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Molecular mechanisms in skeletal muscle underlying insulin resistance in lean women with polycystic ovary syndrome

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@article{c4c9356e24bc416cb470a02f18be3150,
title = "Molecular mechanisms in skeletal muscle underlying insulin resistance in lean women with polycystic ovary syndrome",
abstract = "Context: Skeletal muscle molecular mechanisms underlying insulin resistance in women with polycystic ovary syndrome (PCOS) are poorly understood.Objective: To provide insight into mechanisms regulating skeletal muscle insulin resistance in lean women with PCOS.Participants and Methods: A hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies was performed. Thirteen lean, hyperandrogenic women with PCOS and seven age- and BMI-matched healthy control subjects were enrolled. Skeletal muscle protein expression and phosphorylation were analyzed by western blotting and intramuscular lipid content was measured by thin layer chromatography.Results: Women with PCOS had 25% lower whole body insulin sensitivity and 40% lower plasma adiponectin concentration than control subjects. IMTG (intramuscular triacylglycerol), sn-1.3 DAG (diacylglycerol) and ceramide contents in skeletal muscle were higher (40%, 50%, and 300%, respectively) in women with PCOS than control subjects. Activation of insulin signaling did not differ between groups. In women with PCOS, the insulin-stimulated glucose oxidation was reduced and insulin-stimulated dephosphorylation of PDH (pyruvate dehydrogenase) Ser293 was absent. AMPK (AMP-activated protein kinase) α2 protein expression and basal Thr172 phosphorylation were 45% and 50% lower in women with PCOS than control subjects, respectively.Conclusion: Whole body insulin resistance in lean, hyperandrogenic women with PCOS was not related to changes in the proximal part of the insulin signaling cascade in skeletal muscle despite lipid accumulation. Rather, reduced insulin sensitivity was potentially related to plasma adiponectin levels playing a modulating role in human skeletal muscle via AMPK. Furthermore, abnormal PDH regulation may contribute to reduced whole body metabolic flexibility and thereby insulin resistance.",
author = "Hansen, {Solvejg L} and Svendsen, {Pernille F} and Jeppesen, {Jacob F} and Hoeg, {Louise D} and Andersen, {Nicoline R} and Kristensen, {Jonas M} and Lisbeth Nilas and Anne-Marie Lundsgaard and Wojtaszewski, {J{\o}rgen F P} and Sten Madsbad and Bente Kiens",
year = "2019",
month = may,
day = "1",
doi = "10.1210/jc.2018-01771",
language = "English",
volume = "104",
pages = "1841--1854",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The/Endocrine Society",
number = "5",

}

RIS

TY - JOUR

T1 - Molecular mechanisms in skeletal muscle underlying insulin resistance in lean women with polycystic ovary syndrome

AU - Hansen, Solvejg L

AU - Svendsen, Pernille F

AU - Jeppesen, Jacob F

AU - Hoeg, Louise D

AU - Andersen, Nicoline R

AU - Kristensen, Jonas M

AU - Nilas, Lisbeth

AU - Lundsgaard, Anne-Marie

AU - Wojtaszewski, Jørgen F P

AU - Madsbad, Sten

AU - Kiens, Bente

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Context: Skeletal muscle molecular mechanisms underlying insulin resistance in women with polycystic ovary syndrome (PCOS) are poorly understood.Objective: To provide insight into mechanisms regulating skeletal muscle insulin resistance in lean women with PCOS.Participants and Methods: A hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies was performed. Thirteen lean, hyperandrogenic women with PCOS and seven age- and BMI-matched healthy control subjects were enrolled. Skeletal muscle protein expression and phosphorylation were analyzed by western blotting and intramuscular lipid content was measured by thin layer chromatography.Results: Women with PCOS had 25% lower whole body insulin sensitivity and 40% lower plasma adiponectin concentration than control subjects. IMTG (intramuscular triacylglycerol), sn-1.3 DAG (diacylglycerol) and ceramide contents in skeletal muscle were higher (40%, 50%, and 300%, respectively) in women with PCOS than control subjects. Activation of insulin signaling did not differ between groups. In women with PCOS, the insulin-stimulated glucose oxidation was reduced and insulin-stimulated dephosphorylation of PDH (pyruvate dehydrogenase) Ser293 was absent. AMPK (AMP-activated protein kinase) α2 protein expression and basal Thr172 phosphorylation were 45% and 50% lower in women with PCOS than control subjects, respectively.Conclusion: Whole body insulin resistance in lean, hyperandrogenic women with PCOS was not related to changes in the proximal part of the insulin signaling cascade in skeletal muscle despite lipid accumulation. Rather, reduced insulin sensitivity was potentially related to plasma adiponectin levels playing a modulating role in human skeletal muscle via AMPK. Furthermore, abnormal PDH regulation may contribute to reduced whole body metabolic flexibility and thereby insulin resistance.

AB - Context: Skeletal muscle molecular mechanisms underlying insulin resistance in women with polycystic ovary syndrome (PCOS) are poorly understood.Objective: To provide insight into mechanisms regulating skeletal muscle insulin resistance in lean women with PCOS.Participants and Methods: A hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies was performed. Thirteen lean, hyperandrogenic women with PCOS and seven age- and BMI-matched healthy control subjects were enrolled. Skeletal muscle protein expression and phosphorylation were analyzed by western blotting and intramuscular lipid content was measured by thin layer chromatography.Results: Women with PCOS had 25% lower whole body insulin sensitivity and 40% lower plasma adiponectin concentration than control subjects. IMTG (intramuscular triacylglycerol), sn-1.3 DAG (diacylglycerol) and ceramide contents in skeletal muscle were higher (40%, 50%, and 300%, respectively) in women with PCOS than control subjects. Activation of insulin signaling did not differ between groups. In women with PCOS, the insulin-stimulated glucose oxidation was reduced and insulin-stimulated dephosphorylation of PDH (pyruvate dehydrogenase) Ser293 was absent. AMPK (AMP-activated protein kinase) α2 protein expression and basal Thr172 phosphorylation were 45% and 50% lower in women with PCOS than control subjects, respectively.Conclusion: Whole body insulin resistance in lean, hyperandrogenic women with PCOS was not related to changes in the proximal part of the insulin signaling cascade in skeletal muscle despite lipid accumulation. Rather, reduced insulin sensitivity was potentially related to plasma adiponectin levels playing a modulating role in human skeletal muscle via AMPK. Furthermore, abnormal PDH regulation may contribute to reduced whole body metabolic flexibility and thereby insulin resistance.

U2 - 10.1210/jc.2018-01771

DO - 10.1210/jc.2018-01771

M3 - Journal article

C2 - 30544235

VL - 104

SP - 1841

EP - 1854

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 5

ER -

ID: 59087503