Diabetologia

, Volume 48, Issue 6, pp 1038–1050 | Cite as

An immune origin of type 2 diabetes?

Review

Abstract

Subclinical, low-grade systemic inflammation has been observed in patients with type 2 diabetes and in those at increased risk of the disease. This may be more than an epiphenomenon. Alleles of genes encoding immune/inflammatory mediators are associated with the disease, and the two major environmental factors the contribute to the risk of type 2 diabetes—diet and physical activity—have a direct impact on levels of systemic immune mediators. In animal models, targeting of immune genes enhanced or suppressed the development of obesity or diabetes. Obesity is associated with the infiltration and proinflammatory activity of macrophages in adipose tissue, and immune mediators may be important regulators of insulin resistance, mitochondrial function, ectopic lipid storage and beta cell dysfunction or death. Intervention studies targeting these pathways would help to determine the contribution of an activated innate immune system to the development of type 2 diabetes.

Keywords

Adipocytes Beta cells IL-6 Innate immunity Insulin resistance Macrophages Metabolic syndrome Mitochondria Type 2 diabetes Subclinical inflammation 

Abbreviations

CRP

C-reactive protein

FasL

Fas ligand

FLIP

Fas-associated death domain protein-like IL-1β converting enzyme-inhibitory protein

ICAM

intercellular adhesion molecule

MCP-1

monocyte chemotactic protein-1

NF-κB

nuclear factor-κB

PAI-1

plasminogen activator inhibitor-1

RANTES

regulated upon activation normal T cell expressed and secreted

SOCS

suppressor of cytokine signalling

Introduction

Type 2 diabetes is caused by the failure of beta cells to compensate for insulin resistance. Inflammatory or immunological factors are implicated in both insulin resistance and beta cell failure, and this review will consider evidence suggesting that these might be linked by a common mechanism.

Association of subclinical inflammation with type 2 diabetes

Subclinical systemic inflammation [1, 2, 3, 4, 5, 6] and abnormalities of virtually all systemic indicators of inflammation have been reported in type 2 diabetes. These include increases in acute-phase proteins, cytokines and mediators associated with endothelial activation (Table 1), although it is important to note that the degree of immune activation is far below that seen in acute infections. For example, median plasma C-reactive protein (CRP) levels were only twice as high in patients with diabetes as compared with matched control subjects in a population-based German cohort, and serum levels of IL-6 largely overlapped (Fig. 1). We recently extended this study to include chemokines (C. Herder et al., unpublished results). Interestingly, we observed the selective upregulation of certain chemokines rather than a uniform upregulation of all inflammatory mediators. Systemic concentrations of RANTES (regulated upon activation normal T cell expressed and secreted) and IL-8 were elevated, whereas levels of monocyte chemotactic protein-1 (MCP-1) and eotaxin were not.
Table 1

Markers of subclinical inflammation in type 2 diabetes or the metabolic syndrome

Acute-phase proteins

 α-1 Acid glycoprotein

Haptoglobin

 CRP

Fibrinogen

 Serum amyloid A protein

Orosomucoid

Systemic cytokines/chemokines

 IL-6

Soluble IL-6 receptor

 TNF-α

Soluble TNF-α receptors 1 and 2

 IL-10

MIF

 IL-1+IL-6

MCP-1

 IL-18

RANTES

Blood/endothelial cell activation

 Soluble ICAM-1

Soluble VCAM-1

 Soluble E-selectin

Soluble P-selectin

 von Willebrand factor

Soluble CD40 ligand

 TAFI

PAI-1

 t-PA

Leucocyte count

All parameters exhibit increased levels in blood of patients with type 2 diabetes and/or in individuals with metabolic syndrome, except for systemic levels of IL-10 which are reported to be decreased [102, 105, 106, 183, 184, 185, 186, 187, 188]

MIF Macrophage migration inhibitory factor, TAFI thrombin-activatable fibrinolysis inhibitor, t-PA tissue plasminogen activator, VCAM-1 vascular cell adhesion molecule-1

Fig. 1

Elevated systemic levels of CRP (a) and IL-6 (b) in type 2 diabetes. Comparison of patients with type 2 diabetes (n=152) with non-diabetic control subjects matched for age and sex (n=77) from a population-based sample. Modified after Müller et al. [218] Box and whisker plots show the 10th, 25th, 50th (median), 75th and 90th percentiles

The possibility that these inflammatory changes might be a consequence of type 2 diabetes rather than a contributor to its development can be rejected on two grounds. First, similar degrees of subclinical inflammation are seen in subjects with IGT and those with overt type 2 diabetes (Table 1). Second, prospective studies (Table 2) have reported subtle proinflammatory changes, including raised leucocyte counts and modest increases in circulating inflammatory mediators, many years before the diagnosis of type 2 diabetes [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22] and at a stage when few would be expected to have IGT or impaired fasting blood glucose levels. Very high levels of CRP did not further increase diabetes risk [17].
Table 2

Prospective studies of incident type 2 diabetes

Study

Age at entry (years)

Number of subjects

Follow-up for diabetes

Incident diabetes (n)

Immunological risk factor

Atherosclerosis Risk in Communities Study (ARIC) [7, 8]

45–64

12,330

7 years

1,335

Factor VIII ↑

von Willenbrand factor ↑

Leucocyte count ↑

Orosomucoid ↑

Fibrinogen ↑

Sialic acid ↑

Serum albumin ↓

Women’s Health Study (WHS) [9]

≥45

27,628

4 years

188

CRP ↑

IL-6 ↑

Cardiovascular Health Study (CHS) [10]

≥65

5,888

3–4 years

45

CRP ↑

Pima Indian Population [11]

≥5

2,088

15 years

695

γ-globulin ↑

Pima Indian Population [12]

18–50

272

5.5 years

54

Leucocyte count ↑

West of Scotland Coronary Prevention Study (WOSCOPS) [13, 189]

45–64

5,974

4.9 years

127

CRP ↑

National Health and Nutrition Survey Epidemiological follow-up Study (NHANES I) [14]

25–74

8,352

20 years

878

Leucocyte count ↑

Japanese male office worker study [15]

35–59

2,953

6 years

154 (263 IFG)

Leucocyte count ↑

Insulin Resistance Atherosclerosis Study (IRAS) [16]

40–69

1,047

5 years

144

PAI-1 ↑

Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg cohort Study [17]

45–74

2,052

7.2 years

101

CRP ↑

EPIC-Potsdam study [18]

35–65

27,548

2.3 years

188

IL-6 ↑, IL-6+IL-1 ↑

Mexico City Diabetes Study [19]

35–64

1,244

6 years

190 (metabolic syndrome)

CRP ↑ in women only

Hong Kong Cardiovascular Risk Factors Prevalence Study [20]

25–74

228 IGT 228 NGT

2 years

21

CRP ↑

Hoorn study [22]

 

279

6.4 years

54

CRP ↑ in men only

Nurses’ Health Study [21]

30–55

32,826

10 years

737

TNF-α Rec 2 ↑

IL-6 ↑

CRP ↑

Genetic studies support a pathogenic role for immune mediators

Although low-grade inflammatory changes precede type 2 diabetes by many years, immune activation might nonetheless simply reflect an underlying, but unrelated disease process. One way of assessing whether immune reactivity plays a causal or contributory role in the pathogenesis of type 2 diabetes is to search for an association between diabetes risk and immune genes. The number of immune genes identified as containing one or more alleles associated with type 2 diabetes is steadily increasing. However, most studies are small and are not population-based, and the reported associations have yet to be confirmed in different populations. Nonetheless, it is worth noting that alleles in HLA loci and in the genes encoding TNF-α, TNF-β, TNF-α receptor 80, IL-6, IL-6 receptor-α, CRP, TGF-β and plasminogen activator inhibitor-1 (PAI-1) have been reported to be associated with type 2 diabetes and/or the metabolic syndrome [23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36]. Most of these alleles are functional in that they modify the inflammatory response, and the concept of an inflammatory contribution to the pathogenesis of type 2 diabetes would indeed require functional alleles such as these to be associated with diabetes risk.

Lessons from animal models

Another way of investigating the relationship between inflammatory immune reactivity and type 2 diabetes is to study immune gene defects in animals to determine whether these cause or prevent the development of diabetes. While such studies do not allow firm conclusions to be drawn concerning the pathogenesis of human diabetes, they can provide the necessary proof of principle. Several of the immune genes associated with diabetes have been studied in animal models and, as shown in Table 3, immune gene disruption or transgenic overexpression in mice had a major effect on the risk of developing insulin resistance or diabetes in response to a high-caloric diet [37, 38, 39, 40, 41, 42, 43]. A straightforward explanation is that, in these animal models, TNF-α, IL-6, intercellular adhesion molecule-1 (ICAM-1) or PAI-1 are either directly or indirectly involved in the development of severe obesity and diabetes. However, one important caveat is that, as previously observed [44], the phenotype caused by a gene defect strongly depends on the overall genetic background, i.e. a defective PAI-1 or ICAM-1 gene may not exhibit diabetes- or obesity-regulating properties if introduced onto another genetic background (S. Martin and H. Kolb, unpublished results). It should, however, be acknowledged that immune genes do affect diabetes risk.
Table 3

Animal models that prove the link between inflammatory/immune genes and type 2 diabetes

Inflammatory/immune defects that cause insulin resistance or type 2 diabetes in mice on a high-caloric diet

 ICAM-1 gene disruption [38]

 CD11b gene disruption [38]

 IL-6 gene disruption [39]

Inflammatory/immune defects that prevent insulin resistance or type 2 diabetes in mice on a high-caloric diet

 TNF-α/TNF-α receptors 1 and 2 gene disruption [37]

 PAI-1 gene disruption [40, 41]

 PAI-1 gene overexpression [42]

 Inducible nitric oxide synthase gene disruption [43]

Immune mechanisms in diabetes pathogenesis: insulin resistance

No randomised controlled trial has provided formal proof that high-caloric diets and insufficient muscle work are the major environmental factors promoting the pathogenesis of obesity and type 2 diabetes, and it is unlikely that any such trial will ever be undertaken. The indirect evidence is, however, overwhelming, and we will assume that this concept is valid.

