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Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily

Nature Reviews Endocrinology volume 6, pages 94–101 (2010)Cite this article

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Abstract

Among the most serious consequences of diabetes mellitus is the development of diabetic angiopathy, of which the clinical features are cardiovascular disease, retinopathy, nephropathy and neuropathy. Diabetic kidney problems affect up to one third of all patients with diabetes mellitus and are a major cause of end-stage renal failure. Although a huge number of pharmaceutical interventions are available today, diabetic angiopathy remains a leading cause of mortality and morbidity in diabetes mellitus, therefore, an urgent need exists to develop new therapeutic strategies. Recent data support the hypothesis that dysregulation of the complement system and of members of the tumor necrosis factor (TNF) superfamily may be involved in the development of diabetic vascular complications. The mannose-binding lectin pathway—an overall regulatory component of the complement system—is a particularly promising biomarker as it is directly involved in the development of diabetic angiopathy. In addition, two components of the TNF superfamily, namely TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and osteoprotegerin, may be involved in the pathogenesis of diabetic angiopathy. Several ways of specifically manipulating the complement and TNF superfamily systems already exist, but whether or not these drugs provide new targets for intervention for late diabetic complications is still to be revealed.

Key Points

  • The development of diabetic angiopathy has serious individual and societal consequences because of the substantial impact on morbidity and mortality

  • Despite lifestyle changes and drug intervention against hyperglycemia, hypertension and dyslipidemia, microvascular and macrovascular complications are still a clinical problem in patients with diabetes mellitus

  • An ongoing need exists to develop better risk markers of diabetic angiopathy and drugs that act more specifically

  • Emerging evidence supports a role of the complement system and of members of the tumor necrosis factor superfamily in the pathogenesis of diabetic vascular complications

  • Mannose-binding lectin and osteoprotegerin are strong and independent biomarkers of microvascular and macrovascular complications in diabetes mellitus

  • Agonists and antagonists against components of the complement system and the tumor necrosis factor superfamily may prove effective in the treatment of diabetic vascular complications

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Figure 1: Schematic depiction of the complement system, which can be activated through three different pathways.
Figure 2: Serum level of MBL is a strong predictor of both the development of albuminuria and overall mortality in patients with type 2 diabetes mellitus (T2DM).
Figure 3: Schematic depiction of the actions and interactions between the TNF superfamily components: TRAIL, TRAIL receptors 1 to 4, osteoprotegerin, RANKL and RANK.
Figure 4: Osteoprotegerin level is a strong predictor of late diabetic complications and mortality.

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  1. Medical Department of Endocrinology and Internal Medicine, Aarhus University Hospital and The Medical Research Laboratories, Clinical Institute, Nørrebrogade 44, Aarhus C, DK-8000, Denmark

    Allan Flyvbjerg

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Flyvbjerg, A. Diabetic angiopathy, the complement system and the tumor necrosis factor superfamily. Nat Rev Endocrinol 6, 94–101 (2010). https://doi.org/10.1038/nrendo.2009.266

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