{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:14:57Z","timestamp":1788520497568,"version":"build-2803163510"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":942,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,2]]},"abstract":"\n \n \n The pathogenesis of type 2 diabetes is characterized by impaired insulin action and increased hepatic glucose production (HGP). Despite the importance of hepatic metabolic aberrations in diabetes development, there is currently no molecular probe that allows measurement of hepatic gluconeogenic pathways<\/jats:bold>\n in vivo<\/jats:bold>\n and in a noninvasive manner. In this study, we used hyperpolarized carbon 13 (13C)-labeled pyruvate magnetic resonance spectroscopy (MRS) to determine changes in hepatic gluconeogenesis in a high-fat diet (HFD)-induced mouse model of type 2 diabetes. Compared with mice on chow diet, HFD-fed mice displayed higher levels of oxaloacetate, aspartate, and malate, along with increased 13C label exchange rates between hyperpolarized [1-13C]pyruvate and its downstream metabolites, [1-13C]malate and [1-13C]aspartate. Biochemical assays using liver extract revealed up-regulated malate dehydrogenase activity, but not aspartate transaminase activity, in HFD-fed mice. Moreover, the 13C label exchange rate between [1-13C]pyruvate and [1-13C]aspartate (kpyr->asp) exhibited apparent correlation with gluconeogenic pyruvate carboxylase (PC) activity in hepatocytes. Finally, up-regulated HGP by glucagon stimulation was detected by an increase in aspartate signal and<\/jats:bold>\n k<\/jats:bold>\n pyr<\/jats:bold>\n -><\/jats:bold>\n asp<\/jats:bold>\n , whereas HFD mice treated with metformin for 2 weeks displayed lower production of aspartate and malate, as well as reduced<\/jats:bold>\n k<\/jats:bold>\n pyr<\/jats:bold>\n -><\/jats:bold>\n asp<\/jats:bold>\n and 13C-label exchange rate between pyruvate and malate, consistent with down-regulated gluconeogenesis.<\/jats:bold>\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion:<\/jats:title>\n \n Taken together, we demonstrate that increased PC flux is an important pathway responsible for increased HGP in diabetes development, and that pharmacologically induced metabolic changes specific to the liver can be detected<\/jats:bold>\n in vivo<\/jats:bold>\n with a hyperpolarized 13C-biomolecular probe. Hyperpolarized 13C MRS and the determination of metabolite exchange rates may allow longitudinal monitoring of liver function in disease development.<\/jats:bold>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/hep.26028","type":"journal-article","created":{"date-parts":[[2012,8,22]],"date-time":"2012-08-22T04:28:24Z","timestamp":1345609704000},"page":"515-524","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":87,"title":["In Vivo Hyperpolarized Carbon-13 Magnetic Resonance Spectroscopy Reveals Increased Pyruvate Carboxylase Flux in an Insulin-Resistant Mouse Model"],"prefix":"10.1097","volume":"57","author":[{"given":"Philip","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waifook","family":"Leong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trish","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miangkee","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George K.","family":"Radda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-12-20241201","doi-asserted-by":"crossref","first-page":"840846","DOI":"10.1038\/nature05482","article-title":"Mechanisms linking obesity to insulin resistance and type 2 diabetes.","volume":"444","author":"Kahn","year":"2006","journal-title":"Nature"},{"key":"R2-12-20241201","doi-asserted-by":"crossref","first-page":"1429414308","DOI":"10.1016\/S0021-9258(17)43859-2","article-title":"Simultaneous 13C and 31P NMR studies of perfused rat liver. Effects of insulin and glucagon and a 13C NMR assay of free Mg2.","volume":"258","author":"Cohen","year":"1983","journal-title":"J Biol Chem"},{"key":"R3-12-20241201","first-page":"1015810163","article-title":"Increase in signaltonoise ratio of 10,000 times in liquidstate NMR.","volume":"100","author":"ArdenkjaerLarsen","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R4-12-20241201","doi-asserted-by":"crossref","first-page":"1908419089","DOI":"10.1073\/pnas.1111247108","article-title":"Flux through hepatic pyruvate carboxylase and phosphoenolpyruvate carboxykinase detected by hyperpolarized 13C magnetic