Environmental factors seem to act via two major targets. One is the processing of glucose, fatty acids and other metabolites, as regulated by insulin and other hormones in the majority of tissues, and the other is beta cell function. The resulting insulin resistance and impaired insulin secretion precede the onset of hyperglycaemia by many years, if not decades [45, 46]. The hypothesis of an immune origin of type 2 diabetes is based on the concept that immune inflammatory mediators are responsible for the effects of these environmental factors on insulin resistance and beta cell function. As depicted in Fig. 2, the metabolic concept of the pathogenesis of diabetes considers that tissue function is directly affected by the toxic effect of excess glucose, NEFA and triglycerides, probably mediated by increased oxidative stress. The immunological concept assumes that the production of proinflammatory immune mediators is an essential step in glucotoxicity and lipotoxicity. Conversely, anti-inflammatory immune mediators such as IL-10 would be expected to counteract glucotoxicity and lipotoxicity.
Fig. 2

Metabolic vs immunologic concepts of the pathogenesis of type 2 diabetes. The two major pathogenic factors causing type 2 diabetes appear to be insulin resistance of major peripheral tissues and impairment and gradual loss of beta cell function, both of which are closely associated with vascular damage. The metabolic concept assumes a direct detrimental effect of high levels of glucose and NEFA or triglycerides on target cells limited by the functional capacity of mitochondria. The immunological concept suggests that an essential step in macronutrient toxicity is the induction of inflammatory mediators, which regulate mitochondrial function and damage target cells. Without such an inflammatory response, excess macronutrient supply (including advanced glycation and lipoxation end products) would not be diabetogenic

In animal models, both insulin resistance and diabetes can result from diverse genetic defects affecting the function of individual organs, including liver, fat, muscle, islet and neuronal tissue [47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67]. However, as described above, insulin resistance may also result from defects in various inflammatory/immune genes (Table 3). What mediates the effects of environmental factors on insulin resistance? There are indications that dietary effects may be immune mediated and that monocytes, endothelial cells and other cell types respond to elevated concentrations of glucose or NEFA by releasing inflammatory mediators, such as PAI-1, IL-6, TNF-α, soluble ICAM-1, prostaglandins, MCP-1 and IL-1β [68, 69, 70, 71, 72, 73, 74, 75].

These responses can be suppressed by experimental strategies aimed at blocking the production or action of free radicals or superoxide [69, 72, 73, 76, 77, 78, 79]. It has therefore been proposed that increased mitochondrial activity accounts for increased oxidative stress, which, in turn, causes the expression of several critical immune genes via redox-regulated transcription factors, such as nuclear factor-κB (NF-κB) or stress kinases. The recent observation of a close association between impaired mitochondrial function and insulin resistance or type 2 diabetes supports this concept [80, 81].

The upregulation of proinflammatory gene expression in response to high levels of glucose or fat has also been observed in vivo within a few hours of enteral uptake or parenteral administration of nutrients [82, 83, 84, 85, 86, 87]. Furthermore, levels of circulating immune mediators, such as IL-6 or IL-18, released in healthy subjects in response to the macronutrient challenge were similar to those seen in type 2 diabetes. An additional, interesting argument is that western diets are usually rich in advanced glycation and lipoxation end-products. Both are glucose-derived compounds that have been shown to elicit a profound proinflammatory response in vitro as well as in vivo [88, 89].

It may be argued that the inflammatory response observed is only an epiphenomenon attributable to excess radical production in mitochondria, whereas the consequences of impaired or unbalanced mitochondrial activity relevant to diabetes are immediate functional defects in fat cells, hepatocytes, beta cells or other cells [90]. The only available experimental evidence to address this comes from animal studies. It has been shown that a high-calorie diet does not induce insulin resistance if certain proinflammatory genes, such as PAI-1 and TNF-α, are non-functional [37, 41]. Furthermore, deletion of other immune genes, such as ICAM-1, renders a high-caloric diet prodiabetic [38]. The intercellular adhesion molecule ICAM-1 is not expressed in mitochondria and is not considered to regulate mitochondrial function. Conversely, immune or inflammatory mediators such as PAI-1 appear to have major effects on mitochondrial function and ectopic triglyceride accumulation in non-adipocytes [41]. Many proinflammatory genes are induced by the transcription factor NF-κB. Impaired activation of NF-κB by deletion of the gene encoding IκB kinase-β in myeloid cells alone protected mice from high-fat-diet-induced insulin resistance in liver and muscle, indicating a key role for activated leucocytes [91]. We recently observed that cytokines modulate the expression of uncoupling protein-2, a major regulator of thermogenesis and substrate oxidation [92]. The capacity of mitochondria to process large quantities of substrate may therefore be modulated by low-grade inflammation.

The induction of low-grade inflammation by a high-caloric diet may also occur via the concomitant growth of adipocytes. The observation that systemic levels of many immune mediators are strongly correlated with BMI, fat mass and/or waist circumference [93] has led to the assumption that many circulating immune mediators originate from adipocytes; however, this view may be too simple. Two recent studies in mice and humans provide evidence that obese adipose tissue exhibits macrophage infiltration and that these macrophages are a major source of inflammatory mediators [94, 95]. Infiltrated macrophages account for almost all TNF-α expression and much of the IL-6 expression in adipose tissue. It should be noted that the upregulation of proinflammatory genes in macrophages occurs before circulating insulin levels increase (a marker of insulin resistance). The infiltration of adipose tissue by macrophages is strongly correlated with BMI in humans, suggesting that fat accumulation in adipocytes triggers the influx of macrophages and their activation. This may occur through the release of chemokines from adipocytes [94, 95, 96] and/or via the expression of stress proteins on the fat cell surface [97, 98]. Hence, obesity would only result in insulin resistance and type 2 diabetes if macrophage infiltration and activation—‘adipositis’—evolved and persisted.

How do proinflammatory immune mediators cause insulin resistance? Many studies have analysed this question, and these will only be summarised here. Immune mediators such as TNF-α and IL-6 can directly interfere with insulin signalling [99, 100, 101, 102, 103], and the binding of these cytokines to their cognate receptor on muscle cells or hepatocytes has been shown to induce an intracellular response that interferes with the ability of the insulin receptor to phosphorylate its intracellular targets. The cellular response to insulin is dampened in consequence. One well-described example of this is the induction of the protein suppressor of cytokine signalling-3 (SOCS-3) by IL-6 in hepatocytes. This protein associates with the insulin receptor and suppresses insulin-dependent receptor autophosporylation and IRS-1 phosphorylation [100]. SOCS-3 also binds to IRS-1 and IRS-2, leading to their ubiquitination and proteasomal degradation [104]. Immune mediators also affect insulin sensitivity indirectly by modulating the regulatory function of fat, nerve or other cells, e.g. by influencing the release of leptin or by activating the hypothalamic–pituitary–adrenal axis [105, 106, 107, 108, 109].

One final aspect of immune-mediated insulin resistance to consider is the way in which physical exercise/muscle work might counteract insulin resistance. Muscle work is intimately linked with the production of certain immune mediators, and skeletal muscle expresses a large amount of IL-6, which is released into the circulation in response to exercise [110, 111, 112]. In contrast, the expression of low levels of TNF-α is unaltered [113]. The production of IL-6 is modulated by the glycogen content of muscle tissue [114], and IL-6 may also be released from the human brain during prolonged exercise [115]. Muscle-derived IL-6 may have beneficial effects, at least within a certain concentration range, since IL-6 inhibits low-grade TNF-α production and stimulates lipolysis and fat oxidation [116, 117]. Intra-arterial acute infusion of IL-6 does not impair whole-body glucose disposal in healthy humans [118]. Although IL-6 administration has been shown to induce hepatic and skeletal muscle insulin resistance in mice [119], the fact that IL-6 deficiency was associated with the development of diabetes in the same species cannot be ignored (Table 3). In obese subjects, IL-6 levels in the central nervous system are negatively correlated with fat mass, and intracerebroventricular IL-6 treatment decreases body fat in rats [120]. Taken together, these findings suggest that the glucose-lowering effect of exercise may indeed be immune mediated.

