Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo

2009 ◽  
Vol 418 (3) ◽  
pp. 665-671 ◽  
Author(s):  
Madhurima Rajkhowa ◽  
Sandra Brett ◽  
Daniel J. Cuthbertson ◽  
Christopher Lipina ◽  
Antonio J. Ruiz-Alcaraz ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Polycystic Ovary Syndrome ◽  
Insulin Signalling ◽  
Polycystic Ovary ◽  
Insulin Stimulation ◽  
Ovary Syndrome ◽  
Stimulation Of

Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present study compares the major insulin signalling pathways in skeletal muscle isolated from PCOS and controls. We measured whole-body insulin sensitivity and insulin signalling in skeletal muscle biopsies taken before and after acute exposure to hyperinsulinaemia in nine women diagnosed with PCOS and seven controls. We examined the expression, basal activity and response to in vivo insulin stimulation of three signalling molecules within these human muscle samples, namely IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was a severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and an accompanying trend towards higher basal phosphorylation of ERK1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported as defective in some previous PCOS studies. Most importantly, the molecular defect identified was independent of adiposity. The altered response of ERK to insulin in PCOS was the most obvious signalling defect associated with insulin resistance in muscle from these patients.

scholarly journals Molecular Mechanisms of Insulin Resistance in Polycystic Ovary Syndrome: Unraveling the Conundrum in Skeletal Muscle?

2019 ◽  
Vol 104 (11) ◽  
pp. 5372-5381 ◽  
Author(s):  
Nigel K Stepto ◽  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Kirsty A Walters ◽  
Raymond J Rodgers
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Polycystic Ovary Syndrome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Polycystic Ovary ◽  
Evidence Synthesis ◽  
Basic Research ◽  
Future Research ◽  
Ovary Syndrome

Abstract Context Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting 8% to 13% of women across the lifespan. PCOS affects reproductive, metabolic, and mental health, generating a considerable health burden. Advances in treatment of women with PCOS has been hampered by evolving diagnostic criteria and poor recognition by clinicians. This has resulted in limited clinical and basic research. In this study, we provide insights into the current and future research on the metabolic features of PCOS, specifically as they relate to PCOS-specific insulin resistance (IR), that may affect the most metabolically active tissue, skeletal muscle. Current Knowledge PCOS is a highly heritable condition, yet it is phenotypically heterogeneous in both reproductive and metabolic features. Human studies thus far have not identified molecular mechanisms of PCOS-specific IR in skeletal muscle. However, recent research has provided new insights that implicate energy-sensing pathways regulated via epigenomic and resultant transcriptomic changes. Animal models, while in existence, have been underused in exploring molecular mechanisms of IR in PCOS and specifically in skeletal muscle. Future Directions Based on the latest evidence synthesis and technologies, researchers exploring molecular mechanisms of IR in PCOS, specifically in muscle, will likely need to generate new hypothesis to be tested in human and animal studies. Conclusion Investigations to elucidate the molecular mechanisms driving IR in PCOS are in their early stages, yet remarkable advances have been made in skeletal muscle. Overall, investigations have thus far created more questions than answers, which provide new opportunities to study complex endocrine conditions.

scholarly journals Hyperandrogenism and Insulin Resistance, Not Changes in Body Weight, Mediate the Development of Endothelial Dysfunction in a Female Rat Model of Polycystic Ovary Syndrome (PCOS)

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4071-4080 ◽  
Author(s):  
Amanda Hurliman ◽  
Jennifer Keller Brown ◽  
Nicole Maille ◽  
Maurizio Mandala ◽  
Peter Casson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Endothelial Dysfunction ◽  
Polycystic Ovary Syndrome ◽  
Rat Model ◽  
Polycystic Ovary ◽  
Phase 1 ◽  
Ovary Syndrome

