Skip to main content
Top
Published in: Cardiovascular Diabetology 1/2016

Open Access 01-12-2016 | Original investigation

Impact of individual metabolic risk components or its clustering on endothelial and smooth muscle cell function in men

Authors: Michio Shimabukuro, Namio Higa, Hiroaki Masuzaki, Masataka Sata, Shinichiro Ueda

Published in: Cardiovascular Diabetology | Issue 1/2016

Login to get access

Abstract

Background

Impaired vasoreactivity is often observed in subjects with metabolic syndrome, a condition that includes the presence of a specific cluster of risk factors for obesity and cardiovascular disease. However, hierarchical causes in the impaired vasoreactivity have not been clarified. We evaluated the impact of individual metabolic risk components or its clustering under the condition of insulin resistance on endothelial and smooth muscle cell function.

Methods

Vascular reactivity to acetylcholine (Ach), with or without nitric oxide synthase (NOS) inhibitor N G-monomethyl-l-arginine (L-NMMA), or sodium nitroprusside (SNP) by forearm venous occlusion plethysmography and insulin sensitivity index (M mg/kg/min) in euglycemic clamp were measured in men without (n = 18, control group) or with (n = 19, metabolic syndrome group) metabolic syndrome.

Results

(1) Ach-induced maximal forearm blood flow (maxFBF) was impaired in subjects with metabolic syndrome. In particular, the NOS-dependent component of Ach-induced maxFBF was selectively decreased, while the NOS-independent component remained relatively unchanged. (2) Ach-induced maxFBF and ∆Ach-induced maxFBF with L-NMMA were correlated with waist circumference, glucose, and triglycerides, and most strongly correlated with visceral fat area, adiponectin, and M. (3) Multivariate regression analysis indicated that individual metabolic risk components explained Ach-induced maxFBF by 4–21 %. Clustering of all metabolic risk components increased this to 35 %, and the presence of metabolic syndrome explained 30 %, indicating that defining metabolic syndrome can effectively predict impairment of endothelial dysfunction.

