Publications by authors named "Michael J Quon"

149 Publications

Endothelial dysfunction due to selective insulin resistance in vascular endothelium: insights from mechanistic modeling.

Am J Physiol Endocrinol Metab 2020 09 10;319(3):E629-E646. Epub 2020 Aug 10.

Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

Previously, we have used mathematical modeling to gain mechanistic insights into insulin-stimulated glucose uptake. Phosphatidylinositol 3-kinase (PI3K)-dependent insulin signaling required for metabolic actions of insulin also regulates endothelium-dependent production of the vasodilator nitric oxide (NO). Vasodilation increases blood flow that augments direct metabolic actions of insulin in skeletal muscle. This is counterbalanced by mitogen-activated protein kinase (MAPK)-dependent insulin signaling in endothelium that promotes secretion of the vasoconstrictor endothelin-1 (ET-1). In the present study, we extended our model of metabolic insulin signaling into a dynamic model of insulin signaling in vascular endothelium that explicitly represents opposing PI3K/NO and MAPK/ET-1 pathways. Novel NO and ET-1 subsystems were developed using published and new experimental data to generate model structures/parameters. The signal-response relationships of our model with respect to insulin-stimulated NO production, ET-1 secretion, and resultant vascular tone, agree with published experimental data, independent of those used for model development. Simulations of pathological stimuli directly impairing only insulin-stimulated PI3K/Akt activity predict altered dynamics of NO and ET-1 consistent with endothelial dysfunction in insulin-resistant states. Indeed, modeling pathway-selective impairment of PI3K/Akt pathways consistent with insulin resistance caused by glucotoxicity, lipotoxicity, or inflammation predict diminished NO production and increased ET-1 secretion characteristic of diabetes and endothelial dysfunction. We conclude that our mathematical model of insulin signaling in vascular endothelium supports the hypothesis that pathway-selective insulin resistance accounts, in part, for relationships between insulin resistance and endothelial dysfunction. This may be relevant for developing novel approaches for the treatment of diabetes and its cardiovascular complications.
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http://dx.doi.org/10.1152/ajpendo.00247.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642854PMC
September 2020

Race affects the association of obesity measures with insulin sensitivity.

Am J Clin Nutr 2020 03;111(3):515-525

Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Race differences in body composition and fat distribution may in part explain the differences in insulin sensitivity and the disproportionate burden of type 2 diabetes in African Americans.

Objective: To determine if differences in body composition and fat distribution explain race differences in insulin sensitivity and identify obesity measures that were independently associated with insulin sensitivity.

Methods: Participants were 113 lean, overweight, and obese African-American and Caucasian-American adults without diabetes. Skeletal muscle insulin sensitivity was determined using a hyperinsulinemic-euglycemic clamp (SIClamp, insulin rate:120 mU/m2/min). Subcutaneous abdominal adipose tissue (SAAT), intra-abdominal adipose tissue (IAAT), and liver fat were measured by MRI; leg fat, total fat, and lean mass were measured by DXA.

Results: Race-by-adiposity interactions were significant in cross-sectional analyses utilizing multiple linear regression models for SIClamp (P < 0.05); higher BMI, fat mass, SAAT, leg fat, and liver fat were associated with lower SIClamp in Caucasian Americans but not African Americans. Race-by-IAAT interaction was not significant (P = 0.65). A central fat distribution (SAAT adjusted for leg fat) was associated with lower SIClamp in African Americans (β = -0.45, SE = 0.11, P < 0.001) but not Caucasian Americans (β = -0.42, SE = 0.30, P = 0.17). A peripheral fat distribution (leg fat adjusted for IAAT/SAAT) was associated with a higher SIClamp in African Americans (β = 0.11, SE = 0.05, P = 0.02) but lower SIClamp in Caucasian Americans (β = -0.28, SE = 0.14, P = 0.049). Lean mass was inversely associated with SIClamp in African Americans (β = -0.05, SE = 0.03, P = 0.04) but not Caucasian Americans (β = 0.08, SE = 0.05, P = 0.10) in the model for leg fat.

Conclusions: Measures of overall adiposity were more strongly associated with SIClamp in Caucasian Americans, whereas body fat distribution and lean mass showed stronger correlations with SIClamp in African Americans. Insulin sensitivity may have a genetic basis in African Americans that is reflected in the pattern of body fat distribution. These findings suggest a race-specific pathophysiology of insulin resistance, which has implications for the prevention of diabetes and related cardiometabolic diseases.
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http://dx.doi.org/10.1093/ajcn/nqz309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049529PMC
March 2020

Anticoagulant Use and Risk of Ischemic Stroke and Bleeding in Patients With Secondary Atrial Fibrillation Associated With Acute Coronary Syndromes, Acute Pulmonary Disease, or Sepsis.

JACC Clin Electrophysiol 2018 03 27;4(3):386-393. Epub 2017 Sep 27.

Division of General Internal Medicine, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada; Divisions of General Internal Medicine and of Clinical Epidemiology, Department of Medicine, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada. Electronic address:

Objectives: The purpose of this study was to determine if anticoagulation of patients with new onset secondary atrial fibrillation (AF) occurring with acute coronary syndromes (ACS), acute pulmonary disease, or sepsis is associated with a reduction in ischemic stroke or an increase in bleeding risk.

