title: The Akt substrate Girdin is a regulator of insulin signaling in myoblast cells.
abstract: Akt kinases are important mediators of the insulin signal, and some Akt substrates are directly involved in glucose homeostasis. Recently, Girdin has been described as an Akt substrate that is expressed ubiquitously in mammals. Cells overexpressing Girdin show an enhanced Akt activity. However, not much is known about Girdin's role in insulin signaling. We therefore analyzed the role of Girdin in primary human myotubes and found a correlation between Girdin expression and insulin sensitivity of the muscle biopsy donors, as measured by a hyperinsulinemic-euglycemic clamp. To understand this finding on a cellular level, we then investigated the function of Girdin in C2C12 mouse myoblasts. Girdin knock-down reduced Akt and insulin receptor substrate-1 phosphorylation. In contrast, stable overexpression of Girdin in C2C12 cells strikingly increased insulin sensitivity through a massive upregulation of the insulin receptor and enhanced tyrosine phosphorylation of insulin receptor substrate-1. Furthermore, Akt and c-Abl kinases were constitutively activated. To investigate medium-term insulin responses we measured glucose incorporation into glycogen. The Girdin overexpressing cells showed a high basal glycogen synthesis that peaked already at 1nM insulin. Taken together, we characterized Girdin as a new and major regulator of the insulin signal in myoblasts and skeletal muscle.
authors.affiliation: Department of Internal Medicine IV, Otfried-Müller Str.10, 72076 Tübingen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Hartung
authors.affiliation: Department of Internal Medicine IV, Otfried-Müller Str.10, 72076 Tübingen, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Ordelheide
authors.affiliation: Department of Internal Medicine IV, Otfried-Müller Str.10, 72076 Tübingen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.affiliation: Department of Internal Medicine IV, Otfried-Müller Str.10, 72076 Tübingen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Melzer
authors.affiliation: Department of Internal Medicine IV, Otfried-Müller Str.10, 72076 Tübingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Department of Internal Medicine IV, Otfried-Müller Str.10, 72076 Tübingen, Germany. Electronic address: reiner.lammers@med.uni-tuebingen.de.
authors.forename: Reiner
authors.initials: R
authors.lastname: Lammers
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D006003:Glycogen; D007328:Insulin; D008840:Microfilament Proteins; D016315:Proto-Oncogene Proteins c-abl; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D011972:Receptor, Insulin; D033921:Vesicular Transport Proteins; C502451:CCDC88A protein, human; C527550:Ccdc88a protein, mouse
keywords: Abl; Akt; C2C12; Girdin; Insulin sensitivity