only respond to frequency or meal size. The effect of nutrition or food-borne components on gene transcription, proteomics, and metabolism (nutrigenomic) may further increase this inflammatory state. Because modern eating patterns, especially in western societies, produce an almost endless postprandial state throughout the day, a chronic activation of the innate immune system could exist even before obesity develops. Thus, a proinflammatory state could be a pathogenic factor in the development of obesity, as proposed by Das (107) and others. Consistent with this hypothesis, two prospective studies (108,109) reported that elevated levels of inflammatory markers predicted weight gain in two different populations. Finally, a recent study (110) showed that removal of significant amounts of subcutaneous fat tissue had no effect on inflammation markers or insulin sensitivity.
Thus, contrary to evidence presented earlier in the manuscript, it is possible that it is not the mass of the adipose tissue per se but the underlying changes in energy flux that determine its size that is responsible for the modulation of the innate immune response. However, the adipose tissue is not a homogeneous tissue, and characteristics between depots and even between cells in different parts of the same depot differ within and between individuals. Of particular interest to this discussion is the idea that perivascular fat tissue may be especially detrimental in obese people. Increased perivascular fat may not only contribute to the systemic low-grade inflammation associated with obesity but may also interact in an autocrine/paracrine manner, with the closely related endothelial cells and perivascular smooth muscle fibers contributing to the endothelial dysfunction that has often been observed in association with markers of inflammation. Whereas impaired endothelial dysfunction in large arterial beds may have an influence on the pathogenesis of cardiovascular disease, endothelial dysfunction in arteriole and capillaries, in intimate contact with a vast surface of metabolically active and insulin-sensitive tissues, may lead to type 2 diabetes (111,112). This is obviously an area that will require further research.
CONCLUSIONS
Does an adipokine-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes We interpret the literature reviewed in this manuscript as indicating that a reasonable case can be made for overnutrition causing an activation of the innate immune system, most likely by excessive production of adipokines. There is increasing evidence that the proinflammatory state, which characterizes overnourished individuals, may be etiologically linked with the insulin resistance that is often observed in their peripheral tissues. Surprisingly, we could not find convincing evidence for an association between inflammation and insulin secretory dysfunction.
Thus, we propose that inflammation should be viewed as a risk factor for insulin resistance not a global risk factor for type 2 diabetes. In our opinion, the question of how -cells fail in the presence of inflammation-induced insulin resistance remains largely unanswered. Moreover, this may help explain why diabetes does not develop in all subjects with chronic inflammatory diseases.
Notwithstanding these considerations, we believe that elucidation of the link between inflammation and insulin resistance remains a very worthwhile research endeavor. We and others have provided evidence suggesting that interindividual variability of many of these inflammatory markers may be genetically determined. It has been hypothesized that an insulin-resistant genotype, associated with a heightened cytokine response, may have been advantageous in the historical conditions of a short life span, injury, and infectious disease (113). A further selection for these traits may have taken place in American Indians and other native populations after first contact with explorers from other parts of the world, which exposed them to a range of novel infectious diseases to which they had no immunity, leading to repeated epidemics and declines in population. It will be interesting to see if this theory is confirmed when the results of ongoing positional cloning efforts to find the genes that cause diabetes in several populations around the world become available.
In more practical terms, more fully understanding the link between inflammation and insulin resistance holds the promise of revealing novel ways to prevent and/or treat type 2 diabetes. If it can be demonstrated that reducing the underlying activity of the immune system in nondiabetic subjects with high markers of inflammation can improve their degree of insulin sensitivity, then perhaps a case can be made for anti-inflammatory therapy as a way to prevent and/or delay the onset of type 2 diabetes. Early clinical trials are showing promising results when anti-inflammatory drugs are given to diabetic subjects. This indicates that as the chain of molecular events linking inflammation to impairment of insulin signaling will continue to be clarified, novel targets will become available for drug development. Thus, we see many reasons to be optimistic and expect that the question of the link between inflammation, insulin resistance, and type 2 diabetes may no longer be a burning one in the not so distant future.
ACKNOWLEDGMENTS
We are grateful to Dr. Rich Pratley, Dr. Norbert Stefan, Dr. Christian Weyer, and Dr. Barbora Vozarova for their invaluable contributions to the study of inflammation and type 2 diabetes in the Pima Indians of Arizona. We thank Dr. Michael Stumvoll, Dr. Clifton Bogardus, Dr. Arline Salbe, and Inge Harper for critical reading of the manuscript. We also acknowledge the members and leaders of the Gila River Indian Community for their continuing cooperation in our studies.
FOOTNOTES
P.A.T. is currently affiliated with Sanofi Aventis, Paris, France.
AP, activating protein; FFA, free fatty acid; IKK, IB kinase; IL, interleukin; IRS, insulin receptor substrate; JNK, Jun NH2-terminal kinase; NF-B, nuclear factor-B; PI, phosphatidylinositol; TNF-, tumor necrosis factor-; TZD, thiazolidinedione
REFERENCES
Neel JV: Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress" Am J Hum Genet14 :353 eC362,1962
Ebstein W: Zur therapie des diabetes mellitus, insbesondere eer die Anwendung des salicylsauren natron bei demselben. Berlin KlinWochenschrift13 :337 eC340,1876
Stern MP: Diabetes and cardiovascular disease: the "common soil" hypothesis. Diabetes44 :369 eC374,1995
Pickup JC, Crook MA: Is type II diabetes mellitus a disease of the innate immune system Diabetologia41 :1241 eC1248,1998
Leinonen E, Hurt-Camejo E, Wiklund O, Hulten LM, Hiukka A, Taskinen MR: Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis166 :387 eC394,2003
Pickup JC, Mattock MB, Chusney GD, Burt D: NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia40 :1286 eC1292,1997
Weyer C, Bogardus C, Mott DM, Pratley RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest104 :787 eC794,1999
Lindsay RS, Krakoff J, Hanson RL, Bennett PH, Knowler WC: Gamma globulin levels predict type 2 diabetes in the Pima Indian population. Diabetes50 :1598 eC1603,2001
Eriksson H, Svardsudd K, Larsson B, Welin L, Ohlson LO, Wilhelmsen L: Body temperature in general population samples: the study of men born in 1913 and 1923. Acta Med Scand.217 :347 eC352,1985
Pratley RE, Wilson C, Bogardus C: Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. Obes Res3 :563 eC571,1995
Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB: Elevated C-reactive protein levels in overweight and obese adults. JAMA282 :2131 eC2135,1999
Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, Muggeo M: Metabolic syndrome: epidemiology and more extensive phenotypic description: cross-sectional data from the Bruneck Study. Int J Obes Relat Metab Disord27 :1283 eC1289,2003
Facchini F, Hollenbeck CB, Chen YN, Chen YD, Reaven GM: Demonstration of a relationship between white blood cell count, insulin resistance, and several risk factors for coronary heart disease in women. J Intern Med232 :267 eC272,1992
Vozarova B, Weyer C, Bogardus C, Ravussin E, Tataranni PA: Differences in oral temperature and body shape in two populations with different propensities for obesity. Ann N Y Acad Sci967 :516 eC521,2002
Festa A, D’Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM: Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation102 :42 eC47,2000
Fritsche A, Haring H, Stumvoll M: [White blood cell count as a predictor of glucose tolerance and insulin sensitivity: the role of inflammation in the pathogenesis of type 2 diabetes mellitus]. Dtsch Med Wochenschr129 :244 eC248,2004
Hak AE, Pols HA, Stehouwer CD, Meijer J, Kiliaan AJ, Hofman A, Breteler MM, Witteman JC: Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study. J Clin Endocrinol Metab86 :4398 eC4405,2001
Pradhan AD, Cook NR, Buring JE, Manson JE, Ridker PM: C-reactive protein is independently associated with fasting insulin in nondiabetic women. Arterioscler Thromb Vasc Biol23 :650 eC655,2003
Raynaud E, Perez-Martin A, Brun J, Aissa-Benhaddad A, Fedou C, Mercier J: Relationships between fibrinogen and insulin resistance. Atherosclerosis150 :365 eC370,2000
