Prediabetes as a toxic environment for the initiation of microvascular and macrovascular complications

Abstract

Prediabetes is a state characterized by impaired fasting glucose or impaired glucose tolerance. Evidence is increasingly demonstrating that prediabetes is a toxic state, in addition to being a harbinger of future development of diabetes mellitus. This minireview discusses the pathophysiology and clinical significance of prediabetes, and approach to its management, in the context of the worldwide diabetes epidemic. The pathophysiologic defects underlying prediabetes include insulin resistance, β cell dysfunction, increased lipolysis, inflammation, suboptimal incretin effect, and possibly hepatic glucose overproduction. Recent studies have revealed that the long-term complications of diabetes may manifest in some people with prediabetes; these complications include classical microvascular and macrovascular disorders, and our discussion explores the role of glycemia in their development. Finally, landmark intervention studies in prediabetes, including lifestyle modification and pharmacologic treatment, are reviewed.

Keywords: Impaired fasting glucose; impaired glucose tolerance; macrovascular; microvascular; prediabetes complications; prevention.

© 2016 by the Society for Experimental Biology and Medicine.

Figures

Figure 1

Pathophysiology of prediabetes: skeletal muscle insulin resistance, impaired insulin secretion by the pancreatic β-cells, dysregulated hepatic glucose production and increased lipolysis are among the documented defects underlying the development of prediabetes. (A color version of this figure is available in the online journal.)

Figure 2

The toxic environment of prediabetes increases the risks for macrovascular and microvascular complications

Figure 3

Toxic pathways linking blood glucose levels to tissue damage in susceptible persons. Intracellular hyperglycemia activates the aldose reductase (polyol) pathway as well as other pathways involving advanced glycosylation, PKC activation and increased flux through nutrient-sensing the hexosamine pathway. These activated pathways further lead to induction of downstream processes that mediate fibrosis, vascular dysfunction, inflammation, free radical generation, and tissue damage. AGE: advanced glycosylation end products; eNOS: endothelial nitric oxide synthase; NF-kB: nuclear factor-kB; PAI-1: plasminogen activator inhibitor-1; PKC: protein kinase C; RAGE: receptor for AGE; TGF-b: transforming growth factor-b; UDP: uridine diphosphate; VEGF: vascular endothelial growth factor. (A color version of this figure is available in the online journal.)