Diabetes Mellitus and Macrovascular Disease: Mechanisms and Mediators
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
References (36)
- et al.
The metabolic syndrome
Lancet
(2005) - et al.
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
Biochem Biophys Res Commun
(1999) - et al.
AdipoQ is a novel adipose-specific gene dysregulated in obesity
J Biol Chem
(1996) - et al.
Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21–q24
Am J Hum Genet
(2000) - et al.
A prostglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation
Cell
(1995) - et al.
15-Deoxy-Δ12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ
Cell
(1995) - et al.
Metabolic effects of pioglitazone and rosiglitazone in patients with diabetes and the metabolic syndrome treated with glimepiride: a twelve-month multi-center, double blind, randomized, controlled, parallel group trial
Clin Ther
(2004) - et al.
Macrophages in human arthroma contain PPARγ: differentiation-dependent peroxisomal proliferator-activated receptor γ (PPAR-γ) expression and reduction of MMP-9 activity through PPAR-γ activation in mononuclear phagocytes in vitro
Am J Pathol
(1998) - et al.
Heart disease and stroke statistics—2006 update: a report from the AHA Statistics Committee and Stroke Statistics Committee
Circulation
(2006) - et al.
Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes
N Engl J Med
(2004)
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
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