Vozarova B, Weyer C, Lindsay RS, Pratley RE, Bogardus C, Tataranni PA: High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes51 :455 eC461,2002
Weyer C, Yudkin JS, Stehouwer CD, Schalkwijk CG, Pratley RE, Tataranni PA: Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians. Atherosclerosis161 :233 eC242,2002
Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW: C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue Arterioscler Thromb Vasc Biol19 :972 eC978,1999
Hak AE, Stehouwer CD, Bots ML, Polderman KH, Schalkwijk CG, Westendorp IC, Hofman A, Witteman JC: Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol19 :1986 eC1991,1999
Temelkova-Kurktschiev T, Siegert G, Bergmann S, Henkel E, Koehler C, Jaross W, Hanefeld M: Subclinical inflammation is strongly related to insulin resistance but not to impaired insulin secretion in a high risk population for diabetes. Metabolism51 :743 eC749,2002
Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP: The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes50 :2384 eC2389,2001
Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, Hoogeveen R, Folsom AR, Heiss G: Low-grade systemic inflammation and the development of type 2 diabetes: the Atherosclerosis Risk in Communities Study. Diabetes52 :1799 eC1805,2003
Festa A, D’Agostino R Jr, Tracy RP, Haffner SM: Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes51 :1131 eC1137,2002
Freeman DJ, Norrie J, Caslake MJ, Gaw A, Ford I, Lowe GD, O’Reilly DS, Packard CJ, Sattar N: C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes51 :1596 eC1600,2002
Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME, Haffner SM: Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care25 :2016 eC2021,2002
Hu FB, Meigs JB, Li TY, Rifai N, Manson JE: Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes53 :693 eC700,2004
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA286 :327 eC334,2001
Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G: Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities Study): a cohort study. Lancet353 :1649 eC1652,1999
Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF: Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes52 :812 eC817,2003
Thorand B, Lowel H, Schneider A, Kolb H, Meisinger C, Frohlich M, Koenig W: C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984eC1998. Arch Intern Med163 :93 eC99,2003
Laaksonen DE, Niskanen L, Nyyssonen K, Punnonen K, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT: C-reactive protein and the development of the metabolic syndrome and diabetes in middle-aged men. Diabetologia47 :1403 eC1410,2004
Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno N: Elevated C-reactive protein is a risk factor for the development of type 2 diabetes in Japanese Americans. Diabetes Care26 :2754 eC2757,2003
Pickup JC: Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care27 :813 eC823,2004
Siiteri PK: Adipose tissue as a source of hormones. Am J Clin Nutr45 :277 eC282,1987
Kershaw EE, Flier JS: Adipose tissue as an endocrine organ. J Clin Endocrinol Metab89 :2548 eC2556,2004
Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ: Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A99 :10730 eC10735,2002
Trayhurn P, Wood IS: Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr92 :347 eC355,2004
Lindsay RS, Wake DJ, Nair S, Bunt J, Livingstone DE, Permana PA, Tataranni PA, Walker BR: Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. J Clin Endocrinol Metab88 :2738 eC2744,2003
Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS: A transgenic model of visceral obesity and the metabolic syndrome. Science294 :2166 eC2170,2001
Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, Penicaud L, Casteilla L: Preadipocyte conversion to macrophage: evidence of plasticity. J Biol Chem278 :9850 eC9855,2003
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest112 :1821 eC1830,2003
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest112 :1796 eC1808,2003
Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science259 :87 eC91,1993
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM: Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest95 :2409 eC2415,1995
Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB: The expression of tumor necrosis factor in human adipose tissue: regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest95 :2111 eC2119,1995
Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T: Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab83 :2907 eC2910,1998
Van der PT, Romijn JA, Endert E, Borm JJ, Buller HR, Sauerwein HP: Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol261 :E457 eCE465,1991
Di Rocco P, Manco M, Rosa G, Greco AV, Mingrone G: Lowered tumor necrosis factor receptors, but not increased insulin sensitivity, with infliximab. Obes Res12 :734 eC739,2004
Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW: Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab82 :4196 eC4200,1997
Gabay C, Kushner I: Acute-phase proteins and other systemic responses to inflammation. N Engl J Med340 :448 eC454,1999
Senn JJ, Klover PJ, Nowak IA, Mooney RA: Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes51 :3391 eC3399,2002
Kim HJ, Higashimori T, Park SY, Choi H, Dong J, Kim YJ, Noh HL, Cho YR, Cline G, Kim YB, Kim JK: Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes53 :1060 eC1067,2004
Fernandez-Real JM, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J, Ricart W: Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab86 :1154 eC1159,2001
Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE: Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res9 :414 eC417,2001
Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM: Leptin regulates proinflammatory immune responses. FASEB J12 :57 eC65,1998
Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R, Bouloumie A: From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes53 :1285 eC1292,2004
Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F: Effects of the obese gene product on body weight regulation in ob/ob mice. Science269 :540 eC543,1995
Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI: Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest109 :1345 eC1350,2002
Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR: Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun309 :286 eC290,2003
Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, Manabe I, Utsunomiya K, Nagai R: Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun314 :415 eC419,2004
Rajala MW, Obici S, Scherer PE, Rossetti L: Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest111 :225 eC230,2003
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature409 :307 eC312,2001
Fain JN, Cheema PS, Bahouth SW, Lloyd HM: Resistin release by human adipose tissue explants in primary culture. Biochem Biophys Res Commun300 :674 eC678,2003
Volarova de Court B, Degawa-Yamauchi M, Considine RV, Tataranni PA: High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians. Diabetes53 :1279 eC1284,2004
Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV: Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab88 :5452 eC5455,2003
Vozarova B, Stephan N, Hanson R, Lindsay RS, Bogardus C, Tataranni PA, Metz C, Bucala R: Plasma concentrations of macrophage migration inhibitory factor are elevated in Pima Indians compared to Caucasians and are associated with insulin resistance. Diabetologia45 :1739 eC1741,2002
Weyer C, Tataranni PA, Pratley RE: Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration. Diabetes Care23 :779 eC785,2000
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA: Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab86 :1930 eC1935,2001
Pittas AG, Joseph NA, Greenberg AS: Adipocytokines and insulin resistance. J Clin Endocrinol Metab89 :447 eC452,2004
Daimon M, Oizumi T, Saitoh T, Kameda W, Hirata A, Yamaguchi H, Ohnuma H, Igarashi M, Tominaga M, Kato T: Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population: the Funagata study. Diabetes Care26 :2015 eC2020,2003
Duncan BB, Schmidt MI, Pankow JS, Bang H, Couper D, Ballantyne CM, Hoogeveen RC, Heiss G: Adiponectin and the development of type 2 diabetes: the Atherosclerosis Risk in Communities Study. Diabetes53 :2473 eC2478,2004
Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, Knowler WC, Krakoff J: Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet360 :57 eC58,2002
Snehalatha C, Mukesh B, Simon M, Viswanathan V, Haffner SM, Ramachandran A: Plasma adiponectin is an independent predictor of type 2 diabetes in Asian indians. Diabetes Care26 :3226 eC3229,2003
Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF: Adiponectin and protection against type 2 diabetes mellitus. Lancet361 :226 eC228,2003
Krakoff J, Funahashi T, Stehouwer CD, Schalkwijk CG, Tanaka S, Matsuzawa Y, Kobes S, Tataranni PA, Hanson RL, Knowler WC, Lindsay RS: Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care26 :1745 eC1751,2003
Esposito K, Pontillo A, Giugliano F, Giugliano G, Marfella R, Nicoletti G, Giugliano D: Association of low interleukin-10 levels with the metabolic syndrome in obese women. J Clin Endocrinol Metab88 :1055 eC1058,2003
Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW: Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology145 :2273 eC2282,2004
