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

Solvejg Lis Hansen; Pernille F Svendsen; Jacob Fuglsbjerg Jeppesen; Louise Dalgas Høeg; Nicoline Resen Andersen; Jonas Møller Kristensen; Lisbeth Nilas; Anne-Marie Lundsgaard; Jørgen Wojtaszewski; Sten Madsbad; Bente Kiens

doi:10.1210/jc.2018-01771

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

Solvejg Lis Hansen, Pernille F Svendsen, Jacob Fuglsbjerg Jeppesen, Louise Dalgas Høeg, Nicoline Resen Andersen, Jonas Møller Kristensen, Lisbeth Nilas, Anne-Marie Lundsgaard, Jørgen Wojtaszewski, Sten Madsbad, Bente Kiens

August Krogh Sektionen for Molekylær Fysiologi

15 Citationer (Scopus)

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 women who are lean with PCOS. Participants and Methods: A hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies was performed. Thirteen women who are lean who have hyperandrogenism and PCOS and seven age- and body mass index-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 in control subjects. Intramuscular triacylglycerol, sn-1.3 diacylglycerol, and ceramide contents in skeletal muscle were higher (40%, 50%, and 300%, respectively) in women with PCOS than in 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 pyruvate dehydrogenase (PDH) Ser293 was absent. AMP-activated protein kinase (AMPK) α2 protein expression and basal Thr172 phosphorylation were 45% and 50% lower in women with PCOS than in control subjects, respectively. Conclusions: Whole-body insulin resistance in women who are lean who have hyperandrogenism and 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.

Originalsprog	Engelsk
Tidsskrift	Journal of Clinical Endocrinology and Metabolism
Vol/bind	104
Udgave nummer	5
Sider (fra-til)	1841-1854
Antal sider	14
ISSN	0021-972X
DOI	https://doi.org/10.1210/jc.2018-01771
Status	Udgivet - 2019

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10.1210/jc.2018-01771

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Hansen, S. L., Svendsen, P. F., Jeppesen, J. F., Høeg, L. D., Andersen, N. R., Kristensen, J. M., Nilas, L., Lundsgaard, A.-M., Wojtaszewski, J., Madsbad, S., & Kiens, B. (2019). Molecular mechanisms in skeletal muscle underlying insulin resistance in women who are lean with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism, 104(5), 1841-1854. https://doi.org/10.1210/jc.2018-01771

Molecular mechanisms in skeletal muscle underlying insulin resistance in women who are lean with polycystic ovary syndrome. / Hansen, Solvejg Lis; Svendsen, Pernille F; Jeppesen, Jacob Fuglsbjerg et al.
I: Journal of Clinical Endocrinology and Metabolism, Bind 104, Nr. 5, 2019, s. 1841-1854.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Hansen, SL, Svendsen, PF, Jeppesen, JF, Høeg, LD, Andersen, NR , Kristensen, JM, Nilas, L, Lundsgaard, A-M , Wojtaszewski, J , Madsbad, S & Kiens, B 2019, 'Molecular mechanisms in skeletal muscle underlying insulin resistance in women who are lean with polycystic ovary syndrome', Journal of Clinical Endocrinology and Metabolism, bind 104, nr. 5, s. 1841-1854. https://doi.org/10.1210/jc.2018-01771

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title = "Molecular mechanisms in skeletal muscle underlying insulin resistance in women who are lean 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 women who are lean with PCOS. Participants and Methods: A hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies was performed. Thirteen women who are lean who have hyperandrogenism and PCOS and seven age- and body mass index-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 in control subjects. Intramuscular triacylglycerol, sn-1.3 diacylglycerol, and ceramide contents in skeletal muscle were higher (40%, 50%, and 300%, respectively) in women with PCOS than in 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 pyruvate dehydrogenase (PDH) Ser293 was absent. AMP-activated protein kinase (AMPK) α2 protein expression and basal Thr172 phosphorylation were 45% and 50% lower in women with PCOS than in control subjects, respectively. Conclusions: Whole-body insulin resistance in women who are lean who have hyperandrogenism and 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 Lis} and Svendsen, {Pernille F} and Jeppesen, {Jacob Fuglsbjerg} and H{\o}eg, {Louise Dalgas} and Andersen, {Nicoline Resen} and Kristensen, {Jonas M{\o}ller} and Lisbeth Nilas and Anne-Marie Lundsgaard and J{\o}rgen Wojtaszewski and Sten Madsbad and Bente Kiens",

note = "CURIS 2019 NEXS 134",

year = "2019",

doi = "10.1210/jc.2018-01771",

language = "English",

volume = "104",

pages = "1841--1854",

journal = "Journal of Clinical Endocrinology and Metabolism",

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TY - JOUR

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

AU - Hansen, Solvejg Lis

AU - Svendsen, Pernille F

AU - Jeppesen, Jacob Fuglsbjerg

AU - Høeg, Louise Dalgas

AU - Andersen, Nicoline Resen

AU - Kristensen, Jonas Møller

AU - Nilas, Lisbeth

AU - Lundsgaard, Anne-Marie

AU - Wojtaszewski, Jørgen

AU - Madsbad, Sten

AU - Kiens, Bente

N1 - CURIS 2019 NEXS 134

PY - 2019

Y1 - 2019

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 women who are lean with PCOS. Participants and Methods: A hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies was performed. Thirteen women who are lean who have hyperandrogenism and PCOS and seven age- and body mass index-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 in control subjects. Intramuscular triacylglycerol, sn-1.3 diacylglycerol, and ceramide contents in skeletal muscle were higher (40%, 50%, and 300%, respectively) in women with PCOS than in 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 pyruvate dehydrogenase (PDH) Ser293 was absent. AMP-activated protein kinase (AMPK) α2 protein expression and basal Thr172 phosphorylation were 45% and 50% lower in women with PCOS than in control subjects, respectively. Conclusions: Whole-body insulin resistance in women who are lean who have hyperandrogenism and 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 women who are lean with PCOS. Participants and Methods: A hyperinsulinemic-euglycemic clamp with skeletal muscle biopsies was performed. Thirteen women who are lean who have hyperandrogenism and PCOS and seven age- and body mass index-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 in control subjects. Intramuscular triacylglycerol, sn-1.3 diacylglycerol, and ceramide contents in skeletal muscle were higher (40%, 50%, and 300%, respectively) in women with PCOS than in 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 pyruvate dehydrogenase (PDH) Ser293 was absent. AMP-activated protein kinase (AMPK) α2 protein expression and basal Thr172 phosphorylation were 45% and 50% lower in women with PCOS than in control subjects, respectively. Conclusions: Whole-body insulin resistance in women who are lean who have hyperandrogenism and 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

SN - 0021-972X

VL - 104

SP - 1841

EP - 1854

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 5

ER -

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

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