Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications

Abstract

Polycystic ovary syndrome (PCOS) is now recognized as an important metabolic as well as reproductive disorder conferring substantially increased risk for type 2 diabetes. Affected women have marked insulin resistance, independent of obesity. This article summarizes the state of the science since we last reviewed the field in the Endocrine Reviews in 1997. There is general agreement that obese women with PCOS are insulin resistant, but some groups of lean affected women may have normal insulin sensitivity. There is a post-binding defect in receptor signaling likely due to increased receptor and insulin receptor substrate-1 serine phosphorylation that selectively affects metabolic but not mitogenic pathways in classic insulin target tissues and in the ovary. Constitutive activation of serine kinases in the MAPK-ERK pathway may contribute to resistance to insulin's metabolic actions in skeletal muscle. Insulin functions as a co-gonadotropin through its cognate receptor to modulate ovarian steroidogenesis. Genetic disruption of insulin signaling in the brain has indicated that this pathway is important for ovulation and body weight regulation. These insights have been directly translated into a novel therapy for PCOS with insulin-sensitizing drugs. Furthermore, androgens contribute to insulin resistance in PCOS. PCOS may also have developmental origins due to androgen exposure at critical periods or to intrauterine growth restriction. PCOS is a complex genetic disease, and first-degree relatives have reproductive and metabolic phenotypes. Several PCOS genetic susceptibility loci have been mapped and replicated. Some of the same susceptibility genes contribute to disease risk in Chinese and European PCOS populations, suggesting that PCOS is an ancient trait.

Figures

Figure 1.

A new field—PCOS and insulin resistance. The first article reporting an association between PCOS and hyperinsulinemia was published in 1980 (21). There are approximately 103,000 citations in a Web of Science (Thomson Reuters, New York, NY) Citation Report for 1980–2011 on the topics of PCOS or hyperandrogenism and hyperinsulinemia, insulin resistance, glucose intolerance, or diabetes mellitus. The annual citations have increased steadily from 1 in 1980 to approximately 12,000 in 2011. This figure was created from the Web of Science Citation Report.

Figure 2.

Pathophysiology of the PCOS reproductive phenotype. There is increased frequency of pulsatile GnRH release that selectively increases LH secretion. LH stimulates ovarian theca cell T production. T is incompletely aromatized by the adjacent granulosa cells because of relative FSH deficiency. There are also constitutive increases in the activity of multiple steroidogenic enzymes in polycystic ovaries contributing to increased androgen production. Increased adrenal androgen production may also be present in PCOS. T acts in the periphery to produce signs of androgen excess, such as hirsutism, acne, and alopecia. T and androstenedione can also be aromatized extragonadally to estradiol and estrone, respectively, resulting in unopposed estrogen action on the endometrium. T feeds back on the hypothalamus to decrease the sensitivity to the normal feedback effects of estradiol and progesterone to slow GnRH pulse frequency. This figure is used with the permission of Andrea Dunaif.

Figure 3.

Features of PCOS. The diagnostic criteria for PCOS (Table 1) include two or more of these features: hyperandrogenism (blue circle), anovulation (pink circle), and PCO (green circle), resulting in several PCOS phenotypes depending on the diagnostic criteria applied (Table 3). This figure is used with the permission of Andrea Dunaif.

Figure 4.

Insulin responses basally and after a 40 g/m2 oral glucose load in obese and lean PCOS women (black circles), ovulatory hyperandrogenic (HA) women (gray circles), and age- and weight-comparable ovulatory control women (white circles). Insulin responses are significantly increased only in PCOS women (P < 0.001 obese PCOS vs. obese HA and obese control; P < 0.01 lean PCOS vs. lean HA and control), suggesting that hyperinsulinemia is a unique feature of PCOS and not hyperandrogenic states in general. [Adapted from A. Dunaif et al.: Characterization of groups of hyperandrogenic women with acanthosis nigricans, impaired glucose tolerance, and/or hyperinsulinemia. J Clin Endocrinol Metab 65:499–507, 1987 (34), with permission. © The Endocrine Society.]

Figure 5.

Prevalence of glucose intolerance and T2D in PCOS. The prevalence of IGT and T2D in four large multiethnic PCOS cohorts is substantially increased. The true prevalence of diabetes was likely underestimated in these studies because diagnosed women with type 1 or type 2 diabetes were not included in the cohorts. NGT, Normal glucose tolerance.* [The University of Chicago data were reported by D. A. Ehrmann et al.: Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22:141–146, 1999 (124), with permission. © American Diabetes Association.** The Penn State University and Mt. Sinai data were reported by R. S. Legro 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. J Clin Endocrinol Metab 84:165–169, 1999 (123), with permission. © The Endocrine Society.*** The Rezulin (troglitazone) Collaborative Group data were reported by R. Azziz et al.: Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86:1626–1632, 2001 (392), with permission. © The Endocrine Society.] The figure is used with the permission of David Ehrmann.