van Exel E, Gussekloo J, de Craen AJ, Frolich M, Bootsma-Van Der Wiel A, Westendorp RG: Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-Plus Study. Diabetes51 :1088 eC1092,2002
Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol20 :197 eC216,2002
Bjorkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, Halmen K, Luster AD, Golenbock DT, Freeman MW: Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med10 :416 eC421,2004
Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J: Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3eCL1 adipocytes. Mol Endocrinol18 :2024 eC2034,2004
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS: A central role for JNK in obesity and insulin resistance. Nature420 :333 eC336,2002
Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE: Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science293 :1673 eC1677,2001
Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI: Prevention of fat-induced insulin resistance by salicylate. J Clin Invest108 :437 eC446,2001
Cai D, Yuan M, Lee J, Shoelson SE: Prevention of insulin resistance by NF-kB inhibition in fat or liver of transgenic FISR or LISR mice (Abstract). Diabetes53 (Suppl. 2) :A19 ,2004
Nakatani Y, Kaneto H, Kawamori D, Hatazaki M, Miyatsuka T, Matsuoka TA, Kajimoto Y, Matsuhisa M, Yamasaki Y, Hori M: Modulation of the JNK pathway in liver affects insulin resistance status. J Biol Chem279 :45803 eC45809,2004 [Epub 24 August 2004]
Jaeschke A, Czech MP, Davis RJ: An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue. Genes Dev18 :1976 eC1980,2004
Waeber G, Delplanque J, Bonny C, Mooser V, Steinmann M, Widmann C, Maillard A, Miklossy J, Dina C, Hani EH, Vionnet N, Nicod P, Boutin P, Froguel P: The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat Genet24 :291 eC295,2000
Yin MJ, Yamamoto Y, Gaynor RB: The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature396 :77 eC80,1998
Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J: Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem278 :24944 eC24950,2003
Shi X, Ding M, Dong Z, Chen F, Ye J, Wang S, Leonard SS, Castranova V, Vallyathan V: Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production. Mol Cell Biochem199 :93 eC102,1999
Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI: Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest109 :1321 eC1326,2002
Silver RB, Aldhahi W, Shoelson SE, Goldfine AB: FDA-approved dose of salsalate improves glucose and lipid metabolism in type 2 diabetes (Abstract). Diabetes 53 (Suppl. 2): A161,2004
Moller DE, Berger JP: Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. Int J Obes27 (Suppl. 3) :S17 eCS21,2003
Weitz-Schmidt G: Statins as anti-inflammatory agents. Trends Pharmacol Sci23 :482 eC486,2002
Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A: Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation103 :357 eC362,2001
Donath MY, Storling J, Maedler K, Mandrup-Poulsen T: Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med81 :455 eC470,2003
Rakatzi I, Mueller H, Ritzeler O, Tennagels N, Eckel J: Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1. Diabetologia47 :249 eC258,2004
Shimabukuro M, Wang MY, Zhou YT, Newgard CB, Unger RH: Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. Proc Natl Acad Sci U S A95 :9558 eC9561,1998
Carroll MF, Schade DS: Timing of antioxidant vitamin ingestion alters postprandial proatherogenic serum markers. Circulation108 :24 eC31,2003
Nappo F, Esposito K, Cioffi M, Giugliano G, Molinari AM, Paolisso G, Marfella R, Giugliano D: Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol39 :1145 eC1150,2002
Van Oostrom AJ, Sijmonsma TP, Verseyden C, Jansen EH, de Koning EJ, Rabelink TJ, Castro CM: Postprandial recruitment of neutrophils may contribute to endothelial dysfunction. J Lipid Res44 :576 eC583,2003
Das UN: Is obesity an inflammatory condition Nutrition17 :953 eC966,2001
Duncan BB, Schmidt MI, Chambless LE, Folsom AR, Carpenter M, Heiss G: Fibrinogen, other putative markers of inflammation, and weight gain in middle-aged adults: the ARIC study: Atherosclerosis Risk in Communities. Obes Res8 :279 eC286,2000
Engstrom G, Hedblad B, Stavenow L, Lind P, Janzon L, Lindgarde F: Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes52 :2097 eC2101,2003
Klein S, Fontana L, Young VL, Coggan AR, Kilo C, Patterson BW, Mohammed BS: Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med350 :2549 eC2557,2004
Meigs JB, Hu FB, Rifai N, Manson JE: Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA291 :1978 eC1986,2004
Pinkney JH, Stehouwer CD, Coppack SW, Yudkin JS: Endothelial dysfunction: cause of the insulin resistance syndrome. Diabetes46 (Suppl. 2) :S9 eCS13,1997
Fernandez-Real JM, Ricart W: Insulin resistance and inflammation in an evolutionary perspective: the contribution of cytokine genotype/phenotype to thriftiness. Diabetologia42 :1367 eC1374,1999(Pietro A. Tataranni, and )
ABSTRACT
There is growing support for the hypothesis that obesity is an inflammatory condition leading to chronic activation of the innate immune system, which ultimately causes progressive impairment of glucose tolerance. Experimental studies in animals and evidence from prospective and longitudinal studies in humans are consistent with an etiologic role of subclinical inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance. However, the exact chain of molecular events linking overnutrition, activation of the innate immune system, and impairment of insulin signaling in peripheral tissues remains incompletely understood. Notwithstanding this limitation, treating the underlying subclinical inflammation may constitute a novel approach to prevention and/or treatment of type 2 diabetes.
Through the story of evolution, animals and humans have developed redundant mechanisms that promote the accumulation of fat tissue during periods of "feast," thus enabling survival during periods of "famine" (1). However, what once was an asset has become a liability in the current "obesigenic" environment of readily available high-energy foods and little need for physical activity. As a consequence, obesity has reached epidemic proportions in both industrialized and developing countries around the world, which is a major public health problem because obesity is associated with significant comorbidities and increased mortality.
Clinicians have long observed that fatter people are more likely to develop type 2 diabetes, and overwhelming scientific evidence has proven this clinical impression to be accurate. The association of obesity with type 2 diabetes has been observed in comparisons of different populations and within populations. Prospective studies of pre-diabetic subjects have conclusively shown that obesity and its duration are major risk factors for type 2 diabetes. Despite the remarkable consistency of the association between the two diseases, obesity is neither sufficient nor necessary for the development of type 2 diabetes. For example, many U.S. whites are overweight or obese, but <10% of this population has type 2 diabetes.
How does obesity cause type 2 diabetes and why in only certain people Experimental weight gain results in hyperinsulinemia and insulin resistance in animals and humans. It is clear how type 2 diabetes develops in the absence of insulin secretion, but how does insulin resistance gradually result in the disease
The concepts of glucotoxicity, lipotoxicity, and cellular nutrient overload to explain the pathogenesis of type 2 diabetes in obese individuals have been advanced previously, but these theories have evidently failed to provide a universally accepted and pathophysiologically conclusive explanation that would link excessive adiposity to insulin resistance and insulin secretory dysfunction. Thus, new theories continue to emerge.
In this review, we will present the growing body of evidence indicating that obesity may be an inflammatory condition leading to chronic activation of the innate immune system, which ultimately causes progressive impairment of glucose tolerance and eventually type 2 diabetes.
ORIGIN OF THE HYPOTHESIS
The theory that inflammation may be involved in the pathogenesis of type 2 diabetes is not new. The first indication of this pathophysiological connection can be traced to Ebstein (2) who, >100 years ago, reported in the German scientific literature that high doses of salycilate improved glycosuria in diabetic patients. This idea was then forgotten until a group of epidemiologists in the mid-1990s discussed the possibility that diabetes and atherosclerosis, an inflammatory condition in its own right, have common antecedents (the "common soil hypothesis" [3]). But it was the 1998 publication "Is Type II Diabetes Mellitus a Disease of the Innate Immune System" by Pickup and Crook (4) that finally laid out a more specific pathophysiological hypothesis. Based on the observation that the dyslipidemia common to people with type 2 diabetes (high triglycerides and low HDL cholesterol) is also a feature of experimental and naturally occurring acute-phase reactions, Pickup and Crook proposed that in individuals with an innately hypersensitive acute-phase response, long-term lifestyle and environmental stressors, such as nutrition, produce disease (type 2 diabetes) instead of repair.
