Diabetes Mellitus and Macrovascular Disease: Mechanisms and Mediators

doi:10.1016/j.amjmed.2007.07.003

The American Journal of Medicine

Volume 120, Issue 9, Supplement 2, September 2007, Pages S12-S17

https://doi.org/10.1016/j.amjmed.2007.07.003 Get rights and content

Abstract

Atherosclerosis is a chronic inflammatory condition initiated in the endothelium in response to injury and maintained through the interactions between modified lipoproteins, macrophages, and arterial wall constituents. Risk for macrovascular disease is substantially increased in patients with type 2 diabetes mellitus. Factors underlying the link between insulin resistance/type 2 diabetes and macrovascular disease include reduced adiponectin concentration, increased expression of vascular cell adhesion molecule–1 and consequent adhesion of T-lymphocytes to the coronary endothelium, procoagulability with increased expression of plasminogen activator inhibitor–1 (PAI)-1, and instability of atherosclerotic plaques resulting from increased expression by macrophages of matrix metalloproteinases (MMPs). Thiazolidinediones (TZDs) are agonists of peroxisome proliferator-activated receptor (PPAR)–γ and increase adiponectin. TZD therapy is associated with decreases in hepatic fat content and glycosylated hemoglobin and an increase in hepatic glucose disposal. TZDs lower circulating free fatty acid concentration and triglyceride content in the liver, but not in skeletal muscle. Effects of PPAR-γ agonists in vitro and in animal models provide evidence for additional potential antiatherosclerotic benefits in patients with diabetes beyond the treatment of hyperglycemia and dyslipidemia, including the reduction of expression of macrophage MMPs and scavenger receptor-1, and indirect reduction of PAI-1 and inhibition of vascular smooth muscle cell proliferation, via suppression of type 1 angiotensin-2 receptor expression. Dual PPAR-α/γ agonists, retinoid receptor agonists, and, to a lesser extent, TZDs, also stimulate cholesterol efflux from macrophages in vitro.

Section snippets

Insulin resistance: A mitochondrial defect

The basis of insulin resistance has been investigated in the young, lean, insulin-resistant offspring of a parent or grandparent with type 2 diabetes, i.e., individuals unlikely to have other confounding factors.³ In comparison with insulin-sensitive control subjects matched for age, height, weight, and physical activity, insulin-resistant individuals showed moderate but statistically significant hyperglycemia and hyperinsulinemia before and during a glucose tolerance test, although there was

The role of adiponectin

If insulin resistance is the result of a mitochondrial defect, what, then, are the implications for cardiovascular disease? Adipose tissue plays an important role in insulin resistance through the production and secretion of a variety of proteins, including TNF-α, plasminogen activator inhibitor (PAI)–1, resistin, components of the renin-angiotensin system, and adiponectin, that may modulate insulin sensitivity and glucose and lipid metabolism.4, 5 Of these, adiponectin is of particular

Adiponectin as a therapeutic target

Adiponectin has antiatherogenic properties. It appears to be an antagonist of TNF-α, counteracting its proinflammatory effects on arterial walls, and, in isolated human coronary endothelium, inhibits TNF-α–mediated adhesion of monocytes and induction of VCAM-1.13, 14 Because binding to VCAM-1 is required for T-lymphocytes to gain access to the subendothelial space, increased adiponectin concentrations could reduce subendothelial inflammation and oppose atherosclerotic processes.

Apolipoprotein

Raising adiponectin via peroxisome proliferator–activated receptor activation

The promoter sequence for the adiponectin gene contains a peroxisome proliferator-activated receptor (PPAR)–γ response element.¹⁷ PPARs, of which there are 3 subtypes (α, β, and γ), are ligand-activated transcription factors that act as mediators of inflammatory responses and regulators of lipid metabolism. PPARs form a functional heterodimer with the retinoid X receptor (RXR)–α and bind to specific DNA sequences in the promoter regions of target genes, such as the adiponectin gene. Eicosanoids

Additional effects of peroxisome proliferator–activated receptor activation

Prostaglandin D₂ metabolites are major products of arachidonic acid metabolism in macrophages, and PPAR-γ can be identified in monocytes and macrophages from human atherosclerotic lesions but not in normal artery specimens.²⁸ In vitro, the expression of markers of macrophage activation, nitric oxide synthase, matrix metalloproteinase (MMP)–9 (gelatinase B), and SRA-1, is inhibited by activation of PPAR-γ using a TZD or 15d-PGJ₂.²⁹ Although the uptake of oxidized LDL by macrophages via SRA-1 is

Procoagulability and plaque rupture

The ultimate problem in atherosclerosis is plaque rupture, thrombosis, and major vessel occlusion. The driving factor for this increased risk in diabetes is procoagulability, an increase in platelet aggregation, coupled with an increase in plasma concentrations of PAI-1 and other thrombotic factors.³³ Insulin, proinsulin-like molecules, glucose, and very-low-density lipoprotein directly stimulate transcription and secretion of PAI-1 in endothelial and smooth muscle cells. Immunohistochemical

Summary

The link between insulin resistance/type 2 diabetes and cardiovascular disease is based on procoagulability. Angiotensin II is a positive regulator of PAI-1 production and also stimulates vascular smooth muscle cell proliferation.

Expression of AT-R1 can be suppressed by PPAR-γ activators, including TZDs. Atherosclerotic plaques are destabilized by MMPs released by macrophages. Activation of PPAR-γ is strongly inhibited by concurrent PPAR-γ activation. Finally, there are low adiponectin

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Diabetes Mellitus and Macrovascular Disease: Mechanisms and Mediators

Abstract

Section snippets

Insulin resistance: A mitochondrial defect

The role of adiponectin

Adiponectin as a therapeutic target

Raising adiponectin via peroxisome proliferator–activated receptor activation

Additional effects of peroxisome proliferator–activated receptor activation

Procoagulability and plaque rupture

Summary

Lancet

Biochem Biophys Res Commun

J Biol Chem

Am J Hum Genet

Cell

Cell

Clin Ther

Am J Pathol

Heart disease and stroke statistics—2006 update: a report from the AHA Statistics Committee and Stroke Statistics Committee

Circulation

Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes

N Engl J Med

Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndrome

Diabetes

Adipose tissue as an endocrine organ

J Clin Endocrinol Metab

Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome

J Clin Invest

Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia

J Clin Endocrinol Metab

Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients

Arterioscler Thromb Vasc Biol

Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome

Proc Natl Acad Sci U S A

Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin

Circulation

Recent advances in the relationship between obesity, inflammation, and insulin resistance

Eur Cytokine Netw