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Insulin resistance in women with polycystic ovary syndrome
Insulin resistance in women with polycystic ovary syndrome Andrea Dunaif, M.D. Feinberg School of Medicine, Northwestern University, Chicago, Illinois
Polycystic ovary syndrome (PCOS) is associated with insulin resistance. There are also defects in pancreatic -cell function in affected women. These abnormalities are heritable. There are post-binding defects in insulin receptor signaling, with selective resistance to insulin’s metabolic actions and constitutively activated mitogenic signaling in skeletal muscle. Intrinsic and environmental abnormalities interact to produce peripheral insulin resistance in PCOS. A susceptibility gene region for PCOS is located on chromosome 19p13.2. The susceptibility allele is also associated with a metabolic phenotype. (Fertil Steril威 2006;86(Suppl 1):S13– 4. ©2006 by American Society for Reproductive Medicine.) Key Words: Polycystic ovary syndrome, insulin resistance, metabolic disorders, androgens
In the last 25 years, it has become clear that polycystic ovary syndrome (PCOS) is an important metabolic disorder. Women with PCOS have profound peripheral insulin resistance. Insulin-mediated glucose uptake is decreased by 35%– 40% compared with age- and weight-comparable control women. There is increased basal insulin secretion and decreased hepatic insulin extraction. Glucose-stimulated insulin release, however, is inappropriately low when assessed in the context of peripheral insulin sensitivity. This finding suggests that there are defects in pancreatic -cell function in PCOS. Further, these defects can occur in the absence of obesity and glucose intolerance. Both premenopausal women and adolescent girls with PCOS are at markedly increased risk for type 2 diabetes mellitus (DM). Although obesity and age significantly increase this risk, both nonobese and young PCOS women can be affected. The risk for impaired glucose tolerance is two- to three-fold greater in PCOS, and the rate of conversion to type 2 DM may be rapid. Insulin resistance in PCOS is due to a unique post-binding defect in signal transduction. There is constitutively increased serine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)–1 that inhibits metabolic signaling (1, 2). A serine kinase extrinsic to the insulin receptor causes the abnormal pattern of phosphorylation (3). These abnormalities persist in cultured cells, consistent with an intrinsic, possibly genetic, defects (1, 2). Insulin acting through its cognate receptor can stimulate ovarian steroidogenesis in PCOS women, despite resistance to insulin action on glucose metabolism. This Received January 31, 2006; revised and accepted April 7, 2006. Reprint requests: Andrea Dunaif, M.D., Division of Endocrinology, Metabolism and Molecular Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 (FAX: 312-908-3870; E-mail: [email protected]).
0015-0282/06/$32.00 doi:10.1016/j.fertnstert.2006.04.011
paradox may be explained by the presence of a selective defect affecting the metabolic but not the mitogenic actions of insulin, which has been identified in PCOS cultured skin fibroblasts (4, 5). Indeed, we have recently found that mitogenic pathways are constitutively activated in PCOS skeletal muscle and that mitogen-activated protein kinase may be one kinase contributing to increased serine phosphorylation of IRS-1 in PCOS (5). Recent family studies suggest that hyperandrogenemia per se is the major reproductive endocrine phenotype in premenopausal sisters as well as in brothers of PCOS probands (6). Of ⬃40% of sisters thus affected, approximately half have PCOS and half have hyperandrogenemia with regular menstrual cycles. In sisters, the distribution of testosterone levels is bimodal, consistent with a monogenic trait controlled by two alleles at an autosomal locus. A candidate gene would regulate ovarian and adrenal androgen biosynthesis. Insulin resistance also demonstrates familial aggregation consistent with a genetic trait. Insulin resistance and hyperandrogenemia track together in affected sisters. Genetic analyses have shown evidence for linkage and association of a marker locus on chromosome 19 near the insulin receptor with the hyperandrogenemia phenotype in PCOS families (7). Carriers of the linked allele also have a metabolic phenotype. These findings suggest that variation in a gene or genetic element near the insulin receptor may cause reproductive and metabolic phenotypes in PCOS. This gene or genetic element may be a novel diabetes susceptibility gene. REFERENCES 1. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995;96:801–10.
Fertility and Sterility姞 Vol. 86, Suppl 1, July 2006 Copyright ©2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
S13
2. Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, Dunaif A. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 2005;288:E1047–54. 3. Li M, Youngren JF, Dunaif A, Goldfine ID, Maddux BA, Zhang BB, Evans JL. Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators. J Clin Endocrinol Metab 2002;87:4088 –93. 4. Book CB, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1999;84:3110 – 6.
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Dunaif
Insulin Resistance in PCOS
5. Corbould A, Zhao H, Mirzoeva S, Aird F, Dunaif A. Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. Diabetes 2006;55:751–9. 6. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A 1998;95:14956 – 60. 7. Urbanek M, Woodroffe A, Ewens KG, DiamantiKandarakis E, Legro RS, Strauss JF 3rd, et al. Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2. J Clin Endocrinol Metab 2005; 90:6623–9.
