Elsevier

Diabetes & Metabolism

Volume 38, Issue 3, June 2012, Pages 183-191
Diabetes & Metabolism

Review
Inflammation and type 2 diabetesInflammation et diabète de type 2

https://doi.org/10.1016/j.diabet.2011.11.006Get rights and content

Abstract

Low-grade inflammation is a common feature in subjects with type 2 diabetes (T2D). Heart disease, the metabolic syndrome and T2D all have in common the increased concentration of circulatory cytokines as a result of inflammation. Inflammatory cytokines are produced by different cell types and secreted into the circulation, where they regulate different tissues through their local, central and peripheral actions. This review focuses on C-reactive protein (CRP), a well-established marker of the development of inflammation, on tumour necrosis factor (TNF)-α, an inflammatory marker strongly associated with diabetes, and on adiponectin, a cytokine produced by adipose tissue and associated with insulin sensitivity. While it is clear from the literature that these cytokines play a major role in the development of T2D or, in the case of adiponectin, its prevention, the best strategy for favourably altering the inflammatory response is still a matter of debate.

Résumé

La présence d’une inflammation chronique est une caractéristique fréquente des patients atteints de diabète de type 2 (DT2). Les maladies cardiovasculaires, le syndrome métabolique et DT2 ont en commun une augmentation des cytokines sanguines qui résultent de l’inflammation. Les cytokines inflammatoires sont produites par différents types de cellules et sont secrétées dans le sang ou elles régulent les différents tissues à travers leurs actions locales, centrales ou périphériques. Cette revue se focalisera sur la protéine C réactive (CRP), marqueur bien établi de l’inflammation, sur le facteur de nécrose tumoral alpha (TNF-α), marqueur inflammatoire fortement associe au diabète et sur l’adiponectine, cytokine produite par le tissu adipeux et associée à l’insulinosensibilité. S’il est clair dans la littérature scientifique que les cytokines jouent un rôle majeur dans le développement ou, dans le cas de l’adiponectine, dans la prévention du DT2, l’intérêt de réduire la réponse inflammatoire fait encore débat.

Introduction

Heart disease, the metabolic syndrome and type 2 diabetes (T2D) all have in common the increased concentration of circulatory cytokines as a result of inflammation [1], [2]. Inflammatory cytokines are produced by different cell types and secreted into the circulation, where they regulate different tissues through their local, central and peripheral actions [3].

Low-grade systemic inflammation is characterized by a two- to threefold increase in systemic plasma concentrations of cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-6 and C-reactive protein (CRP) [4]. Cytokines are small proteins (25 kDa) that are released in response to an activating stimulus and induce responses through binding to specific receptors [5]. The cytokines produced by adipose tissue have a key role in promoting atherosclerosis and, therefore, cardiovascular disease (CVD) [6]. The term ‘adipokines’ includes a group of polypeptide hormones that are expressed predominantly, but not exclusively, by adipose tissue [6]. Adiponectin is the only cytokine discussed in the present report that is produced mainly by adipose tissue [4]. In contrast, although TNF-α is produced by adipose tissue, it is also secreted by macrophages and other cells. This cytokine plays a major role in the inflammatory process and, at elevated concentrations, may promote the synthesis of interleukins such as IL-8, the function of which is to induce monocyte adherence, thereby contributing to the atherosclerotic process [7]. TNF-α is also an inflammatory cytokine that has been implicated in metabolic disorders, including obesity and insulin resistance (IR) [8]. CRP is a cytokine that is mainly produced by the liver. Elevated concentrations of CRP have been associated with coronary heart disease (CHD), obesity, diabetes, smoking and a sedentary lifestyle [9]. In contrast, high concentrations of adiponectin are related to greater insulin sensitivity and a lower risk of CVD [4].

Section snippets

Obesity, inflammation and diabetes

Inflammation appears to be a common link between atherosclerosis, obesity and IR [10]. The increase in adipose tissue mass observed in obesity can lead to chronic activation of the innate immune system that, in turn, can lead to IR and T2D over time. Although implicated in the pathogenesis of chronic disease, the innate immune system serves as the critical first line of defense against invading organisms. Innate immune cells recognize molecular prototypes present on pathogens through

C-reactive protein

There are several metabolic consequences specific to T2D due to chronic elevation of proinflammatory cytokines. Elevated concentrations of CRP have been associated with CVD, obesity, diabetes, inflammation, smoking and a sedentary lifestyle. CRP is produced in the liver upon stimulation by IL-6 and TNF-α [27], but it can also be released by mature adipocytes under inflammatory stimulation by LPS, TNF-α and resistin [28]. CRP increases the production of intracellular adhesion molecule-1 (ICAM-1)

Tumor necrosis factor (TNF)-α

TNF-α belongs to the TNF family, which is produced by macrophages, natural killer cells and T cells. In adipose tissue, infiltrated macrophages are the main source of TNF-α [40]. The cytokine is produced 7.5 times more by adipose tissue in obese subjects than in their lean counterparts [8]. TNF-α promotes inflammation and endothelial activation, increasing vascular permeability [5]. The acute local release of TNF-α induces a local inflammatory response to contain infections and, thus, can be

Adiponectin

Adiponectin is an adipose-specific plasma protein with anti-inflammatory [49] and insulin-sensitizing effects [50] induced by activity of the nuclear receptor PPARγ [51]. A decrease in adipose tissue has been associated with increases in adiponectin [52]. Adiponectin is unique in that, unlike other adipokines, its circulating concentrations are reduced in obesity [53]. Data from epidemiological studies indicate that circulating adiponectin is reduced in patients with CVD and diabetes [54]. More

Diabetes and proinflammatory cytokines

As shown in Fig. 1, a genetic predisposition combined with an ‘obesogenic’ environment can lead to obesity and central adiposity. An obesogenic environment is characterized by excess caloric intake and a lack of PA [63]. This may ultimately lead to increases in body weight, resulting in adipose tissue dysfunction, macrophage infiltration [64], and the greater release of cytokines such as IL-6 and TNF-α. Chronically elevated levels of these molecules promote IR in skeletal muscle [64] and

Gut microbiota and diabetes

Over the past few years, intestinal microbiota have been reported to have a causal relationship in the development of metabolic diseases, including diabetes [74]. Recent advances in DNA sequencing have permitted the collection of microbial communities associated with the human gut [75]. Although there are changes in the microbiota between newborns and the elderly, the adult intestinal microflora have been shown to be stable over time [76]. However, metabolic abnormalities have been associated

Diet and proinflammatory cytokines in people at risk of or with type 2 diabetes

There is a fair amount of evidence from epidemiological studies confirming the relationship between diet and variations in inflammatory markers. It is also known that a diet poor in fruits and vegetables is often characterized by low fibre content, and there are also epidemiological data from single-nutrient approaches on how a low intake of fibre is associated with more inflammatory markers and higher T2D risk. The British Regional Heart Study was a case-control study in which 3428 men (aged

Conclusion

There is now a growing body of knowledge on the modes of action of CRP, TNF-α and adiponectin, and their specific roles in the regulation of inflammation and its implications for the development of diabetes. Population studies have reported important correlations between plasma levels of CRP and TNF-α, and an increased risk of heart disease and diabetes. However, increased concentrations of plasma adiponectin are related to insulin sensitivity and a lower risk of heart disease. While there is a

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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