Background: Studies evaluating the benefits and risks of anticoagulation in secondary AF are infrequent, and the optimal management of these patients is not well understood.

Methods: A retrospective study cohort was identified of 2,304 patients age 65 years or older, hospitalized with a primary diagnosis of ACS, acute pulmonary disease (chronic obstructive pulmonary disease, pneumonia/influenza, pulmonary embolism, or pleural effusion) or sepsis, and a complication of new-onset AF during admission from 1999 to 2015.

Results: Over a follow-up of ∼3 years, we did not identify any association between anticoagulation and a lower incidence of ischemic stroke in patients with new-onset AF occurring with ACS, acute pulmonary disease, or sepsis (odds ratio [OR]: 1.22 [95% confidence interval (CI): 0.65 to 2.27], OR: 0.97 [95% CI: 0.53 to 1.77], and OR: 1.98 [95% CI: 0.29 to 13.47]), after adjusting for confounders. However, anticoagulation was associated with a higher risk of bleeding in patients with AF associated with acute pulmonary disease (OR: 1.72 [95% CI: 1.23 to 2.39]), but not in ACS or sepsis (OR: 1.42 [95% CI: 0.94 to 2.14], OR: 0.96 [95% CI: 0.29 to 3.21]).

Conclusions: Our study demonstrates that the benefit of anticoagulation in secondary AF is not strong and can be associated with a higher risk of bleeding. Careful individual assessment regarding decisions on anticoagulation is warranted in these patients.
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http://dx.doi.org/10.1016/j.jacep.2017.08.003DOI Listing
March 2018

Simvastatin Treatment Protects Myocardium in Noncoronary Artery Cardiac Surgery by Inhibiting Apoptosis Through miR-15a-5p Targeting.

J Cardiovasc Pharmacol 2018 10;72(4):176-185

Division of Cardiac Surgery, Heart Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.

Simvastatin treatment is cardioprotective in patients undergoing noncoronary artery cardiac surgery. However, the mechanisms by which simvastatin treatment protects the myocardium under these conditions are not fully understood. Seventy patients undergoing noncoronary cardiac surgery, 35 from a simvastatin treatment group and 35 from a control treatment group, were enrolled in our clinical study. Simvastatin (20 mg/d) was administered preoperatively for 5-7 days. Myocardial tissue biopsies were taken before and after surgery. Apoptosis was detected by TUNEL staining. The expressions of Bcl-2 and Bak in myocardial tissue were detected by immunoblotting. The expressions of miRNA and Bcl-2 mRNA were detected by quantitative real-time polymerase chain reaction assays. Cardiomyocytes were isolated from rat and cultured cells. MiR-15a-5p mimic was transfected into cardiomyocytes, and the Bcl-2 was detected by immunoblotting. TUNEL staining showed significantly less myocardial apoptosis in the simvastatin treatment group when compared with the control treatment group. Protein expression of Bcl-2 was increased in the simvastatin treatment group before surgery, and Bak expression was increased in the control treatment group after surgery. Further comparisons showed that Bcl-2/Bak ratios were reduced in the control treatment group but were not significantly changed in the simvastatin treatment group after surgery. Furthermore, microarray assays revealed that miR-15a-5p was significantly decreased by simvastatin treatment. This was validated by quantitative real-time polymerase chain reaction analysis. MiR-15a-5p was predicted to target Bcl-2 mRNA at nucleotide positions 2529-2536. This was validated by luciferase binding assays. Coincident with the change in miR-15a-5p, the mRNA expression of Bcl-2 was increased in the simvastatin treatment group. MiR-15a-5p mimic significantly inhibited Bcl-2 expression in cardiomyocytes. Our findings strongly suggest that simvastatin treatment preoperatively protected the myocardium in patients undergoing noncoronary artery cardiac surgery, at least in part, by inhibiting apoptosis via suppressing miR-15a-5p expression, leading to increasing expression of Bcl-2 and decreasing expression of Bak.
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http://dx.doi.org/10.1097/FJC.0000000000000611DOI Listing
October 2018

Transgenic mice with ectopic expression of constitutively active TLR4 in adipose tissues do not show impaired insulin sensitivity.

Immun Inflamm Dis 2017 12 4;5(4):526-540. Epub 2017 Aug 4.

Department of Nutrition, University of California, Davis, California.

Introduction: Chronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll-like receptor 4 (TLR4) mediates both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenous molecules, respectively. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)-induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance.

Methods: We generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance.

Results: TG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild-type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet.

Conclusions: Together, these results suggest that constitutively active TLR4-induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation.
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http://dx.doi.org/10.1002/iid3.162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691308PMC
December 2017

Combining Potent Statin Therapy with Other Drugs to Optimize Simultaneous Cardiovascular and Metabolic Benefits while Minimizing Adverse Events.

Korean Circ J 2017 Jul 26;47(4):432-439. Epub 2017 Jul 26.

Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, USA.