Conclusions

Endothelial dysfunction was correlated with individual metabolic risk components, but more strongly with clustering of the components under a condition with low insulin sensitivity. We suggest that in subjects with metabolic syndrome, endothelial function is impaired by multiple cardiovascular risk factors exclusively when under the condition of insulin insensitivity and also that defining metabolic syndrome can effectively predict impairment of endothelial dysfunction.
Literature
1.
go back to reference Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109(3):433–8.CrossRefPubMed Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109(3):433–8.CrossRefPubMed
2.
go back to reference Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28(9):2289–304.CrossRefPubMed Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28(9):2289–304.CrossRefPubMed
3.
go back to reference Simmons RK, Alberti KG, Gale EA, Colagiuri S, Tuomilehto J, Qiao Q, Ramachandran A, Tajima N, Brajkovich Mirchov I, Ben-Nakhi A, et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010;53(4):600–5.CrossRefPubMed Simmons RK, Alberti KG, Gale EA, Colagiuri S, Tuomilehto J, Qiao Q, Ramachandran A, Tajima N, Brajkovich Mirchov I, Ben-Nakhi A, et al. The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia. 2010;53(4):600–5.CrossRefPubMed
4.
go back to reference Guize L, Thomas F, Pannier B, Bean K, Jego B, Benetos A. All-cause mortality associated with specific combinations of the metabolic syndrome according to recent definitions. Diabetes Care. 2007;30(9):2381–7.CrossRefPubMed Guize L, Thomas F, Pannier B, Bean K, Jego B, Benetos A. All-cause mortality associated with specific combinations of the metabolic syndrome according to recent definitions. Diabetes Care. 2007;30(9):2381–7.CrossRefPubMed
5.
go back to reference Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285–95.PubMed Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285–95.PubMed
6.
go back to reference Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101(16):1899–906.CrossRefPubMed Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000;101(16):1899–906.CrossRefPubMed
7.
go back to reference Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001;104(2):191–6.CrossRefPubMed Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001;104(2):191–6.CrossRefPubMed
8.
go back to reference Dell’Omo G, Penno G, Pucci L, Mariani M, Del Prato S, Pedrinelli R. Abnormal capillary permeability and endothelial dysfunction in hypertension with comorbid Metabolic Syndrome. Atherosclerosis. 2004;172(2):383–9.CrossRefPubMed Dell’Omo G, Penno G, Pucci L, Mariani M, Del Prato S, Pedrinelli R. Abnormal capillary permeability and endothelial dysfunction in hypertension with comorbid Metabolic Syndrome. Atherosclerosis. 2004;172(2):383–9.CrossRefPubMed
9.
go back to reference Walther G, Obert P, Dutheil F, Chapier R, Lesourd B, Naughton G, Courteix D, Vinet A. Metabolic syndrome individuals with and without type 2 diabetes mellitus present generalized vascular dysfunction: cross-sectional study. Arterioscler Thromb Vasc Biol. 2015;35(4):1022–9.CrossRefPubMed Walther G, Obert P, Dutheil F, Chapier R, Lesourd B, Naughton G, Courteix D, Vinet A. Metabolic syndrome individuals with and without type 2 diabetes mellitus present generalized vascular dysfunction: cross-sectional study. Arterioscler Thromb Vasc Biol. 2015;35(4):1022–9.CrossRefPubMed
10.
go back to reference Alberti KG, Zimmet P, Shaw J. Metabolic syndrome–a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med. 2006;23(5):469–80.CrossRefPubMed Alberti KG, Zimmet P, Shaw J. Metabolic syndrome–a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med. 2006;23(5):469–80.CrossRefPubMed
11.
go back to reference Fujita K, Nishizawa H, Funahashi T, Shimomura I, Shimabukuro M. Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome. Circ J. 2006;70(11):1437–42.CrossRefPubMed Fujita K, Nishizawa H, Funahashi T, Shimomura I, Shimabukuro M. Systemic oxidative stress is associated with visceral fat accumulation and the metabolic syndrome. Circ J. 2006;70(11):1437–42.CrossRefPubMed