Pickup and Crook explained that the innate immune system, a rapid first-line defense system based on nonlymphoid tissue, is primarily responsible for the acute-phase response, a self-limiting process induced by a variety of stressors (infection, tissue injury, and malignancy) causing a number of cells (macrophages, adipocytes, and endothelial cells) to secrete cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor- [TNF-]), which act on the liver to synthesize acute-phase proteins (fibrinogen, C-reactive protein, serum amyloid A, and others). Due to its self-limiting nature, the acute-phase response is aimed at restoring the homeostasis disturbed by an acute stressor. However, in response to chronic stressors, the system may become allostatic, i.e., the sustained effort to acutely battle challenges may ultimately result in an overload of the system resources. Eventually when the allostatic load exceeds these resources, the system breaks down.
While brilliant, Pickup and Crook’s theory had a few shortcomings. It was based primarily on cross-sectional observations, and, although it predicted that the most likely chronic stressors are nutritional ones, it did not explain how this could result in increased secretion of cytokines by multiple cell types and gave no molecular explanation as to how these cytokines could inhibit insulin action in peripheral tissues and/or glucose-stimulated insulin secretion in the pancreas.
CHRONIC ACTIVATION OF THE IMMUNE SYSTEM AND TYPE 2 DIABETES: CAUSE OR CONSEQUENCE
A number of studies (5,6) have reported increased acute-phase proteins and other nonspecific markers of inflam-mation in type 2 diabetes. This is not particularly surprising, since inflammatory processes in affected tissues accompany some of the chronic complications of type 2 diabetes. However, studies in nondiabetic individuals have challenged this interpretation.
Healthy people who go on to develop diabetes, when compared with those who remain nondiabetic, are more obese (particularly centrally), insulin resistant, and have abnormal insulin secretory function (7). Interestingly, obesity and insulin resistance seem to be positively associated with elevated markers of inflammation in most studies, whereas no convincing evidence of a relationship between insulin secretory dysfunction and inflammation has been reported. Obesity was found to be associated with nonspecific measures of activation of the immune system, such us total -globulin concentration (8), body temperature (9), white blood cell count (10), and C-reactive protein (11). Associations between fibrinogen and clinical features of the metabolic syndrome (12), as well as associations between oral temperature or white blood cell count and insulin sensitivity (10,13,14), have also been reported. Because in most (15eC22) if not all (23,24) cases the association between inflammatory markers and insulin resistance was found to be independent of adiposity, it has been suggested that inflammation is a possible pathophysiological link between obesity and insulin resistance. How-ever, whether or not inflammation is a pre-diabetic abnormality cannot be determined from cross-sectional studies alone. Such conclusions are better drawn from prospective and longitudinal studies.
Many prospective studies (8,20,25eC36), in diverse human populations, have identified proinflammatory cytokines, acute-phase proteins, and several indirect markers of inflammation as predictors of type 2 diabetes. This predictive effect of inflammation on the risk of type 2 diabetes does not seem to depend on subclinical cardiovascular disease (25,30,32,35), undiagnosed diabetes at baseline (8,20,29eC31,33,36), or, surprisingly, initial degree of insulin resistance (20,25,27,29eC32,35,36). Although this association is substantially lessened by obesity, in most of the studies at least one of the inflammatory markers identifies people at risk of diabetes independent of their degree of adiposity or upper body fat distribution (Table 1). Very few longitudinal studies have investigated whether inflammation may cause diabetes by reducing insulin sensitivity and/or insulin secretory function. We addressed this issue in a study (20) of 81 Pima Indians with normal glucose tolerance at baseline, after adjustment for several covariates including concomitant changes in adiposity, and found that white blood cell count was associated with a decline in insulin sensitivity but not insulin secretory function.
Thus, while an inconsistent use of inflammatory markers to biochemically define chronic activation of the immune system makes it very difficult to summarize this body of literature, it seems that the evidence from prospective and longitudinal studies is consistent with an etiologic role of inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance (Fig. 1A). Pickup (37) reached a similar conclusion in a recently published reappraisal of the original 1998 theory.
OVERNUTRITION AND CHRONIC ACTIVATION OF THE INNATE IMMUNE SYSTEM: THE ROLE OF ADIPOKINES
The traditional view of adipose tissue as a passive energy storage depot was challenged when it was identified as a major site for the metabolism of steroid hormones (38), and it is no longer valid after the discovery that adipose tissue secretes a number of bioactive proteins. These proteins, known as adipokines, have local autocrine/paracrine effects as well as systemic hormonal effects and span a vast array of chemical structures and functional classes (Fig. 2), as recently reviewed by Kershaw and Flier (39).
Why is obesity associated with inflammation Pickup and Crook’s (4) prediction of nutritional factors as a chronic activator of the innate immune response makes sense if one extends the concept to include overnutrition and the resulting increase in adiposity. Thus, the simplest explanation for why obesity is associated with inflammation is that the hyperplastic/hypertrophic expansion of the adipocyte mass results in altered circulating levels of proinflammatory cytokines. Other hypotheses include elevated local production of TNF-, which is both a local adipostatic signal (inhibitor of lipoprotein lipase) and a trigger of the inflammatory response. Adipose tissue expansion, like tumors, is angiogenesis dependent (40). It has been suggested that adipocytes may become hypoxic during a rapid expansion of adipose tissue and start secreting inflammatory cytokines, which serve to increase blood flow, and some of them (such us leptin and vascular endothelial growth factor) may directly stimulate angiogenic factors (41). Adipose tissue from obese humans has been shown to have increased 11-hydroxysteroid dehydrogenase type 1 activity (42). In rodents, selective overexpression of 11-hydroxysteroid dehydrogenase type 1 in adipose tissue is accompanied by proinflammatory changes in the adipokine expression profile (leptin, resistin, adiponectin, and TNF-) (43). Finally, adipose tissue is now recognized as a complex organ containing adipocytes as well as connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. Lately, the presence of immune cells has received increased attention owing to significant functional and molecular overlap between adipocytes and macrophages, as in the recent discovery that adipocyte precursors can be transformed into macrophage-like cells in response to the appropriate stimuli (44) and that adipose tissue, but not liver or muscle, in obese people is characterized by macrophage infiltration (45,46). Increased levels of monocyte chemotactic protein-1 secreted by adipocyte or preadipocytes in response to TNF- could be one of the chemokines implicated in this recruitment of macrophages, which would perpetuate the inflammatory response.
Interestingly, adipose tissue secretes proteins that have both stimulatory and inhibitory effects on the inflammatory process. Among the proinflammatory adipokines, TNF- and IL-6 have been studied most extensively. The effects of TNF- on glucose metabolism may be mediated in an autocrine/paracrine manner by regulating secretion of other adipokines or by promoting lipolysis and raising serum free fatty acid (FFA) levels. TNF- is overexpressed in different models of murine (47) and in human obesity (48,49), whereas weight reduction decreases its expression and/or plasma concentration (48eC50). In humans, a single bolus intravenous injection of recombinant human TNF- increased plasma glucose concentrations and plasma FFAs (51); TNF- neutralization affects direct measures of whole-body insulin sensitivity in rats (47) but not in humans (52).
While TNF- in human plasma has been found at very low concentrations, adipose tissue accounts for 30% of the circulating IL-6, suggesting an endocrine role for this adipokine (53). In the liver, IL-6 is the primary stimulator for the production of most of the acute-phase proteins (54). IL-6 in vitro reduces insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, as well as IRS-1eCassociated phosphatidylinositol (PI) 3-kinase activity (55), and in mice, IL-6 treatment causes insulin resistance in skeletal muscle and in liver most likely due to defects in IRS-1 (and IRS-2, respectively)-associated PI 3-kinase activity (56). In humans, IL-6 is related to insulin resistance, independent of obesity (57,58). In the Atherosclerosis Risk in Communities study (26) and Nurses Health study (30), IL-6 at baseline was independently associated with future risk of diabetes (Table 1). Similar results were reported in the European Prospective Investigation into Cancer and NutritioneCPotsdam study (33), in which participants with elevated IL-6 and IL-1 had a threefold increase in risk for developing diabetes when compared with the reference group.