Figure 6.

Fasting and post-challenge dysglycemia in PCOS. The individual fasting and 2-h post-75 g oral glucose challenge glucose data from 254 women with PCOS are shown. The dotted vertical line is the fasting glucose threshold for impaired fasting glucose (100 mg/dl), the dashed vertical line is the fasting glucose threshold for diabetes (T2D) (126 mg/dl), the dotted horizontal line is the post-challenge glucose threshold for IGT (140 mg/dl), and the horizontal dashed line is the post-challenge glucose threshold (200 mg/dl) for T2D, according to the American Diabetes Association criteria (158). Most women with PCOS have post-challenge rather than fasting dysglycemia. NGT, Normal glucose tolerance. [Adapted from R. S. Legro 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. J Clin Endocrinol Metab 84:165–169, 1999 (123), with permission. © The Endocrine Society.]

Figure 7.

Decreased IMGD in PCOS. IMGD at steady-state insulin levels of 100 μU/ml is significantly decreased by 35–40% in women with PCOS (gray bars), independent of obesity, compared with age- and weight-matched control women (NL, open bars). This decrease is similar in magnitude to that reported in T2D (open bars) (160). This figure is used with the permission of Andrea Dunaif.

Figure 8.

Insulin action in isolated sc adipocytes and in vivo. The dose-response of insulin-stimulated glucose uptake was determined in isolated sc adipocytes in vitro and in vivo during sequential multiple insulin dose euglycemic glucose clamp studies. Maximal rates of glucose uptake (insulin responsiveness) in isolated sc adipocytes are depicted in vitro (A, left) and in vivo, which reflects primarily skeletal muscle glucose uptake (B, left). Rates of postabsorptive endogenous glucose production (EGP) (C, left) and its suppression by insulin were also assessed during the euglycemic glucose clamp study. The ED50 insulin (insulin sensitivity) for stimulation of glucose uptake and suppression of EGP are depicted in the graphs on the right (A, sc adipocytes in vitro; B, in vivo; C, EGP). Women with PCOS, gray bars; normal control women (NL), open bars. A two-way ANOVA with PCOS and obesity as factors was applied: *, P < 0.01 PCOS groups vs. NL groups; †, P < 0.05 obese groups vs. lean groups; ††, P < 0.01 obese groups vs. lean groups; †††, P < 0.001 obese groups vs. lean groups; ‡, P < 0.05 interaction PCOS and obesity. [Adapted from data published in A. Dunaif et al.: Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 41:1257–1266, 1992 (192), with permission. © American Diabetes Association.]

Figure 9.

Fasting and dynamic measures of insulin resistance. Fasting measure of insulin sensitivity, the glucose:insulin ratio (185) and insulin levels are shown in the top graphs. Dynamic measures of insulin sensitivity, the euglycemic glucose clamp determined IMGD, and sensitivity index (SI) assessed by minimal model analysis of FSIGT are shown in the bottom graphs. For all measures of insulin action, there is considerable overlap between control (open triangles) and PCOS (gray circles) women. The data have been previously published (81, 185, 301) and were adapted for use in this figure, which is used with the permission of Andrea Dunaif.

Figure 10.

Insulin receptor signaling pathways. The insulin receptor is a heterotetramer consisting of two α, β dimers linked by disulfide bonds. The α-subunit contains the ligand binding domain, and the β-subunit contains a ligand-activated tyrosine kinase. Tyrosine autophosphorylation increases the receptor's intrinsic tyrosine kinase activity, whereas serine phosphorylation inhibits it. The tyrosine-phosphorylated insulin receptor phosphorylates intracellular substrates, such as IRS 1–4, Shc, and APS, initiating signal transduction pathways mediating the pleiotropic actions of insulin. The major pathway for the metabolic actions of insulin is mediated through activation of PI3-K and Akt/PKB, resulting in the translocation for the insulin responsive glucose transporter, GLUT4, from intracellular vesicles to the plasma membrane. Insulin activation of PI3-K and Akt/PKB also leads to serine phosphorylation of GSK3, resulting in inhibition of its kinase activity. The inhibition of GSK3 results in dephosphorylation of glycogen synthase increasing glycogen synthesis. The Ras-ERK/MAPK pathway regulates gene expression. Insulin modulates protein synthesis and degradation via mTOR, which is activated via PI3-K and Akt/PKB. The mTOR pathway is also important in nutrient sensing. Insulin-stimulated inhibition of GSK3 via PI3-K and Akt/PKB also results in dephosphorylation of eIF2B increasing protein synthesis. Insulin signaling can be terminated by dephosphorylation of the receptor by tyrosine phosphatases, such as PTP1B, or dephosphorylation of PI3-K by PTEN. Serine phosphorylation of the insulin receptor and IRSs can also decrease insulin signaling and may be mediated by serine kinases in the insulin signaling pathway providing a feedback mechanism to terminate insulin action. There is a post-binding defect in insulin signaling in PCOS affecting metabolic but not mitogenic pathways (see Fig. 11 for details). The signaling steps that are compromised in PCOS are circled with a dotted line. Signaling steps downstream of these abnormalities may also be compromised. SOS, Son-of-sevenless. This figure is used with the permission of Andrea Dunaif.