12.
go back to reference Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.PubMed Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18(6):499–502.PubMed
13.
go back to reference Ueda S, Wada A, Umemura S. Methodological validity and feasibility of the nitric oxide clamp technique for nitric oxide research in human resistant vessels. Hypertens Res. 2004;27(5):351–7.CrossRefPubMed Ueda S, Wada A, Umemura S. Methodological validity and feasibility of the nitric oxide clamp technique for nitric oxide research in human resistant vessels. Hypertens Res. 2004;27(5):351–7.CrossRefPubMed
14.
go back to reference Shimabukuro M, Higa N, Tagawa T, Yamakawa K, Sata M, Ueda S. Defects of vascular nitric oxide bioavailability in subjects with impaired glucose tolerance: a potential link to insulin resistance. Int J Cardiol. 2013;167(1):298–300.CrossRefPubMed Shimabukuro M, Higa N, Tagawa T, Yamakawa K, Sata M, Ueda S. Defects of vascular nitric oxide bioavailability in subjects with impaired glucose tolerance: a potential link to insulin resistance. Int J Cardiol. 2013;167(1):298–300.CrossRefPubMed
15.
go back to reference Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Investig. 1996;97(11):2601–10.CrossRefPubMedPubMedCentral Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Investig. 1996;97(11):2601–10.CrossRefPubMedPubMedCentral
16.
go back to reference Weil BR, Stauffer BL, Mestek ML, DeSouza CA. Influence of abdominal obesity on vascular endothelial function in overweight/obese adult men. Obesity (Silver Spring). 2011;19(9):1742–6.CrossRef Weil BR, Stauffer BL, Mestek ML, DeSouza CA. Influence of abdominal obesity on vascular endothelial function in overweight/obese adult men. Obesity (Silver Spring). 2011;19(9):1742–6.CrossRef
17.
go back to reference Petrie JR, Ueda S, Morris AD, Murray LS, Elliott HL, Connell JM. How reproducible is bilateral forearm plethysmography? Br J Clin Pharmacol. 1998;45(2):131–9.CrossRefPubMedPubMedCentral Petrie JR, Ueda S, Morris AD, Murray LS, Elliott HL, Connell JM. How reproducible is bilateral forearm plethysmography? Br J Clin Pharmacol. 1998;45(2):131–9.CrossRefPubMedPubMedCentral
18.
go back to reference Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discovery. 2006;5(9):755–68.CrossRefPubMed Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discovery. 2006;5(9):755–68.CrossRefPubMed
20.
go back to reference Fernandes IA, Sales AR, Rocha NG, Silva BM, Vianna LC, da Nobrega AC. Preserved flow-mediated dilation but delayed time-to-peak diameter in individuals with metabolic syndrome. Clin Physiol Funct Imaging. 2014;34(4):270–6.CrossRefPubMed Fernandes IA, Sales AR, Rocha NG, Silva BM, Vianna LC, da Nobrega AC. Preserved flow-mediated dilation but delayed time-to-peak diameter in individuals with metabolic syndrome. Clin Physiol Funct Imaging. 2014;34(4):270–6.CrossRefPubMed
21.
go back to reference Weissgerber TL. Flow-mediated dilation: can new approaches provide greater mechanistic insight into vascular dysfunction in preeclampsia and other diseases? Curr Hypertens Rep. 2014;16(11):487.CrossRefPubMedPubMedCentral Weissgerber TL. Flow-mediated dilation: can new approaches provide greater mechanistic insight into vascular dysfunction in preeclampsia and other diseases? Curr Hypertens Rep. 2014;16(11):487.CrossRefPubMedPubMedCentral
22.
go back to reference Loh KP, Huang SH, Tan BK, Zhu YZ. Cerebral protection of purified Herba Leonuri extract on middle cerebral artery occluded rats. J Ethnopharmacol. 2009;125(2):337–43.CrossRefPubMed Loh KP, Huang SH, Tan BK, Zhu YZ. Cerebral protection of purified Herba Leonuri extract on middle cerebral artery occluded rats. J Ethnopharmacol. 2009;125(2):337–43.CrossRefPubMed
23.
