Selective Insulin Resistance in the Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia that is amplified by insulin in the presence of resistance to insulin’s action to stimulate glucose uptake in muscle and fat. To explore the mechanisms for this paradox, we examined the metabolic and mitogenic actions of insulin and insulin-like growth factor I (IGF-I) in cultured skin fibroblasts from PCOS (n = 16) and control (n = 11) women. There were no significant decreases in the number or affinity of insulin- or IGF-I-binding sites in PCOS compared to control fibroblasts. Basal rates were similar, but there were significant decreases in insulin-stimulated (control, 51.8 ± 7.0; PCOS, 29.5 ± 2.9 nmol/106 cells·2 h at 1,000,000 pmol/L; P < 0.005) and IGF-I-stimulated (control, 48.9 ± 6.7; PCOS, 33.0 ± 3.2 PCOS nmol/106 cells·2 h at 100,000 pmol/L IGF-I; P < 0.05) glucose incorporation into glycogen in PCOS fibroblasts, a metabolic action of insulin. Stimulation of thymidine incorporation, a mitogenic action of insulin, was similar ...

[1]  J. Martens,et al.  Enzymatic activities of P450c17 stably expressed in fibroblasts from patients with the polycystic ovary syndrome. , 2000, The Journal of clinical endocrinology and metabolism.

[2]  C. Kahn,et al.  Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. , 1999, The Journal of clinical investigation.

[3]  D. Driscoll,et al.  Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[4]  T. Key,et al.  Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. , 1998, The Journal of clinical endocrinology and metabolism.

[5]  J. Olefsky,et al.  Lack of insulin resistance in fibroblasts from subjects with polycystic ovary syndrome. , 1998, Metabolism: clinical and experimental.

[6]  D. Finegood,et al.  A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. , 1998, The Journal of clinical endocrinology and metabolism.

[7]  T. Mckenna,et al.  Decline in insulin-like growth factor I levels after clomiphene citrate does not correct hyperandrogenemia in polycystic ovary syndrome. , 1998, The Journal of clinical endocrinology and metabolism.

[8]  D. Jakubowicz,et al.  Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. , 1998, The Journal of clinical endocrinology and metabolism.

[9]  B. Kahn.  Type 2 Diabetes: When Insulin Secretion Fails to Compensate for Insulin Resistance , 1998, Cell.

[10]  S. O’Rahilly,et al.  Impaired activation of phosphoinositide 3-kinase by insulin in fibroblasts from patients with severe insulin resistance and pseudoacromegaly. A disorder characterized by selective postreceptor insulin resistance. , 1998, The Journal of clinical investigation.

[11]  G. Shulman,et al.  Disruption of IRS-2 causes type 2 diabetes in mice , 1998, Nature.

[12]  A. Dunaif,et al.  Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. , 1997, Endocrine reviews.

[13]  P. Roach,et al.  New Insights Into the Role and Mechanism of Glycogen Synthase Activation by Insulin , 1997, Diabetes.

[14]  P. Arner,et al.  Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance? , 1997, The Journal of clinical endocrinology and metabolism.

[15]  J. Florini,et al.  The Mitogenic and Myogenic Actions of Insulin-like Growth Factors Utilize Distinct Signaling Pathways* , 1997, The Journal of Biological Chemistry.

[16]  N. Barzilai,et al.  Increased Hexosamine Availability Similarly Impairs the Action of Insulin and IGF-1 on Glucose Disposal , 1996, Diabetes.

[17]  D. Finegood,et al.  The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. , 1996, The Journal of clinical endocrinology and metabolism.

[18]  S. Mudaliar,et al.  Glycogen synthase activity is reduced in cultured skeletal muscle cells of non-insulin-dependent diabetes mellitus subjects. Biochemical and molecular mechanisms. , 1996, The Journal of clinical investigation.

[19]  D. Le Roith,et al.  Signaling via the insulin-like growth factor-I receptor: does it differ from insulin receptor signaling? , 1996, Cytokine & growth factor reviews.

[20]  S. Mudaliar,et al.  Acquired Defects of Glycogen Synthase Activity in Cultured Human Skeletal Muscle Cells: Influence of High Glucose and Insulin Levels , 1996, Diabetes.

[21]  D. Finegood,et al.  Beta-cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. , 1996, The Journal of clinical endocrinology and metabolism.

[22]  S. Franks,et al.  Insulin action in human granulosa cells from normal and polycystic ovaries is mediated by the insulin receptor and not the type-I insulin-like growth factor receptor. , 1995, The Journal of clinical endocrinology and metabolism.

[23]  A. Dunaif,et al.  Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. , 1995, The Journal of clinical investigation.

[24]  R. Henry,et al.  Insulin Action and Glucose Metabolism in Nondiabetic Control and NIDDM Subjects: Comparison Using Human Skeletal Muscle Cell Cultures , 1995, Diabetes.

