The missing link: A single unifying mechanism for diabetic complications

T. Nishikawa, D. Edelstein, M. Brownlee

Research output: Contribution to journalReview articlepeer-review

421 Scopus citations


A causal relationship between chronic hyperglycemia and diabetic microvascular disease, long inferred from various animal and clinical studies, has now been definitely established by data from the Diabetes Control and Complications Trial (DCCT), a multicenter, randomized, prospective, controlled clinical study. A relationship between chronic hyperglycemia and diabetic macrovascular disease in patients with non-insulin-dependent diabetes mellitus (NIDDM) is also supported by the Kumamoto study. How does hyperglycemia induce the functional and morphologic changes that define diabetic complications? Vascular endothelial cells are a major target of hyperglycemic damage, but the mechanisms underlying this damage remain incompletely understood. Three seemingly independent biochemical pathways are involved in the pathogenesis: glucose-induced activation of protein kinase C (PKC) isoforms; increased formation of glucose-derived advanced glycation end products; and increased glucose flux through the aldose reductase pathway. The relevance of each of these three pathways is supported by animal studies in which pathway-specific inhibitors prevent various hyperglycemia-induced abnormalities. Hyperglycemia increases reactive oxygen species (ROS) production inside cultured bovine aortic endothelial cells. In this paper, we show that ROS may activate aldose reductase, induce diacylglycerol, activate PKC, induce advanced glycation end product formation, and activate the pleiotropic transcription factor nuclear factor-kappa B (NF-κB). These data demonstrate that a single unifying mechanism of induction, increased production of ROS, serves as a causal link between elevated glucose and each of the three major pathways responsible for diabetic damage.

Original languageEnglish (US)
Pages (from-to)S26-S30
JournalKidney International, Supplement
Issue number77
StatePublished - 2000


  • Diabetes mellitus
  • Hyperglycemia
  • NF-κB
  • Protein kinase C

ASJC Scopus subject areas

  • Nephrology


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