Hypercholesterolemia and hypertension are among the most important risk factors for cardiovascular (CV) disease. They are also important contributors to metabolic diseases including diabetes that further increase CV risk. Updated guidelines emphasize targeted reduction of overall CV risks but do not explicitly incorporate potential adverse metabolic outcomes that also influence CV health. Hypercholesterolemia and hypertension have synergistic deleterious effects on interrelated insulin resistance and endothelial dysfunction. Dysregulation of the renin-angiotensin system is an important pathophysiological mechanism linking insulin resistance and endothelial dysfunction to atherogenesis. Statins are the reference standard treatment to prevent CV disease in patients with hypercholesterolemia. Statins work best for secondary CV prevention. Unfortunately, most statin therapies dose-dependently cause insulin resistance, increase new onset diabetes risk and exacerbate existing type 2 diabetes mellitus. Pravastatin is often too weak to achieve target low-density lipoprotein cholesterol levels despite having beneficial metabolic actions. Renin-angiotensin system inhibitors improve both endothelial dysfunction and insulin resistance in addition to controlling blood pressure. In this regard, combined statin-based and renin-angiotensin system (RAS) inhibitor therapies demonstrate additive/synergistic beneficial effects on endothelial dysfunction, insulin resistance, and other metabolic parameters in addition to lowering both cholesterol levels and blood pressure. This combined therapy simultaneously reduces CV events when compared to either drug type used as monotherapy. This is mediated by both separate and interrelated mechanisms. Therefore, statin-based therapy combined with RAS inhibitors is important for developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity. This combined therapy can help prevent or treat CV disease while minimizing adverse metabolic consequences.
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http://dx.doi.org/10.4070/kcj.2016.0406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537141PMC
July 2017

Deletion of interleukin 1 receptor-associated kinase 1 () improves glucose tolerance primarily by increasing insulin sensitivity in skeletal muscle.

J Biol Chem 2017 07 1;292(29):12339-12350. Epub 2017 Jun 1.

Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201.

Chronic inflammation may contribute to insulin resistance via molecular cross-talk between pathways for pro-inflammatory and insulin signaling. Interleukin 1 receptor-associated kinase 1 (IRAK-1) mediates pro-inflammatory signaling via IL-1 receptor/Toll-like receptors, which may contribute to insulin resistance, but this hypothesis is untested. Here, we used male null (k/o) mice to investigate the metabolic role of IRAK-1. C57BL/6 wild-type (WT) and k/o mice had comparable body weights on low-fat and high-fat diets (LFD and HFD, respectively). After 12 weeks on LFD (but not HFD), k/o mice ( WT) had substantially improved glucose tolerance (assessed by the intraperitoneal glucose tolerance test (IPGTT)). As assessed with the hyperinsulinemic euglycemic glucose clamp technique, insulin sensitivity was 30% higher in the k/o mice on chow diet, but the deletion did not affect IPGTT outcomes in mice on HFD, suggesting that the deletion did not overcome the impact of obesity on glucose tolerance. Moreover, insulin-stimulated glucose-disposal rates were higher in the k/o mice, but we detected no significant difference in hepatic glucose production rates (± insulin infusion). Positron emission/computed tomography scans indicated higher insulin-stimulated glucose uptake in muscle, but not liver, in k/o mice Moreover, insulin-stimulated phosphorylation of Akt was higher in muscle, but not in liver, from k/o mice In conclusion, deletion improved muscle insulin sensitivity, with the effect being most apparent in LFD mice.
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http://dx.doi.org/10.1074/jbc.M117.779108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519380PMC
July 2017

Acute vascular and metabolic actions of the green tea polyphenol epigallocatechin 3-gallate in rat skeletal muscle.

J Nutr Biochem 2017 02 14;40:23-31. Epub 2016 Oct 14.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. Electronic address:

Epidemiological studies show a dose-dependent relationship between green tea consumption and reduced risk for type 2 diabetes and cardiovascular disease. Bioactive compounds in green tea including the polyphenol epigallocatechin 3-gallate (EGCG) have insulin-mimetic actions on glucose metabolism and vascular function in isolated cell culture studies. The aim of this study is to explore acute vascular and metabolic actions of EGCG in skeletal muscle of Sprague-Dawley rats. Direct vascular and metabolic actions of EGCG were investigated using surgically isolated constant-flow perfused rat hindlimbs. EGCG infused at 0.1, 1, 10 and 100 μM in 15 min step-wise increments caused dose-dependent vasodilation in 5-hydroxytryptamine pre-constricted hindlimbs. This response was not impaired by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin or the AMP-kinase inhibitor Compound C. The nitric oxide synthase (NOS) inhibitor N-Nitro-l-Arginine Methyl Ester (L-NAME) completely blocked EGCG-mediated vasodilation at 0.1-10 μM, but not at 100 μM. EGCG at 10 μM did not alter muscle glucose uptake nor did it augment insulin-stimulated muscle glucose uptake. The acute metabolic and vascular actions of 10 μM EGCG in vivo were investigated in anaesthetised rats during a hyperinsulinemic-euglycemic clamp (10 mU min kg insulin). EGCG and insulin both stimulated comparable increases in muscle microvascular blood flow without an additive effect. EGCG-mediated microvascular action occurred without altering whole body or muscle glucose uptake. We concluded that EGCG has direct NOS-dependent vasodilator actions in skeletal muscle that do not acutely alter muscle glucose uptake or enhance the vascular and metabolic actions of insulin in healthy rats.
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http://dx.doi.org/10.1016/j.jnutbio.2016.10.005DOI Listing
February 2017

Infliximab therapy restores adiponectin expression in perivascular adipose tissue and improves endothelial nitric oxide-mediated vasodilation in mice with type 1 diabetes.