[25]  E. Van Obberghen,et al.  Wortmannin inhibits the action of insulin but not that of okadaic acid in skeletal muscle: comparison with fat cells. , 1995, Endocrinology.

[26]  T. Ciaraldi,et al.  Rat fibroblast cells overexpressing kinase-inactive human insulin receptors are insulin responsive: influence of growth conditions. , 1995, Endocrinology.

[27]  S. Taylor,et al.  Absence of insulin receptor gene mutations in three insulin-resistant women with the polycystic ovary syndrome. , 1994, Metabolism: clinical and experimental.

[28]  J. Blenis,et al.  Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation , 1994, Molecular and cellular biology.

[29]  A. Motala,et al.  Evaluation of WHO and NDDG criteria for impaired glucose tolerance. , 1994, Diabetes research and clinical practice.

[30]  T. Okada,et al.  Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. , 1994, The Journal of biological chemistry.

[31]  Y. Ebina,et al.  Insulin-stimulated GLUT4 translocation is relevant to the phosphorylation of IRS-1 and the activity of PI3-kinase. , 1993, Biochemical and biophysical research communications.

[32]  S. O’Rahilly,et al.  Insulin-mediated pseudoacromegaly: clinical and biochemical characterization of a syndrome of selective insulin resistance. , 1993, The Journal of clinical endocrinology and metabolism.

[33]  R. Taylor,et al.  Abnormal Activation of Glycogen Synthesis in Fibroblasts from NIDDM Subjects: Evidence for an Abnormality Specific to Glucose Metabolism , 1993, Diabetes.

[34]  D. Rosenbaum,et al.  Insulin resistance in polycystic ovary syndrome: decreased expression of GLUT-4 glucose transporters in adipocytes. , 1993, The American journal of physiology.

[35]  K. Segal,et al.  Evidence for Distinctive and Intrinsic Defects in Insulin Action in Polycystic Ovary Syndrome , 1992, Diabetes.

[36]  C. Kahn,et al.  Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation. , 1992, The Journal of biological chemistry.

[37]  S. Franks,et al.  Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome , 1992 .

[38]  J. Walsh,et al.  Formation of phosphatidylinositol 3-phosphate by isomerization from phosphatidylinositol 4-phosphate. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Olefsky,et al.  Mutation of the two carboxyl-terminal tyrosines results in an insulin receptor with normal metabolic signaling but enhanced mitogenic signaling properties. , 1991, The Journal of biological chemistry.

[40]  W. Garvey,et al.  Glucose and insulin regulate insulin sensitivity in primary cultured adipocytes without affecting insulin receptor kinase activity. , 1991, Endocrinology.

[41]  L. Cantley,et al.  Activation of phosphatidylinositol 3-kinase by insulin. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[42]  H. Halkin,et al.  Evaluation of WHO and NDDG Criteria for Impaired Glucose Tolerance: Results From Two National Samples , 1989, Diabetes.

[43]  K. Segal,et al.  Profound Peripheral Insulin Resistance, Independent of Obesity, in Polycystic Ovary Syndrome , 1989, Diabetes.

[44]  J. Clore,et al.  Suppression of serum insulin by diazoxide reduces serum testosterone levels in obese women with polycystic ovary syndrome. , 1989, The Journal of clinical endocrinology and metabolism.

[45]  J. Roth,et al.  Specificity spillover at the hormone receptor--exploring its role in human disease. , 1989, The New England journal of medicine.

[46]  R. Pietrzyk,et al.  Autophosphorylation of Cultured Skin Fibroblast Insulin Receptors From Patients With Severe Insulin Resistance and Acanthosis Nigricans , 1989, Diabetes.

[47]  T. Sasaoka,et al.  Clarification of Signaling Pathways Mediated by Insulin and Insulin-Like Growth Factor I Receptors in Fibroblasts From Patients With Specific Defect in Insulin Receptor , 1988, Diabetes.

[48]  J. Olefsky,et al.  Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. Effect of weight loss. , 1988, The Journal of clinical investigation.

[49]  A. Dunaif,et al.  Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. , 1987, The Journal of clinical endocrinology and metabolism.

[50]  R. Barbieri,et al.  Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. , 1986, The Journal of clinical endocrinology and metabolism.

[51]  P. Usher,et al.  Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[52]  J. Olefsky,et al.  Insulin Binding, Internalization, and Insulin Receptor Regulation in Fibroblasts from Type II, Non-insulin-dependent Diabetic Subjects , 1981, Diabetes.

[53]  C. Kahn,et al.  Insulin Activates Glycogen Synthase in Cultured Human Fibroblasts , 1980, Diabetes.

[54]  W. Dodson,et al.  Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. , 1999, The Journal of clinical endocrinology and metabolism.

[55]  M. White,et al.  The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action. , 1998, Recent progress in hormone research.