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Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity
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- Chaudhari, Aditi (författare)
- University of Gothenburg
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- Ejeskär, Katarina, 1969- (författare)
- Högskolan i Skövde,Institutionen för hälsa och lärande,Forskningsspecialiseringen Hälsa och Lärande,Translationell medicin TRIM
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- Wettergren, Yvonne, 1957 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery
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- Kahn, Ronald (författare)
- Joslin Diabetes Center and Harvard Medical School, United States
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- Rotter Sopasakis, Victoria (författare)
- University of Gothenburg / Joslin Diabetes Center and Harvard Medical School, United states
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(creator_code:org_t)
- 2018-06-05
- Engelska.
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Ingår i: F1000 Research. - : Faculty of 1000 Ltd.. - 2046-1402 .- 1759-796X. ; 6
- Relaterad länk:
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https://doi.org/10.1...
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https://his.diva-por... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://gup.ub.gu.se...
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Abstract
Ämnesord
Stäng
- Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis.Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks.Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K.Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine (hsv//eng)
Nyckelord
- phosphatidylinositol-4
- 5-bisphosphate 3-kinase
- p110
- p85
- insulin receptor substrate
- insulin resistance
- glucose intolerance
- Translationell medicin TRIM
- Translational Medicine TRIM
- 5-bisphosphate 3-kinase
- Glucose intolerance
- Insulin receptor substrate
- Insulin resistance
- P110
- P85
- Phosphatidylinositol-4
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)