Vascul Pharmacol 2016 12 24;87:83-91. Epub 2016 Aug 24.

Department of Biomedical Sciences and Human Oncology, Pharmacology Section, Medical School, University of Bari "Aldo Moro", Bari, Italy. Electronic address:

Increased TNFα-mediated JNK signaling in the perivascular adipose tissue (PVAT) may contribute to the pathogenesis of vascular complications in T1DM by reducing adiponectin (Ad) synthesis and therefore impairing Ad-mediated activity in the contiguous blood vessel system. We evaluated whether in vivo treatment with the TNFα blocking antibody infliximab normalized expression of Ad and Ad receptors in various fat depots, and whether this effect correlated with improved endothelial activity and vasodilator function in streptozotocin (STZ)-induced diabetic mice. STZ mice were studied at 1 and 2weeks after diabetes onset, and compared to age-matched infliximab-treated diabetic (I-STZ) and control animals (CTRL) (n=10 each group). In STZ mice, activation of pro-inflammatory JNK signaling was faster in PVAT (P<0.01) than in visceral (VAT), epididymal (EAT) and subcutaneous (SAT) adipose depots, and associated with decreased Ad synthesis and dysregulated AdipoR1/R2 levels. In parallel, activation of JNK in aortic endothelial cells and mesenteric arteries was associated with decreased expression/phosphorylation of eNOS and impaired ACh-mediated vasodilation (P<0.05 vs. CTRL). Treatment with infliximab abrogated JNK activation, ameliorated Ad protein expression, and normalized expression of both AdipoR1 and AdipoR2 in PVAT, concomitantly improving eNOS expression and vessel relaxation in mesenteric arteries from I-STZ mice (P<0.01 vs. STZ). These observations underline the early susceptibility of PVAT to activation of pro-inflammatory JNK signaling, and highlight its potential importance in early vascular changes of T1DM. Further elucidation of the role of PVAT in cardiovascular complications may allow for the design of novel therapeutic strategies directly addressing PVAT pathophysiology.
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http://dx.doi.org/10.1016/j.vph.2016.08.007DOI Listing
December 2016

Estrogen deprivation in primate pregnancy leads to insulin resistance in offspring.

J Endocrinol 2016 08 20;230(2):171-83. Epub 2016 May 20.

Department of ObstetricsGynecology, and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA

This study tested the hypothesis that estrogen programs mechanisms within the primate fetus that promote insulin sensitivity and glucose homeostasis in offspring. Glucose tolerance tests were performed longitudinally in prepubertal offspring of baboons untreated or treated on days 100 to 165/175 of gestation (term is 184 days) with the aromatase inhibitor letrozole, which decreased fetal estradiol levels by 95%. Basal plasma insulin levels were over two-fold greater in offspring delivered to letrozole-treated than untreated animals. Moreover, the peak 1min, average of the 1, 3, and 5min, and area under the curve blood glucose and plasma insulin levels after an i.v. bolus of glucose were greater (P<0.05 and P<0.01, respectively) in offspring deprived of estrogen in utero than in untreated animals and partially or completely restored in letrozole plus estradiol-treated baboons. The value for the homeostasis model assessment of insulin resistance was 2.5-fold greater (P<0.02) and quantitative insulin sensitivity check index lower (P<0.01) in offspring of letrozole-treated versus untreated animals and returned to almost normal in letrozole plus estradiol-treated animals. The exaggerated rise in glucose and insulin levels after glucose challenge in baboon offspring deprived of estrogen in utero indicates that pancreatic beta cells had the capacity to secrete insulin, but that peripheral glucose uptake and/or metabolism were impaired, indicative of insulin resistance and glucose intolerance. We propose that estrogen normally programs mechanisms in utero within the developing primate fetus that lead to insulin sensitivity, normal glucose tolerance, and the capacity to metabolize glucose after birth.
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http://dx.doi.org/10.1530/JOE-15-0530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946970PMC
August 2016

Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure.

Sci Rep 2015 Dec 14;5:17927. Epub 2015 Dec 14.

Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China.

A close link between heart failure (HF) and systemic insulin resistance has been well documented, whereas myocardial insulin resistance and its association with HF are inadequately investigated. This study aims to determine the role of myocardial insulin resistance in ischemic HF and its underlying mechanisms. Male Sprague-Dawley rats subjected to myocardial infarction (MI) developed progressive left ventricular dilation with dysfunction and HF at 4 wk post-MI. Of note, myocardial insulin sensitivity was decreased as early as 1 wk after MI, which was accompanied by increased production of myocardial TNF-α. Overexpression of TNF-α in heart mimicked impaired insulin signaling and cardiac dysfunction leading to HF observed after MI. Treatment of rats with a specific TNF-α inhibitor improved myocardial insulin signaling post-MI. Insulin treatment given immediately following MI suppressed myocardial TNF-α production and improved cardiac insulin sensitivity and opposed cardiac dysfunction/remodeling. Moreover, tamoxifen-induced cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic ventricular remodeling and dysfunction compared with controls. In conclusion, MI induces myocardial insulin resistance (without systemic insulin resistance) mediated partly by ischemia-induced myocardial TNF-α overproduction and promotes the development of HF. Our findings underscore the direct and essential role of myocardial insulin signaling in protection against post-ischemic HF.
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http://dx.doi.org/10.1038/srep17927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677294PMC
December 2015

Dominant negative FADD dissipates the proapoptotic signalosome of the unfolded protein response in diabetic embryopathy.

