Impaired insulin-stimulated phosphorylation of Akt and AS160 in skeletal muscle of women with polycystic ovary syndrome is reversed by pioglitazone treatment.
OBJECTIVE
Insulin resistance in skeletal muscle is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). However, the molecular mechanisms underlying skeletal muscle insulin resistance and the insulin-sensitizing effect of thiazolidinediones in PCOS in vivo are less well characterized.


METHODS
We determined molecular mediators of insulin signaling to glucose transport in skeletal muscle biopsies of 24 PCOS patients and 14 matched control subjects metabolically characterized by euglycemic-hyperinsulinemic clamps and indirect calorimetry, and we examined the effect of 16 weeks of treatment with pioglitazone in PCOS patients.


RESULTS
Impaired insulin-mediated total (R(d)) oxidative and nonoxidative glucose disposal (NOGD) was paralleled by reduced insulin-stimulated Akt phosphorylation at Ser473 and Thr308 and AS160 phosphorylation in muscle of PCOS patients. Akt phosphorylation at Ser473 and Thr308 correlated positively with R(d) and NOGD in the insulin-stimulated state. Serum free testosterone was inversely related to insulin-stimulated R(d) and NOGD in PCOS. Importantly, the pioglitazone-mediated improvement in insulin-stimulated glucose metabolism, which did not fully reach normal levels, was accompanied by normalization of insulin-mediated Akt phosphorylation at Ser473 and Thr308 and AS160 phosphorylation. AMPK activity and phosphorylation were similar in the two groups and did not respond to pioglitazone in PCOS patients.


CONCLUSIONS
Impaired insulin signaling through Akt and AS160 in part explains insulin resistance at the molecular level in skeletal muscle in PCOS, and the ability of pioglitazone to enhance insulin sensitivity involves improved signaling through Akt and AS160. Moreover, our data provide correlative evidence that hyperandrogenism in PCOS may contribute to insulin resistance.
Højlund
Kurt
K
Department of Endocrinology, Odense University Hospital, Kloevervaenget 6, DK-5000 Odense C, Denmark. k.hojlund@dadlnet.dk
Glintborg
Dorte
D
Andersen
Nicoline R
NR
Birk
Jesper B
JB
Treebak
Jonas T
JT
Frøsig
Christian
C
Beck-Nielsen
Henning
H
Wojtaszewski
Jørgen F P
JF
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020690:GTPase-Activating Proteins / Q000187:drug effects / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology*; D009765:Obesity; D010766:Phosphorylation; D000077205:Pioglitazone; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D045162:Thiazolidinediones / Q000627:therapeutic use*
D001786:Blood Glucose; D020690:GTPase-Activating Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; C518767:TBC1D4 protein, human; D045162:Thiazolidinediones; D051057:Proto-Oncogene Proteins c-akt; D000077205:Pioglitazone