Immune mechanisms in diabetes pathogenesis: beta cell destruction

The other major issue in the pathogenesis of type 2 diabetes is whether and, if so, how immune mediators are involved in the steady loss of beta cell function which predates the onset of diabetes [121, 122, 123]. Metabolic stress resulting from a high-caloric diet and the concomitant detrimental effects of increased glucose or NEFA concentrations on beta cells are considered major contributors to beta cell loss [74, 122, 124, 125, 126, 127], which occurs mainly by apoptosis [128, 129]. The question at issue is whether beta cell damage and apoptosis are direct consequences of the increased mitochondrial generation of oxygen radicals or whether immune/inflammatory mediators are responsible (Fig. 3).
Fig. 3

A model for inflammatory beta cell dysfunction and apoptosis in (pre) type 2 diabetes. Metabolic stressors can cause beta cell dysfunction via increased cytokine action or reduced cytokine antagonist action, and increased free radical production. A reduced expression of the Fas/FasL signalling inhibitor FLIP may accelerate this phenomenon. Toxic actions may be enhanced by products of metabolically stressed endothelial cells and by increased systemic levels of beta cell toxic immune mediators. IL-1 Ra IL-1 receptor antagonist; ROS reactive oxygen species; EC endothelial cells

Evidence favouring oxidative stress as a mediator of beta cell apoptosis in type 2 diabetic patients has recently been published [130], and lipid peroxidation was shown to be increased in the islets of patients with type 2 diabetes as compared with control subjects. The islets of diabetic patients contained less cytoplasmic Cu/Zn superoxide dismutase, and there was a clear inverse correlation between oxidative DNA damage and islet beta cell volume density in these patients.

There is controversy as to whether in vitro exposure of human islets to high glucose levels leads directly to beta cell apoptosis [68, 131, 132]. High glucose increased TUNEL staining (evidence of apoptosis) in a dose-dependent manner, and increased expression of the Fas receptor, leading to cleavage of pro-caspase 3 and activation of caspase 3. This probably occurred through transactivation of Fas by Fas ligand (FasL) expressed constitutively by neighbouring islet cells [68, 131, 132]. In contrast, glucose oxidation was unaffected in human islets exposed to high glucose in vitro, and human islets transplanted to hyperglycaemic nude mice did not exhibit ultrastructural signs of apoptosis [68, 132]. One of the differences between the in vitro studies cited above is in the method used to culture human islets. In the former study, human islets were cultured on an extracellular matrix from bovine corneal epithelial cells, whereas in the latter the islets were cultured in free-floating organ cultures. Clarification is needed as to whether this methodological difference affected the outcome of these and other studies, and may explain discrepancies in the literature concerning the expression of FasL on human beta cells [131, 133].

It is intriguing that glucose-stimulated IL-1 synthesis and secretion and high-glucose-induced beta cell apoptosis were prevented by an IL-1 receptor antagonist [134], although this observation requires independent confirmation. IL-1 expression has also been detected in pancreases from type 2 diabetic patients, but not in control subjects, as well as in Psammomys obesus fed a high-energy diet leading to hyperglycaemia [134]. In this model, IL-1 expression in islet beta cells was reversed by the administration of phlorizin, leading to normoglycaemia. It is surprising that IL-1, which usually does not cause beta cell apoptosis in human islets [133, 134], induced apoptosis in these experiments. It is not clear whether this relates to the culture conditions, or to the secretion of cytokines such as TNF-α or IFN-γ in these particular islet preparations. A very recent study from the same group suggested that an IL-1 receptor antagonist is a physiological regulator of beta cell viability, since small interfering RNAs directed against the IL-1 receptor antagonist increased the apoptotic rate, even at basal glucose levels at which beta cell IL-1 production is low [135]. In the same study, leptin, an important adipokine and a member of the IL-6 cytokine family, was shown to induce beta cell apoptosis in human islets by reducing levels of IL-1 receptor antagonist and increasing IL-1β synthesis and secretion [135].

The reduced level of the Fas-associated death domain protein-like IL-1β converting enzyme-inhibitory protein (FLIP) observed in the pancreases of type 2 diabetic patients may also contribute to glucose-induced apoptosis [136]. Interestingly, this inhibitor determines whether Fas-signalling will lead to apoptosis or cell proliferation. This concept is consistent with the observation that the signalling intermediates involved in glucose- and IL-induced beta cell apoptosis in human islets are strikingly similar [137]. The toxic actions of NEFA on beta cell function may be mediated by similar pathways; several lines of evidence point to this. Exposure to NEFA causes oxidative stress [76, 125, 127, 138, 139, 140, 141] followed by apoptosis [142], and IL-1 potentiates NEFA toxicity [143]. Exogenous IL-1 or other toxic immune mediators from the islet endothelium [144, 145, 146, 147] or from the circulation may act in concert with dietary fatty acids to damage beta cells, although the signalling pathways involved may differ in some respects. While cytokines induce activation of NF-κB and nitric-oxide-dependent endoplasmic reticulum stress, NEFA induce endoplasmic reticulum stress independently of NF-κB and nitric oxide in beta cells [148]. Since recent studies have questioned the role of nitric oxide in cytokine-induced beta cell destruction in vivo [149], and have emphasised mitochondrial perturbation as an important feature, the main effector mechanisms elicited by cytokines and metabolic factors may not differ to a great extent.

In conclusion, there is emerging, although controversial, evidence that metabolic factors—particularly glucose in (pre) type 2 diabetes—may contribute to beta cell dysfunction and apoptosis. This is thought to occur via metabolic stress leading to the synthesis of inflammatory mediators that elicit intracellular responses that are largely similar to those involved in immune-mediated beta cell destruction in type 1 diabetes.

Immune or inflammatory?

As described above, low-grade inflammation in (pre) type 2 diabetes is generally considered to be a non-specific consequence of metabolic stress. This type of ‘inflammatory’ response would not require the infiltration of ‘inflamed’ tissues by (auto)antigen-reactive immune cells—the hallmark of classic inflammation. Although it is conceivable that inflammation is fuelled by non-antigen-specific reactions, we would like to point out that a chronic inflammatory state, such as that observed in (pre) type 2 diabetes, may be driven by antigens, and that chronicity may result from deficient anti-inflammatory feedback loops. Antigens known to be expressed on stressed cells or released from damaged cells, notably stress proteins or certain lipid compounds, are candidates for this role [97, 150, 151, 152]. Such stress antigens may drive inflammation in obese adipose tissue, islets or the vessel wall, and heat shock protein 60 and oxidised lipids have already been identified in animal models as antigens that either cause or maintain the atherosclerotic disease process in the vessel wall [153, 154, 155].

Limited data are available on islet histology in type 2 diabetes. Although a decrease in beta cell volume, an increased number of alpha cells and the deposition of islet amyloid have been reported, it is not known whether tissue macrophages, dendritic cells or endothelial cells exhibit a proinflammatory phenotype [128, 129, 139, 156, 157, 158]. In diabetic patients, the presence of extensive islet amyloidosis does not appear to be associated with the influx of macrophages [159]. However, there are no data on the type of morphological or inflammatory changes that occur in pancreatic islets prior to diabetes onset, for example, in obese individuals with IGT.

Intervention studies

The classical treatment modalities for type 2 diabetes are diet and exercise for weight reduction, and pharmacological intervention by oral hypoglycaemic drugs or insulin, all of which affect the inflammatory state. Weight reduction and/or physical exercise markedly reduce circulating levels of inflammatory mediators such as CRP and IL-6 (Table 4), a response that probably indicates the remission of macrophage-mediated inflammation in adipose tissue as a consequence of altered fat cell metabolism. It could be argued that the remission of systemic low-grade inflammation by lifestyle changes is an epiphenomenon, but, once again, genetic studies imply a causal relationship. For example, it was reported by the Finnish Diabetes Prevention Study that the protective effect of lifestyle changes was associated with polymorphisms in the promoters of the genes encoding TNF-α and IL-6 [160].
Table 4

Interventions that have an impact on the inflammatory state

Inflammatory mediators whose concentrations are reduced by weight loss and/or physical exercise [190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207]

 

 CRP, TNF-α, soluble TNF-α receptor 2, IL-6, IL-18, MCP-1, PAI-1, t-PA, soluble ICAM-1, soluble VCAM-1, P-selectin

 

Inflammatory mediators whose concentrations are reduced by glucose-lowering drugs [186, 188, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217]

 

 Sulphonylurea: TNF-α

 

 Metformin: CRP

 

 Glitazones: CRP, SAA, TNF-α, soluble CD40 ligand, PAI-1

 

 Insulin: CRP, IL-1, IL-6, TNF-α, soluble ICAM-1, MCP-1, PAI-1

 

SAA Serum amyloid A, t-PA tissue plasminogen activator, VCAM-1 vascular cell adhesion molecule-1

As shown in Table 4, all oral hypoglycaemic agents have anti-inflammatory properties. It is therefore conceivable that a dampening of innate immune reactivity contributes to their therapeutic effects and those of insulin. To date, the preventive or therapeutic potential of anti-inflammatory/immunosuppressive therapy has not been evaluated. Pilot trials with antibodies directed against TNF-α have not shown a beneficial effect on insulin action, in contrast to the observations in mice [161, 162, 163, 164]. However, it is not known whether sufficiently high concentrations of TNF-α antagonist were reached in target tissues, or whether immune mediators other than TNF-α are more important for the induction of insulin resistance in humans. Recent studies with TNF-α infusion demonstrated its ability to cause insulin resistance in vivo [165]. The results of therapeutic studies on high-dose aspirin in type 2 diabetes patients are more encouraging: in parallel with a reduction of systemic CRP levels there was a 25% reduction in fasting blood glucose and an even larger decrease in serum triglyceride levels [166].