Am J Physiol Endocrinol Metab 2015 Nov 29;309(10):E861-73. Epub 2015 Sep 29.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Institut de Biologie de Valrose, UMR CNRS 7277, UMR Institut National de la Sante et de la Recherche Medicale 1091, Université de Nice-Sophia-Antipolis, Nice, France

Endoplasmic reticulum (ER) stress and caspase 8-dependent apoptosis are two interlinked causal events in maternal diabetes-induced neural tube defects (NTDs). The inositol-requiring enzyme 1α (IRE1α) signalosome mediates the proapoptotic effect of ER stress. Diabetes increases tumor necrosis factor receptor type 1R-associated death domain (TRADD) expression. Here, we revealed two new unfolded protein response (UPR) regulators, TRADD and Fas-associated protein with death domain (FADD). TRADD interacted with both the IRE1α-TRAF2-ASK1 complex and FADD. In vivo overexpression of a FADD dominant negative (FADD-DN) mutant lacking the death effector domain disrupted diabetes-induced IRE1α signalosome and suppressed ER stress and caspase 8-dependent apoptosis, leading to NTD prevention. FADD-DN abrogated ER stress markers and blocked the JNK1/2-ASK1 pathway. Diabetes-induced mitochondrial translocation of proapoptotic Bcl-2 members mitochondrial dysfunction and caspase cleavage were also alleviated by FADD-DN. In vitro TRADD overexpression triggered UPR and ER stress before manifestation of caspase 3 and caspase 8 cleavage and apoptosis. FADD-DN overexpression repressed high glucose- or TRADD overexpression-induced IRE1α phosphorylation, its downstream proapoptotic kinase activation and endonuclease activities, and apoptosis. FADD-DN also attenuated tunicamycin-induced UPR and ER stress. These findings suggest that TRADD participates in the IRE1α signalosome and induces UPR and ER stress and that the association between TRADD and FADD is essential for diabetes- or high glucose-induced UPR and ER stress.
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http://dx.doi.org/10.1152/ajpendo.00215.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652069PMC
November 2015

ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development.

Am J Physiol Endocrinol Metab 2015 Sep 14;309(5):E487-99. Epub 2015 Jul 14.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland

Maternal diabetes in mice induces heart defects similar to those observed in human diabetic pregnancies. Diabetes enhances apoptosis and suppresses cell proliferation in the developing heart, yet the underlying mechanism remains elusive. Apoptosis signal-regulating kinase 1 (ASK1) activates the proapoptotic c-Jun NH2-terminal kinase 1/2 (JNK1/2) leading to apoptosis, suggesting a possible role of ASK1 in diabetes-induced heart defects. We aimed to investigate whether ASK1 is activated in the heart and whether deleting the Ask1 gene blocks diabetes-induced adverse events and heart defect formation. The ASK1-JNK1/2 pathway was activated by diabetes. Deleting Ask1 gene significantly reduced the rate of heart defects, including ventricular septal defects (VSDs) and persistent truncus arteriosus (PTA). Additionally, Ask1 deletion diminished diabetes-induced JNK1/2 phosphorylation and its downstream transcription factors and endoplasmic reticulum (ER) stress markers. Consistent with this, caspase activation and apoptosis were blunted. Ask1 deletion blocked the increase in cell cycle inhibitors (p21 and p27) and the decrease in cyclin D1 and D3 and reversed diabetes-repressed cell proliferation. Ask1 deletion also restored the expression of BMP4, NKX2.5, and GATA5, Smad1/5/8 phosphorylation, whose mutations or deletion result in reduced cell proliferation, VSD, and PTA formation. We conclude that ASK1 may mediate the teratogenicity of diabetes through activating the JNK1/2-ER stress pathway and inhibiting cell cycle progression, thereby impeding the cardiogenesis pathways essential for ventricular septation and outflow tract development.
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http://dx.doi.org/10.1152/ajpendo.00121.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556884PMC
September 2015

Cellular Stress, Excessive Apoptosis, and the Effect of Metformin in a Mouse Model of Type 2 Diabetic Embryopathy.

Diabetes 2015 Jul 26;64(7):2526-36. Epub 2015 Feb 26.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD

Increasing prevalence of type 2 diabetes in women of childbearing age has led to a higher incidence of diabetes-associated birth defects. We established a model of type 2 diabetic embryopathy by feeding 4-week-old female mice a high-fat diet (HFD) (60% fat). After 15 weeks on HFD, the mice showed characteristics of type 2 diabetes mellitus (DM) and were mated with lean male mice. During pregnancy, control dams fed a normal diet (10% fat) were maintained on either normal diet or HFD, serving as a control group with elevated circulating free fatty acids. DM dams produced offspring at a rate of 11.3% for neural tube defect (NTD) formation, whereas no embryos in the control groups developed NTDs. Elevated markers of oxidative stress, endoplasmic reticulum stress, caspase activation, and neuroepithelial cell apoptosis (causal events in type 1 diabetic embryopathy) were observed in embryos of DM dams. DM dams treated with 200 mg/kg metformin in drinking water ameliorated fasting hyperglycemia, glucose intolerance, and insulin resistance with consequent reduction of cellular stress, apoptosis, and NTDs in their embryos. We conclude that cellular stress and apoptosis occur and that metformin effectively reduces type 2 diabetic embryopathy in a useful rodent model.
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http://dx.doi.org/10.2337/db14-1683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477360PMC
July 2015

Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels.

