Type 2 diabetes - autoimmune aspects

Type 2 diabetes (T2DM) causation is not restricted to metabolic factors but can include loss of immune tolerance for components of the glucose and insulin regulating systems. A paper published recently in the journal Gerontology reminds that interventions that ameliorate autoimmune inflammation can help to lower blood sugar. The authors state:

"Sustained research over the last 30 years has challenged the stereotypical view that T2DM is solely a metabolic disease by identifying autoimmunity as an overlapping feature of type 1 diabetes (T1DM) and T2DM, which leads to impaired insulin secretion in β cells and promotes hyperglycaemia. Diabetes development based on combined cellular autoimmunity and insulin resistance has been reflected by various terms, such as double diabetes, latent autoimmune diabetes of the adult (LADA) or the young (LADY) or type 1.5 diabetes mellitus."

It's of great importance in type 2 diabetes that...

"Its nosographic characterization is yet a matter of debate, thus many T2DM patients may go undiagnosed for autoimmune β-cell alterations, which may have therapeutic consequences. LADA patients, who are generally defined by age of diagnosis >30 years, presence of circulating islet autoantibodies, and lack of insulin requirement for 6 months after diagnosis, need insulin earlier during disease progression, are likely to respond poorly to oral anti-diabetic mediation, but they could respond favourably to immunomodulator therapy. However, anti-inflammatory and immunomodulatory therapies have also proven effective in improving the metabolic profile of many T2DM patients, possibly by interfering with autoimmune processes and thereby halting the decline of β-cell function."

Important mechanisms for autoimmunity in type 2 diabetes include:

"The chronic inflammatory state in T2DM is characterized by an increased production of cytokines, most notably interleukin (IL)-1β, which destroy [pancreatic] β cells. When tissue inflammation-induced tissue destruction occurs, ‘self' antigens, which are generally not accessible to T cells, can be released from the affected tissues and thus promote autoimmune activation. Concomitantly, many more alarm signals such as various cytokines or extracellular matrix breakdown products can be released into the circulation if cellular death occurs by dysfunctional apoptosis. For approaching autoimmunity in the context of T2DM, one also has to take into account the role of apoptosis-related molecules Fas and Fas ligand and defects in active suppression of self-reactivity by regulatory T cells (Tregs), immune deviations in the T-helper 1/T-helper 2 (Th1/Th2) ratio or defects in B-cell tolerance."

The authors elaborate further on factors associated with loss of immune tolerance in type 2 diabetes that apply to numerous other conditions as well:

"Depending on the immunological model one adheres to, autoimmunity occurs due to defects in self-tolerance or the persistence of danger signals stemming from chronic inflammation and tissue destruction. The latter model...would favour the concept of autoimmune activation in T2DM, as plenty of pathological alterations characteristic of this disease - such as obesity-associated chronic adipose tissue inflammation and β-cell stress induced by gluco- and lipotoxicity - continuously provide danger signals which cause an activation of both innate and adaptive immunity. Danger signals can include any molecules resulting from cellular distress which binds to pattern recognition receptors, such as toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) receptors and cause a local or generalized immune response. This response...triggers IL-1β production."

Simply higher levels of glucose and fatty acids in circulation can promote autoimmunity in type 2 diabetes:

"Increased circulating glucose concentrations activate the NLRP3 inflammasome while increased free fatty acid concentration activate TLR2 and TLR4, which leads to recruitment of macrophages and eventually β-cell stress...‘Glucolipotoxicity'-induced β-cell apoptosis could favour the release of ‘danger signals', autoantibody production, and activation of T cells reactive to β-cell antigens, culminating in further autoimmune destruction of β cells. Indeed, the expression of several β-cell antigens is increased when β cells are stimulated by glucose and decreased when the β cells are less active."

Furthermore...

"From the perspective of the ‘self/non-self' model, the release of ‘cryptic' β-cell antigens through β-cell destruction can have immunogenic potential too: if self-reactive T cells, which have escaped deletion in the thymus, encounter such a β-cell antigen presented in primary lymph nodes by dendritic cells, T-cell priming might occur, followed by further T-cell-mediated β-cell destruction. Stress antigens might drive inflammation in β cells, but also in other metabolically affected tissues in T2DM, such as adipose tissue or the vessel wall."

As for Th17 activity which plays a role in most autoimmune disorders:

"Th17, participates in the induction of autoimmunity and inflammation and their abundance is enhanced in obesity. The increased number of Th17 and CD8+ T cells in T2DM and obesity may also link inflammation to islet autoimmune destruction."

