Elevated fasting insulin concentrations associate with impaired insulin signaling in skeletal muscle of healthy subjects independent of obesity

Korsheninnikova, Elena; Seppälä-Lindroos, Anneli; Vehkavaara, Satu; Goto, Takashi; Virkamäki, Antti

doi:10.1002/dmrr.272

Cited by 8 publications

(9 citation statements)

References 37 publications

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“…8). This suggests desensitization of the insulin action after a prolonged exposure of cells, as reported earlier (21). However, in GRK-2-deficient cells, chronic treatment with insulin increased glycogen synthesis.…”

Section: Effect Of Chronic Insulin Treatment On Glycogen Synthesis Insupporting

confidence: 81%

“…GSK3␣ was modestly inhibited. Insulin caused additional Ser 21 phosphorylation of GSK3␣ in both the GRK2-deficient and control cells; the effect was greater in the GRK2-deficient group. Therefore, it appears that depletion of GRK2 reduces basal GSK3␣ inhibition of glycogen synthase.…”

Section: Discussionmentioning

confidence: 87%

“…Insulin (100 nM) treatment (5 and 10 min) caused an increase in the Ser 21 phosphorylation of GSK3␣ over respective basals. However, the insulin-stimulated Ser 21 phosphorylation of GSK-3␣ was greater in GRK2-deficient cells (Fig. 4).…”

Section: Effect Of Insulin Treatment On Grk2mentioning

confidence: 90%

“…Fig. 4, Ser(P) 21 -GSK3␣ antibody labeled a single band (ϳ51 kDa). After the bands were recorded, the blot was stripped and reprobed with anti-GSK-3 antibody.…”

Section: Effect Of Insulin Treatment On Grk2mentioning

confidence: 94%

“…After the bands were recorded, the blot was stripped and reprobed with anti-GSK-3 antibody. Density of Ser(P) 21 -GSK-3␣ was normalized with total GSK-3␣. The data revealed that the basal phosphorylation of Ser 21 at GSK-3␣ was increased in GRK2 deficient compared with control cells.…”

Section: Effect Of Insulin Treatment On Grk2mentioning

confidence: 99%

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GRK2 Negatively Regulates Glycogen Synthesis in Mouse Liver FL83B Cells

Shahid

Hussain

2007

Journal of Biological Chemistry

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G-protein-coupled receptor (GPCR) kinases (GRKs) are serine/threonine kinases that desensitize agonist-occupied classical GPCRs. Although the insulin receptor (IR) is a tyrosine kinase receptor, the IR also couples to G-proteins and utilizes G-protein signaling components. The present study was designed to test the hypothesis that GRK2 negatively regulates IR signaling. FL83B cells, derived from mouse liver, were treated with insulin and membrane translocation of GRK2 was determined using immunofluoresecence and Western blotting. Insulin caused an increase in the translocation of GRK-2 from cytosol to the plasma membrane. To determine the role of GRK2 in IR signaling, GRK2 was selectively down-regulated (ϳby 90%) in FL83B cells using a small interfering RNA technique. The primary biological effect of insulin is maintenance of glucose homeostasis. The effects of insulin are mediated by binding to the insulin receptor, a member of the tyrosine kinase receptor family (1). The insulin receptor is a heterotetrameric receptor, consisting of two extracellular ␣ and two transmembrane ␤ subunits (2). Insulin binding to the ␣-subunit of insulin receptor causes autophosphorylation of the ␤-subunit at specific tyrosine residues (3). Autophosphorylation of the ␤-subunit increases the tyrosine kinase activity of the receptor toward other protein substrates, resulting in the tyrosine phosphorylation of a family of insulin receptor substrate proteins including IRS1, 2 IRS2, and Shc. The IRS proteins serve as docking proteins for other intracellular proteins containing Src homology 2 domains such as phosphatidylinositol 3-kinase (PI 3-kinase) and Grb2. The binding of these proteins to IRS proteins transmits the signal downstream, leading to the metabolic and mitogenic effects of insulin (4). For example, the interaction of phosphorylated IRS1/2 with PI 3-kinase leads to activation of protein kinase B/Akt, producing many effects such as GLUT4 translocation, protein synthesis, and inactivation of glycogen synthase kinase 3 (GSK3). The GSK3, a serine/threonine kinase, phosphorylates glycogen synthase and inactivates it. As glycogen synthase is a rate-limiting enzyme in glycogen synthesis, inactivation of GSK3 by insulin removes the inhibitory effect of GSK3 on glycogen synthase and leads to increased glycogen synthesis (5-7).In addition to signaling via its tyrosine kinase activity, the insulin receptor also couples to the G-proteins G i and G q (8,9). This IR/G-protein coupling is required for some actions of insulin. For example, insulin resistance develops in adipocytes when G␣ i is down-regulated (10). Moreover, in 3T3L1 adipocytes IR signaling via G␣ q/11 is required for insulin-induced GLUT4 translocation (11). The signaling of receptors via G-proteins is regulated by G protein-coupled receptor kinases (GRKs), a family of serine/threonine kinases that participate in G protein-coupled receptor (GPCR) desensitization. GRK2 can produce GPCR desensitization either by phosphorylation-dependent or phosphorylation-independent mechan...

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Section: Effect Of Chronic Insulin Treatment On Glycogen Synthesis Insupporting

confidence: 81%

Section: Discussionmentioning

confidence: 87%

Section: Effect Of Insulin Treatment On Grk2mentioning

confidence: 90%

“…Fig. 4, Ser(P) 21 -GSK3␣ antibody labeled a single band (ϳ51 kDa). After the bands were recorded, the blot was stripped and reprobed with anti-GSK-3 antibody.…”

Section: Effect Of Insulin Treatment On Grk2mentioning

confidence: 94%

Section: Effect Of Insulin Treatment On Grk2mentioning

confidence: 99%

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GRK2 Negatively Regulates Glycogen Synthesis in Mouse Liver FL83B Cells

Shahid

Hussain

2007

Journal of Biological Chemistry

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Current literature in diabetes

2002

Diabetes Metabolism Res

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In order to keep subscribers up‐to‐date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of diabetes/metabolism. Each bibliography is divided into 17 sections: 1 Books, Reviews & Symposia; 2 General; 3 Genetics; 4 Epidemiology; 5 Immunology; 6 Prediction; 7 Prevention; 8 Intervention: a) General; b) Pharmacology; 9 Pathology: a) General; b) Cardiovascular; c) Neurological; d) Renal; 10 Endocrinology & Metabolism; 11 Nutrition; 12 Animal Studies; 13 Techniques. Within each section, articles are listed in alphabetical order with respect to author (9 Weeks journals ‐ Search completed at 25th September 2002)

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