resonance.","volume":"108","author":"Merritt","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R5-12-20241201","doi-asserted-by":"crossref","first-page":"399407","DOI":"10.1007\/s11307-009-0218-z","article-title":"In vivo carbon13 dynamic MRS and MRSI of normal and fasted rat liver with hyperpolarized 13Cpyruvate.","volume":"11","author":"Hu","year":"2009","journal-title":"Mol Imaging Biol"},{"key":"R6-12-20241201","doi-asserted-by":"crossref","first-page":"313320","DOI":"10.1016\/j.cmet.2007.03.004","article-title":"Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver.","volume":"5","author":"Burgess","year":"2007","journal-title":"Cell Metab"},{"key":"R7-12-20241201","first-page":"379389","article-title":"Control of gluconeogenesis in rat liver cells. Flux control coefficients of the enzymes in the gluconeogenic pathway in the absence and presence of glucagon.","volume":"237","author":"Groen","year":"1986","journal-title":"Biochem J"},{"key":"R8-12-20241201","doi-asserted-by":"crossref","first-page":"39923997","DOI":"10.1073\/pnas.0711700105","article-title":"Impaired insulin secretion and glucose intolerance in synaptotagmin7 null mutant mice.","volume":"105","author":"Gustavsson","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R9-12-20241201","doi-asserted-by":"crossref","first-page":"281285","DOI":"10.1002\/jmri.1880050311","article-title":"Proton MR spectroscopy in quantitative in vivo determination of fat content in human liver steatosis.","volume":"5","author":"Longo","year":"1995","journal-title":"J Magn Reson Imaging"},{"key":"R10-12-20241201","doi-asserted-by":"crossref","first-page":"8291","DOI":"10.1093\/cvr\/cvp396","article-title":"Measuring intracellular pH in the heart using hyperpolarized carbon dioxide and bicarbonate: a 13C and 31P magnetic resonance spectroscopy study.","volume":"86","author":"Schroeder","year":"2010","journal-title":"Cardiovasc Res"},{"key":"R11-12-20241201","doi-asserted-by":"crossref","first-page":"4883","DOI":"10.1210\/er.2006-0035","article-title":"The genetic landscape of type 2 diabetes in mice.","volume":"28","author":"Clee","year":"2007","journal-title":"Endocr Rev"},{"key":"R12-12-20241201","doi-asserted-by":"crossref","first-page":"478481","DOI":"10.1002\/mrc.1260230615","article-title":"Carbon13 nuclear magnetic resonance spectra of the hydrate, keto and enol forms of oxalacetic acid.","volume":"23","author":"Buldain","year":"1985","journal-title":"Magn Reson Chem"},{"key":"R13-12-20241201","doi-asserted-by":"crossref","first-page":"1205112056","DOI":"10.1073\/pnas.0805953105","article-title":"In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon13 magnetic resonance.","volume":"105","author":"Schroeder","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R14-12-20241201","doi-asserted-by":"crossref","first-page":"E685E692","DOI":"10.1152\/ajpendo.00253.2003","article-title":"Novel concepts in insulin regulation of hepatic gluconeogenesis.","volume":"285","author":"Barthel","year":"2003","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"R15-12-20241201","doi-asserted-by":"crossref","first-page":"799806","DOI":"10.1038\/414799a","article-title":"Insulin signalling and the regulation of glucose and lipid metabolism.","volume":"414","author":"Saltiel","year":"2001","journal-title":"Nature"},{"key":"R16-12-20241201","first-page":"601608","article-title":"Effect of streptozotocininduced diabetes mellitus on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase.","volume":"188","author":"Weinberg","year":"1980","journal-title":"Biochem J"},{"key":"R17-12-20241201","doi-asserted-by":"crossref","first-page":"415422","DOI":"10.1007\/s00125-010-1950-2","article-title":"Delayed onset of hyperglycaemia in a mouse model with impaired glucagon secretion demonstrates that dysregulated glucagon secretion promotes hyperglycaemia and type 2 diabetes.","volume":"54","author":"Gustavsson","year":"2011","journal-title":"Diabetologia"},{"key":"R18-12-20241201","doi-asserted-by":"crossref","first-page":"E671E678","DOI":"10.1152\/ajpendo.00492.2002","article-title":"Glucagon and regulation of glucose metabolism.","volume":"284","author":"Jiang","year":"2003","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"R19-12-20241201","first-page":"181186","article-title":"Hormonal control of pyruvate dehydrogenase activity in rat liver.","volume":"224","author":"Oviasu","year":"1984","journal-title":"Biochem J"},{"key":"R20-12-20241201","doi-asserted-by":"crossref","first-page":"32673273","DOI":"10.2337\/diabetes.53.12.3267","article-title":"A novel glucagon receptor antagonist inhibits