Immune cells link obesity-associated type 2 diabetes and periodontitis

Abstract

The clinical association between obesity-associated type 2 diabetes (T2D) and periodontitis, coupled with the increasing prevalence of these diseases, justifies studies to identify mechanisms responsible for the vicious feed-forward loop between systemic and oral disease. Changes in the immune system are critical for both obesity-associated T2D and periodontitis and therefore may link these diseases. Recent studies at the intersection of immunology and metabolism have greatly advanced our understanding of the role the immune system plays in the transition between obesity and obesity-associated T2D and have shown that immune cells exhibit similar functional changes in obesity/T2D and periodontitis. Furthermore, myeloid and lymphoid cells likely synergize to promote obesity/T2D-associated periodontitis despite complexities introduced by disease interaction. Thus the groundwork is being laid for researchers to exploit existing models to understand immune cell dysfunction and break the devastating relationship between obesity-associated T2D and oral disease.

Keywords: cell biology; cytokine(s); inflammation; periodontal disease.

Figure 1.

The relationships among obesity, type 2 diabetes (T2D), and periodontitis. (A) Obesity and T2D are highly interrelated in humans. Under conditions of calorie excess (diet-induced obesity), many people develop metabolically abnormal obesity (MAO), which includes individuals with obesity-associated T2D. However, some with T2D are not obese, and this is more prevalent in some genetic backgrounds. There are also individuals labeled ‘metabolically healthy obese’ (MHO) who are relatively protected from obese-associated co-morbidities including inflammation and insulin resistance. These distinct populations are not seen in wild-type mouse models, since mice usually develop obesity and metabolic abnormalities simultaneously. (B) The recognition of obesity as a cause of T2D and the bi-directional relationship between T2D and periodontitis are well-appreciated. It has been recently established that there is an association between obesity and periodontitis. Analysis of accumulating data, taken together with evidence that T2D potentiates periodontitis, suggests a three-way relationship among obesity, T2D, and periodontitis, with each condition influencing the other 2. The altered microbiota and dysregulated host response (including immune cell dysfunction) could be dynamic drivers (arrows) of these disease gears. Studies often fail to identify obese individuals adequately as MHO or as metabolically unhealthy; thus the location of MHO in this panel is unknown.

Figure 2.

Working hypothesis of the link between obesity-associated type 2 diabetes (T2D) and periodontitis. Obesity-associated T2D results in increased pro-inflammatory metabolites such as free fatty acids and glucose as well as endotoxin from increased gut permeability. Obesity also results in higher concentrations of adipocyte cytokines, as well as the altered intestinal microbiota, all of which trigger surface signaling molecules including Toll-like receptors (TLRs) and cytokine receptors. These receptors activate a wide array of immunological cells types, including most immune system cells as shown, and structural cells with innate immune responses such as adipocytes, gingival epithelial cells, and fibroblasts (not shown). Thus, obesity/T2D primes immune mechanisms for an inappropriately robust response to oral pathogens that results in periodontal inflammation and exaggerated tissue destruction.