Other proinflammatory adipokines have been studied. Leptin, in vitro, has been found to have proinflammatory properties (59) and may promote monocyte diapedesis and the accumulation of macrophages in adipose tissue (60). However, because leptin improved insulin sensitivity in rodents (61) and in humans (62) with lipodystrophy, this makes it an unlikely contributor to the inflammatory response associated with obesity. Resistin was originally reported as an adipose tissueeCspecific hormone that provided a link between obesity and diabetes. Resistin is part of a new class of cysteine-rich secreted proteins that were found, by one of the groups who discovered it, to be induced during lung inflammation (found in inflammatory zone 1 [FIZZ1]). In vitro studies have shown that resistin mRNA expression is increased by proinflammatory cytokines in human mononuclear cells (63) and that resistin has a direct proinflammatory effect, probably mediated through nuclear factor-B (NF-kB) signaling pathway on vascular endothelial human cells (64). In rodents, resistin affects glucose tolerance and is related with whole-body and hepatic insulin resistance (65,66). Differences in resistin gene expression have been observed between human and mice tissues. While in mice adipocytes are the mayor source of circulating resistin, in humans secretion or expression is predominantly found in mononuclear cells, and the release of resistin by explants of adipose tissue in primary culture is largely derived from the nonfat cells present in the explants (67). Resistin is detectable in human serum, and its circulating levels were found to be elevated in proportion to the degree of adiposity (68,69). Although these data might suggest a contribution of resistin to inflammation and insulin resistance, the role of resistin in obesity has not been proven (68,69). Finally, other proinflammatory adipokines, such as complement C3 and macrophage inhibitor factor, were inversely and independently associated with insulin sensitivity (70,71).
Adiponectin is the anti-inflammatory adipokine that has been studied most extensively. It is produced exclusively by white adipocytes but is paradoxically lower in obese versus lean individuals (72). Adiponectin has been related to insulin resistance and diabetes not only because of its AMP-activated protein kinase effects on FFA metabolism and glucose uptake but also because of its anti-inflammatory properties. Inhibition of phagocyte activity and TNF- production by macrophages and inhibition of the TNF-eCinduced expression of adhesion molecules (through NF-B signaling pathways) are some of the known mechanisms by which adiponectin mediate its anti-inflammatory effects (73). Many studies have now suggested that in humans adiponectin is more closely related to insulin resistance than to obesity (73). Prospective and longitudinal studies (74eC78) have found a correlation between low adiponectin levels and a higher risk of diabetes, independent of many confounders including obesity and other inflammatory markers (75,79). Krakoff et al. (79) hypothesized that in studies in which substantial baseline differences in the degree of adiposity exist, the predictive value of inflammatory markers may be a result of their association with obesity, i.e., they may be acting as surrogate markers of hypoadiponectinemia and may be only indirectly associated with the development of diabetes (Fig. 1B) (Table 2).
Adipose tissue is also a source of other anti-inflammatory cytokines whose roles are mostly unknown. IL-10 is an anti-inflammatory cytokine produced by immune cells (T-helper, B-cells, and macrophages). In mice, IL-10 treatment prevented IL-6eCinduced defects in both hepatic and skeletal insulin action (56). Circulating IL-10 is elevated in human obesity (80); in adipose tissue, IL-10 is primarily produced by nonfat cells (81). In humans, lower serum concentrations of IL-10 were associated with the metabolic syndrome (80) and with diabetes (82).
CHRONIC ACTIVATION OF THE INNATE IMMUNE SYSTEM AND IMPAIRMENT OF INSULIN SIGNALING AND/OR INSULIN SECRETION: PUTATIVE MOLECULAR MECHANISMS
Since it was first proposed that chronic activation of the innate immune system could be a possible pathogenic factor in the development of obesity-associated type 2 diabetes, the challenge has been to identify the molecular link between these two entities. The innate immune response and the process of inflammation are inextricably interwoven. Signaling receptors of the immune system (such as the mammalian toll-like receptors) induce signal transduction pathways that lead to the activation of transcription factors (83) that are also activated in response to proinflammatory cytokines. At this point, the leading theory is that activation of some inflammatory pathways, by some of the adipokines previously discussed, ultimately results in suppression of the insulin signal transduction by serine/threonine (Ser/Thr) phosphorylation (inactivation) of the IRS. Two major inflammatory transcription factors, NF-B and activating protein (AP)-1, and their key enzymes IB kinase (IKK) and c-Jun NH2-terminal kinase (JNK), respectively, have been studied more extensively. However, obesity may cause activation of the innate immune/inflammatory system not only by its secreted adipokines. Hyper-lipidemia in mice seems to mediate an inflammatory response by the same signaling cascade (engaged by a receptor complex comprising mammalian toll-like receptor 4, CD14, and MD-2) through which lipopolysaccharide activates the innate immune system (84). FFAs, probably through protein kinase C, can activate IKK and JNK (85). Furthermore, oxidative stress (closely associated with obesity, hyperglycemia, and elevation of FFAs) not only leads to mitochondrial dysfunction but can also induce key redox-sensitive transcription factors (NF-B and AP-1) involved in the innate immune response.
Genetic disruption of these pathways improves insulin resistance (86,87). Heterozygous IKK+/eC mice, fed with a high-fat diet or crossed with obese ob/ob mice, showed a significant decrease in blood glucose levels and improved insulin resistance (87). Furthermore, lipid infusioneCinduced decreases in insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-1eCassociated PI 3-kinase activity in skeletal muscle were prevented in the IKK+/eC mice (88). Recently, this same laboratory has found that selective IKK activation (transgenic mice) in fat or liver but not muscle causes systemic insulin resistance. In agreement with these results, selective inhibition of NF-B (by expressing IB super-repressor) in fat (FISR) and liver, but not in muscle, showed protection against the development of insulin resistance in diet-induced and genetically obese mice, with the additional benefit of preventing weight gain in FISR mice (89)
Total JNK activity, predominantly JNK1, is increased in obese mice (86); JNK1 knockout mice gain less weight and are protected against diet-induced insulin resistance or insulin resistance associated with a genetic model of obesity (ob/ob) (86). It appears that in these mice, serine-307 phosphorylation of IRS-1 was reduced (86). Moreover, suppression of the JNK pathway in liver decreases whole-body insulin resistance and improves glucose tolerance in diabetic animal models (90). Furthermore, loss-of-function mutations in JNK-interacting protein 1, a negative and essential modulator of JNK (91), causes type 2 diabetes in humans (92).
Additional evidence of the involvement of these inflammatory pathways is supported by the protective effect of some anti-inflammatory drugs against obesity-induced insulin resistance. Aspirin may inhibit not only IKK and JNK (93,94) but other Ser/Thr kinases (mamalian target of rapamycin and protein kinase B/Akt) related to TNF- insulin resistance by phosphorylation of IRS-1 at serine residues (94). Furthermore, through its antioxidant properties, aspirin has been shown to reduce the activation of NF-B or AP-1 associated with reactive oxygen species (95). Yuan et al. (87) first hypothesized and then demonstrated that salicylate treatment improves the severe insulin resistance seen in genetically obese rodents. Furthermore, pretreatment in rats with salicylates prevented lipid-induced skeletal insulin resistance by inhibiting lipid-induced decreases in insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1eCassociated PI 3-kinase activation (88). In humans, treatment with high doses of aspirin (7 g/day) or salsalate (3 g/day) improved peripheral insulin sensitivity in subjects with type 2 diabetes (96,97). Although these results are intriguing, randomized controlled trials are needed to clarify the role of these drugs on glucose metabolism and insulin resistance.
