title: The combined deletion of S6K1 and Akt2 deteriorates glycemic control in a high-fat diet.
abstract: Signaling downstream of mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) controls specific and distinct aspects of insulin action and nutrient homeostasis in an interconnected and as yet unclear way. Mice lacking the mTORC1 substrate S6 kinase 1 (S6K1) maintain proper glycemic control with a high-fat diet. This phenotype is accompanied by insulin hypersensitivity, Akt- and AMP-activated kinase upregulation, and increased lipolysis in adipose tissue and skeletal muscle. Here, we show that, when S6K1 inactivation is combined with the deletion of the mTORC2 substrate Akt2, glucose homeostasis is compromised due to defects in both insulin action and β-cell function. After a high-fat diet, the S6K1(-/-) Akt2(-/-) double-mutant mice do not become obese, though they are severely hyperglycemic. Our data demonstrate that S6K1 is required for pancreatic β-cell growth and function during adaptation to insulin resistance states. Strikingly, the inactivation of two targets of mTOR and phosphatidylinositol 3-kinase signaling is sufficient to reproduce major hallmarks of type 2 diabetes.
authors.affiliation: INSERM U845, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Treins
authors.forename: Samira
authors.initials: S
authors.lastname: Alliouachene
authors.forename: Rim
authors.initials: R
authors.lastname: Hassouna
authors.forename: Yun
authors.initials: Y
authors.lastname: Xie
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics* / Q000378:metabolism; D015430:Weight Gain
chemical_list: D007328:Insulin; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D005947:Glucose