Hum Mol Genet 2015 Apr 9;24(8):2390-400. Epub 2015 Jan 9.

Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA,

Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10(-8) to 3.91 × 10(-19)) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10(-14)) and rs10455872 (P = 1.85 × 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation.
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http://dx.doi.org/10.1093/hmg/ddu731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380064PMC
April 2015

Man shall not live by bread alone.

Nutrition 2015 Jan 24;31(1):244-7. Epub 2014 Oct 24.

Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1016/j.nut.2014.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890622PMC
January 2015

Vascular and metabolic actions of the green tea polyphenol epigallocatechin gallate.

Curr Med Chem 2015 ;22(1):59-69

Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, 7000, Australia.

Epidemiological studies demonstrate robust correlations between green tea consumption and reduced risk of type 2 diabetes and its cardiovascular complications. However, underlying molecular, cellular, and physiological mechanisms remain incompletely understood. Health promoting actions of green tea are often attributed to epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea. Insulin resistance and endothelial dysfunction play key roles in the pathogenesis of type 2 diabetes and its cardiovascular complications. Metabolic insulin resistance results from impaired insulin-mediated glucose disposal in skeletal muscle and adipose tissue, and blunted insulin-mediated suppression of hepatic glucose output that is often associated with endothelial/ vascular dysfunction. This endothelial dysfunction is itself caused, in part, by impaired insulin signaling in vascular endothelium resulting in reduced insulin-stimulated production of NO in arteries, and arterioles that regulate nutritive capillaries. In this review, we discuss the considerable body of literature supporting insulin-mimetic actions of EGCG that oppose endothelial dysfunction and ameliorate metabolic insulin resistance in skeletal muscle and liver. We conclude that EGCG is a promising therapeutic to combat cardiovascular complications associated with the metabolic diseases characterized by reciprocal relationships between insulin resistance and endothelial dysfunction that include obesity, metabolic syndrome and type 2 diabetes. There is a strong rationale for well-powered randomized placebo controlled intervention trials to be carried out in insulin resistant and diabetic populations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909506PMC
http://dx.doi.org/10.2174/0929867321666141012174553DOI Listing
July 2015

Response to comment on Sarkar et al. Exenatide treatment for 6 months improves insulin sensitivity in adults with type 1 diabetes. Diabetes care 2014;37:666-670.

Diabetes Care 2014 Oct;37(10):e219-20

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

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http://dx.doi.org/10.2337/dc14-1482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170128PMC
October 2014

Modulation of adiponectin as a potential therapeutic strategy.

Atherosclerosis 2014 Apr 7;233(2):721-728. Epub 2014 Feb 7.

Cardiology, Gachon University Gil Medical Center, Incheon, Republic of Korea; Gachon Cardiovascular Research Institute, Incheon, Republic of Korea. Electronic address:

Adiponectin is produced predominantly by adipocytes and plays an important role in metabolic and cardiovascular homeostasis through its insulin-sensitizing actions and anti-inflammatory and anti-atherogenic properties. Recently, it has been observed that lower levels of adiponectin can substantially increase the risk of developing type 2 diabetes, metabolic syndrome, atherosclerosis, and cardiovascular disease in patients who are obese. Circulating adiponectin levels are inversely related to the inflammatory process, oxidative stress, and metabolic dysregulation. Intensive lifestyle modifications and pharmacologic agents, including peroxisome proliferator-activated receptor-γ or α agonists, some statins, renin-angiotensin-aldosterone system blockers, some calcium channel blockers, mineralocorticoid receptor blockers, new β-blockers, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular and metabolic disorders. Therefore, it is important for investigators to have a thorough understanding of the interventions that can modulate adiponectin. Such knowledge may lead to new therapeutic approaches for diseases such as type 2 diabetes, metabolic syndrome, cardiovascular disease, and obesity. This review focuses on recent updates regarding therapeutic interventions that might modulate adiponectin.
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http://dx.doi.org/10.1016/j.atherosclerosis.2014.01.051DOI Listing
April 2014

New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate.

Redox Biol 2014 10;2:187-95. Epub 2014 Jan 10.

Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA ; Department of Cell, Developmental and Integrative Biology, UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Green tea is rich in polyphenol flavonoids including catechins. Epigallocatechin 3-gallate (EGCG) is the most abundant and potent green tea catechin. EGCG has been extensively studied for its beneficial health effects as a nutriceutical agent. Based upon its chemical structure, EGCG is often classified as an antioxidant. However, treatment of cells with EGCG results in production of hydrogen peroxide and hydroxyl radicals in the presence of Fe (III). Thus, EGCG functions as a pro-oxidant in some cellular contexts. Recent investigations have revealed many other direct actions of EGCG that are independent from anti-oxidative mechanisms. In this review, we discuss these novel molecular mechanisms of action for EGCG. In particular, EGCG directly interacts with proteins and phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function, and autophagy to exert many of its beneficial biological actions.
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http://dx.doi.org/10.1016/j.redox.2013.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909779PMC
March 2015

Exenatide treatment for 6 months improves insulin sensitivity in adults with type 1 diabetes.

