Metformin treatment corrects vascular insulin resistance in hypertension

Verma, Subodh; Yao, Linfu; Dumont, Aaron S.; McNeill, John H.

doi:10.1097/00004872-200018100-00012

Cited by 53 publications

(36 citation statements)

References 7 publications

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“…Unlike traditionally used glucose-lowering reagents, such as sulfonylureas or insulin, metformin improves cardiovascular functions and reduces cardiovascular risks in diabetes (10 -15). Several studies both in vitro and in vivo have shown that metformin has insulin-sensitizing effects (13)(14)(15). Despite the long history and success of metformin as a treatment for type II diabetes, its mechanism of action remains an enigma.…”

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confidence: 99%

Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo

Zou

Kirkpatrick

Davis

et al. 2004

Journal of Biological Chemistry

430

283

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Metformin, one of the most commonly used drugs for the treatment of type II diabetes, was recently found to exert its therapeutic effects, at least in part, by activating the AMP-activated protein kinase (AMPK). However, the site of its action, as well as the mechanism to activate AMPK, remains elusive. Here we report how metformin activates AMPK. In cultured bovine aortic endothelial cells, metformin dose-dependently activated AMPK in parallel with increased detection of reactive nitrogen species (RNS). Further, either depletion of mitochondria or adenoviral overexpression of superoxide dismutases, as well as inhibition of nitric-oxide synthase, abolished the metformin-enhanced phosphorylations and activities of AMPK, implicating that activation of AMPK by metformin might be mediated by the mitochondria-derived RNS. Furthermore, administration of metformin, which increased 3-nitrotyrosine staining in hearts of C57BL6, resulted in parallel activation of AMPK in the aorta and hearts of C57BL6 mice but not in those of endothelial nitric-oxide synthase (eNOS) knockout mice in which metformin had no effect on 3-nitrotyrosine staining. Because the eNOS knockout mice expressed normal levels of AMPK-␣ that was activated by 5-aminoimidazole-4-carboxamide riboside, an AMPK agonist, these data indicate that RNS generated by metformin is required for AMPK activation in vivo. In addition, metformin significantly increased the coimmunoprecipitation of AMPK and its upstream kinase, LKB1, in C57BL6 mice administered to metformin in vivo. Using pharmacological and genetic inhibitors, we found that inhibition of either c-Src or PI3K abolished AMPK that was enhanced by metformin. We conclude that activation of AMPK by metformin might be mediated by mitochondria-derived RNS, and activation of the c-Src/PI3K pathway might generate a metabolite or other molecule inside the cell to promote AMPK activation by the LKB1 complex.

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mentioning

confidence: 99%

Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo

Zou

Kirkpatrick

Davis

et al. 2004

Journal of Biological Chemistry

430

283

View full text Add to dashboard Cite

show abstract

“…Most animal models mimic end-stage type 2 diabetes (e.g., Zucker diabetic fatty and LA/N corpulent rats). However, chronic high-sugar diets produce whole body insulin resistance and hypertriglyceridemia without obesity or hyperglycemia (24,44), thereby mimicking the metabolic changes that precede the development of type 2 diabetes. We (10) have previously shown that treatment with metformin prevents both whole body insulin resistance and cardiomyocyte dysfunction, thus establishing an association between the two.…”