Figure 11.

Insulin signaling defects in PCOS. There is a post-binding defect in insulin signaling in PCOS resulting in marked decreases in insulin sensitivity (see Fig. 8). There is a more modest defect in insulin responsiveness. The signaling defect is due to serine phosphorylation of the insulin receptor and IRS-1 secondary to intracellular serine kinases. This results in decreased insulin-mediated activation of PI3-K and resistance to the metabolic actions of insulin. There is constitutive activation of kinases in the ERK/MAPK mitogenic pathway in PCOS, and these kinases contribute to inhibitory serine phosphorylation of IRS-1 in PCOS skeletal muscle. Serine phosphorylation of P450c17 increases its activity, and it has been postulated that the same kinase may inhibit insulin signaling and increase androgen production in PCOS. S-S, Disulfide bond; Y, tyrosine; S, serine; P, phosphate. This figure is used with the permission of Andrea Dunaif.

Figure 12.

β-Cell dysfunction in PCOS. Under normal circumstances, there is a compensatory increase in insulin secretion when insulin sensitivity decreases. This hyperbolic relationship is known as the DI. The majority of women with PCOS fall below the normal curve determined in concurrently studied age- and weight-comparable control women as well as normative data in the literature (292), which places them at increased risk for T2D. DI is decreased independent of obesity. Insulin secretion was determined as AIRg and insulin sensitivity by minimal model analysis of FSIGT glucose and insulin data. Circles, Obese PCOS; triangles, lean PCOS. [Adapted from A. Dunaif and D. T. Finegood: β-Cell dysfunction independent of obesity and glucose intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:942–947, 1996 (301) with permission. © The Endocrine Society.]

Figure 13.

Two affected phenotypes in sisters of women with PCOS. Approximately 40% of the sisters of women with PCOS have hyperandrogenemia with similar T elevations (middle graph). About half of these affected women fulfill NICHD criteria for PCOS; the remaining hyperandrogenemic (HA) sisters have regular menses and normal fertility, suggesting that their menstrual cycles are ovulatory. Sisters with the PCOS phenotype are heavier (left graph) and more insulin resistant [significantly increased homeostasis model assessment of insulin resistance (HOMA IR), right graph] than sisters with the HA phenotype and sisters with normal androgen levels and regular menses (unaffected, UA). Black bars, PCOS; gray bars, HA; hatched bars, UA; open bars, reproductively normal control women. One-way ANOVA was applied, *, P < 0.05 vs. HA and UA; **, P < 0.05 vs. PCOS and HA; ***, P < 0.05 vs. PCOS, HA, and UA; †, P < 0.05 vs. UA and control; ††, P < 0.05 vs. control. [Adapted from R. S. Legro et al.: Insulin resistance in the sisters of women with polycystic ovary syndrome: association with hyperandrogenemia rather than menstrual irregularity. J Clin Endocrinol Metab 87:2128–2133, 2002 (443), with permission. © The Endocrine Society.]

Figure 14.

Determinants of PCOS phenotypes. The affected sisters of women with PCOS have either highly irregular menstrual cycles characteristic of chronic anovulation or regular cycles consistent with ovulation. Circulating T levels are similar in both affected phenotypes, PCOS and hyperandrogenemia. Both affected groups also have PCO. Possible factors that determine the ovulatory status of affected sisters are obesity, insulin resistance, additional modifier genes, and environmental factors such as lifestyle or diet. This figure is used with the permission of Andrea Dunaif.

Figure 15.

TGFβ signaling family. The TGFβ signaling family regulates cell proliferation and differentiation in diverse biological processes including reproduction, cancer progression, extracellular matrix formation, inflammation, metabolism, and development of bone, skeletal muscle, and fat. The family consists of extracellular antagonists that bind TGFβ ligands and modulate their biological availability. The receptors in this family are serine/threonine kinases. Ligands bind to type II receptors, which then recruit and phosphorylate the type I receptor, initiating signaling through phosphorylation of intracellular Smads. Fibrillins and follistatin are extracellular antagonists of ligands in the TGFβ signaling family. A variant within an intron in the fibrillin-3 gene has been linked and associated with PCOS. The follistatin gene has been linked with PCOS in an affected sib pair study. The fibrillin-3 variant is also associated with a metabolic phenotype in women with PCOS and their brothers. These observations suggest that genes in the TGFβ signaling family are candidate genes for PCOS.