Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

Abstract

The objective of this comprehensive review is to summarize and discuss the available evidence of how adipose tissue inflammation affects insulin sensitivity and glucose tolerance. Low-grade, chronic adipose tissue inflammation is characterized by infiltration of macrophages and other immune cell populations into adipose tissue, and a shift towards more pro-inflammatory subtypes of leukocytes. The infiltration of pro-inflammatory cells in adipose tissue is associated with an increased production of key chemokines such as C-C motif chemokine ligand 2, pro-inflammatory cytokines including tumor necrosis factor α and interleukins 1β and 6, as well as reduced expression of the key insulin sensitizing adipokine, adiponectin. In both rodent models and humans, adipose tissue inflammation is consistently associated with excess fat mass and insulin resistance. In humans, associations with insulin resistance are stronger and more consistent for inflammation in visceral as opposed to subcutaneous fat. Further, genetic alterations in mouse models of obesity that reduce adipose tissue inflammation are – almost without exception - associated with improved insulin sensitivity. However, a dissociation between adipose tissue inflammation and insulin resistance can be observed in very few rodent models of obesity as well as in humans following bariatric surgery- or low-calorie diet-induced weight loss, illustrating that the etiology of insulin resistance is multifactorial. Taken together, adipose tissue inflammation is a key factor in the development of insulin resistance and type 2 diabetes in obesity, along with other factors that likely include inflammation and fat accumulation in other metabolically active tissues.

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease

“…While the precise mechanisms that lead to beta cell dysfunction are not completely understood, ectopic fat accumulation may contribute, as discussed earlier. Nonetheless, ample evidence suggests that excess adiposity and adipose tissue inflammation contribute to insulin resistance [reviewed in (64, 367)]. Many studies have demonstrated that excess adiposity is correlated with insulin resistance in humans.…”

“…Several hypotheses have been put forth to account for the relationship between adipose tissue inflammation and insulin resistance. These include production of pro-inflammatory cytokines by adipocytes and adipose tissue macrophages (discussed previously in the section on WAT Inflammation), excess FFA, decreased adiponectin, increased resistin and retinol binding protein, ceramide accumulation, and ectopic fat accumulation in liver and skeletal muscle (367).…”

Serum Cytokine Dependent Hematopoietic Cell Linker (CLNK) as a Predictor for the Duration of Illness in Type 2 Diabetes Mellitus

“…The major finding of the present study is the increase in serum CLNK level in T2DM patients in comparison with the control group as presented in patients, the factor that may underpin the explanation of increased CLNK is via the LGI associated with T2DM disease (Burhans et al 2018;Esser et al 2014). The disease is started with chronic LGI associated obesity, which is involved in the development of IR that increases the risk of T2DM (McGill et al 2008).…”

Insulin resistance is improved in high‐fat fed mice by photobiomodulation therapy at 630 nm

“…A very interesting result of this study was a reduction in inflammatory infiltrate in epididymal and mesenteric adipose tissues in high‐fat fed PBMT‐treated mice. Expansion of adipose tissue leads to immune cells infiltration, forming crown‐like structures around the adipocyte , to a shift toward more pro‐inflammatory subtypes of leukocytes, and to the release of pro‐inflammatory cytokines that promote insulin resistance . Strategies, such as physical exercise training, reduce leucocyte infiltration into adipose tissue and its polarization to a pro‐inflammatory phenotype , improving insulin resistance .…”