Diabetic complications and dysregulated innate immunity

Abstract

Diabetes mellitus is a metabolic disorder that leads to the development of a number of complications. The etiology of each diabetic complication is undoubtedly multifactorial. We will focus on one potential component that may be common in many diabetic complications, dysregulation of innate immunity associated with an increased inflammatory response. High glucose levels lead to shunting through the polyol pathway, an increase in diacylglycerol which activates protein kinase C, an increase in the release of electrons that react with oxygen molecules to form superoxides, and the non-enzymatic glycosylation of proteins that result in greater formation of advanced glycation end products. Each of these can lead to aberrant cell signalling that affects innate immunity for example, by activating the MAP kinase pathway or inducing activation of transcription factors such as NF-kappaB. This may be a common feature of several complications including periodontal disease, atherosclerosis, nephropathy, impaired healing and retinopathy. These complications are frequently associated with increased expression of inflammatory cytokines such as TNF-alpha, IL-1beta and IL-6 and enhanced generation of reactive oxygen species. Cause and effect relationship between dysregulation of key components of innate immunity and diabetic complications in many instances have been demonstrated with the use of cytokine blockers and antioxidants.

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

“…Oxidative stress is inextricably linked with chronic inflammation (Chapple et al 1996, Graves & Kayal 2008. Biochemical markers of systemic oxidative stress are elevated in both diabetes and periodontitis (Bullon et al 2009) and are positively correlated with CRP in periodontitis patients as compared to healthy controls (D'Aiuto et al 2010).…”

“…For example, it is known that reactive oxygen species stimulate pro-inflammatory cytokine production through activation of intracellular signalling pathways such as MAP kinase, NF-jB and the NALP3 inflammasome (Graves & Kayal 2008, Martinon 2010. Reactive oxygen species also have more wide ranging effects including effects on bone formation and recently revealed pathways involving the interaction of reactive oxygen species, Wnt signalling and activation of FoxO transcription factors in the regulation of osteoblast activity suggest another novel pathway which may link periodontitis and diabetes (Almeida et al 2011, Galli et al 2011.…”

“…In addition, hyperglycaemia may lead to oxidative stress via a number of pathways with subsequent effects on inflammatory responses, but their role in periodontal pathogenesis remains largely obscure (Graves & Kayal 2008). For example, it is known that reactive oxygen species stimulate pro-inflammatory cytokine production through activation of intracellular signalling pathways such as MAP kinase, NF-jB and the NALP3 inflammasome (Graves & Kayal 2008, Martinon 2010.…”

“…Systemic changes in cytokine levels are central to pathogenesis in T2DM (Pickup & Crook 1998) and these immune changes (often described as chronic, low-grade inflammation) can underpin insulin resistance and islet cell apoptosis leading to insulin deficiency and therefore progression of the diabetic state (Donath & Shoelson 2011, Fernandez-Real & Pickup 2012. Critically, localized effects of immune dysregulation may underpin complications associated with T2DM; these include vascular disease, retinopathy, nephropathy and impaired healing (Graves & Kayal 2008, King 2008. A number of clinical trials provide evidence for the utility of cytokine analysis in pre-clinical diagnosis of T2DM (Carstensen et al 2010) and for cytokine blockade in therapy for T2DM (Larsen et al 2009).…”

Impact of Resolvin E1 on Murine Neutrophil Phagocytosis in Type 2 Diabetes

“…A major link between T2D and its complications is inflammation (2,3). Enhanced inflammation is well characterized in T2D (4), and prolonged inflammation is an important aspect of periodontitis complications (5). Tumor necrosis factor alpha (TNF-␣), which has been implicated as a proinflammatory adipokine in T2D and obesity, seems to play an important role.…”