A clinical trial has been launched to investigate the importance of proinflammatory cytokines in the generation of insulin resistance and beta cell failure in type 2 diabetes. This will test the effect of subcutaneous human recombinant IL-1 receptor antagonist (100 mg/day) vs placebo in patients with type 2 diabetes (collaboration between M. Donath, Division of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland and The Steno Diabetes Centre, Denmark).

Low-grade inflammation and health

Cross-sectional and prospective studies in the general population, the elderly, and centenarians have shown that mildly elevated levels of CRP and proinflammatory cytokines are associated with, or predict, atherosclerosis, myocardial infarction, stroke, depression and Alzheimer’s disease, and that longevity is associated with decreased systemic inflammation [105, 167, 168, 169, 170, 171]. Here, again, polymorphisms in immune genes modulate risk, implying a pathogenetic significance for immune gene products [171, 172, 173]. Where studied, the upregulation of inflammatory mediators was linked to increased oxidative stress, impaired mitochondrial function and abnormal cholesterol metabolism [174, 175, 176]. Interventions targeting cholesterol metabolism or oxidative stress also ameliorated inflammation [167, 177, 178, 179, 180, 181, 182]. We therefore conclude that the metabolic concept and the immunological concept are simply two views of the same process, seen from different angles.

Notes

Acknowledgements

We thank R. Schreiner for help with preparing the manuscript. This work was supported by the German Federal Ministry of Health and Social Security (Bundesministerium für Gesundheit und Soziale Sicherung), by the Ministry of Science and Research of the State of Nordrhein-Westfalen (Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen) and Novo Nordisk.

