{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:20:07Z","timestamp":1787746807304,"version":"build-2784847793"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The serine\/threonine kinase AKT is a key regulator of glucose and energy metabolism. Prevailing dogma suggests that AKT is an obligate intermediate for glucose uptake in all metabolic tissues and that impaired AKT signalling is a major molecular driver of insulin resistance in obesity. However, whether AKT is universally required for insulin\u2010stimulated glucose uptake across tissues in\u00a0vivo has remained unresolved.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      Several mouse models of adipose\u2010specific AKT2 deletion (F\u2010AKT2KO) and skeletal muscle\u2010specific AKT1, AKT2 and combined AKT1\/AKT2 knockout mice (M\u2010AKT1KO, M\u2010AKT2KO and M\u2010AKTDKO) were generated. Skeletal muscle and adipose tissues were analysed following in\u00a0vivo administration of insulin (2\u2009U\/kg), using Western blotting, phosphoproteomics, PI(3,4,5)P3 ELISA and mitochondrial respiration assays. Glucose metabolism was assessed using [\n                      <jats:sup>3<\/jats:sup>\n                      H]\u20102\u2010deoxyglucose uptake, hyperinsulinemic\u2010euglycemic clamps, glucose and insulin tolerance tests. Global phosphoproteomics was performed in insulin\u2010stimulated skeletal muscle lacking AKT isoforms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Loss of AKT2 in adipose tissue impaired insulin signalling, including reduced pAS160\n                      <jats:sup>Thr649<\/jats:sup>\n                      , and markedly decreased insulin\u2010stimulated glucose uptake (~2\u20133 fold reduction in F\u2010AKT2KO vs F\u2010Control,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001,\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20097\u201311), resulting in systemic insulin resistance. In contrast, M\u2010AKTDKO mice exhibited a robust increase in insulin\u2010stimulated glucose uptake (~3\u20134 fold increase) despite complete loss of AKT signalling, including pAS160\n                      <jats:sup>Thr649<\/jats:sup>\n                      . Phosphoproteomic analysis of M\u2010AKTDKO (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093\u20134) identified ~7088 phosphosites, with 795 uniquely upregulated in insulin\u2010stimulated M\u2010AKTDKO muscle (fold change &gt;\u20092,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), enriched in PI3K and AMPK pathways. Consistently, ~8\u2010fold (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) increase in PIP3 levels was observed in M\u2010AKTDKO muscle in response to insulin. Additionally, AKT deficiency was associated with reduced complex I\u2013dependent mitochondrial respiration (~37% decrease in state 3 respiration), consistent with altered energetic status and AMPK activation. Genetic epistasis experiments demonstrated that both AKT and AMPK activity are required for insulin\u2010stimulated glucose uptake, systemic glucose homeostasis and whole body insulin sensitivity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings challenge the long\u2010standing assumption that AKT is universally required for insulin\u2010stimulated glucose uptake in\u00a0vivo. The study demonstrates that while AKT is essential in adipose tissue, it is dispensable for insulin\u2010stimulated glucose uptake in skeletal muscle. AKT exerts negative feedback on PI3K signalling in both tissues; however, only skeletal muscle engages AMPK in the abscence of AKT to preserve glucose uptake. These findings redefine tissue\u2010specific insulin signalling mechanisms and identify AMPK as a critical downstream target of PI3K that coordinates with AKT to regulate glucose uptake.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70335","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:11:25Z","timestamp":1783516285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Divergent AKT Signalling Mechanisms Regulate GLUT4 Translocation and Glucose Uptake in Skeletal Muscle and Adipose Tissue"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4666-5430","authenticated-orcid":false,"given":"Natasha","family":"Jaiswal","sequence":"first","affiliation":[{"name":"Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Physiology Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Health and Kinesiology Purdue University  West Lafayette USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Gavin","sequence":"additional","affiliation":[{"name":"Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Lantier","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University School of Medicine  Nashville Tennessee USA"},{"name":"Vanderbilt Mouse Metabolic Phenotyping Center Vanderbilt University School of Medicine  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia Yu Yu","family":"Ong","sequence":"additional","affiliation":[{"name":"Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Wasserman","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University School of Medicine  Nashville Tennessee USA"},{"name":"Vanderbilt Mouse Metabolic Phenotyping Center Vanderbilt University School of Medicine  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Titchenell","sequence":"additional","affiliation":[{"name":"Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"},{"name":"Department of Physiology Perelman School of Medicine at the University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302847200"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI16885"},{"key":"e_1_2_10_4_1","first-page":"1728","article-title":"Insulin Resistance and a Diabetes Mellitus \u2013 Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKB Beta)","volume":"292","author":"Birnbaum M. 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