{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:10:21Z","timestamp":1785215421092,"version":"3.55.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T00:00:00Z","timestamp":1409529600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T00:00:00Z","timestamp":1409529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nutr &amp; Diabetes"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Objectives:<\/jats:title>\n                <jats:p>Plasma-free amino acid (PFAA) profiles have been associated with a future risk of developing diabetes or cardiovascular disease in nondiabetic subjects. These PFAA alterations might predominantly result from the metabolic shift caused by insulin resistance and visceral fat deposition. The variety of PFAA profiles within diabetic subjects is not well researched. In this study, we focused on type 2 diabetic subjects and examined the association between PFAA profiles and insulin- and glucose-related variables.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods:<\/jats:title>\n                <jats:p>Fifty-one Japanese subjects diagnosed with type 2 diabetes were recruited from an outpatient clinic. The plasma concentrations of 21 amino acids; glucose-related markers including glucose, hemoglobin A1c (HbA1c), glycoalbumin and 1,5-anhydroglucitol; insulin-related markers including insulin, C-peptide, and the homeostasis model assessment of insulin resistance; and adipocytokines including adiponectin and leptin were determined. The association of PFAA and other metabolic profiles were analyzed, and stratified analyses of the PFAAs and clinical characteristics were performed according to the fasting plasma insulin and HbA1c levels. In addition, the PFAA indices that correlate to visceral fat obesity were evaluated.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results:<\/jats:title>\n                <jats:p>Although strong correlations between PFAAs and glucose-related markers were not observed, several amino acids (branched-chain amino acids, tryptophan, alanine, tyrosine, glutamate and proline) and PFAA indices that evaluate visceral obesity were highly correlated with insulin-related markers and adiponectin (<jats:italic>P<\/jats:italic>&lt;0.001). In the group of diabetic patients with hyperinsulinemia, the amino acid levels were significantly increased, which generally demonstrated good concordance with insulin-related markers and adiponectin levels.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions:<\/jats:title>\n                <jats:p>The PFAA profiles in diabetic patients were strongly associated with hyperinsulinemia and hypoadiponectinemia, which might become risk evaluation factors for the development of cardiovascular diseases.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1038\/nutd.2014.32","type":"journal-article","created":{"date-parts":[[2014,9,1]],"date-time":"2014-09-01T14:17:37Z","timestamp":1409581057000},"page":"e133-e133","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":102,"title":["Plasma amino acid profiles are associated with insulin, C-peptide and adiponectin levels in type 2 diabetic patients"],"prefix":"10.1038","volume":"4","author":[{"given":"H","family":"Nakamura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Jinzu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Nagao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Noguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Shimba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Miyano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Iseki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,9,1]]},"reference":[{"key":"BFnutd201432_CR1","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/nm.2307","volume":"17","author":"TJ Wang","year":"2011","unstructured":"Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E et al. Metabolite profiles and the risk of developing diabetes. Nat Med 2011; 17: 448\u2013453.","journal-title":"Nat Med"},{"key":"BFnutd201432_CR2","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1093\/eurheartj\/ehs424","volume":"34","author":"M Magnusson","year":"2013","unstructured":"Magnusson M, Lewis GD, Ericson U, Orho-Melander M, Hedblad B, Engstrom G et al. A diabetes-predictive amino acid score and future cardiovascular disease. Eur Heart J 2013; 34: 1982\u20131989.","journal-title":"Eur Heart J"},{"key":"BFnutd201432_CR3","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1111\/j.1758-8111.2012.00039.x","volume":"2","author":"M Yamakado","year":"2012","unstructured":"Yamakado M, Tanaka T et al. Plasma amino acid profile is associated with visceral fat accumulation in obese Japanese subjects. Clin Obes 2012; 2: 29\u201340.","journal-title":"Clin Obes"},{"key":"BFnutd201432_CR4","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1172\/JCI101300","volume":"21","author":"JA Luetscher","year":"1942","unstructured":"Luetscher JA . The metabolism of amino acids in diabetes mellitus. J Clin Invest 1942; 21: 275\u2013279.","journal-title":"J Clin Invest"},{"key":"BFnutd201432_CR5","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.diabres.2003.09.010","volume":"63","author":"KG Park","year":"2004","unstructured":"Park KG, Park KS, Kim MJ, Kim HS, Suh YS, Ahn JD et al. Relationship between serum adiponectin and leptin concentrations and body fat distribution. Diabetes Res Clin Pract 2004; 63: 135\u2013142.","journal-title":"Diabetes Res Clin Pract"},{"key":"BFnutd201432_CR6","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/j.1467-789X.2009.00623.x","volume":"11","author":"MM Ibrahim","year":"2010","unstructured":"Ibrahim MM . Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 2010; 11: 11\u201318.","journal-title":"Obes Rev"},{"key":"BFnutd201432_CR7","doi-asserted-by":"publisher","first-page":"1784","DOI":"10.1172\/JCI29126","volume":"116","author":"T Kadowaki","year":"2006","unstructured":"Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K . Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784\u20131792.","journal-title":"J Clin Invest"},{"key":"BFnutd201432_CR8","doi-asserted-by":"publisher","first-page":"258S","DOI":"10.3945\/ajcn.2009.28449C","volume":"91","author":"F Ziemke","year":"2010","unstructured":"Ziemke F, Mantzoros CS . Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr 2010; 91: 258S\u2013261S.","journal-title":"Am J Clin Nutr"},{"key":"BFnutd201432_CR9","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1001\/jama.2009.976","volume":"302","author":"S Li","year":"2009","unstructured":"Li S, Shin HJ, Ding EL, van Dam RM . Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2009; 302: 179\u2013188.","journal-title":"JAMA"},{"key":"BFnutd201432_CR10","doi-asserted-by":"publisher","first-page":"3052","DOI":"10.1161\/hc5001.101061","volume":"104","author":"AM Wallace","year":"2001","unstructured":"Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A et al. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation 2001; 104: 3052\u20133056.","journal-title":"Circulation"},{"key":"BFnutd201432_CR11","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1007\/BF00280883","volume":"28","author":"DR Matthews","year":"1985","unstructured":"Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412\u2013419.","journal-title":"Diabetologia"},{"key":"BFnutd201432_CR12","doi-asserted-by":"publisher","first-page":"1483","DOI":"10.1002\/rcm.4026","volume":"23","author":"K Shimbo","year":"2009","unstructured":"Shimbo K, Oonuki T, Yahashi A, Hirayama K, Miyano H . Precolumn derivatization reagents for high-speed analysis of amines and amino acids in biological fluid using liquid chromatography\/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 2009; 23: 1483\u20131492.","journal-title":"Rapid Commun Mass Spectrom"},{"key":"BFnutd201432_CR13","doi-asserted-by":"publisher","first-page":"5172","DOI":"10.1021\/ac900470w","volume":"81","author":"K Shimbo","year":"2009","unstructured":"Shimbo K, Yahashi A, Hirayama K, Nakazawa M, Miyano H . Multifunctional and highly sensitive precolumn reagents for amino acids in liquid chromatography\/tandem mass spectrometry. Anal Chem 2009; 81: 5172\u20135179.","journal-title":"Anal Chem"},{"key":"BFnutd201432_CR14","doi-asserted-by":"publisher","first-page":"e24143","DOI":"10.1371\/journal.pone.0024143","volume":"6","author":"Y Miyagi","year":"2011","unstructured":"Miyagi Y, Higashiyama M, Gochi A, Akaike M, Ishikawa T, Miura T et al. Plasma free amino acid profiling of five types of cancer patients and its application for early detection. PLoS One 2011; 6: e24143.","journal-title":"PLoS One"},{"key":"BFnutd201432_CR15","doi-asserted-by":"publisher","first-page":"e263","DOI":"10.1371\/journal.pmed.0040263","volume":"4","author":"DA Lawlor","year":"2007","unstructured":"Lawlor DA, Fraser A, Ebrahim S, Smith GD . Independent associations of fasting insulin, glucose, and glycated haemoglobin with stroke and coronary heart disease in older women. PLoS Med 2007; 4: e263.","journal-title":"PLoS Med"},{"key":"BFnutd201432_CR16","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1001\/jama.294.3.334","volume":"294","author":"E Ingelsson","year":"2005","unstructured":"Ingelsson E, Sundstrom J, Arnlov J, Zethelius B, Lind L . Insulin resistance and risk of congestive heart failure. JAMA 2005; 294: 334\u2013341.","journal-title":"JAMA"},{"key":"BFnutd201432_CR17","doi-asserted-by":"publisher","first-page":"e73445","DOI":"10.1371\/journal.pone.0073445","volume":"8","author":"FP Martin","year":"2013","unstructured":"Martin FP, Montoliu I, Collino S, Scherer M, Guy P, Tavazzi I et al. Topographical body fat distribution links to amino acid and lipid metabolism in healthy non-obese women. PLoS One 2013; 8: e73445.","journal-title":"PLoS One"},{"key":"BFnutd201432_CR18","doi-asserted-by":"publisher","first-page":"513S","DOI":"10.1093\/ajcn\/83.2.513S","volume":"83","author":"Y Noguchi","year":"2006","unstructured":"Noguchi Y, Zhang QW, Sugimoto T, Furuhata Y, Sakai R, Mori M et al. Network analysis of plasma and tissue amino acids and the generation of an amino index for potential diagnostic use. Am J Clin Nutr 2006; 83: 513S\u2013519S.","journal-title":"Am J Clin Nutr"},{"key":"BFnutd201432_CR19","doi-asserted-by":"publisher","first-page":"107","DOI":"10.2337\/diacare.17.2.107","volume":"17","author":"N Yamada","year":"1994","unstructured":"Yamada N, Yoshinaga H, Sakurai N, Shimano H, Gotoda T, Ohashi Y et al. Increased risk factors for coronary artery disease in Japanese subjects with hyperinsulinemia or glucose intolerance. Diabetes Care 1994; 17: 107\u2013114.","journal-title":"Diabetes Care"},{"key":"BFnutd201432_CR20","doi-asserted-by":"publisher","first-page":"3455","DOI":"10.1021\/pr500416v","volume":"13","author":"F Badoud","year":"2014","unstructured":"Badoud F, Lam KP, DiBattista A, Perreault