glucagonmediated biological effects.","volume":"53","author":"Qureshi","year":"2004","journal-title":"Diabetes"},{"key":"R21-12-20241201","doi-asserted-by":"crossref","first-page":"821827","DOI":"10.1038\/414821a","article-title":"New drug targets for type 2 diabetes and the metabolic syndrome.","volume":"414","author":"Moller","year":"2001","journal-title":"Nature"},{"key":"R22-12-20241201","doi-asserted-by":"crossref","first-page":"11251131","DOI":"10.1172\/JCI0215593","article-title":"SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.","volume":"109","author":"Horton","year":"2002","journal-title":"J Clin Invest"},{"key":"R23-12-20241201","doi-asserted-by":"crossref","first-page":"21592170","DOI":"10.2337\/db06-0200","article-title":"Liverspecific inhibition of ChREBP improves hepatic steatosis and insulin resistance in obob mice.","volume":"55","author":"Dentin","year":"2006","journal-title":"Diabetes"},{"key":"R24-12-20241201","doi-asserted-by":"crossref","first-page":"G852G858","DOI":"10.1152\/ajpgi.00521.2005","article-title":"Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation.","volume":"290","author":"Reddy","year":"2006","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R25-12-20241201","doi-asserted-by":"crossref","first-page":"147152","DOI":"10.1172\/JCI200422422","article-title":"Molecular mediators of hepatic steatosis and liver injury.","volume":"114","author":"Browning","year":"2004","journal-title":"J Clin Invest"},{"key":"R26-12-20241201","doi-asserted-by":"crossref","first-page":"804810","DOI":"10.1016\/j.cmet.2011.11.004","article-title":"Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease.","volume":"14","author":"Sunny","year":"2011","journal-title":"Cell Metab"},{"key":"R27-12-20241201","doi-asserted-by":"crossref","first-page":"581589","DOI":"10.1021\/bi00376a033","article-title":"13C NMR study of effects of fasting and diabetes on the metabolism of pyruvate in the tricarboxylic acid cycle and the utilization of pyruvate and ethanol in lipogenesis in perfused rat liver.","volume":"26","author":"Cohen","year":"1987","journal-title":"Biochemistry"},{"key":"R28-12-20241201","doi-asserted-by":"crossref","first-page":"25522561","DOI":"10.1161\/CIRCULATIONAHA.110.011387","article-title":"Role of pyruvate dehydrogenase inhibition in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy study.","volume":"123","author":"Atherton","year":"2011","journal-title":"Circulation"},{"key":"R29-12-20241201","doi-asserted-by":"crossref","first-page":"25292538","DOI":"10.1096\/fj.09-129171","article-title":"Realtime assessment of Krebs cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy.","volume":"23","author":"Schroeder","year":"2009","journal-title":"FASEB J"},{"key":"R30-12-20241201","doi-asserted-by":"crossref","first-page":"11671174","DOI":"10.1172\/JCI13505","article-title":"Role of AMPactivated protein kinase in mechanism of metformin action.","volume":"108","author":"Zhou","year":"2001","journal-title":"J Clin Invest"},{"key":"R31-12-20241201","doi-asserted-by":"crossref","first-page":"523531","DOI":"10.1007\/s00723-008-0115-7","article-title":"Application of hyperpolarized magnetic resonance in the study of cardiac metabolism.","volume":"34","author":"Tyler","year":"2008","journal-title":"Appl Magn Reson"},{"key":"R32-12-20241201","doi-asserted-by":"crossref","first-page":"201209","DOI":"10.1161\/CIRCIMAGING.111.969451","article-title":"The Cycling of acetylCoA through acetylcarnitine buffers cardiac substrate supply: a hyperpolarised 13C magnetic resonance study.","volume":"5","author":"Schroeder","year":"2012","journal-title":"Circ Cardiovasc Imaging"},{"key":"R33-12-20241201","doi-asserted-by":"crossref","first-page":"8592","DOI":"10.1016\/j.jmr.2009.10.003","article-title":"Kinetic modeling of hyperpolarized 13C1pyruvate metabolism in normal rats and TRAMP mice.","volume":"202","author":"Zierhut","year":"2010","journal-title":"J Magn Reson"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.26028","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201302000-00012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T09:06:32Z","timestamp":1733043992000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201302000-00012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,2]]},"references-count":33,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2013]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.26028","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2013,2]]}}}