This study was designed to differentiate the contributions of hyperandrogenism, insulin resistance (IR), and body weight to the development of endothelial dysfunction in polycystic ovary syndrome and determine the effectiveness of insulin sensitization and antiandrogenic therapy after the establishment of vascular and metabolic dysfunction using a rat model of polycystic ovary syndrome. We hypothesized that the observed endothelial dysfunction was a direct steroidal effect, as opposed to changes in insulin sensitivity or body weight. Prepubertal female rats were randomized to the implantation of a pellet containing DHT or sham procedure. In phase 1, DHT-exposed animals were randomized to pair feeding to prevent weight gain or metformin, an insulin-sensitizing agent, from 5 to 14 weeks. In phase 2, DHT-exposed animals were randomized to treatment with metformin or flutamide, a nonsteroidal androgen receptor blocker from 12 to 16 weeks. Endothelial function was assessed by the vasodilatory response of preconstricted arteries to acetylcholine. Serum steroid levels were analyzed in phase 1 animals. Fasting blood glucose and plasma insulin were analyzed and homeostasis model assessment index calculated in all animals. Our data confirm the presence of endothelial dysfunction as well as increased body weight, hypertension, hyperinsulinemia, and greater IR among DHT-treated animals. Even when normal weight was maintained through pair feeding, endothelial dysfunction, hyperinsulinemia, and IR still developed. Furthermore, despite weight gain, treatment with metformin and flutamide improved insulin sensitivity and blood pressure and restored normal endothelial function. Therefore, the observed endothelial dysfunction is most likely a direct result of hyperandrogenism-induced reductions in insulin sensitivity, as opposed to weight gain.

Intense electroacupuncture normalizes insulin sensitivity, increases muscle GLUT4 content, and improves lipid profile in a rat model of polycystic ovary syndrome

2010 ◽  
Vol 299 (4) ◽  
pp. E551-E559 ◽  
Author(s):  
Julia Johansson ◽  
Yi Feng ◽  
Ruijin Shao ◽  
Malin Lönn ◽  
Håkan Billig ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Polycystic Ovary Syndrome ◽  
Lipid Profile ◽  
Muscle Protein ◽  
Polycystic Ovary ◽  
Low Frequency ◽  
Density Lipoprotein ◽  
Female Rats ◽  
Ovary Syndrome

Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance, possibly reflecting defects in skeletal muscle and adipocyte insulin signaling. Low-frequency (2 Hz) electroacupuncture (EA) increases insulin sensitivity in female rats with dihydrotestosterone (DHT)-induced PCOS, but the mechanism is unclear. We hypothesized that low-frequency EA regulates mediators involved in skeletal muscle glucose uptake and metabolism and alters the lipid profile in rats with DHT-induced PCOS. To test this hypothesis, we implanted in prepubescent female rats 90-day continuous-release pellets containing DHT (PCOS). At 70 days of age, the rats were randomly subdivided into two groups: one received low-frequency EA (evoking muscle twitches) for 20–25 min five times/wk for 4–5 wk; the other did not. Controls were implanted with pellets containing vehicle only. All three groups were otherwise handled similarly. Lipid profile was measured in fasting blood samples. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp, soleus muscle protein expression of glucose transporter 4 (GLUT4), and phosphorylated and nonphosphorylated Akt, and Akt substrate of 160 kDa was determined by Western blot analysis and GLUT4 location by immunofluorescence staining. PCOS EA rats had normalized insulin sensitivity, lower levels of total high-density lipoprotein and low-density lipoprotein cholesterol, and increased expression of GLUT4 in different compartments of skeletal muscle compared with PCOS rats. Total weight and body composition did not differ in the groups. Thus, in rats with DHT-induced PCOS, low-frequency EA has systemic and local effects involving intracellular signaling pathways in muscle that may, at least in part, account for the marked improved insulin sensitivity.

scholarly journals Association of Androgen Excess with Glucose Intolerance in Women with Polycystic Ovary Syndrome

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Bingjie Zhang ◽  
Jing Wang ◽  
Shanmei Shen ◽  
Jiayi Liu ◽  
Jie Sun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Polycystic Ovary Syndrome ◽  
Glucose Intolerance ◽  
Cell Function ◽  
Polycystic Ovary ◽  
Sensitivity Index ◽  
Androgen Excess ◽  
Ovary Syndrome ◽  
Family History Of Diabetes

Women with polycystic ovary syndrome (PCOS) show high prevalence of glucose intolerance. This study aimed to investigate the association of androgen excess with glucose intolerance in PCOS. A total of 378 women with PCOS participated in the study. Free androgen index (FAI) was selected as indicator of hyperandrogenism. Insulin sensitivity was assessed by 1/homeostasis model assessment of insulin resistance (1/HOMA-IR) and Matsuda insulin sensitivity index (ISIM); β-cell function was assessed by disposition index (DI). We found that women with glucose intolerance had higher FAI levels compared to women with normal glucose tolerance (NGT) (prediabetes 6.2, T2DM 7.9 versus NGT 5.0, resp.; p<0.001). Furthermore, there was a direct association between FAI levels and frequency of glucose intolerance (OR = 2.480, 95% CI 1.387–4.434), even after adjusting for age, BMI, waist circumference, hypertension, fasting insulin, testosterone, SHBG, and family history of diabetes. In addition, with FAI increase, glycosylated hemoglobin (HbA1c), plasma glucose concentrations, and serum insulin levels increased, while insulin sensitivity and β-cell function decreased. Our results suggested that androgen excess indicated by high FAI levels might serve as indicator of glucose intolerance, as it might promote insulin resistance and β-cell dysfunction in women with PCOS.