Other drugs with documented anti-inflammatory effects, such as thiazolidinediones (TZDs) and statins, have shown antidiabetic effects. TZDs are potent insulin sensitizers, and TZD treatment has been associated with suppression of local TNF- production by adipocytes and reduction of TNF- action in adipose and other tissues (98). TZDs can also act by increasing plasma levels of adiponectin, and some studies have suggested that peroxisome proliferatoreCactivated receptor (like peroxisome proliferatoreCactivated receptor ) activation in selected cell types can repress NF-B and, therefore, cytokine-mediated signaling (98). Statins are potent cholesterol-lowering drugs. Statin treatment has been associated with modulation in the endothelial adhesion and transendothelial migration of leukocytes, inhibition of the release of cytokines, and chemokines and direct interference with the NF-B pathway (99). Interestingly, the use of statins has also been associated with a decrease in the risk of developing type 2 diabetes (100).
We have discussed how activation of protein kinases and transcription factors, such as AP-1 and NF-B, are possible mediators of insulin resistance in peripheral tissues. Because the same molecules are directly involved in -cell apoptosis (101), it is possible that an adipokine-induced activation of the immune system associated with overnutrition and obesity may also explain the -cell failure that precedes the development of type 2 diabetes. Here, data from the literature do not paint a very clear picture. For example, adiponectin has been shown in vitro to have protective effects against both cytokine- and FFA-induced impairment of the -cell (102), an effect that would be lost in obese individuals with hypoadiponectinemia. Leptin, which is very high in obese individuals, has been shown in vitro to have both stimulatory and inhibitory effects on -cell apoptosis (103). More important, thus far there are no reports in the literature from in vivo animal or human studies of an independent association between (markers of) inflammation and -cell dysfunction.
IS EXCESSIVE FATNESS AN OBLIGATORY PATHOPHYSIOLOGICAL FACTOR
While we have developed this review around the pathophysiological construct that overnutrition leads to obesity which in turn is associated with a chronic activation of the immune system, we would like to acknowledge experimental and circumstantial evidence that challenges this course of events.
The postprandial period following a single meal is associated with an increase in plasma levels of proinflammatory cytokines, recruitment of neutrophils, and oxidative stress (104eC106). The quality, intensity, and duration of this inflammatory response may not only respond to frequency or meal size. The effect of nutrition or food-borne components on gene transcription, proteomics, and metabolism (nutrigenomic) may further increase this inflammatory state. Because modern eating patterns, especially in western societies, produce an almost endless postprandial state throughout the day, a chronic activation of the innate immune system could exist even before obesity develops. Thus, a proinflammatory state could be a pathogenic factor in the development of obesity, as proposed by Das (107) and others. Consistent with this hypothesis, two prospective studies (108,109) reported that elevated levels of inflammatory markers predicted weight gain in two different populations. Finally, a recent study (110) showed that removal of significant amounts of subcutaneous fat tissue had no effect on inflammation markers or insulin sensitivity.
Thus, contrary to evidence presented earlier in the manuscript, it is possible that it is not the mass of the adipose tissue per se but the underlying changes in energy flux that determine its size that is responsible for the modulation of the innate immune response. However, the adipose tissue is not a homogeneous tissue, and characteristics between depots and even between cells in different parts of the same depot differ within and between individuals. Of particular interest to this discussion is the idea that perivascular fat tissue may be especially detrimental in obese people. Increased perivascular fat may not only contribute to the systemic low-grade inflammation associated with obesity but may also interact in an autocrine/paracrine manner, with the closely related endothelial cells and perivascular smooth muscle fibers contributing to the endothelial dysfunction that has often been observed in association with markers of inflammation. Whereas impaired endothelial dysfunction in large arterial beds may have an influence on the pathogenesis of cardiovascular disease, endothelial dysfunction in arteriole and capillaries, in intimate contact with a vast surface of metabolically active and insulin-sensitive tissues, may lead to type 2 diabetes (111,112). This is obviously an area that will require further research.
CONCLUSIONS
Does an adipokine-induced activation of the immune system mediate the effect of overnutrition on type 2 diabetes We interpret the literature reviewed in this manuscript as indicating that a reasonable case can be made for overnutrition causing an activation of the innate immune system, most likely by excessive production of adipokines. There is increasing evidence that the proinflammatory state, which characterizes overnourished individuals, may be etiologically linked with the insulin resistance that is often observed in their peripheral tissues. Surprisingly, we could not find convincing evidence for an association between inflammation and insulin secretory dysfunction.
Thus, we propose that inflammation should be viewed as a risk factor for insulin resistance not a global risk factor for type 2 diabetes. In our opinion, the question of how -cells fail in the presence of inflammation-induced insulin resistance remains largely unanswered. Moreover, this may help explain why diabetes does not develop in all subjects with chronic inflammatory diseases.
Notwithstanding these considerations, we believe that elucidation of the link between inflammation and insulin resistance remains a very worthwhile research endeavor. We and others have provided evidence suggesting that interindividual variability of many of these inflammatory markers may be genetically determined. It has been hypothesized that an insulin-resistant genotype, associated with a heightened cytokine response, may have been advantageous in the historical conditions of a short life span, injury, and infectious disease (113). A further selection for these traits may have taken place in American Indians and other native populations after first contact with explorers from other parts of the world, which exposed them to a range of novel infectious diseases to which they had no immunity, leading to repeated epidemics and declines in population. It will be interesting to see if this theory is confirmed when the results of ongoing positional cloning efforts to find the genes that cause diabetes in several populations around the world become available.
In more practical terms, more fully understanding the link between inflammation and insulin resistance holds the promise of revealing novel ways to prevent and/or treat type 2 diabetes. If it can be demonstrated that reducing the underlying activity of the immune system in nondiabetic subjects with high markers of inflammation can improve their degree of insulin sensitivity, then perhaps a case can be made for anti-inflammatory therapy as a way to prevent and/or delay the onset of type 2 diabetes. Early clinical trials are showing promising results when anti-inflammatory drugs are given to diabetic subjects. This indicates that as the chain of molecular events linking inflammation to impairment of insulin signaling will continue to be clarified, novel targets will become available for drug development. Thus, we see many reasons to be optimistic and expect that the question of the link between inflammation, insulin resistance, and type 2 diabetes may no longer be a burning one in the not so distant future.
ACKNOWLEDGMENTS
We are grateful to Dr. Rich Pratley, Dr. Norbert Stefan, Dr. Christian Weyer, and Dr. Barbora Vozarova for their invaluable contributions to the study of inflammation and type 2 diabetes in the Pima Indians of Arizona. We thank Dr. Michael Stumvoll, Dr. Clifton Bogardus, Dr. Arline Salbe, and Inge Harper for critical reading of the manuscript. We also acknowledge the members and leaders of the Gila River Indian Community for their continuing cooperation in our studies.
FOOTNOTES
P.A.T. is currently affiliated with Sanofi Aventis, Paris, France.