References

  1. 1.
    Winzler RJ (1960) Glycoproteins. In: Putnam FW (ed) The plasma proteins. London Academic, New York, p 309Google Scholar
  2. 2.
    Cogan DG, Merola L, Laibson PR (1961) Blood viscosity, serum hexosamine and diabetic retinopathy. Diabetes 10:393–395PubMedGoogle Scholar
  3. 3.
    Bergstrand CG, Furst P, Larsson Y, Sterky G (1962) Serum haptoglobin in juvenile diabetes. Scand J Clin Lab Invest 14:629–632PubMedGoogle Scholar
  4. 4.
    Ganrot PO, Gydell K, Ekelund H (1967) Serum concentration of alpha-2-macroglobulin, haptoglobin and alpha-1-antitrypsin in diabetes mellitus. Acta Endocrinol (Copenh) 55:537–544Google Scholar
  5. 5.
    Cleve H, Alexander K, Mitzkat HJ, Nissen P, Salzmann I (1968) Serum glycoproteins in diabetes mellitus; quantitative immunological determination of acid alpha 1-glycoprotein, Gc, alpha 2-macroglobulin and hemopexin in diabetics with and without angiopathy [article in German]. Diabetologia 4:48–55CrossRefPubMedGoogle Scholar
  6. 6.
    McMillan DE (1970) Changes in serum proteins and protein-bound carbohydrates in diabetes mellitus. Diabetologia 6:597–604CrossRefPubMedGoogle Scholar
  7. 7.
    Schmidt MI, Duncan BB, Sharrett AR et al (1999) Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities Study): a cohort study. Lancet 353:1649–1652CrossRefPubMedGoogle Scholar
  8. 8.
    Duncan BB, Schmidt MI, Offenbacher S, Wu KK, Savage PJ, Heiss G (1999) Factor VIII and other hemostasis variables are related to incident diabetes in adults. The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care 22:767–772PubMedGoogle Scholar
  9. 9.
    Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286:327–334CrossRefPubMedGoogle Scholar
  10. 10.
    Barzilay JI, Abraham L, Heckbert SR et al (2001) The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 50:2384–2389PubMedGoogle Scholar
  11. 11.
    Lindsay RS, Krakoff J, Hanson RL, Bennett PH, Knowler WC (2001) Gamma globulin levels predict type 2 diabetes in the Pima Indian population. Diabetes 50:1598–1603PubMedGoogle Scholar
  12. 12.
    Vozarova B, Weyer C, Lindsay RS, Pratley RE, Bogardus C, Tataranni PA (2002) High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 51:455–461PubMedGoogle Scholar
  13. 13.
    Freeman DJ, Norrie J, Caslake MJ et al (2002) C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 51:1596–1600PubMedGoogle Scholar
  14. 14.
    Ford ES (2002) Leukocyte count, erythrocyte sedimentation rate, and diabetes incidence in a national sample of US adults. Am J Epidemiol 155:57–64CrossRefPubMedGoogle Scholar
  15. 15.
    Nakanishi N, Yoshida H, Matsuo Y, Suzuki K, Tatara K (2002) White blood-cell count and the risk of impaired fasting glucose or type II diabetes in middle-aged Japanese men. Diabetologia 45:42–48CrossRefPubMedGoogle Scholar
  16. 16.
    Festa A, D’Agostino R Jr, Tracy RP, Haffner SM (2002) Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 51:1131–1137PubMedGoogle Scholar
  17. 17.
    Thorand B, Lowel H, Schneider A et al (2003) C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg Cohort Study, 1984–1998. Arch Intern Med 163:93–99CrossRefPubMedGoogle Scholar
  18. 18.
    Spranger J, Kroke A, Mohlig M et al (2003) 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. Diabetes 52:812–817PubMedGoogle Scholar
  19. 19.
    Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME, Haffner SM (2002) Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care 25:2016–2021PubMedGoogle Scholar
  20. 20.
    Tan KC, Wat NM, Tam SC, Janus ED, Lam TH, Lam KS (2003) C-reactive protein predicts the deterioration of glycemia in Chinese subjects with impaired glucose tolerance. Diabetes Care 26:2323–2328PubMedGoogle Scholar
  21. 21.
    Hu FB, Meigs JB, Li TY, Rifai N, Manson JE (2004) Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes 53:693–700PubMedGoogle Scholar
  22. 22.
    Snijder MB, Dekker JM, Visser M et al (2003) Prospective relation of C-reactive protein with type 2 diabetes: response to Han et al. Diabetes Care 26:1656–1657PubMedGoogle Scholar
  23. 23.
    Groop L, Groop PH, Koskimies S (1986) Relationship between B-cell function and HLA antigens in patients with type 2 (non-insulin-dependent) diabetes. Diabetologia 29:757–760CrossRefPubMedGoogle Scholar
  24. 24.
    Rich SS, French LR, Sprafka JM, Clements JP, Goetz FC (1993) HLA-associated susceptibility to type 2 (non-insulin-dependent) diabetes mellitus: the Wadena City Health Study. Diabetologia 36:234–238CrossRefPubMedGoogle Scholar
  25. 25.
    Tuomilehto-Wolf E, Tuomilehto J, Hitman GA et al (1993) Genetic susceptibility to non-insulin dependent diabetes mellitus and glucose intolerance are located in HLA region. BMJ 307:155–159PubMedGoogle Scholar
  26. 26.
    Ghabanbasani MZ, Spaepen M, Buyse I et al (1995) Increased and decreased relative risk for non-insulin-dependent diabetes mellitus conferred by HLA class II and by CD4 alleles. Clin Genet 47:225–230PubMedGoogle Scholar
  27. 27.
    Vendrell J, Gutierrez C, Pastor R, Richart C (1995) A tumor necrosis factor-beta polymorphism associated with hypertriglyceridemia in non-insulin-dependent diabetes mellitus. Metabolism 44:691–694CrossRefPubMedGoogle Scholar
  28. 28.
    Fernandez-Real JM, Gutierrez C, Ricart W et al (1997) The TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels. Diabetes 46:1468–1472PubMedGoogle Scholar
  29. 29.
    Fernandez-Real JM, Vendrell J, Ricart W et al (2000) Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients. Diabetes Care 23:831–837PubMedGoogle Scholar
  30. 30.
    Fernandez-Real JM, Broch M, Vendrell J et al (2000) Interleukin-6 gene polymorphism and insulin sensitivity. Diabetes 49:517–520PubMedGoogle Scholar
  31. 31.
    Hoffstedt J, Andersson IL, Persson L, Isaksson B, Arner P (2002) The common −675 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is strongly associated with obesity. Diabetologia 45:584–587CrossRefPubMedGoogle Scholar
  32. 32.
    Perez-Luque E, Alaez C, Malacara JM et al (2003) Protective effect of DRB1 locus against type 2 diabetes mellitus in Mexican Mestizos. Hum Immunol 64:110–118CrossRefPubMedGoogle Scholar
  33. 33.
    Wolford JK, Gruber JD, Ossowski VM et al (2003) A C-reactive protein promoter polymorphism is associated with type 2 diabetes mellitus in Pima Indians. Mol Genet Metab 78:136–144CrossRefPubMedGoogle Scholar
  34. 34.
    Rosmond R, Chagnon M, Bouchard C, Bjorntorp P (2003) Increased abdominal obesity, insulin and glucose levels in nondiabetic subjects with a T29C polymorphism of the transforming growth factor-beta1 gene. Horm Res 59:191–194CrossRefPubMedGoogle Scholar
  35. 35.
    Escobar-Morreale HF, Calvo RM, Villuendas G, Sancho J, San Millan JL (2003) Association of polymorphisms in the interleukin 6 receptor complex with obesity and hyperandrogenism. Obes Res 11:987–996PubMedGoogle Scholar
  36. 36.
    Illig T, Bongardt F, Schöpfer A et al (2004) Significant association of the interleukin-6 gene polymporphism C-174G and A-598G with type 2 diabetes. J Clin Endocrin Metab 89:5053–5058CrossRefGoogle Scholar
  37. 37.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614CrossRefPubMedGoogle Scholar
  38. 38.
    Dong ZM, Gutierrez-Ramos JC, Coxon A, Mayadas TN, Wagner DD (1997) A new class of obesity genes encodes leukocyte adhesion receptors. Proc Natl Acad Sci U S A 94:7526–7530CrossRefPubMedGoogle Scholar
  39. 39.
    Wallenius V, Wallenius K, Ahren B et al (2002) Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8:75–79CrossRefPubMedGoogle Scholar
  40. 40.
    Schafer K, Fujisawa K, Konstantinides S, Loskutoff DJ (2001) Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J 15:1840–1842PubMedGoogle Scholar
  41. 41.
    Ma LJ, Mao SL, Taylor KL et al (2004) Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 53:336–346PubMedGoogle Scholar
  42. 42.
    Lijnen HR, Maquoi E, Morange P et al (2003) Nutritionally induced obesity is attenuated in transgenic mice overexpressing plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 23:78–84CrossRefPubMedGoogle Scholar
  43. 43.
    Perreault M, Marette A (2001) Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 7:1138–1143CrossRefPubMedGoogle Scholar
  44. 44.
    Morange PE, Lijnen HR, Alessi MC, Kopp F, Collen D, Juhan-Vague I (2000) Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity. Arterioscler Thromb Vasc Biol 20:1150–1154PubMedGoogle Scholar
  45. 45.
    Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46:3–19CrossRefPubMedGoogle Scholar
  46. 46.
    Goldstein BJ (2003) Insulin resistance: from benign to type 2 diabetis mellitus. Rev Cardiovasc Med 4 [Suppl 6]:S3–S10Google Scholar
  47. 47.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432CrossRefPubMedGoogle Scholar
  48. 48.
    Bali D, Svetlanov A, Lee HW et al (1995) Animal model for maturity-onset diabetes of the young generated by disruption of the mouse glucokinase gene. J Biol Chem 270:21464–21467CrossRefPubMedGoogle Scholar
  49. 49.
    Terauchi Y, Sakura H, Yasuda K et al (1995) Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose. J Biol Chem 270:30253–30256CrossRefPubMedGoogle Scholar
  50. 50.
    Grupe A, Hultgren B, Ryan A, Ma YH, Bauer M, Stewart TA (1995) Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis. Cell 83:69–78CrossRefPubMedGoogle Scholar
  51. 51.
    Erickson JC, Clegg KE, Palmiter RD (1996) Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381:415–421CrossRefPubMedGoogle Scholar
  52. 52.
    Erickson JC, Hollopeter G, Palmiter RD (1996) Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274:1704–1707CrossRefPubMedGoogle Scholar
  53. 53.
    Janson J, Soeller WC, Roche PC et al (1996) Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci U S A 93:7283–7288CrossRefPubMedGoogle Scholar
  54. 54.
    Stenbit AE, Tsao TS, Li J et al (1997) GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat Med 3:1096–1101CrossRefPubMedGoogle Scholar
  55. 55.
    Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR (1997) Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88:561–572CrossRefPubMedGoogle Scholar