scholarly journals Responses of Serum Androgen and Insulin Resistance to Metformin and Pioglitazone in Obese, Insulin-Resistant Women with Polycystic Ovary Syndrome

2005 ◽  
Vol 90 (3) ◽  
pp. 1360-1365 ◽  
Author(s):  
C. Ortega-González ◽  
S. Luna ◽  
L. Hernández ◽  
G. Crespo ◽  
P. Aguayo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Mass Index ◽  
Body Weight ◽  
Insulin Sensitivity ◽  
Polycystic Ovary Syndrome ◽  
Body Mass ◽  
Polycystic Ovary ◽  
Obese Women ◽  
Ovary Syndrome ◽  
Waist To Hip Ratio

Severe insulin resistance is a key abnormality in obese women with polycystic ovary syndrome (PCOS). The purpose of this study was to evaluate whether pioglitazone decreases insulin resistance (IR) and hyperandrogenism to the same extent as metformin in obese women with PCOS who have not received any previous treatment. Fifty-two women with PCOS were randomly allocated to receive either pioglitazone (30 mg/d, n = 25) or metformin (850 mg three times daily, n = 27) and were assessed before and after 6 months. Body weight, body mass index, and waist to hip ratio increased significantly (P ≤ 0.05) after pioglitazone treatment but not after metformin treatment. Fasting serum insulin concentration (P &lt; 0.001 for both drugs) and the area under the insulin curve during a 2-h oral glucose tolerance test decreased after pioglitazone (P &lt; 0.002) or metformin (P &lt; 0.05) treatment. IR (homeostasis model of assessment-IR index) decreased and insulin sensitivity (elevation of the quantitative insulin sensitivity check index and the fasting glucose to insulin ratio) increased (P ≤ 0.008) after treatment with either drug. Hirsutism (P &lt; 0.05) and serum concentrations of free testosterone (P &lt; 0.02) and androstenedione (P &lt; 0.01) declined to a similar extent after treatment with the drugs. Treatment with pioglitazone or metformin was associated with the occurrence of pregnancy (n = 5 and n = 3, respectively). These results suggest that pioglitazone is as effective as metformin in improving insulin sensitivity and hyperandrogenism, despite an increase in body weight, body mass index, and the waist to hip ratio associated with pioglitazone.

scholarly journals Subcutaneous adipocytes from obese hyperinsulinemic women with polycystic ovary syndrome exhibit normal insulin sensitivity but reduced maximal insulin responsiveness

2005 ◽  
Vol 153 (6) ◽  
pp. 831-835 ◽  
Author(s):  
Erika Lystedt ◽  
Hanna Westergren ◽  
Jan Brynhildsen ◽  
Lotta Lindh-Åstrand ◽  
Johanna Gustavsson ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Subcutaneous Fat ◽  
Diabetic Control ◽  
Control Group ◽  
Blood Levels ◽  
Ovary Syndrome ◽  
Insulin Effect

Background: Polycystic ovary syndrome (PCOS) has a high prevalence in women and is often associated with insulin resistance and hence with aspects of the so-called metabolic syndrome. Methods: Ten women diagnosed with PCOS were consecutively included (aged 21–39 years, average 30.2 ± 1.9 years; body mass index 28.4–42.5 kg/m2, average 37.5 ± 1.7 kg/m2 (mean ± s.e.)). Adipocytes were isolated from the subcutaneous fat and, after overnight incubation to recover from insulin resistance due to the surgical cell isolation procedures, they were analyzed for insulin sensitivity. Results: The patients with PCOS exhibited marked clinical hyperinsulinemia with 3.6-fold higher blood levels of C-peptide than a healthy lean control group (1.7 ± 0.2 and 0.5 ± 0.02 nmol/l respectively, P < 0.0001). The patients with PCOS also exhibited 2.4-fold higher concentrations of serum triacylglycerol (2.1 ± 0.3 and 0.9 ± 0.06 mmol/l respectively, P < 0.0001), but only slightly elevated blood pressure (118 ± 12/76 ± 6 and 113 ± 7/72 ± 6 mmHg respectively, P = 0.055/0.046). However, insulin sensitivity for stimulation of glucose transport in the isolated adipocytes was indistinguishable from a non-PCOS, non-diabetic control group, while the maximal insulin effect on glucose uptake was significantly lower (2.2 ± 0.2- and 3.8 ± 0.8-fold respectively, P = 0.02). Conclusions: Subcutaneous adipocytes from patients with PCOS do not display reduced insulin sensitivity. The findings show that the insulin resistance of PCOS is qualitatively different from that of type 2 diabetes.