AP, activating protein; FFA, free fatty acid; IKK, IB kinase; IL, interleukin; IRS, insulin receptor substrate; JNK, Jun NH2-terminal kinase; NF-B, nuclear factor-B; PI, phosphatidylinositol; TNF-, tumor necrosis factor-; TZD, thiazolidinedione
REFERENCES
Neel JV: Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress" Am J Hum Genet14 :353 eC362,1962
Ebstein W: Zur therapie des diabetes mellitus, insbesondere eer die Anwendung des salicylsauren natron bei demselben. Berlin KlinWochenschrift13 :337 eC340,1876
Stern MP: Diabetes and cardiovascular disease: the "common soil" hypothesis. Diabetes44 :369 eC374,1995
Pickup JC, Crook MA: Is type II diabetes mellitus a disease of the innate immune system Diabetologia41 :1241 eC1248,1998
Leinonen E, Hurt-Camejo E, Wiklund O, Hulten LM, Hiukka A, Taskinen MR: Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis166 :387 eC394,2003
Pickup JC, Mattock MB, Chusney GD, Burt D: NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia40 :1286 eC1292,1997
Weyer C, Bogardus C, Mott DM, Pratley RE: The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest104 :787 eC794,1999
Lindsay RS, Krakoff J, Hanson RL, Bennett PH, Knowler WC: Gamma globulin levels predict type 2 diabetes in the Pima Indian population. Diabetes50 :1598 eC1603,2001
Eriksson H, Svardsudd K, Larsson B, Welin L, Ohlson LO, Wilhelmsen L: Body temperature in general population samples: the study of men born in 1913 and 1923. Acta Med Scand.217 :347 eC352,1985
Pratley RE, Wilson C, Bogardus C: Relation of the white blood cell count to obesity and insulin resistance: effect of race and gender. Obes Res3 :563 eC571,1995
Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB: Elevated C-reactive protein levels in overweight and obese adults. JAMA282 :2131 eC2135,1999
Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, Muggeo M: Metabolic syndrome: epidemiology and more extensive phenotypic description: cross-sectional data from the Bruneck Study. Int J Obes Relat Metab Disord27 :1283 eC1289,2003
Facchini F, Hollenbeck CB, Chen YN, Chen YD, Reaven GM: Demonstration of a relationship between white blood cell count, insulin resistance, and several risk factors for coronary heart disease in women. J Intern Med232 :267 eC272,1992
Vozarova B, Weyer C, Bogardus C, Ravussin E, Tataranni PA: Differences in oral temperature and body shape in two populations with different propensities for obesity. Ann N Y Acad Sci967 :516 eC521,2002
Festa A, D’Agostino R Jr, Howard G, Mykkanen L, Tracy RP, Haffner SM: Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation102 :42 eC47,2000
Fritsche A, Haring H, Stumvoll M: [White blood cell count as a predictor of glucose tolerance and insulin sensitivity: the role of inflammation in the pathogenesis of type 2 diabetes mellitus]. Dtsch Med Wochenschr129 :244 eC248,2004
Hak AE, Pols HA, Stehouwer CD, Meijer J, Kiliaan AJ, Hofman A, Breteler MM, Witteman JC: Markers of inflammation and cellular adhesion molecules in relation to insulin resistance in nondiabetic elderly: the Rotterdam study. J Clin Endocrinol Metab86 :4398 eC4405,2001
Pradhan AD, Cook NR, Buring JE, Manson JE, Ridker PM: C-reactive protein is independently associated with fasting insulin in nondiabetic women. Arterioscler Thromb Vasc Biol23 :650 eC655,2003
Raynaud E, Perez-Martin A, Brun J, Aissa-Benhaddad A, Fedou C, Mercier J: Relationships between fibrinogen and insulin resistance. Atherosclerosis150 :365 eC370,2000
Vozarova B, Weyer C, Lindsay RS, Pratley RE, Bogardus C, Tataranni PA: High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes51 :455 eC461,2002
Weyer C, Yudkin JS, Stehouwer CD, Schalkwijk CG, Pratley RE, Tataranni PA: Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians. Atherosclerosis161 :233 eC242,2002
Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW: C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue Arterioscler Thromb Vasc Biol19 :972 eC978,1999
Hak AE, Stehouwer CD, Bots ML, Polderman KH, Schalkwijk CG, Westendorp IC, Hofman A, Witteman JC: Associations of C-reactive protein with measures of obesity, insulin resistance, and subclinical atherosclerosis in healthy, middle-aged women. Arterioscler Thromb Vasc Biol19 :1986 eC1991,1999
Temelkova-Kurktschiev T, Siegert G, Bergmann S, Henkel E, Koehler C, Jaross W, Hanefeld M: Subclinical inflammation is strongly related to insulin resistance but not to impaired insulin secretion in a high risk population for diabetes. Metabolism51 :743 eC749,2002
Barzilay JI, Abraham L, Heckbert SR, Cushman M, Kuller LH, Resnick HE, Tracy RP: The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes50 :2384 eC2389,2001
Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, Hoogeveen R, Folsom AR, Heiss G: Low-grade systemic inflammation and the development of type 2 diabetes: the Atherosclerosis Risk in Communities Study. Diabetes52 :1799 eC1805,2003
Festa A, D’Agostino R Jr, Tracy RP, Haffner SM: Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes51 :1131 eC1137,2002
Freeman DJ, Norrie J, Caslake MJ, Gaw A, Ford I, Lowe GD, O’Reilly DS, Packard CJ, Sattar N: C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes51 :1596 eC1600,2002
Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME, Haffner SM: Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care25 :2016 eC2021,2002
Hu FB, Meigs JB, Li TY, Rifai N, Manson JE: Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes53 :693 eC700,2004
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM: C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA286 :327 eC334,2001
Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G: Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities Study): a cohort study. Lancet353 :1649 eC1652,1999
Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF: Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes52 :812 eC817,2003
Thorand B, Lowel H, Schneider A, Kolb H, Meisinger C, Frohlich M, Koenig W: C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984eC1998. Arch Intern Med163 :93 eC99,2003
Laaksonen DE, Niskanen L, Nyyssonen K, Punnonen K, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT: C-reactive protein and the development of the metabolic syndrome and diabetes in middle-aged men. Diabetologia47 :1403 eC1410,2004
Nakanishi S, Yamane K, Kamei N, Okubo M, Kohno N: Elevated C-reactive protein is a risk factor for the development of type 2 diabetes in Japanese Americans. Diabetes Care26 :2754 eC2757,2003
Pickup JC: Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care27 :813 eC823,2004
Siiteri PK: Adipose tissue as a source of hormones. Am J Clin Nutr45 :277 eC282,1987
Kershaw EE, Flier JS: Adipose tissue as an endocrine organ. J Clin Endocrinol Metab89 :2548 eC2556,2004
Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ: Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A99 :10730 eC10735,2002
Trayhurn P, Wood IS: Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr92 :347 eC355,2004
Lindsay RS, Wake DJ, Nair S, Bunt J, Livingstone DE, Permana PA, Tataranni PA, Walker BR: Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. J Clin Endocrinol Metab88 :2738 eC2744,2003
Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS: A transgenic model of visceral obesity and the metabolic syndrome. Science294 :2166 eC2170,2001
Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, Penicaud L, Casteilla L: Preadipocyte conversion to macrophage: evidence of plasticity. J Biol Chem278 :9850 eC9855,2003
Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest112 :1821 eC1830,2003
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest112 :1796 eC1808,2003
Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science259 :87 eC91,1993
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM: Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest95 :2409 eC2415,1995
Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB: The expression of tumor necrosis factor in human adipose tissue: regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest95 :2111 eC2119,1995
Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T: Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab83 :2907 eC2910,1998
Van der PT, Romijn JA, Endert E, Borm JJ, Buller HR, Sauerwein HP: Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. Am J Physiol261 :E457 eCE465,1991
Di Rocco P, Manco M, Rosa G, Greco AV, Mingrone G: Lowered tumor necrosis factor receptors, but not increased insulin sensitivity, with infliximab. Obes Res12 :734 eC739,2004
Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW: Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab82 :4196 eC4200,1997
Gabay C, Kushner I: Acute-phase proteins and other systemic responses to inflammation. N Engl J Med340 :448 eC454,1999
Senn JJ, Klover PJ, Nowak IA, Mooney RA: Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes51 :3391 eC3399,2002
Kim HJ, Higashimori T, Park SY, Choi H, Dong J, Kim YJ, Noh HL, Cho YR, Cline G, Kim YB, Kim JK: Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes53 :1060 eC1067,2004