  56. 56.
    Leiter EH (1997) Carboxypeptidase E and obesity in the mouse. J Endocrinol 155:211–214CrossRefPubMedGoogle Scholar
  57. 57.
    Ren JM, Li PM, Zhang WR et al (1998) Transgenic mice deficient in the LAR protein-tyrosine phosphatase exhibit profound defects in glucose homeostasis. Diabetes 47:493–497PubMedGoogle Scholar
  58. 58.
    Withers DJ, Gutierrez JS, Towery H et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904CrossRefPubMedGoogle Scholar
  59. 59.
    Masuzaki H, Paterson J, Shinyama H et al (2001) A transgenic model of visceral obesity and the metabolic syndrome. Science 294:2166–2170CrossRefPubMedGoogle Scholar
  60. 60.
    Kim JK, Fillmore JJ, Chen Y et al (2001) Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 98:7522–7527CrossRefPubMedGoogle Scholar
  61. 61.
    Laustsen PG, Michael MD, Crute BE et al (2002) Lipoatrophic diabetes in Irs1(−/−)/Irs3(−/−) double knockout mice. Genes Dev 16:3213–3222CrossRefPubMedGoogle Scholar
  62. 62.
    Hribal ML, Oriente F, Accili D (2002) Mouse models of insulin resistance. Am J Physiol Endocrinol Metab 282:E977–E981PubMedGoogle Scholar
  63. 63.
    Mauvais-Jarvis F, Kulkarni RN, Kahn CR (2002) Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Clin Endocrinol (Oxf) 57:1–9CrossRefGoogle Scholar
  64. 64.
    Hirosumi J, Tuncman G, Chang L et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336CrossRefPubMedGoogle Scholar
  65. 65.
    Baudry A, Leroux L, Jackerott M, Joshi RL (2002) Genetic manipulation of insulin signaling, action and secretion in mice. Insights into glucose homeostasis and pathogenesis of type 2 diabetes. EMBO Rep 3:323–328CrossRefPubMedGoogle Scholar
  66. 66.
    Valet P, Tavernier G, Castan-Laurell I, Saulnier-Blache JS, Langin D (2002) Understanding adipose tissue development from transgenic animal models. J Lipid Res 43:835–860PubMedGoogle Scholar
  67. 67.
    Conarello SL, Li Z, Ronan J et al (2003) Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proc Natl Acad Sci U S A 100:6825–6830CrossRefPubMedGoogle Scholar
  68. 68.
    Maedler K, Sergeev P, Ris F et al (2002) Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110:851–860CrossRefPubMedGoogle Scholar
  69. 69.
    Shanmugam N, Reddy MA, Guha M, Natarajan R (2003) High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes 52:1256–1264PubMedGoogle Scholar
  70. 70.
    Chen Y, Schneider DJ (2002) The independence of signaling pathways mediating increased expression of plasminogen activator inhibitor type 1 in HepG2 cells exposed to free fatty acids or triglycerides. Int J Exp Diabetes Res 3:109–118CrossRefPubMedGoogle Scholar
  71. 71.
    Morohoshi M, Fujisawa K, Uchimura I, Numano F (1996) Glucose-dependent interleukin 6 and tumor necrosis factor production by human peripheral blood monocytes in vitro. Diabetes 45:954–959PubMedGoogle Scholar
  72. 72.
    Morigi M, Angioletti S, Imberti B et al (1998) Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion. J Clin Invest 101:1905–1915PubMedGoogle Scholar
  73. 73.
    Guha M, Bai W, Nadler JL, Natarajan R (2000) Molecular mechanisms of tumor necrosis factor alpha gene expression in monocytic cells via hyperglycemia-induced oxidant stress-dependent and -independent pathways. J Biol Chem 275:17728–17739CrossRefPubMedGoogle Scholar
  74. 74.
    Donath MY, Storling J, Maedler K, Mandrup-Poulsen T (2003) Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J Mol Med 81:455–470CrossRefPubMedGoogle Scholar
  75. 75.
    Weigert C, Brodbeck K, Staiger H et al (2004) Palmitate, but not unsaturated fatty acids, induces the expression of interleukin-6 in human myotubes through proteasome-dependent activation of nuclear factor kappa B. J Biol Chem 279:23942–23952CrossRefPubMedGoogle Scholar
  76. 76.
    Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2003) Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 52:1–8PubMedGoogle Scholar
  77. 77.
    Schiekofer S, Andrassy M, Chen J et al (2003) Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappaB in PBMCs. Diabetes 52:621–633PubMedGoogle Scholar
  78. 78.
    Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820CrossRefPubMedGoogle Scholar
  79. 79.
    Hammes HP, Du X, Edelstein D et al (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9:294–299CrossRefPubMedGoogle Scholar
  80. 80.
    Petersen KF, Befroy D, Dufour S et al (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142CrossRefPubMedGoogle Scholar
  81. 81.
    Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671CrossRefPubMedGoogle Scholar
  82. 82.
    Ceriello A, Falleti E, Motz E et al (1998) Hyperglycemia-induced circulating ICAM-1 increase in diabetes mellitus: the possible role of oxidative stress. Horm Metab Res 30:146–149PubMedGoogle Scholar
  83. 83.
    Esposito K, Nappo F, Marfella R et al (2002) Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106:2067–2072CrossRefPubMedGoogle Scholar
  84. 84.
    Esposito K, Nappo F, Giugliano F et al (2003) Meal modulation of circulating interleukin 18 and adiponectin concentrations in healthy subjects and in patients with type 2 diabetes mellitus. Am J Clin Nutr 78:1135–1140PubMedGoogle Scholar
  85. 85.
    Krebs M, Geiger M, Polak K et al (2003) Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man. Thromb Haemost 90:422–428PubMedGoogle Scholar
  86. 86.
    Ceriello A, Quagliaro L, Piconi L et al (2004) Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment. Diabetes 53:701–710PubMedGoogle Scholar
  87. 87.
    van Oostrom AJ, van Dijk H, Verseyden C et al (2004) Addition of glucose to an oral fat load reduces postprandial free fatty acids and prevents the postprandial increase in complement component 3. Am J Clin Nutr 79:510–515PubMedGoogle Scholar
  88. 88.
    Vlassara H, Palace MR (2002) Diabetes and advanced glycation endproducts. J Intern Med 251:87–101CrossRefPubMedGoogle Scholar
  89. 89.
    Peppa M, Goldberg T, Cai W, Rayfield E, Vlassara H (2002) Glycotoxins: a missing link in the “relationship of dietary fat and meat intake in relation to risk of type 2 diabetes in men”. Diabetes Care 25:1898–1899PubMedGoogle Scholar
  90. 90.
    Taylor R (2004) Causation of type 2 diabetes—the Gordian knot unravels. N Engl J Med 350:639–641CrossRefPubMedGoogle Scholar
  91. 91.
    Arkan MC, Hevener AL, Greten FR et al (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11:191–198CrossRefPubMedGoogle Scholar
  92. 92.
    Stumpo R, Kauer M, Martin S, Kolb H (2003) IL-10 induces gene expression in macrophages: partial overlap with IL-5 but not with IL-4 induced genes. Cytokine 24:46–56CrossRefPubMedGoogle Scholar
  93. 93.
    Hanley AJ, Festa A, D’Agostino RB et al (2004) Metabolic and inflammation variable clusters and prediction of type 2 diabetes: factor analysis using directly measured insulin sensitivity. Diabetes 53:1773–1781PubMedGoogle Scholar
  94. 94.
    Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112:1821–1830CrossRefPubMedGoogle Scholar
  95. 95.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796–1808CrossRefPubMedGoogle Scholar
  96. 96.
    Fasshauer M, Klein J, Kralisch S et al (2004) Monocyte chemoattractant protein 1 expression is stimulated by growth hormone and interleukin-6 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 317:598–604CrossRefPubMedGoogle Scholar
  97. 97.
    Chen W, Syldath U, Bellmann K, Burkart V, Kolb H (1999) Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J Immunol 162:3212–3219PubMedGoogle Scholar
  98. 98.
    Ohashi K, Burkart V, Flohé S, Kolb H (2000) Heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 164:558–561PubMedGoogle Scholar
  99. 99.
    Ruan H, Lodish HF (2003) Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha. Cytokine Growth Factor Rev 14:447–455CrossRefPubMedGoogle Scholar
  100. 100.
    Senn JJ, Klover PJ, Nowak IA et al (2003) Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem 278:13740–13746CrossRefPubMedGoogle Scholar
  101. 101.
    Fernandez-Real JM, Ricart W (2003) Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev 24:278–301CrossRefPubMedGoogle Scholar
  102. 102.
    Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4–7CrossRefPubMedGoogle Scholar
  103. 103.
    Peraldi P, Spiegelman B (1998) TNF-alpha and insulin resistance: summary and future prospects. Mol Cell Biochem 182:169–175CrossRefPubMedGoogle Scholar
  104. 104.
    Rui L, Yuan M, Frantz D, Shoelson S, White MF (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 277:42394–42398CrossRefPubMedGoogle Scholar
  105. 105.
    Pickup JC (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27:813–823PubMedGoogle Scholar
  106. 106.
    Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh K (2003) Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol 14:561–566CrossRefPubMedGoogle Scholar
  107. 107.
    Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859CrossRefPubMedGoogle Scholar
  108. 108.
    Kershaw EE, Flier JS (2004) Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 89:2548–2556CrossRefPubMedGoogle Scholar
  109. 109.
    Eskandari F, Webster JI, Sternberg EM (2003) Neural immune pathways and their connection to inflammatory diseases. Arthritis Res Ther 5:251–265CrossRefPubMedGoogle Scholar
  110. 110.
    Pedersen BK, Steensberg A, Schjerling P (2001) Muscle-derived interleukin-6: possible biological effects. J Physiol 536:329–337CrossRefPubMedGoogle Scholar
  111. 111.
    Penkowa M, Keller C, Keller P, Jauffred S, Pedersen BK (2003) Immunohistochemical detection of interleukin-6 in human skeletal muscle fibers following exercise. FASEB J 17:2166–2168PubMedGoogle Scholar
  112. 112.
    Tomiya A, Aizawa T, Nagatomi R, Sensui H, Kokubun S (2004) Myofibers express IL-6 after eccentric exercise. Am J Sports Med 32:503–508CrossRefPubMedGoogle Scholar
  113. 113.
    Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA, Pedersen BK (2002) IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 283:E1272–E1278PubMedGoogle Scholar