scholarly journals SUN-020 Waist Circumference Is Associated with Insulin Resistance in Young Korean Women with Polycystic Ovary Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Do Kyeong Song ◽  
Hyejin Lee ◽  
Young Sun Hong ◽  
Yeon-Ah Sung
Keyword(s):  
Insulin Resistance ◽  
Regression Analysis ◽  
Insulin Sensitivity ◽  
Waist Circumference ◽  
Polycystic Ovary Syndrome ◽  
Young Women ◽  
Polycystic Ovary ◽  
Korean Women ◽  
Ovary Syndrome ◽  
Negatively Associated

Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous disorder and associated with metabolic disturbances such as insulin resistance (IR) and obesity which are risk factors for cardiovascular diseases. Many studies have shown that waist circumference (WC) representing abdominal obesity is an important risk factor for IR. However, there were few studies whether WC were associated with IR in young women with PCOS. We aimed to evaluate the role of WC in IR among young Korean women with PCOS. We enrolled age- and body mass index-matched women with PCOS (n = 100) and controls (n = 100). WC was measured and the 75-gram oral glucose tolerance test (OGTT) was performed. Insulin sensitivity was assessed by the Stumvoll index which was calculated from an OGTT. Multiple linear regression analysis was performed to evaluate the association between WC and IR. WC, fasting glucose, post-load 2-hour glucose, fasting insulin, and post-load 2-hour insulin did not differ between women with PCOS and controls. Women with PCOS had lower values of the Stumvoll index than the controls. In correlation analysis, WC was negatively correlated with the Stumvoll index in women with PCOS, however not in controls. In multiple regression analysis, WC was negatively associated with the Stumvoll index even after adjustment for age, total cholesterol, and total testosterone in women with PCOS. In young Korean women with PCOS, WC was negatively associated with insulin sensitivity independent of hyperandrogenemia. Simply measuring of WC could be used to screen the high risk group having IR in young women with PCOS.

scholarly journals Failure of Mathematical Indices to Accurately Assess Insulin Resistance in Lean, Overweight, or Obese Women with Polycystic Ovary Syndrome

2004 ◽  
Vol 89 (3) ◽  
pp. 1273-1276 ◽  
Author(s):  
Evanthia Diamanti-Kandarakis ◽  
Chryssa Kouli ◽  
Krystallenia Alexandraki ◽  
Giovanna Spina
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Polycystic Ovary Syndrome ◽  
Statistical Difference ◽  
Polycystic Ovary ◽  
Total Testosterone ◽  
Obese Women ◽  
Ovary Syndrome ◽  
Overweight Women ◽  
Euglycemic Clamp

Abstract Insulin resistance is a common metabolic feature of polycystic ovary syndrome (PCOS). In this study, we examined the validity of the mathematical indices [the quantitative insulin sensitivity check index (QUICKI) and the homeostasis model of assessment (HOMA)] that calculate insulin sensitivity and their correlation to glucose utilization with the insulin infusion rate in 40 mU/m2·min by the euglycemic clamp (M) in women with PCOS. We studied 59 women with PCOS (20 lean, 16 overweight, and 23 obese subjects). Euglycemic clamp testing was performed, and QUICKI, HOMA, total testosterone, fasting insulin, fasting glucose, and glucose-to-insulin ratio were estimated. No difference was found in testosterone and glucose levels among the three groups. Lean or overweight women compared with obese women differed in insulin levels, glucose-to-insulin ratio, QUICKI, and HOMA (P &lt; 0.01). No statistical difference was found between lean and overweight women in the above parameters. M differed when lean women were compared with overweight (P &lt; 0.002) or obese women (P &lt; 0.0001); however, no statistical difference was observed between overweight and obese women. No significant correlation was found between M and QUICKI or HOMA. We conclude that mathematical indices should be applied with caution in different insulin-resistant populations and should not be considered a priori equivalent to the euglycemic clamp technique.

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