go back to reference Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Investig. 2004;114(12):1752–61.CrossRefPubMedPubMedCentral Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Investig. 2004;114(12):1752–61.CrossRefPubMedPubMedCentral
24.
go back to reference Shimabukuro M. Cardiac adiposity and global cardiometabolic risk: new concept and clinical implication. Circ J. 2009;73(1):27–34.CrossRefPubMed Shimabukuro M. Cardiac adiposity and global cardiometabolic risk: new concept and clinical implication. Circ J. 2009;73(1):27–34.CrossRefPubMed
25.
go back to reference Chinen I, Shimabukuro M, Yamakawa K, Higa N, Matsuzaki T, Noguchi K, Ueda S, Sakanashi M, Takasu N. Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats. Endocrinology. 2007;148(1):160–5.CrossRefPubMed Chinen I, Shimabukuro M, Yamakawa K, Higa N, Matsuzaki T, Noguchi K, Ueda S, Sakanashi M, Takasu N. Vascular lipotoxicity: endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats. Endocrinology. 2007;148(1):160–5.CrossRefPubMed
26.
go back to reference Fisman EZ, Tenenbaum A. Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol. 2014;13:103.CrossRefPubMedPubMedCentral Fisman EZ, Tenenbaum A. Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol. 2014;13:103.CrossRefPubMedPubMedCentral
27.
29.
go back to reference Limberg JK, Harrell JW, Johansson RE, Eldridge MW, Proctor LT, Sebranek JJ, Schrage WG. Microvascular function in younger adults with obesity and metabolic syndrome: role of oxidative stress. Am J Physiol Heart Circ Physiol. 2013;305(8):H1230–7.CrossRefPubMedPubMedCentral Limberg JK, Harrell JW, Johansson RE, Eldridge MW, Proctor LT, Sebranek JJ, Schrage WG. Microvascular function in younger adults with obesity and metabolic syndrome: role of oxidative stress. Am J Physiol Heart Circ Physiol. 2013;305(8):H1230–7.CrossRefPubMedPubMedCentral
30.
go back to reference Schinzari F, Tesauro M, Rovella V, Galli A, Mores N, Porzio O, Lauro D, Cardillo C. Generalized impairment of vasodilator reactivity during hyperinsulinemia in patients with obesity-related metabolic syndrome. Am J Physiol Endocrinol Metab. 2010;299(6):E947–52.CrossRefPubMed Schinzari F, Tesauro M, Rovella V, Galli A, Mores N, Porzio O, Lauro D, Cardillo C. Generalized impairment of vasodilator reactivity during hyperinsulinemia in patients with obesity-related metabolic syndrome. Am J Physiol Endocrinol Metab. 2010;299(6):E947–52.CrossRefPubMed
31.
go back to reference Aoqui C, Chmielewski S, Scherer E, Eissler R, Sollinger D, Heid I, Braren R, Schmaderer C, Megens RT, Weber C, et al. Microvascular dysfunction in the course of metabolic syndrome induced by high-fat diet. Cardiovasc Diabetol. 2014;13:31.CrossRefPubMedPubMedCentral Aoqui C, Chmielewski S, Scherer E, Eissler R, Sollinger D, Heid I, Braren R, Schmaderer C, Megens RT, Weber C, et al. Microvascular dysfunction in the course of metabolic syndrome induced by high-fat diet. Cardiovasc Diabetol. 2014;13:31.CrossRefPubMedPubMedCentral
32.
go back to reference Nevelsteen I, Van den Bergh A, Van der Mieren G, Vanderper A, Mubagwa K, Bult H, Herijgers P. NO-dependent endothelial dysfunction in type II diabetes is aggravated by dyslipidemia and hypertension, but can be restored by angiotensin-converting enzyme inhibition and weight loss. J Vasc Res. 2013;50(6):486–97.CrossRefPubMed Nevelsteen I, Van den Bergh A, Van der Mieren G, Vanderper A, Mubagwa K, Bult H, Herijgers P. NO-dependent endothelial dysfunction in type II diabetes is aggravated by dyslipidemia and hypertension, but can be restored by angiotensin-converting enzyme inhibition and weight loss. J Vasc Res. 2013;50(6):486–97.CrossRefPubMed
33.
go back to reference Ohno Y, Miyoshi T, Noda Y, Oe H, Toh N, Nakamura K, Kohno K, Morita H, Ito H. Bezafibrate improves postprandial hypertriglyceridemia and associated endothelial dysfunction in patients with metabolic syndrome: a randomized crossover study. Cardiovasc Diabetol. 2014;13:71.CrossRefPubMedPubMedCentral Ohno Y, Miyoshi T, Noda Y, Oe H, Toh N, Nakamura K, Kohno K, Morita H, Ito H. Bezafibrate improves postprandial hypertriglyceridemia and associated endothelial dysfunction in patients with metabolic syndrome: a randomized crossover study. Cardiovasc Diabetol. 2014;13:71.CrossRefPubMedPubMedCentral