  114. 114.
    Steensberg A, van Hall G, Keller C et al (2002) Muscle glycogen content and glucose uptake during exercise in humans: influence of prior exercise and dietary manipulation. J Physiol 541:273–281CrossRefPubMedGoogle Scholar
  115. 115.
    Nybo L, Nielsen B, Pedersen BK, Moller K, Secher NH (2002) Interleukin-6 release from the human brain during prolonged exercise. J Physiol 542:991–995CrossRefPubMedGoogle Scholar
  116. 116.
    Pedersen BK, Steensberg A, Fischer C et al (2003) Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 24:113–119CrossRefPubMedGoogle Scholar
  117. 117.
    van Hall G, Steensberg A, Sacchetti M et al (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88:3005–3010CrossRefPubMedGoogle Scholar
  118. 118.
    Steensberg A, Fischer CP, Sacchetti M et al (2003) Acute interleukin-6 administration does not impair muscle glucose uptake or whole-body glucose disposal in healthy humans. J Physiol 548:631–638PubMedGoogle Scholar
  119. 119.
    Kim HJ, Higashimori T, Park SY et al (2004) Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 53:1060–1067PubMedGoogle Scholar
  120. 120.
    Wallenius K, Wallenius V, Sunter D, Dickson SL, Jansson JO (2002) Intracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem Biophys Res Commun 293:560–565CrossRefPubMedGoogle Scholar
  121. 121.
    Scheen AJ (2004) Pathophysiology of insulin secretion. Ann Endocrinol (Paris) 65:29–36Google Scholar
  122. 122.
    Steppel JH, Horton ES (2004) Beta-cell failure in the pathogenesis of type 2 diabetes mellitus. Curr Diabetes Rep 4:169–175Google Scholar
  123. 123.
    Zethelius B, Byberg L, Hales CN, Lithell H, Berne C (2003) Proinsulin and acute insulin response independently predict type 2 diabetes mellitus in men—report from 27 years of follow-up study. Diabetologia 46:20–26PubMedGoogle Scholar
  124. 124.
    Cnop M, Hannaert JC, Hoorens A, Eizirik DL, Pipeleers DG (2001) Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 50:1771–1777PubMedGoogle Scholar
  125. 125.
    Carlsson C, Borg LA, Welsh N (1999) Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology 140:3422–3428CrossRefPubMedGoogle Scholar
  126. 126.
    Maedler K, Spinas GA, Lehmann R et al (2001) Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets. Diabetes 50:1683–1690PubMedGoogle Scholar
  127. 127.
    Robertson RP, Harmon J, Tran PO, Poitout V (2004) Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53 [Suppl 1]:S119–S124PubMedGoogle Scholar
  128. 128.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110PubMedGoogle Scholar
  129. 129.
    Deng S, Vatamaniuk M, Huang X et al (2004) Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes 53:624–632PubMedGoogle Scholar
  130. 130.
    Jansson L, Eizirik DL, Pipeleers DG, Borg LA, Hellerstrom C, Andersson A (1995) Impairment of glucose-induced insulin secretion in human pancreatic islets transplanted to diabetic nude mice. J Clin Invest 96:721–726PubMedGoogle Scholar
  131. 131.
    Eizirik DL, Jansson L, Flodstrom M, Hellerstrom C, Andersson A (1997) Mechanisms of defective glucose-induced insulin release in human pancreatic islets transplanted to diabetic nude mice. J Clin Endocrinol Metab 82:2660–2663CrossRefPubMedGoogle Scholar
  132. 132.
    Moriwaki M, Itoh N, Miyagawa J et al (1999) Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset type I diabetes mellitus. Diabetologia 42:1332–1340CrossRefPubMedGoogle Scholar
  133. 133.
    Mandrup-Poulsen T (1996) The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 39:1005–1029PubMedGoogle Scholar
  134. 134.
    Eizirik DL, Mandrup-Poulsen T (2001) A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44:2115–2133CrossRefPubMedGoogle Scholar
  135. 135.
    Maedler K, Sergeev P, Ehses JA et al (2004) Leptin modulates beta cell expression of IL-1 receptor antagonist and release of IL-1beta in human islets. Proc Natl Acad Sci U S A 101:8138–8143CrossRefPubMedGoogle Scholar
  136. 136.
    Maedler K, Fontana A, Ris F et al (2002) FLIP switches Fas-mediated glucose signaling in human pancreatic beta cells from apoptosis to cell replication. Proc Natl Acad Sci U S A 99:8236–8241CrossRefPubMedGoogle Scholar
  137. 137.
    Maedler K, Storling J, Sturis J et al (2004) Glucose- and interleukin-1beta-induced beta-cell apoptosis requires Ca2+ influx and extracellular signal-regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets. Diabetes 53:1706–1713PubMedGoogle Scholar
  138. 138.
    Maestre I, Jordan J, Calvo S et al (2003) Mitochondrial dysfunction is involved in apoptosis induced by serum withdrawal and fatty acids in the beta-cell line INS-1. Endocrinology 144:335–345CrossRefPubMedGoogle Scholar
  139. 139.
    Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S (2002) Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese type II diabetic patients. Diabetologia 45:85–96CrossRefPubMedGoogle Scholar
  140. 140.
    Koshkin V, Wang X, Scherer PE, Chan CB, Wheeler MB (2003) Mitochondrial functional state in clonal pancreatic beta-cells exposed to free fatty acids. J Biol Chem 278:19709–19715CrossRefPubMedGoogle Scholar
  141. 141.
    Schrauwen P, Hesselink MK (2004) Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes. Diabetes 53:1412–1417PubMedGoogle Scholar
  142. 142.
    Lupi R, Dotta F, Marselli L et al (2002) Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51:1437–1442PubMedGoogle Scholar
  143. 143.
    Aarnes M, Schonberg S, Grill V (2002) Fatty acids potentiate interleukin-1beta toxicity in the beta-cell line INS-1E. Biochem Biophys Res Commun 296:189–193CrossRefPubMedGoogle Scholar
  144. 144.
    Srinivasan S, Bolick DT, Hatley ME et al (2004) Glucose regulates interleukin-8 production in aortic endothelial cells through activation of the p38 MAP kinase pathway in diabetes. J Biol Chem 279:31930–31936CrossRefPubMedGoogle Scholar
  145. 145.
    Altannavch TS, Roubalova K, Kucera P, Andel M (2004) Effect of high glucose concentrations on expression of ELAM-1, VCAM-1 and ICAM-1 in HUVEC with and without cytokine activation. Physiol Res 53:77–82PubMedGoogle Scholar
  146. 146.
    Takaishi H, Taniguchi T, Takahashi A, Ishikawa Y, Yokoyama M (2003) High glucose accelerates MCP-1 production via p38 MAPK in vascular endothelial cells. Biochem Biophys Res Commun 305:122–128CrossRefPubMedGoogle Scholar
  147. 147.
    Asakawa H, Miyagawa J, Hanafusa T, Kuwajima M, Matsuzawa Y (1997) High glucose and hyperosmolarity increase secretion of interleukin-1 beta in cultured human aortic endothelial cells. J Diabetes Complicat 11:176–179CrossRefPubMedGoogle Scholar
  148. 148.
    Kharroubi I, Ladriere L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL (2004) Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology 145:5087–5096CrossRefPubMedGoogle Scholar
  149. 149.
    Todaro M, Di Gaudio F, Lavitrano M, Stassi G, Papaccio G (2003) Islet beta-cell apoptosis triggered in vivo by interleukin-1beta is not related to the inducible nitric oxide synthase pathway: evidence for mitochondrial function impairment and lipoperoxidation. Endocrinology 144:4264–4271CrossRefPubMedGoogle Scholar
  150. 150.
    Gallucci S, Matzinger P (2001) Danger signals: SOS to the immune system. Curr Opin Immunol 13:114–119CrossRefPubMedGoogle Scholar
  151. 151.
    Lipscomb MF, Masten BJ (2002) Dendritic cells: immune regulators in health and disease. Physiol Rev 82:97–130PubMedGoogle Scholar
  152. 152.
    Pittoni V, Valesini G (2002) The clearance of apoptotic cells: implications for autoimmunity. Autoimmun Rev 1:154–161CrossRefPubMedGoogle Scholar
  153. 153.
    Wick G, Perschinka H, Millonig G (2001) Atherosclerosis as an autoimmune disease: an update. Trends Immunol 22:665–669CrossRefPubMedGoogle Scholar
  154. 154.
    Frostegard J (2002) Autoimmunity, oxidized LDL and cardiovascular disease. Autoimmun Rev 1:233–237CrossRefPubMedGoogle Scholar
  155. 155.
    George J, Yacov N, Breitbart E et al (2004) Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with beta 2-glycoprotein I. Cardiovasc Res 62:603–609CrossRefPubMedGoogle Scholar
  156. 156.
    Clark A, Wells CA, Buley ID et al (1988) Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 9:151–159PubMedGoogle Scholar
  157. 157.
    Hayden MR (2002) Islet amyloid, metabolic syndrome, and the natural progressive history of type 2 diabetes mellitus. JOP 3:126–138PubMedGoogle Scholar
  158. 158.
    Yoon KH, Ko SH, Cho JH et al (2003) Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88:2300–2308CrossRefPubMedGoogle Scholar
  159. 159.
    de Koning EJ, van den Brand JJ, Mott VL et al (1998) Macrophages and pancreatic islet amyloidosis. Amyloid 5:247–254PubMedGoogle Scholar
  160. 160.
    Kubaszek A, Pihlajamaki J, Komarovski V et al (2003) Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes 52:1872–1876PubMedGoogle Scholar
  161. 161.
    Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87–91PubMedGoogle Scholar
  162. 162.
    Paquot N, Castillo MJ, Lefebvre PJ, Scheen AJ (2000) No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J Clin Endocrinol Metab 85:1316–1319CrossRefPubMedGoogle Scholar
  163. 163.
    Di Rocco P, Manco M, Rosa G, Greco AV, Mingrone G (2004) Lowered tumor necrosis factor receptors, but not increased insulin sensitivity, with infliximab. Obes Res 12:734–739PubMedGoogle Scholar
  164. 164.
    Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R (1996) Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45:881–885PubMedGoogle Scholar
  165. 165.
    Rask-Madsen C, Dominguez H, Ihlemann N, Hermann T, Kober L, Torp-Pedersen C (2003) Tumor necrosis factor-alpha inhibits insulin’s stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans. Circulation 108:1815–1821CrossRefPubMedGoogle Scholar
  166. 166.
    Shoelson SE, Lee J, Yuan M (2003) Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord 27 [Suppl 3]:S49–S52CrossRefPubMedGoogle Scholar
  167. 167.
    Willerson JT, Ridker PM (2004) Inflammation as a cardiovascular risk factor. Circulation 109:II2–II10PubMedGoogle Scholar