And there is good reason for clinicians to bear in mind the importance of vitamin D in type 2 diabetes considering the necessity of vitamin D for Treg activity and IL-10 production:

"When compared to B cells of healthy subjects, B cells of patients with T2DM fail to secrete the anti-inflammatory interleukin-10 (IL-10) in response to stimulation through TLR2, TLR4 or TLR9. IL-10 secreted by B cells is important for controlling autoimmune processes. Accordingly, low IL-10 production in response to stimulation with lipopolysaccharide was associated with a high risk for T2DM in elderly subjects. It is thus conceivable that dysfunctional B cells might add to altered IL-10 production observed in T2DM....Tregs [regulatory T cells] are necessary for maintaining self-tolerance and immune regulation and include several subsets. They exert their suppressive function through direct cell-cell contact and production of anti-inflammatory cytokines such as IL-10. In mouse models of obesity and T2DM, the number of Tregs in visceral adipose tissue is drastically reduced, whereas induction of Tregs reduces inflammation and mitigates autoimmune reactions, insulin resistance and end-organ complications."

Clinical note: there are the usual wide range of considerations in case management of autoimmunity in type 2 diabetes and a simplistic approach to suppressing inflammation is hardly sufficient, but the authors include interesting comments on a few agents:

"...keeping in mind the prominent role of innate immune system activation in adipose tissue inflammation and T2DM, anti-inflammatory and immunomodulatory therapeutic approaches may be beneficial in improving metabolic regulation in T2DM...Promising results have initially been achieved by targeting IL-1β, an inflammatory cytokine with a pivotal role in islet inflammation in T2DM."

This certainly suggests the use of low dose cytokine therapy with anti-interleukin-1 combined with IL-10. Interestingly...

"High doses of salicylates block the NF-κB pathway and increase circulating adiponectin, an important adipokine counteracting insulin resistance. In a randomized clinical trial, a high dose of salsalate improved metabolic control and HbA1c levels in T2DM patients."

Although high doses of salsalate come with a serious warning for cardiovascular complications and GI bleeding. Omega-3 fatty acids, however, come up benignly as usual:

"Long-chain n-3 polyunsaturated fatty acids (PUFA) are known for their anti-inflammatory actions and immunomodulating effects on T cells. We have recently shown in a randomized controlled trial that treatment of obese, mostly insulin-resistant but non-diabetic patients that the resolving lipid mediator precursors eicosapentaenoic acid (EPA) and docosahexaenoidic acid (DHA) lead to a reduced expression of key inflammatory genes adipose tissue, lower circulating IL-6 concentration parallel to a substantial increase in anti-inflammatory resolving lipid mediators resolvins D1 and E1 as well as protectin D1."

A common anti-hypertensive could possibly do double duty:

"TLRs can be inappropriately activated by self-components and cause inflammation and autoimmunity and have been hypothesized to play a role in the pathogenesis of T2DM. TLRs are downregulated by angiotensin receptor blockers and these substances protected pancreatic islets and reduced adipose tissue inflammation in mice fed a high-fat diet."

And the diabetes drug sitagliplin may have potential to oppose autoimmunity:

"Dipeptidyl peptidase (DPP) inhibitors and GLP-1 analogues alter the inflammatory profile and reduce inflammatory cytokine secretion, while improving glucose metabolism [55]. Interestingly, the DPP-4 inhibitor sitagliplin reduces autoimmunity by decreasing the homing of CD4+ cells into pancreatic β cells in NOD mice and helps preserve islet cell mass."

Finally, practitioners should bear these points in mind:

"Autoimmunity may be both cause and consequence of β-cell dysfunction, imposing in either case a further disturbance in glucose homeostasis. The prevalence of T2DM is on the rise and if 10% of these patients are positive for islet autoantibodies, then testing for islet autoantibodies as part of the diagnostic assessment in T2DM is relevant to a great number of adult patients, as it may contribute to the rate of progression to insulin requirement, particularly in the absence of gross visceral obesity. Autoantibodies indeed help distinguish adult patients with T1DM, LADA or T2DM, but also the presence of self-reactive T cells in autoantibody-negative T2DM patients identifies an autoimmunity that is associated with the metabolic dysregulation...Surely sustained future research is needed in order to understand the complex immune interactions relevant to T2DM, but we should remember that basic measures in the prevention and management of T2DM such as lifestyle changes also repress inflammation and autoimmune reactions, and are therefore a major tool to help decrease β-cell stress and compensate for the relative lack of insulin."