Diabetes Care 2014 5;37(3):666-70. Epub 2013 Nov 5.

Corresponding author: Kristina I. Rother,

Objective: Exenatide treatment improves glycemia in adults with type 2 diabetes and has been shown to reduce postprandial hyperglycemia in adolescents with type 1 diabetes. We studied the effects of exenatide on glucose homeostasis in adults with long-standing type 1 diabetes.

Research Design And Methods: Fourteen patients with type 1 diabetes participated in a crossover study of 6 months' duration on exenatide (10 μg four times a day) and 6 months off exenatide. We assessed changes in fasting and postprandial blood glucose and changes in insulin sensitivity before and after each study period.

Results: High-dose exenatide therapy reduced postprandial blood glucose but was associated with higher fasting glucose concentrations without net changes in hemoglobin A1c. Exenatide increased insulin sensitivity beyond the effects expected as a result of weight reduction.

Conclusions: Exenatide is a promising adjunctive agent to insulin therapy because of its beneficial effects on postprandial blood glucose and insulin sensitivity in patients with type 1 diabetes.
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http://dx.doi.org/10.2337/dc13-1473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931382PMC
August 2015

Differential metabolic actions of specific statins: clinical and therapeutic considerations.

Antioxid Redox Signal 2014 Mar 24;20(8):1286-99. Epub 2013 Sep 24.

1 Division of Endocrinology, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam, Korea.

Significance: Statins, the most widely prescribed drugs in clinical practice, mainly act by reducing the plasma level of low-density lipoprotein (LDL)-cholesterol. A shift in redox homeostasis to an imbalance between reactive oxygen species generation and endogenous antioxidant mechanisms results in oxidative stress that has been implicated in the pathogenesis of various diseases, including those of the cardiovascular system. Beyond their efficacy in lowering LDL cholesterol, statins modulate redox systems that are implicated in the development of atherosclerosis, cardiovascular morbidity, and mortality.

Recent Advances: Differences in specific statins or their dosages result in differential metabolic actions arising from off-target or unknown mechanisms of action that can have important implications for overall patient morbidity and mortality.

Critical Issues: A recent meta-analysis and a combined analysis have suggested that high doses of statins increase the risk of developing type 2 diabetes mellitus, but reduce the risk of cardiovascular events. Thus, it is important to consider the cardiovascular and metabolic context and natural history of diseases when choosing a specific statin therapy for optimal individual patient health over the long term.

Future Directions: More information is needed regarding the metabolism of statins, and the off-target or unknown actions of statins in affecting insulin resistance and metabolic homeostasis. The differential metabolic effects of specific statins should be considered in formulating optimal therapeutic strategies to reduce not just cardiovascular-related but also overall patient morbidity and mortality.
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http://dx.doi.org/10.1089/ars.2013.5531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692132PMC
March 2014

Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats.

Am J Physiol Heart Circ Physiol 2013 Oct 2;305(8):H1111-9. Epub 2013 Aug 2.

Department of Physiology, The Fourth Military Medical University, Xi'an, China;

Exercise training lowers blood pressure and is a recommended nonpharmacological strategy and useful adjunctive therapy for hypertensive patients. Studies demonstrate that physical activity attenuates progression of hypertension. However, underlying mechanisms remain elusive. Vascular insulin resistance and endothelial dysfunction plays a critical role in the development of hypertension. The present study investigated whether long-term physical exercise starting during the prehypertensive period prevents the development of hypertension via improving vascular insulin sensitivity. Young (4 wk old) prehypertensive spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) control rats were subjected to a 10-wk free-of-loading swim training session (60 min/day, 5 days/wk). Blood pressure, mesenteric arteriolar vasorelaxation, G protein-coupled receptor kinase-2 (GRK2) expression and activity, and insulin-stimulated Akt/endothelial nitric oxide synthase (eNOS) activation were determined. SHRs had higher systolic blood pressure, systemic insulin resistance, and impaired vasodilator actions of insulin in resistance vessels when compared with WKY rats. Systolic blood pressure in SHRs postexercise was significantly lower than that in sedentary rats. Vascular insulin sensitivity in mesenteric arteries was improved after exercise training as evidenced by an increased vasodilator response to insulin. In addition, exercise downregulated vascular GRK2 expression and activity, which further increased insulin-stimulated vascular Akt/eNOS activation in exercised SHRs. Specific small interfering RNA knockdown of GRK2 in endothelium mimicked the effect of exercise-enhanced vascular insulin sensitivity. Likewise, upregulation of GRK2 by Chariot-mediated delivery opposed exercise-induced vascular insulin sensitization. Taken together, our results suggest that long-term exercise beginning at the prehypertensive stage improves vascular insulin sensitivity via downregulation of vascular GRK2 that may help to limit the progression of hypertension.
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http://dx.doi.org/10.1152/ajpheart.00290.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747915PMC
October 2013

Mechanisms for food polyphenols to ameliorate insulin resistance and endothelial dysfunction: therapeutic implications for diabetes and its cardiovascular complications.