Vol. 86, Suppl 1, July 2006
Polycystic ovary syndrome (PCOS) is associated with insulin resistance. There are also defects in pancreatic -cell function in affected women. These abnormalities are heritable. There are post-binding defects in insulin receptor signaling, with selective resistance to insulin’s metabolic actions and constitutively activated mitogenic signaling in skeletal muscle. Intrinsic and environmental abnormalities interact to produce peripheral insulin resistance in PCOS. A susceptibility gene region for PCOS is located on chromosome 19p13.2. The susceptibility allele is also associated with a metabolic phenotype. (Fertil Steril威 2006;86(Suppl 1):S13– 4. ©2006 by American Society for Reproductive Medicine.) Key Words: Polycystic ovary syndrome, insulin resistance, metabolic disorders, androgens
In the last 25 years, it has become clear that polycystic ovary syndrome (PCOS) is an important metabolic disorder. Women with PCOS have profound peripheral insulin resistance. Insulin-mediated glucose uptake is decreased by 35%– 40% compared with age- and weight-comparable control women. There is increased basal insulin secretion and decreased hepatic insulin extraction. Glucose-stimulated insulin release, however, is inappropriately low when assessed in the context of peripheral insulin sensitivity. This finding suggests that there are defects in pancreatic -cell function in PCOS. Further, these defects can occur in the absence of obesity and glucose intolerance. Both premenopausal women and adolescent girls with PCOS are at markedly increased risk for type 2 diabetes mellitus (DM). Although obesity and age significantly increase this risk, both nonobese and young PCOS women can be affected. The risk for impaired glucose tolerance is two- to three-fold greater in PCOS, and the rate of conversion to type 2 DM may be rapid. Insulin resistance in PCOS is due to a unique post-binding defect in signal transduction. There is constitutively increased serine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)–1 that inhibits metabolic signaling (1, 2). A serine kinase extrinsic to the insulin receptor causes the abnormal pattern of phosphorylation (3). These abnormalities persist in cultured cells, consistent with an intrinsic, possibly genetic, defects (1, 2). Insulin acting through its cognate receptor can stimulate ovarian steroidogenesis in PCOS women, despite resistance to insulin action on glucose metabolism. This Received January 31, 2006; revised and accepted April 7, 2006. Reprint requests: Andrea Dunaif, M.D., Division of Endocrinology, Metabolism and Molecular Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 (FAX: 312-908-3870; E-mail: [email protected]).
0015-0282/06/$32.00 doi:10.1016/j.fertnstert.2006.04.011
paradox may be explained by the presence of a selective defect affecting the metabolic but not the mitogenic actions of insulin, which has been identified in PCOS cultured skin fibroblasts (4, 5). Indeed, we have recently found that mitogenic pathways are constitutively activated in PCOS skeletal muscle and that mitogen-activated protein kinase may be one kinase contributing to increased serine phosphorylation of IRS-1 in PCOS (5). Recent family studies suggest that hyperandrogenemia per se is the major reproductive endocrine phenotype in premenopausal sisters as well as in brothers of PCOS probands (6). Of ⬃40% of sisters thus affected, approximately half have PCOS and half have hyperandrogenemia with regular menstrual cycles. In sisters, the distribution of testosterone levels is bimodal, consistent with a monogenic trait controlled by two alleles at an autosomal locus. A candidate gene would regulate ovarian and adrenal androgen biosynthesis. Insulin resistance also demonstrates familial aggregation consistent with a genetic trait. Insulin resistance and hyperandrogenemia track together in affected sisters. Genetic analyses have shown evidence for linkage and association of a marker locus on chromosome 19 near the insulin receptor with the hyperandrogenemia phenotype in PCOS families (7). Carriers of the linked allele also have a metabolic phenotype. These findings suggest that variation in a gene or genetic element near the insulin receptor may cause reproductive and metabolic phenotypes in PCOS. This gene or genetic element may be a novel diabetes susceptibility gene. REFERENCES 1. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest 1995;96:801–10.
Fertility and Sterility姞 Vol. 86, Suppl 1, July 2006 Copyright ©2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
S13
2. Corbould A, Kim YB, Youngren JF, Pender C, Kahn BB, Lee A, Dunaif A. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab 2005;288:E1047–54. 3. Li M, Youngren JF, Dunaif A, Goldfine ID, Maddux BA, Zhang BB, Evans JL. Decreased insulin receptor (IR) autophosphorylation in fibroblasts from patients with PCOS: effects of serine kinase inhibitors and IR activators. J Clin Endocrinol Metab 2002;87:4088 –93. 4. Book CB, Dunaif A. Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1999;84:3110 – 6.
S14
Dunaif
Insulin Resistance in PCOS
5. Corbould A, Zhao H, Mirzoeva S, Aird F, Dunaif A. Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. Diabetes 2006;55:751–9. 6. Legro RS, Driscoll D, Strauss JF 3rd, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A 1998;95:14956 – 60. 7. Urbanek M, Woodroffe A, Ewens KG, DiamantiKandarakis E, Legro RS, Strauss JF 3rd, et al. Candidate gene region for polycystic ovary syndrome on chromosome 19p13.2. J Clin Endocrinol Metab 2005; 90:6623–9.
Vol. 86, Suppl 1, July 2006