Type 2 Diabetes: How Much of an Autoimmune Disease?

Abstract

Type 2 diabetes (T2D) is characterized by a progressive status of chronic, low-grade inflammation (LGI) that accompanies the whole trajectory of the disease, from its inception to complication development. Accumulating evidence is disclosing a long list of possible "triggers" of inflammatory responses, many of which are promoted by unhealthy lifestyle choices and advanced age. Diabetic patients show an altered number and function of immune cells, of both innate and acquired immunity. Reactive autoantibodies against islet antigens can be detected in a subpopulation of patients, while emerging data are also suggesting an altered function of specific T lymphocyte populations, including T regulatory (Treg) cells. These observations led to the hypothesis that part of the inflammatory response mounting in T2D is attributable to an autoimmune phenomenon. Here, we review recent data supporting this framework, with a specific focus on both tissue resident and circulating Treg populations. We also propose that selective interception (or expansion) of T cell subsets could be an alternative avenue to dampen inappropriate inflammatory responses without compromising immune responses.

Keywords: T cells; autoimmunity; diabetes; immunometabolism; inflammation.

Figure 1

The continuous range of diabetes. Notwithstanding the different risk factors, instead of being clearly confined, T1D, LADA, and T2D patients are now known to present overlaying/overlapping clinical characteristics. LADA patients range from showing clear signs of β cell dysfunction (insulin deficiency and low levels of C-peptide) associated with strong markers of autoimmunity (presence of islet-cell autoantibodies) to patients showing a higher grade of insulin resistance and other pathological components resembling T2D condition [metabolic syndrome and systemic low-grade inflammation (LGI)]. The pathological features of the different forms of diabetes manifest as an uninterrupted spectrum that fails to clearly discriminate T1D and T2D.

Figure 2

The inflammatory/autoimmune components of type 2 diabetes. Low-grade inflammation (LGI) induced by a high adipocyte mass, together with an elevated abundance of pro-inflammatory cytokines and adipocytokines produced by fat tissue, may hamper the number and function of anti-inflammatory Treg cells and diminish the level of anti-inflammatory cytokines, hence promoting immune responses by the CD4⁺ and CD8⁺ T cell subsets, including those with an autoreactive potential. The pancreatic β cell death leads to two pathological consequences in a vicious cycle of autoimmunity and metabolic dysregulation: (i) the potential increase of pancreatic cryptic self-antigens and (ii) a diminished ability to respond to insulin demand, with consequent further dysregulation of glucose levels. The presence of these phenomena is possibly significantly variable from patient to patient.