Section: Discussionmentioning

confidence: 99%

Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments

Davidoff¹,

Mason²,

Davidson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments. Am J Physiol Endocrinol Metab 286: E718 -E724, 2004; 10.1152/ajpendo.00358.2003.-We recently identified cardiomyocyte dysfunction in the early stage of type 2 diabetes (i.e., diet-induced insulin resistance). The present investigation was designed to determine whether a variety of clinically relevant interventions are sufficient to prevent and reverse cardiomyocyte dysfunction in sucrose (SU)-fed insulin-resistant rats. Subsets of animals were allowed to exercise (free access to wheel attached to cage) or were treated with bezafibrate in drinking water to determine whether these interventions would prevent the adverse effects of SU feeding on cardiomyocyte function. After 6 -8 wk on diet and treatment, animals were surgically prepared to assess whole body insulin sensitivity (intravenous glucose tolerance test), and isolated ventricular myocyte mechanics were evaluated (video edge recording). SU feeding produced hyperinsulinemia and hypertriglyceridemia, with euglycemia, and induced characteristic whole body insulin resistance. Both exercise and bezafibrate treatment prevented these metabolic abnormalities. Ventricular myocyte shortening and relengthening were slower in SU-fed rats (42-63%) compared with starch (ST)-fed controls, and exercise or bezafibrate completely prevented cardiomyocyte dysfunction in SU-fed rats. In separate cohorts of animals, after 5 wk of SU feeding, animals were either switched back to an ST diet or given menhaden oil for an additional 7-9 wk to determine whether the cardiomyocyte dysfunction was reversible. Both interventions have previously been shown to have favorable metabolic effects, and both improved myocyte mechanics, but only the ST diet reversed all indications of cardiomyocyte dysfunction induced by SU feeding. Thus phenotypic changes in cardiomyocyte mechanics associated with early stages of type 2 diabetes were found to be both preventable and reversible with clinically relevant treatments, suggesting that the cellular processes contributing to this dysfunction are modifiable. type 2 diabetes; fish oil; exercise; fibrates TYPE 2 DIABETES is a progressive, multifactorial disease that typically involves comorbidities such as dyslipidemia, obesity, hypertension, and insulin resistance (15). The type 2 form accounts for Ͼ90% of all diabetic cases and has recently been recognized as a serious health threat that is growing significantly worldwide (40). The increased incidence of insulin resistance and diabetes in young adults is particularly disturbing, given the potential for high rates of morbidity and mortality, predominantly due to heart disease (40).It is well established that diabetes-related heart disease in humans (and animal models) involves ventricular dysfunction, with diastolic abnormalities developing earlier than changes in systole (2,32,35,38). Diabetic cardiomyocyte dysfunction is characterized by phenotypic changes in ventricular myocytes that occ...

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“…To assess the effect of insulin on NO production, we compared the cumulative dose response to PE (1 nmol/l to 10 mol/l) before and after a 2-h incubation with insulin (100 mU/ml Actrapid; Novo Nordisk) (22,23). This dose of insulin was found to be optimal in preliminary experiments.…”

Section: Methodsmentioning

confidence: 99%

Preserved Glucoregulation but Attenuation of the Vascular Actions of Insulin in Mice Heterozygous for Knockout of the Insulin Receptor

Wheatcroft

Shah

et al. 2004

Diabetes

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Type 2 diabetes is preceded by years of insulin resistance and is characterized by reduced bioavailability of the antiatherosclerotic signaling molecule nitric oxide (NO) and premature atherosclerosis. The relationship between resistance to the glucoregulatory actions of insulin and its effects on the vasculature (in particular NO-dependent responses) is poorly characterized. We studied this relationship in mice heterozygous for knockout of the insulin receptor (IRKO), which have a mild perturbation of insulin signaling. Male heterozygous IRKO mice aged 8 -12 weeks were compared with age-and sex-matched littermates. IRKO mice had fasting blood glucose, insulin, free fatty acid, and triglyceride levels similar to those of wild-type mice. Intraperitoneal glucose and insulin tolerance tests were also similar in the two groups. Insulin levels in response to a glucose load were approximately twofold higher in IRKO compared with wild-type mice (1.08 ؎ 0.11 vs. 0.62 ؎ 0.13 ng/ml; P ‫؍‬ 0.004). Despite this mild metabolic phenotype, IRKO mice had increased systolic blood pressure (124 ؎ 4 vs. 110 ؎ 3 mmHg; P ‫؍‬ 0.01). Basal NO bioactivity, assessed from the increase in tension of phenylephrine preconstricted aortic rings in response to the NO synthase inhibitor N G -monomethyl-L-arginine, was reduced in IRKO (61 ؎ 14 vs. 152 ؎ 30%; P ‫؍‬ 0.005). Insulin-mediated NO release in aorta, assessed as the reduction in phenylephrine constrictor response after insulin preincubation, was lost in IRKO mice (5 ؎ 8% change vs. 66 ؎ 9% reduction in wild-type; P ‫؍‬ 0.03). Insulin-stimulated aortic endothelial NO synthase phosphorylation was also significantly blunted in IRKO mice (P < 0.05). These data demonstrate that insulin-stimulated NO responses in the vasculature are exquisitely sensitive to changes in insulin-signaling pathways in contrast to the glucoregulatory actions of insulin. These findings underscore the importance of early intervention in insulin-resistant states, where glucose homeostasis may be normal but substantial abnormalities of the vascular effects of insulin may already be present.

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Metformin treatment corrects vascular insulin resistance in hypertension

Cited by 53 publications

References 7 publications

Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo

Activation of the AMP-activated Protein Kinase by the Anti-diabetic Drug Metformin in Vivo

Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments

Preserved Glucoregulation but Attenuation of the Vascular Actions of Insulin in Mice Heterozygous for Knockout of the Insulin Receptor

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