M, Zulyniak MA, Cattrysse B et al. Serum and adipose tissue amino Acid homeostasis in the metabolically healthy obese. J Proteome Res 2014; 13: 3455\u20133466.","journal-title":"J Proteome Res"},{"key":"BFnutd201432_CR21","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.cmet.2009.02.002","volume":"9","author":"CB Newgard","year":"2009","unstructured":"Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009; 9: 311\u2013326.","journal-title":"Cell Metab"},{"key":"BFnutd201432_CR22","doi-asserted-by":"publisher","first-page":"1678","DOI":"10.2337\/dc08-2075","volume":"32","author":"KM Huffman","year":"2009","unstructured":"Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer M, Slentz CA et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care 2009; 32: 1678\u20131683.","journal-title":"Diabetes Care"},{"key":"BFnutd201432_CR23","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1007\/s00125-009-1637-8","volume":"53","author":"ES Tai","year":"2010","unstructured":"Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 2010; 53: 757\u2013767.","journal-title":"Diabetologia"},{"key":"BFnutd201432_CR24","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1172\/JCI106193","volume":"48","author":"T Pozefsky","year":"1969","unstructured":"Pozefsky T, Felig P, Tobin JD, Soeldner JS, Cahill GF Jr . Amino acid balance across tissues of the forearm in postabsorptive man. Effects of insulin at two dose levels. J Clin Invest 1969; 48: 2273\u20132282.","journal-title":"J Clin Invest"},{"key":"BFnutd201432_CR25","doi-asserted-by":"publisher","first-page":"11348","DOI":"10.1074\/jbc.M109.075184","volume":"285","author":"MA Herman","year":"2010","unstructured":"Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB . Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem 2010; 285: 11348\u201311356.","journal-title":"J Biol Chem"},{"key":"BFnutd201432_CR26","doi-asserted-by":"publisher","first-page":"E1175","DOI":"10.1152\/ajpendo.00630.2012","volume":"304","author":"DE Lackey","year":"2013","unstructured":"Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH et al. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab 2013; 304: E1175\u2013E1187.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"BFnutd201432_CR27","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1586\/14737159.8.1.9","volume":"8","author":"KM Dungan","year":"2008","unstructured":"Dungan KM . 1,5-anhydroglucitol (GlycoMark) as a marker of short-term glycemic control and glycemic excursions. Expert Rev Mol Diagn 2008; 8: 9\u201319.","journal-title":"Expert Rev Mol Diagn"},{"key":"BFnutd201432_CR28","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1038\/90984","volume":"7","author":"T Yamauchi","year":"2001","unstructured":"Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941\u2013946.","journal-title":"Nat Med"},{"key":"BFnutd201432_CR29","doi-asserted-by":"publisher","first-page":"743","DOI":"10.2337\/db12-0687","volume":"62","author":"Y Liu","year":"2013","unstructured":"Liu Y, Turdi S, Park T, Morris NJ, Deshaies Y, Xu A et al. Adiponectin corrects high-fat diet-induced disturbances in muscle metabolomic profile and whole-body glucose homeostasis. Diabetes 2013; 62: 743\u2013752.","journal-title":"Diabetes"},{"key":"BFnutd201432_CR30","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1161\/01.CIR.98.5.398","volume":"98","author":"M Pyorala","year":"1998","unstructured":"Pyorala M, Miettinen H, Laakso M, Pyorala K . Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki Policemen Study. Circulation 1998; 98: 398\u2013404.","journal-title":"Circulation"},{"key":"BFnutd201432_CR31","doi-asserted-by":"publisher","first-page":"721","DOI":"10.2169\/internalmedicine.49.2897","volume":"49","author":"T Yamashita","year":"2010","unstructured":"Yamashita T, Matsuda M, Nishimoto O, Nakamoto K, Nishiyama H, Matsumoto K et al. Combination of serum adiponectin level and metabolic syndrome is closely associated with coronary artery disease in Japanese subjects with good glycemic control. Intern Med 2010; 49: 721\u2013727.","journal-title":"Intern Med"}],"container-title":["Nutrition &amp; Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/nutd201432.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/nutd201432","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/nutd201432.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T21:14:40Z","timestamp":1672953280000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/nutd201432"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,1]]},"references-count":31,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2014,9]]}},"alternative-id":["BFnutd201432"],"URL":"https:\/\/doi.org\/10.1038\/nutd.2014.32","relation":{},"ISSN":["2044-4052"],"issn-type":[{"value":"2044-4052","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,9,1]]},"assertion":[{"value":"29 May 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2014","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 July 2014","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2014","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"HN, HJ, KN, YN, NS and HM are employees of Ajinomoto Co., Inc. TW is the CEO of Link and Communication Co., Inc. TW and KI received research grants from Ajinomoto Co., Inc. No other potential conflicts of interest relevant to this article are declared.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}