Pathogenesis of Macrovascular Complications in Diabetes

Stephen P. Gray, Elyse Di Marco, Riccardo Candido, Mark E. Cooper, Karin A. M. Jandeleit-Dahm

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Macrovascular disease develops in type 1 (T1DM) and type 2 diabetes mellitus (T2DM) and promotes the earlier and premature development of long-term cardiovascular complications in diabetes. A range of hemodynamic and metabolic factors have been considered to contribute to the accelerated development of cardiovascular disease, in particular vasoactive hormone systems such as the renin–angiotensin system and the endothelin and urotensin systems. There are many new players in the renin–angiotensin cascade that have recently been shown to play a significant role in diabetes, including ACE2 and the angiotensin-2 (AT2) receptor. Metabolic pathways including epigenetic modulation and the metabolic memory and also glucose-derived formation of reactive dicarbonyls and advanced glycation end-products (AGEs) have also been shown to be important. Not only do these factors accumulate in the vascular wall but they also activate the pro-inflammatory and pro-fibrotic receptor for AGE (RAGE) leading to vascular inflammation and plaque development. More recently the increased formation of reactive oxygen species (ROS) and reduced antioxidant defense in diabetes resulting in increased vascular oxidative stress has been shown to be a common downstream pathway of many of the other pathways. In addition, immune modulatory mechanisms such as tumor necrosis factor-α (TNF-α) related apoptosis inducing ligand and the complement system have been shown to contribute to macrovascular disease development.

Based on these discoveries novel treatments are currently been developed and evaluated, for example inhibitor of NADPH oxidase derived ROS formation. The cardiovascular benefits of these new agents in addition to established conventional vasculoprotective treatments needs to be demonstrated in early phase clinical trials
Original languageEnglish
Title of host publicationTextbook of Diabetes
EditorsRichard I. G. Holt, Clive S. Cockram, Allan Flyvbjerg, Barry J. Goldstein
Number of pages18
ISBN (Electronic)9781118924853
ISBN (Print)9781118912027
Publication statusPublished - 2017


  • advanced glycation end-products
  • complement system
  • diabetes
  • endothelin
  • inflammation
  • macrovascular complications
  • microvascular complications
  • NADPH oxidases
  • osteoprotegerin
  • oxidative stress
  • plaque formation
  • RAGE
  • reactive oxygen species
  • renin–angiotensin system
  • tumor necrosis factor-related apoptosis-inducing ligands
  • vasoactive hormone
  • urotensin

Cite this

Gray, S. P., Di Marco, E., Candido, R., Cooper, M. E., & Jandeleit-Dahm, K. A. M. (2017). Pathogenesis of Macrovascular Complications in Diabetes. In R. I. G. Holt, C. S. Cockram, A. Flyvbjerg, & B. J. Goldstein (Eds.), Textbook of Diabetes (pp. 611-628). Wiley-Blackwell.