  168. 168.
    Zheng Z, Lee JE, Yenari MA (2003) Stroke: molecular mechanisms and potential targets for treatment. Curr Mol Med 3:361–372CrossRefPubMedGoogle Scholar
  169. 169.
    Casserly I, Topol E (2004) Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet 363:1139–1146CrossRefPubMedGoogle Scholar
  170. 170.
    Franceschi C, Bonafe M (2003) Centenarians as a model for healthy aging. Biochem Soc Trans 31:457–461CrossRefPubMedGoogle Scholar
  171. 171.
    Grimble RF (2003) Inflammatory response in the elderly. Curr Opin Clin Nutr Metab Care 6:21–29CrossRefPubMedGoogle Scholar
  172. 172.
    Yucesoy B, Kashon ML, Luster MI (2003) Cytokine polymorphisms in chronic inflammatory diseases with reference to occupational diseases. Curr Mol Med 3:39–48CrossRefPubMedGoogle Scholar
  173. 173.
    McGeer PL, McGeer EG (2001) Polymorphisms in inflammatory genes and the risk of Alzheimer disease. Arch Neurol 58:1790–1792CrossRefPubMedGoogle Scholar
  174. 174.
    Duchen MR (2004) Roles of mitochondria in health and disease. Diabetes 53 [Suppl 1]:S96–S102PubMedGoogle Scholar
  175. 175.
    McCord JM (2002) Superoxide dismutase in aging and disease: an overview. Methods Enzymol 349:331–341PubMedGoogle Scholar
  176. 176.
    Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53 [Suppl 3]:S26–S36CrossRefPubMedGoogle Scholar
  177. 177.
    Yoshida M (2003) Potential role of statins in inflammation and atherosclerosis. J Atheroscler Thromb 10:140–144PubMedGoogle Scholar
  178. 178.
    Santangelo F (2003) Intracellular thiol concentration modulating inflammatory response: influence on the regulation of cell functions through cysteine prodrug approach. Curr Med Chem 10:2599–2610CrossRefPubMedGoogle Scholar
  179. 179.
    Rosenson RS (2004) Statins in atherosclerosis: lipid-lowering agents with antioxidant capabilities. Atherosclerosis 173:1–12CrossRefPubMedGoogle Scholar
  180. 180.
    Violi F, Loffredo L, Musella L, Marcoccia A (2004) Should antioxidant status be considered in interventional trials with antioxidants? Heart 90:598–602CrossRefPubMedGoogle Scholar
  181. 181.
    Cuzzocrea S, Thiemermann C, Salvemini D (2004) Potential therapeutic effect of antioxidant therapy in shock and inflammation. Curr Med Chem 11:1147–1162PubMedGoogle Scholar
  182. 182.
    Green K, Brand MD, Murphy MP (2004) Prevention of mitochondrial oxidative damage as a therapeutic strategy in diabetes. Diabetes 53 [Suppl 1]:S110–S118PubMedGoogle Scholar
  183. 183.
    Schmidt MI, Duncan BB (2003) Diabesity: an inflammatory metabolic condition. Clin Chem Lab Med 41:1120–1130CrossRefPubMedGoogle Scholar
  184. 184.
    Theuma P, Fonseca VA (2003) Inflammation and emerging risk factors in diabetes mellitus and atherosclerosis. Curr Diabetes Rep 3:248–254Google Scholar
  185. 185.
    Garg R, Tripathy D, Dandona P (2003) Insulin resistance as a proinflammatory state: mechanisms, mediators, and therapeutic interventions. Curr Drug Targets 4:487–492CrossRefPubMedGoogle Scholar
  186. 186.
    Haffner SM (2003) Insulin resistance, inflammation, and the prediabetic state. Am J Cardiol 92:18J–26JCrossRefPubMedGoogle Scholar
  187. 187.
    Aldhahi W, Hamdy O (2003) Adipokines, inflammation, and the endothelium in diabetes. Curr Diabetes Rep 3:293–298Google Scholar
  188. 188.
    Yudkin JS, Panahloo A, Stehouwer C et al (2000) The influence of improved glycaemic control with insulin and sulphonylureas on acute phase and endothelial markers in type II diabetic subjects. Diabetologia 43:1099–1106CrossRefPubMedGoogle Scholar
  189. 189.
    Sattar N, Gaw A, Scherbakova O et al (2003) Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 108:414–419CrossRefPubMedGoogle Scholar
  190. 190.
    Milani RV, Lavie CJ, Mehra MR (2004) Reduction in C-reactive protein through cardiac rehabilitation and exercise training. J Am Coll Cardiol 43:1056–1061CrossRefPubMedGoogle Scholar
  191. 191.
    Clifton PM, Noakes M, Keogh J, Foster P (2003) How effective are meal replacements for treating obesity? Asia Pac J Clin Nutr 12 [Suppl]:S51Google Scholar
  192. 192.
    Brinkworth GD, Noakes M, Keogh JB, Luscombe ND, Wittert GA, Clifton PM (2004) Long-term effects of a high-protein, low-carbohydrate diet on weight control and cardiovascular risk markers in obese hyperinsulinemic subjects. Int J Obes Relat Metab Disord 28:661–670CrossRefPubMedGoogle Scholar
  193. 193.
    Marfella R, Esposito K, Siniscalchi M et al (2004) Effect of weight loss on cardiac synchronization and proinflammatory cytokines in premenopausal obese women. Diabetes Care 27:47–52PubMedGoogle Scholar
  194. 194.
    Clifton PM (2003) Diet and C-reactive protein. Curr Atheroscler Rep 5:431–436PubMedGoogle Scholar
  195. 195.
    Kopp HP, Kopp CW, Festa A et al (2003) Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients. Arterioscler Thromb Vasc Biol 23:1042–1047CrossRefPubMedGoogle Scholar
  196. 196.
    Esposito K, Pontillo A, Di Palo C et al (2003) Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 289:1799–1804CrossRefPubMedGoogle Scholar
  197. 197.
    Hanusch-Enserer U, Cauza E, Spak M et al (2003) Acute-phase response and immunological markers in morbid obese patients and patients following adjustable gastric banding. Int J Obes Relat Metab Disord 27:355–361CrossRefPubMedGoogle Scholar
  198. 198.
    Laimer M, Ebenbichler CF, Kaser S et al (2002) Markers of chronic inflammation and obesity: a prospective study on the reversibility of this association in middle-aged women undergoing weight loss by surgical intervention. Int J Obes Relat Metab Disord 26:659–662CrossRefPubMedGoogle Scholar
  199. 199.
    Tchernof A, Nolan A, Sites CK, Ades PA, Poehlman ET (2002) Weight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation 105:564–569CrossRefPubMedGoogle Scholar
  200. 200.
    Esposito K, Pontillo A, Ciotola M et al (2002) Weight loss reduces interleukin-18 levels in obese women. J Clin Endocrinol Metab 87:3864–3866CrossRefPubMedGoogle Scholar
  201. 201.
    Heilbronn LK, Noakes M, Clifton PM (2001) Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women. Arterioscler Thromb Vasc Biol 21:968–970PubMedGoogle Scholar
  202. 202.
    Bastard JP, Jardel C, Bruckert E, Vidal H, Hainque B (2000) Variations in plasma soluble tumour necrosis factor receptors after diet-induced weight loss in obesity. Diabetes Obes Metab 2:323–325CrossRefPubMedGoogle Scholar
  203. 203.
    Straczkowski M, Kowalska I, Dzienis-Straczkowska S et al (2001) Changes in tumor necrosis factor-alpha system and insulin sensitivity during an exercise training program in obese women with normal and impaired glucose tolerance. Eur J Endocrinol 145:273–280CrossRefPubMedGoogle Scholar
  204. 204.
    Ziccardi P, Nappo F, Giugliano G et al (2002) Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 105:804–809CrossRefPubMedGoogle Scholar
  205. 205.
    Bruun JM, Verdich C, Toubro S, Astrup A, Richelsen B (2003) Association between measures of insulin sensitivity and circulating levels of interleukin-8, interleukin-6 and tumor necrosis factor-alpha. Effect of weight loss in obese men. Eur J Endocrinol 148:535–542CrossRefPubMedGoogle Scholar
  206. 206.
    Bastard JP, Jardel C, Bruckert E et al (2000) Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 85:3338–3342CrossRefPubMedGoogle Scholar
  207. 207.
    Troseid M, Lappegard KT, Claudi T et al (2004) Exercise reduces plasma levels of the chemokines MCP-1 and IL-8 in subjects with the metabolic syndrome. Eur Heart J 25:349–355CrossRefPubMedGoogle Scholar
  208. 208.
    Fukuzawa M, Satoh J, Qiang X et al (1999) Inhibition of tumor necrosis factor-alpha with anti-diabetic agents. Diabetes Res Clin Pract 43:147–154CrossRefPubMedGoogle Scholar
  209. 209.
    Akbar DH (2003) Effect of metformin and sulfonylurea on C-reactive protein level in well-controlled type 2 diabetics with metabolic syndrome. Endocrine 20:215–218CrossRefPubMedGoogle Scholar
  210. 210.
    Chu NV, Kong AP, Kim DD et al (2002) Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 25:542–549PubMedGoogle Scholar
  211. 211.
    Carlsen SM, Waage A, Grill V, Folling I (1998) Metformin increases circulating tumour necrosis factor-alpha levels in non-obese non-diabetic patients with coronary heart disease. Cytokine 10:66–69CrossRefPubMedGoogle Scholar
  212. 212.
    Ebeling P, Teppo AM, Koistinen HA et al (1999) Troglitazone reduces hyperglycaemia and selectively acute-phase serum proteins in patients with type II diabetes. Diabetologia 42:1433–1438CrossRefPubMedGoogle Scholar
  213. 213.
    Varo N, Vicent D, Libby P et al (2003) Elevated plasma levels of the atherogenic mediator soluble CD40 ligand in diabetic patients: a novel target of thiazolidinediones. Circulation 107:2664–2669CrossRefPubMedGoogle Scholar
  214. 214.
    Katsuki A, Sumida Y, Murata K et al (2000) Troglitazone reduces plasma levels of tumour necrosis factor-alpha in obese patients with type 2 diabetes. Diabetes Obes Metab 2:189–191CrossRefPubMedGoogle Scholar
  215. 215.
    Jeschke MG, Einspanier R, Klein D, Jauch KW (2002) Insulin attenuates the systemic inflammatory response to thermal trauma. Mol Med 8:443–450PubMedGoogle Scholar
  216. 216.
    Dandona P, Aljada A, Mohanty P (2002) The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 45:924–930CrossRefPubMedGoogle Scholar
  217. 217.
    Dandona P, Aljada A, Mohanty P et al (2001) Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86:3257–3265CrossRefPubMedGoogle Scholar
  218. 218.
    Muller S, Martin S, Koenig W et al (2002) Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors. Diabetologia 45:805–812CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.German Diabetes CenterLeibniz-Institute at the University of DüsseldorfDüsseldorfGermany
  2. 2.Steno Diabetes CenterGentofteDenmark
  3. 3.Department of Molecular MedicineKarolinska InstituteStockholmSweden
  4. 4.German Diabetes CenterDüsseldorfGermany

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