:It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammarory therapies could have a place in prevention and treatment of type 2 diabetes.

There has been much concern regarding the role of dietary fructose in the development of metabolic diseases. This concern arises from the continuous increase in fructose (and total added caloric sweeteners consumption) in recent decades, and from the increased use of high-fructose corn syrup (HFCS) as a sweetener. A large body of evidence shows that a high-fructose diet leads to the development of obesity, diabetes, and dyslipidemia in rodents. In humans, fructose has long been known to increase plasma triglyceride concentrations. In addition, when ingested in large amounts as part of a hypercaloric diet, it can cause hepatic insulin resistance, increased total and visceral fat mass, and accumulation of ectopic fat in the liver and skeletal muscle. These early effects may be instrumental in causing, in the long run, the development of the metabolic syndrome. There is however only limited evidence that fructose per se, when consumed in moderate amounts, has deleterious effects. Several effects of a high-fructose diet in humans can be observed with high-fat or high-glucose diets as well, suggesting that an excess caloric intake may be the main factor involved in the development of the metabolic syndrome. The major source of fructose in our diet is with sweetened beverages (and with other products in which caloric sweeteners have been added). The progressive replacement of sucrose by HFCS is however unlikely to be directly involved in the epidemy of metabolic disease, because HFCS appears to have basically the same metabolic effects as sucrose. Consumption of sweetened beverages is however clearly associated with excess calorie intake, and an increased risk of diabetes and cardiovascular diseases through an increase in body weight. This has led to the recommendation to limit the daily intake of sugar calories.Pure, white, and deadly: the dark side of sugar was suspected many years ago, when an association between sugar consumption and coronary heart diseases was recognized and emphasized by John Yudkin [1]. Sugar, a natural sweetener obtained from either sugar cane or beets, is a disaccharide composed of one glucose molecule linked through an α1-4 glycoside bond to a fructose molecule. Fructose, besides contributing to half the total content of sugar, can also be found as a hexose in fruits and honey. More recently, sweeteners started to be produced from corn through starch isolation and hydrolysis to glucose, followed by enzymatic isomerization of part of the glucose into fructose [2,3]. The resulting mixture, known as high-fructose corn syrup (HFCS), has several industrial advantages over sugar, the most important being its low price, and has progressively replaced sugar consumption in North America over the past 30 years.Fructose metabolism has been reviewed extensively elsewhere [4][5][6] and will be only briefly outlined here. In the gut, fructose is transported by specific transporters, GLUT5 [7,8]. In some subjects, fructose absorption is quantitatively limited, and some malabsorption occurs when lar...

Aims/hypothesis Obesity is a heterogeneous condition comprising both individuals who remain metabolically healthy (MHO) and those who develop metabolic disorders (metabolically unhealthy, MUO). Adipose tissue is also heterogeneous in that its visceral component is more frequently associated with metabolic dysfunction than its subcutaneous component. The development of metabolic disorders is partly mediated by the NLR family pyrin domain containing-3 (NLRP3) inflammasome, which increases the secretion of inflammatory cytokines via activation of caspase-1. We compared the immunological profile and NLRP3 activity in adipose tissue between MUO and MHO individuals. Methods MHO and MUO phenotypes were defined, respectively, as the absence and the presence of the metabolic syndrome. Cellular composition and intrinsic inflammasome activity were investigated by flow cytometry, quantitative RT-PCR and tissue culture studies in subcutaneous and visceral adipose tissue from 23 MUO, 21 MHO and nine lean individuals.Results We found significant differences between the three study groups, including an increased secretion of IL-1β, increased expression of IL1B and NLRP3, increased number of adipose tissue macrophages and decreased number of regulatory T cells in the visceral adipose tissue of MUO patients compared with MHO and lean participants. In macrophages derived from visceral adipose tissue, both caspase-1 activity and IL-1β levels were higher in MUO patients than in MHO patients. Furthermore, caspase-1 activity was higher in CD11c + CD206 + adipose tissue macrophages than in CD11c − CD206 + cells. Conclusions/interpretation The MUO phenotype seems to be associated with an increased activation of the NLPR3 inflammasome in macrophages infiltrating visceral adipose tissue, and a less favourable inflammatory profile compared with the MHO phenotype.

The available data supports the concept that targeting inflammation improves insulin sensitivity and β-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity.

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