Am J Physiol Endocrinol Metab 2013 Sep 30;305(6):E679-86. Epub 2013 Jul 30.

Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland; and.

The rising epidemic of diabetes is a pressing issue in clinical medicine worldwide from both healthcare and economic perspectives. This is fueled by overwhelming increases in the incidence and prevalence of obesity. Obesity and diabetes are characterized by both insulin resistance and endothelial dysfunction that lead to substantial increases in cardiovascular morbidity and mortality. Reciprocal relationships between insulin resistance and endothelial dysfunction tightly link metabolic diseases including obesity and diabetes with their cardiovascular complications. Therefore, therapeutic approaches that target either insulin resistance or endothelial dysfunction alone are likely to simultaneously improve both metabolic and cardiovascular pathophysiology and disease outcomes. Moreover, combination therapies with agents targeting distinct mechanisms are likely to have additive or synergistic benefits. Conventional therapies for diabetes and its cardiovascular complications that are both safe and effective are insufficient to meet rising demand. Large, robust, epidemiologic studies demonstrate beneficial metabolic and cardiovascular health effects for many functional foods containing various polyphenols. However, precise molecular mechanisms of action for food polyphenols are largely unknown. Moreover, translation of these insights into effective clinical therapies has not been fully realized. Nevertheless, some functional foods are likely sources for safe and effective therapies and preventative strategies for metabolic diseases and their cardiovascular complications. In this review, we emphasize recent progress in elucidating molecular, cellular, and physiological actions of polyphenols from green tea (EGCG), cocoa (ECG), and citrus fruits (hesperedin) that are related to improving metabolic and cardiovascular pathophysiology. We also discuss a rigorous comprehensive approach to studying functional foods that is essential for developing novel, effective, and safe medications derived from functional foods that will complement existing conventional drugs.
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http://dx.doi.org/10.1152/ajpendo.00377.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073986PMC
September 2013

Combination pravastatin and valsartan treatment has additive beneficial effects to simultaneously improve both metabolic and cardiovascular phenotypes beyond that of monotherapy with either drug in patients with primary hypercholesterolemia.

Diabetes 2013 Oct 17;62(10):3547-52. Epub 2013 Jul 17.

Cardiology, Gachon University Gil Medical Center, Incheon, Korea.

Statin and angiotensin II type 1 receptor blocker therapy improves endothelial dysfunction using distinct mechanisms. We evaluated simultaneous vascular and metabolic responses to pravastatin and valsartan therapy, alone or in combination, in hypercholesterolemic patients. Forty-eight hypercholesterolemic patients (23 had metabolic syndrome) were given pravastatin 40 mg and placebo, pravastatin 40 mg and valsartan 160 mg, or valsartan 160 mg and placebo daily during each 2-month treatment period in a randomized, single-blind, placebo-controlled, crossover trial with three treatment arms and two washout periods (each 2 months). Brachial artery flow-mediated dilation and C-reactive protein improved to a greater extent with combined therapy compared with either monotherapy. Importantly, we also observed simultaneous improvement in metabolic phenotypes, with all three treatments causing increased plasma adiponectin levels, reduced fasting insulin levels, and increased insulin sensitivity relative to baseline measurements. For the first time in a statin combination trial, pravastatin combined with valsartan therapy increased plasma adiponectin, lowered fasting insulin levels, and improved insulin sensitivity in an additive manner when compared with monotherapy alone. In contrast to other statins, hydrophilic pavastatin may be combined with other drugs to safely reach lipid target levels while simultaneously improving the metabolic and cardiovascular phenotype of patients at high risk.
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http://dx.doi.org/10.2337/db13-0566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781478PMC
October 2013

Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin.

Am J Physiol Endocrinol Metab 2013 May 26;304(10):E1077-88. Epub 2013 Mar 26.

Dept. of Medicine, Div. of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Obesity is characterized by a chronic proinflammatory state that leads to endothelial dysfunction. Saturated fatty acids (SFA) stimulate Toll-like receptors (TLR) that promote metabolic insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high-fat diet (HFD) to cause endothelial dysfunction. siRNA knockdown of TLR2 in primary endothelial cells opposed palmitate-stimulated expression of proinflammatory cytokines and splicing of X box protein 1 (XBP-1). Inhibition of unfolding protein response (UPR) reduced SFA-stimulated expression of TNFα. Thus, SFA stimulates UPR and proinflammatory response through activation of TLR2 in endothelial cells. Knockdown of TLR2 also opposed impairment of insulin-stimulated phosphorylation of eNOS and subsequent production of NO. Importantly, insulin-stimulated vasorelaxation of mesenteric arteries from TLR2 knockout mice was preserved even on HFD (in contrast with results from arteries examined in wild-type mice on HFD). We conclude that TLR2 in vascular endothelium mediates HFD-stimulated proinflammatory responses and UPR that accompany impairment of vasodilator actions of insulin, leading to endothelial dysfunction. These results are relevant to understanding the pathophysiology of the cardiovascular complications of diabetes and obesity.
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http://dx.doi.org/10.1152/ajpendo.00578.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651621PMC
May 2013