Fernandez-Real JM, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J, Ricart W: Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab86 :1154 eC1159,2001
Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE: Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res9 :414 eC417,2001
Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM: Leptin regulates proinflammatory immune responses. FASEB J12 :57 eC65,1998
Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R, Bouloumie A: From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes53 :1285 eC1292,2004
Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F: Effects of the obese gene product on body weight regulation in ob/ob mice. Science269 :540 eC543,1995
Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI: Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest109 :1345 eC1350,2002
Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR: Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun309 :286 eC290,2003
Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, Manabe I, Utsunomiya K, Nagai R: Direct reciprocal effects of resistin and adiponectin on vascular endothelial cells: a new insight into adipocytokine-endothelial cell interactions. Biochem Biophys Res Commun314 :415 eC419,2004
Rajala MW, Obici S, Scherer PE, Rossetti L: Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest111 :225 eC230,2003
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature409 :307 eC312,2001
Fain JN, Cheema PS, Bahouth SW, Lloyd HM: Resistin release by human adipose tissue explants in primary culture. Biochem Biophys Res Commun300 :674 eC678,2003
Volarova de Court B, Degawa-Yamauchi M, Considine RV, Tataranni PA: High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians. Diabetes53 :1279 eC1284,2004
Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV: Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab88 :5452 eC5455,2003
Vozarova B, Stephan N, Hanson R, Lindsay RS, Bogardus C, Tataranni PA, Metz C, Bucala R: Plasma concentrations of macrophage migration inhibitory factor are elevated in Pima Indians compared to Caucasians and are associated with insulin resistance. Diabetologia45 :1739 eC1741,2002
Weyer C, Tataranni PA, Pratley RE: Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration. Diabetes Care23 :779 eC785,2000
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA: Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab86 :1930 eC1935,2001
Pittas AG, Joseph NA, Greenberg AS: Adipocytokines and insulin resistance. J Clin Endocrinol Metab89 :447 eC452,2004
Daimon M, Oizumi T, Saitoh T, Kameda W, Hirata A, Yamaguchi H, Ohnuma H, Igarashi M, Tominaga M, Kato T: Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population: the Funagata study. Diabetes Care26 :2015 eC2020,2003
Duncan BB, Schmidt MI, Pankow JS, Bang H, Couper D, Ballantyne CM, Hoogeveen RC, Heiss G: Adiponectin and the development of type 2 diabetes: the Atherosclerosis Risk in Communities Study. Diabetes53 :2473 eC2478,2004
Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, Knowler WC, Krakoff J: Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet360 :57 eC58,2002
Snehalatha C, Mukesh B, Simon M, Viswanathan V, Haffner SM, Ramachandran A: Plasma adiponectin is an independent predictor of type 2 diabetes in Asian indians. Diabetes Care26 :3226 eC3229,2003
Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF: Adiponectin and protection against type 2 diabetes mellitus. Lancet361 :226 eC228,2003
Krakoff J, Funahashi T, Stehouwer CD, Schalkwijk CG, Tanaka S, Matsuzawa Y, Kobes S, Tataranni PA, Hanson RL, Knowler WC, Lindsay RS: Inflammatory markers, adiponectin, and risk of type 2 diabetes in the Pima Indian. Diabetes Care26 :1745 eC1751,2003
Esposito K, Pontillo A, Giugliano F, Giugliano G, Marfella R, Nicoletti G, Giugliano D: Association of low interleukin-10 levels with the metabolic syndrome in obese women. J Clin Endocrinol Metab88 :1055 eC1058,2003
Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW: Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology145 :2273 eC2282,2004
van Exel E, Gussekloo J, de Craen AJ, Frolich M, Bootsma-Van Der Wiel A, Westendorp RG: Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-Plus Study. Diabetes51 :1088 eC1092,2002
Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol20 :197 eC216,2002
Bjorkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, Halmen K, Luster AD, Golenbock DT, Freeman MW: Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med10 :416 eC421,2004
Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J: Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3eCL1 adipocytes. Mol Endocrinol18 :2024 eC2034,2004
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS: A central role for JNK in obesity and insulin resistance. Nature420 :333 eC336,2002
Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE: Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science293 :1673 eC1677,2001
Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI: Prevention of fat-induced insulin resistance by salicylate. J Clin Invest108 :437 eC446,2001
Cai D, Yuan M, Lee J, Shoelson SE: Prevention of insulin resistance by NF-kB inhibition in fat or liver of transgenic FISR or LISR mice (Abstract). Diabetes53 (Suppl. 2) :A19 ,2004
Nakatani Y, Kaneto H, Kawamori D, Hatazaki M, Miyatsuka T, Matsuoka TA, Kajimoto Y, Matsuhisa M, Yamasaki Y, Hori M: Modulation of the JNK pathway in liver affects insulin resistance status. J Biol Chem279 :45803 eC45809,2004 [Epub 24 August 2004]
Jaeschke A, Czech MP, Davis RJ: An essential role of the JIP1 scaffold protein for JNK activation in adipose tissue. Genes Dev18 :1976 eC1980,2004
Waeber G, Delplanque J, Bonny C, Mooser V, Steinmann M, Widmann C, Maillard A, Miklossy J, Dina C, Hani EH, Vionnet N, Nicod P, Boutin P, Froguel P: The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat Genet24 :291 eC295,2000
Yin MJ, Yamamoto Y, Gaynor RB: The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature396 :77 eC80,1998
Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J: Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem278 :24944 eC24950,2003
Shi X, Ding M, Dong Z, Chen F, Ye J, Wang S, Leonard SS, Castranova V, Vallyathan V: Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production. Mol Cell Biochem199 :93 eC102,1999
Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S, Shoelson SE, Shulman GI: Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest109 :1321 eC1326,2002
Silver RB, Aldhahi W, Shoelson SE, Goldfine AB: FDA-approved dose of salsalate improves glucose and lipid metabolism in type 2 diabetes (Abstract). Diabetes 53 (Suppl. 2): A161,2004
Moller DE, Berger JP: Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. Int J Obes27 (Suppl. 3) :S17 eCS21,2003
Weitz-Schmidt G: Statins as anti-inflammatory agents. Trends Pharmacol Sci23 :482 eC486,2002
Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A: Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation103 :357 eC362,2001
Donath MY, Storling J, Maedler K, Mandrup-Poulsen T: Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med81 :455 eC470,2003
Rakatzi I, Mueller H, Ritzeler O, Tennagels N, Eckel J: Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1. Diabetologia47 :249 eC258,2004
Shimabukuro M, Wang MY, Zhou YT, Newgard CB, Unger RH: Protection against lipoapoptosis of beta cells through leptin-dependent maintenance of Bcl-2 expression. Proc Natl Acad Sci U S A95 :9558 eC9561,1998
Carroll MF, Schade DS: Timing of antioxidant vitamin ingestion alters postprandial proatherogenic serum markers. Circulation108 :24 eC31,2003
Nappo F, Esposito K, Cioffi M, Giugliano G, Molinari AM, Paolisso G, Marfella R, Giugliano D: Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol39 :1145 eC1150,2002
Van Oostrom AJ, Sijmonsma TP, Verseyden C, Jansen EH, de Koning EJ, Rabelink TJ, Castro CM: Postprandial recruitment of neutrophils may contribute to endothelial dysfunction. J Lipid Res44 :576 eC583,2003
Das UN: Is obesity an inflammatory condition Nutrition17 :953 eC966,2001
Duncan BB, Schmidt MI, Chambless LE, Folsom AR, Carpenter M, Heiss G: Fibrinogen, other putative markers of inflammation, and weight gain in middle-aged adults: the ARIC study: Atherosclerosis Risk in Communities. Obes Res8 :279 eC286,2000
Engstrom G, Hedblad B, Stavenow L, Lind P, Janzon L, Lindgarde F: Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes52 :2097 eC2101,2003
Klein S, Fontana L, Young VL, Coggan AR, Kilo C, Patterson BW, Mohammed BS: Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med350 :2549 eC2557,2004
Meigs JB, Hu FB, Rifai N, Manson JE: Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA291 :1978 eC1986,2004
Pinkney JH, Stehouwer CD, Coppack SW, Yudkin JS: Endothelial dysfunction: cause of the insulin resistance syndrome. Diabetes46 (Suppl. 2) :S9 eCS13,1997
Fernandez-Real JM, Ricart W: Insulin resistance and inflammation in an evolutionary perspective: the contribution of cytokine genotype/phenotype to thriftiness. Diabetologia42 :1367 eC1374,1999(Pietro A. Tataranni, and )