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.

Figure 1

Diabetes leads to a more persistent inflammatory infiltrate P. gingivalis was inoculated subcutaneously into the scalp. One day after inoculation there was a pronounced and equivalent inflammatory infiltrate in type 2 diabetic (db/db) mice and normoglycemic (db/+) mice (data not shown). A. Three days later the infiltrate was more pronounced in the diabetic mice than control group. B. Inhibition of TNF substantially reverses diabetes-enhanced chemokine dysregulation. Diabetic db/db mice were inoculated with P. gingivalis and treated with etanercept (TNF-inh) or vehicle alone (PBS). RNA was extracted 3 days following inoculation and compared to the zero time point (0). MIP-2 and MCP-1 mRNA levels were substantially improved in the etanercept treated diabetic mice indicating that TNF plays an important role in diabetes-elevated chemokine expression. Adapted with permission from 25).

Figure 2

Diabetes prolongs periodontal inflammation and impairs bone formation following resorption. Ligatures were placed around the molar teeth of ZDF type 2 diabetic and normoglycemic control rats and left in place for seven days. Rats were euthanized prior to placement of ligatures (no ligatures), immediately after removal (7 day) or 4 (4+7) or 9 (9+7) days following ligature removal. A. The interproximal gingiva between the 1st and 2nd and 2nd and 3rd molars was examined for the presence of inflammatory cells (PMNs and mononuclear cells) in HandE stained sections using the following scale: 0 (no inflammation), 1 (slight), 2 (moderate), 3 (severe). B. The area of new bone formation was measured in relationship to a reversal line identified in TRAP stained sections. Each value is the mean of five to seven rats + SE. ¹ indicates significant difference between diabetics and normoglycemic control rats (P<0.05). Adapted with permission from (81).

Figure 3

Diabetes results in enhanced expression of cytokines that regulate osteoclast formation during fracture healing. Fractures were induced in the tibia or streptozotocin induced diabetic and normoglycemic mice. Total RNA from diabetic and normoglycemic mice was extracted, purified and evaluated by real-time PCR. Data for each cytokine were normalized to the value obtained from normoglycemic mice at Day 12, which was set as relative expression = 1. (¹) represents (p<0.05) between normal and diabetic. (²) represents (p<0.05) between one time point and the previous time point. Adapted with permission from (81).

Figure 4

Metabolic dysregulation caused by hyperglycemia alters the innate immune response and contributes to diabetic complications. Due to complexity, the detailed interactions between different pathways are not shown. Hyperglycemia caused by diabetes leads to an increased oxidative stress, activation of the polyol pathway, formation of AGEs and increased PKC activity. These factors affect the innate immune system by increasing proinflammatory cytokine expression such as TNF-alpha, enhancing PMN and monocyte recruitment and impairing bacterial killing. These alterations may contribute to complications seen in diabetes.