Publications (3)11.76 Total impact
Article: Reducing the risk of stroke in type 2 diabetes: pathophysiological and therapeutic perspectives.[show abstract] [hide abstract]
ABSTRACT: Reducing the excess cerebrovascular burden in patients with type 2 diabetes remains a major therapeutic challenge, especially with respect to the high risk of recurrent events. Targeting the traditional metabolic risk factors of hypertension, dyslipidemia, and hyperglycemia has failed to remove this excess risk, and agents targeting thrombotic risk (i.e., antiplatelet and anticoagulant drugs) remain poorly studied in the context of stroke in diabetes. This may relate to the accumulation of risk factors in type 2 diabetes as well as to diabetes-specific pathophysiologic factors. Regrettably, there is a lack of prospective evidence to support the efficacy of interventions in the secondary prevention of cerebrovascular events in type 2 diabetes, particularly recurrent stroke events. Overall, there is a need for rigorous evaluations of new therapeutic approaches in both primary and secondary prevention of stroke and management of acute stroke in patients with type 2 diabetes. This systematic review of the published literature summarizes the evidence regarding current therapeutic interventions and their impact on the risk of stroke in people with type 2 diabetes, and highlights potential strategies for improving outcomes.Journal of Neurology 05/2009; 256(10):1603-19. · 3.47 Impact Factor
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ABSTRACT: Insulin resistance is an independent risk factor for the development of cardiovascular atherosclerosis. A key step in the development of atherosclerosis is endothelial dysfunction, manifest by a reduction in bioactivity of nitric oxide (NO). Insulin resistance is associated with endothelial dysfunction; however, the mechanistic relationship between these abnormalities and the role of impaired endothelial insulin signaling versus global insulin resistance remains unclear. To examine the effects of insulin resistance specific to the endothelium, we generated a transgenic mouse with endothelium-targeted overexpression of a dominant-negative mutant human insulin receptor (ESMIRO). This receptor has a mutation (Ala-Thr(1134)) in its tyrosine kinase domain that disrupts insulin signaling. Humans with the Thr(1134) mutation are insulin resistant. We performed metabolic and vascular characterization of this model. ESMIRO mice had preserved glucose homeostasis and were normotensive. They had significant endothelial dysfunction as evidenced by blunted aortic vasorelaxant responses to acetylcholine (ACh) and calcium ionophore. Furthermore, the vascular action of insulin was lost in ESMIRO mice, and insulin-induced endothelial NO synthase (eNOS) phosphorylation was blunted. Despite this phenotype, ESMIRO mice demonstrate similar levels of eNOS mRNA and protein expression to wild type. ACh-induced relaxation was normalized by the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride. Endothelial cells of ESMIRO mice showed increased superoxide generation and increased mRNA expression of the NADPH oxidase isoforms Nox2 and Nox4. Selective endothelial insulin resistance is sufficient to induce a reduction in NO bioavailability and endothelial dysfunction that is secondary to increased generation of reactive oxygen species. This arises independent of a significant metabolic phenotype.Diabetes 11/2008; 57(12):3307-14. · 8.29 Impact Factor
Article: Insulin and endothelial function: physiological environment defines effect on atherosclerotic risk.[show abstract] [hide abstract]
ABSTRACT: A number of population studies have suggested that hyperinsulinaemia is an independent risk factor for the development of cardiovascular atherosclerosis. Furthermore, there is an emerging body of evidence supporting a role for insulin as both a vasoregulatory and glucoregulatory peptide. Principal amongst insulin's putative vascular effects is to stimulate release of the anti-atherosclerotic signalling molecule nitric oxide (NO) from endothelial cells. Moreover, there is data demonstrating that in parallel to insulin mediated glucose uptake, stimulation of NO release by insulin is blunted in insulin resistant conditions. A number of in-vitro studies have begun to dissect and define the pathway by which insulin stimulates release of NO from endothelial cells and complimentary studies in gene-modified murine models of abnormal insulin signalling and/or hyperinsulinaemia have begun to elucidate the role of hyperinsulinaemia in NO release in-vivo. It is emerging that the effects of insulin on endothelial function are complex and in part dependent on the physiological/pathophysiological environment present when insulin binds to its receptor on the endothelial cell surface. The present article reviews the evidence for insulin being a pro-atherosclerotic and anti-atherosclerotic peptide with particular reference to endothelial cell derived NO bioavailability. In the present review we attempt to clarify the complex relationship between insulin, endothelial function and the risk of atherosclerosis by using data from in-vivo and ex-vivo models.Current Diabetes Reviews 03/2006; 2(1):51-61.