34.
go back to reference Kraemer-Aguiar LG, de Miranda ML, Bottino DA, Lima Rde A, de Souza M, Balarini Mde M, Villela NR, Bouskela E. Increment of body mass index is positively correlated with worsening of endothelium-dependent and independent changes in forearm blood flow. Front Physiol. 2015;6:223.CrossRefPubMedPubMedCentral Kraemer-Aguiar LG, de Miranda ML, Bottino DA, Lima Rde A, de Souza M, Balarini Mde M, Villela NR, Bouskela E. Increment of body mass index is positively correlated with worsening of endothelium-dependent and independent changes in forearm blood flow. Front Physiol. 2015;6:223.CrossRefPubMedPubMedCentral
35.
go back to reference Stefan N, Haring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1(2):152–62.CrossRefPubMed Stefan N, Haring HU, Hu FB, Schulze MB. Metabolically healthy obesity: epidemiology, mechanisms, and clinical implications. Lancet Diabetes Endocrinol. 2013;1(2):152–62.CrossRefPubMed
36.
go back to reference Schinzari F, Iantorno M, Campia U, Mores N, Rovella V, Tesauro M, Di Daniele N, Cardillo C. Vasodilator responses and endothelin-dependent vasoconstriction in metabolically healthy obesity and the metabolic syndrome. Am J Physiol Endocrinol Metab. 2015;309(9):E787–92.CrossRefPubMed Schinzari F, Iantorno M, Campia U, Mores N, Rovella V, Tesauro M, Di Daniele N, Cardillo C. Vasodilator responses and endothelin-dependent vasoconstriction in metabolically healthy obesity and the metabolic syndrome. Am J Physiol Endocrinol Metab. 2015;309(9):E787–92.CrossRefPubMed
37.
go back to reference Li J, Flammer AJ, Lennon RJ, Nelson RE, Gulati R, Friedman PA, Thomas RJ, Sandhu NP, Hua Q, Lerman LO, et al. Comparison of the effect of the metabolic syndrome and multiple traditional cardiovascular risk factors on vascular function. Mayo Clin Proc. 2012;87(10):968–75.CrossRefPubMedPubMedCentral Li J, Flammer AJ, Lennon RJ, Nelson RE, Gulati R, Friedman PA, Thomas RJ, Sandhu NP, Hua Q, Lerman LO, et al. Comparison of the effect of the metabolic syndrome and multiple traditional cardiovascular risk factors on vascular function. Mayo Clin Proc. 2012;87(10):968–75.CrossRefPubMedPubMedCentral
38.
go back to reference Tomiyama H, Kohro T, Higashi Y, Takase B, Suzuki T, Ishizu T, Ueda S, Yamazaki T, Furumoto T, Kario K, et al. Reliability of measurement of endothelial function across multiple institutions and establishment of reference values in Japanese. Atherosclerosis. 2015;242(2):433–42.CrossRefPubMed Tomiyama H, Kohro T, Higashi Y, Takase B, Suzuki T, Ishizu T, Ueda S, Yamazaki T, Furumoto T, Kario K, et al. Reliability of measurement of endothelial function across multiple institutions and establishment of reference values in Japanese. Atherosclerosis. 2015;242(2):433–42.CrossRefPubMed
39.
go back to reference Matsuhisa M, Yamasaki Y, Emoto M, Shimabukuro M, Ueda S, Funahashi T, Matsuzawa Y. A novel index of insulin resistance determined from the homeostasis model assessment index and adiponectin levels in Japanese subjects. Diabetes Res Clin Pract. 2007;77(1):151–4.CrossRefPubMed Matsuhisa M, Yamasaki Y, Emoto M, Shimabukuro M, Ueda S, Funahashi T, Matsuzawa Y. A novel index of insulin resistance determined from the homeostasis model assessment index and adiponectin levels in Japanese subjects. Diabetes Res Clin Pract. 2007;77(1):151–4.CrossRefPubMed
Metadata
Title
Impact of individual metabolic risk components or its clustering on endothelial and smooth muscle cell function in men
Authors
Michio Shimabukuro
Namio Higa
Hiroaki Masuzaki
Masataka Sata
Shinichiro Ueda
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2016
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/s12933-016-0394-5

Other articles of this Issue 1/2016

Cardiovascular Diabetology 1/2016 Go to the issue