Inflammation and Microvascular Complications

Microvascular complications make a major contribution to the burden of diabetic complications, and understanding the common pathogenic mechanisms underlying diabetic retinopathy, neuropathy and nephropathy is an essential step towards effective prevention and management. The role of hyperglycaemia as a risk factor leading to diabetic microvascular complications was identified by landmark studies such as the UKPDS and DCCT. These studies showed that stringent regulation of blood glucose was of key importance in primary prevention of microvascular complications, i.e. preventing their onset. They also showed that glucose control was less effective in modulating the progression of established microvascular complications (secondary prevention). The implication is that other pathways and pathogenic mechanisms must be involved at this stage of the disease. This section considers the possible role of inflammation in diabetic microvascular complications.

Diabetic Complications
Diabetic Complications
Chronic complications associated with diabetes include microvascular complications which affect small blood vessels and macrovascular complications affecting large blood vessels. While diabetes increases the risk of macrovascular diseases such as heart attacks and strokes by 2-3 folds, the silent killers in diabetes are often the microvascular complications. Over the years, a number of biochemical pathways have been studied as potential contributors to the incidence and progression diabetic microvascular complications[1].

One leading candidate is the inflammatory pathway, the body's natural protector. This provides is an intricate and complex response to both exogenous as well as endogenous factors. The Immune Response
The Immune Response

While inflammation is generally considered as acute or chronic in nature, chronic sub-clinical activation of the inflammatory pathway is present in all diabetic microvascular complications. Physiological mechanisms of protection and healing then begin to contribute to cellular damage by amplifying inflammation as well as promoting oxidative stress and tissue remodelling.

The evidence suggesting that inflammation and diabetic complications are somehow linked emerges from several cross-sectional and prospective clinical studies showing that circulating inflammatory markers are systemically increased in patients with T1DM and T2DM, and that their levels might predict the onset and progression of diabetic complications[2].

The involvement of low-grade chronic inflammation in diabetic complications is based on the expression and production of numerous markers of inflammation that include pro-inflammatory cytokines such as, tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP), and monocyte chemoattractant protein-1 (MCP-1). The plasma level of the CRP is an accepted highly sensitive marker of systemic inflammatory activity. CRP is synthesized by the liver, smooth muscle cells, and adipocytes. The production of CRP stimulates TNF-α and IL-1 [3] and the levels are associated with insulin resistance, T2DM and the development of cardiovascular disease [4].

These inflammatory markers also include adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). The soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) released from activated endothelial cells are also regarded as markers of inflammation and control both leukocyte activation and their migration to the site of inflammation. Increased circulating levels of sVCAM-1 and ICAM-1 are closely associated with their increased expression on the surface of endothelial cells.

At the cellular level, these pro-inflammatory signals are linked with the dysfunctional activation of numerous other pathways. Recent interest has centred around the inflammatory response and increased immune cell adhesion as a contributor to capillary occlusion and therefore to altered haemodynamics.

The impact of tissue infiltration by immunological cells
The impact of tissue infiltration by immunological cells
This has been accompanied by an increased appreciation, both at the clinical research level as well as in animal models, of the role of tissue infiltration by activated immune cells. The extent of immune cell infiltration is closely associated with increased tissue damage as well as progression of microvascular complication.

Therapeutic Implications

While inflammation has emerged as a central contributor to the progression of diabetic complications, inhibitors of inflammation alone do not prevent or reverse these complications. Most importantly, these intervention-based findings highlight that there is no single magic bullet and that future interventions are likely to be based around combination therapies. Better understanding of the link between diabetic microvascular complications should eventually lead to refined management strategies and improved patient outcomes in the expanding diabetes epidemic.

References

  1. ^ Sheetz MJ, King GL. Molecular understanding of hyperglycemia's adverse effects for diabetic complications. JAMA 2002;288:1579-88

  2. ^ Kaul, Kirti, et al. "Is inflammation a common retinal-renal-nerve pathogenic link in diabetes?." Current diabetes reviews 6.5 (2010): 294-303.

  3. ^ Chung, Hae Young, et al. "Molecular inflammation: underpinnings of aging and age-related diseases." Ageing research reviews 8.1 (2009): 18-30.

  4. ^ Pickup, John C. "Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes." Diabetes care 27.3 (2004): 813-823.

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