{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:06:11Z","timestamp":1790197571514,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2017,12,2]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">The healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Diabetes mellitus disrupts this metabolic flexibility and promotes cardiomyopathy through mechanisms that are not completely understood. Phosphofructokinase 2 (PFK\u20102) is a primary regulator of cardiac glycolysis and substrate selection, yet its regulation under normal and pathological conditions is unknown. This study was undertaken to determine how changes in insulin signaling affect PFK\u20102 content, activity, and cardiac metabolism.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">Streptozotocin\u2010induced diabetes mellitus, high\u2010fat diet feeding, and fasted mice were used to identify how decreased insulin signaling affects PFK\u20102 and cardiac metabolism. Primary adult cardiomyocytes were used to define the mechanisms that regulate PFK\u20102 degradation. Both type 1 diabetes mellitus and a high\u2010fat diet induced a significant decrease in cardiac PFK\u20102 protein content without affecting its transcript levels. Overnight fasting also induced a decrease in PFK\u20102, suggesting it is rapidly degraded in the absence of insulin signaling. An unbiased metabolomic study demonstrated that decreased PFK\u20102 in fasted animals is accompanied by an increase in glycolytic intermediates upstream of phosphofructokianse\u20101, whereas those downstream are diminished. Mechanistic studies using cardiomyocytes showed that, in the absence of insulin signaling, PFK\u20102 is rapidly degraded via both proteasomal\u2010 and chaperone\u2010mediated autophagy.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">The loss of PFK\u20102 content as a result of reduced insulin signaling impairs the capacity to dynamically regulate glycolysis and elevates the levels of early glycolytic intermediates. Although this may be beneficial in the fasted state to conserve systemic glucose, it represents a pathological impairment in diabetes mellitus.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.117.007159","type":"journal-article","created":{"date-parts":[[2017,12,5]],"date-time":"2017-12-05T01:10:28Z","timestamp":1512436228000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity"],"prefix":"10.1161","volume":"6","author":[{"given":"Lee B.","family":"Bockus","sequence":"first","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK"},{"name":"Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Matsuzaki","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shraddha S.","family":"Vadvalkar","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary T.","family":"Young","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Giorgione","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria F.","family":"Newhardt","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK"},{"name":"Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kinter","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth M.","family":"Humphries","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK"},{"name":"Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161211798357773"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2840-2-1"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2008.03.046"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.2741\/1216"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.300376"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2016.03.020"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-014-3171-6"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.681767"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3290197"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00256.2007"},{"key":"e_1_3_4_12_2","first-page":"H2320","article-title":"Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine\u2010induced work","volume":"271","author":"Hall JL","year":"1996","unstructured":"Hall JL, Stanley WC, Lopaschuk GD, Wisneski JA, Pizzurro RD, Hamilton CD, McCormack JG. 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