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From: Contemporary Endocrinology: Androgen Excess Disorders in Women:
Polycystic Ovary Syndrome and Other Disorders, Second Edition Edited by: R. Azziz et al. © Humana Press Inc., Totowa, NJ
24
Insulin Resistance and Hyperinsulinism in the Polycystic Ovary Syndrome
Paulina A. Essah and John E. Nestler
SUMMARY
Insulin resistance with compensatory hyperinsulinemia has been demonstrated to occur in 50–70% of women with polycystic ovary syndrome (PCOS), regardless of weight. Hyperinsulinemia stimulates excess ovarian androgen production, thereby contributing to the hyperandrogenism and chronic anovulation characteristic of PCOS. The exact cause of insulin resistance in PCOS is unknown, but it appears to be related to a postbinding defect in insulin receptor-mediated signal transduction. Because of insulin resistance, women with PCOS are at risk for several long-term metabolic complications, including type 2 diabetes and cardiovascular disease.
Key Words: Insulin resistance; hyperinsulinism; insulin receptor-mediated signal transduction.
1. INTRODUCTION
Although the pathogenesis of polycystic ovary syndrome (PCOS) remains unknown, the discov- ery that many women with PCOS have underlying insulin resistance and compensatory hyperinsulinemia has led to a much better understanding of the syndrome. This metabolic abnormal- ity contributes to the hyperandrogenism that characterizes PCOS and leads to its clinical signs and symptoms. The recognition of insulin resistance in PCOS has also influenced our understanding of the metabolic complications associated with PCOS. This chapter will provide an overview of the current body of knowledge regarding the prevalence, causes, and consequences of insulin resistance and hyperinsulinism in PCOS.
2. BACKGROUND
2.1. Overview of Insulin Resistance in PCOS
The relationship between PCOS and insulin resistance was first described by Burghen et al. in 1980 (1), with reports of a significant positive correlation between levels of androgens (testosterone and androstenedione) and insulin in a small number of obese women with PCOS. Several studies subsequently supported these findings (2–5).
Insulin resistance is defined as decreased sensitivity of target organ tissues to the action of insulin.
Another way to describe insulin resistance is a decreased glucose response to a given amount of insulin, also known as decreased insulin-mediated glucose uptake. Hyperinsulinism refers to a state of elevated insulin expression, either clinically or biochemically (hyperinsulinemia).
Despite the compensatory hyperinsulinemia that accompanies insulin resistance in nondiabetic
individuals, insulin-mediated glucose uptake remains subnormal (6). Interestingly, insulin resistance
in PCOS does not occur in all tissues, but rather appears to be tissue-specific (7). Skeletal muscle and
adipose tissue become insulin resistant, resulting in decreased glucose uptake and increased lipoly- sis, respectively, whereas the ovary, adrenal, liver, and skin remain insulin sensitive (7).
In PCOS, hyperinsulinemia occurs as a compensatory response to insulin resistance. This result- ing hyperinsulinemia has a stimulatory effect on the ovaries and adrenal glands that leads to enhanced androgen production by these organs. More specifically, excess insulin enhances androgen production in ovarian theca cells in response to luteinizing hormone (LH) stimulation, resulting in follicular arrest and anovulation. In addition, hyperinsulinemia stimulates proliferation of the pilosebaceous unit and sebum production, resulting in hirsutism and acne. In contrast, hyperinsulinemia acts to suppress hepatic production of sex hormone-binding globulin, the primary binding protein for test- osterone in the serum. Therefore, insulin resistance with compensatory hyperinsulinemia results in hyperandrogenemia (Fig. 1).
There is also evidence that women with PCOS may have pancreatic E-cell dysfunction, as occurs in type 2 diabetes (6,8). It has been reported that women with PCOS secrete an inadequate amount of insulin for the degree of peripheral insulin resistance that they experience (6).
2.2. Measurement of Insulin Resistance in PCOS
The gold standard method for measuring insulin sensitivity is the hyperinsulinemic-euglycemic clamp technique, first described by De Fronzo et al. (9), which measures insulin-mediated glucose uptake primarily in skeletal muscle. With this method, insulin is administered intravenously in one arm at a steady rate, while a variable glucose infusion is administered in the other arm in order to
“clamp” the serum glucose level at a normal fasting concentration. Blood samples are taken fre-
Fig. 1. Overview of the role of insulin resistance and hyperinsulinemia in the polycystic ovary syndrome (PCOS). FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; IGFBP-1, insulin-like factor-binding protein-1; LH, luteinizing hormone; SHBG, sex hormone-binding globulin.insulin infusion suppresses hepatic glucose production, so that the amount of glucose infused to maintain a steady fasting level must equal the amount of glucose taken up by the cells of the body (after a small correction for urinary glucose losses). The degree of insulin resistance is inversely proportional to the glucose uptake. Therefore, low glucose uptake reflects lower insulin sensitivity, which is equivalent to greater insulin resistance. A variation of the clamp technique is the hyperinsulinemic hyperglycemic clamp, which takes less time to perform and better measures pan- creatic E-cell function, but is less physiological than the euglycemic technique (7,10).
Unfortunately, the hyperinsulinemic-euglycemic clamp technique is expensive, time-consuming, and labor intensive. Therefore, several other measures of insulin sensitivity have been devised. These include the insulin tolerance test (ITT), frequently sampled intravenous glucose tolerance test (FSIVGTT), oral glucose tolerance test (OGTT) with determinations of both insulin and glucose, fasting glucose-to-insulin ratio (G:I ratio), homeostasis model assessment (HOMA), and quantitative sensitivity check index (QUICKI), all of which have been shown to correlate well with the hyperinsulinemic-euglycemic clamp technique (7). The FSIVGTT and OGTT methods are consid- ered to be minimal models, meaning that, unlike the clamp technique and the ITT, they require a minimum of glucose administration only without any insulin administration (although insulin is used in the modified FSIVGTT method). A detailed discussion of each of these techniques is beyond the scope of this chapter. Table 1 summarizes these measures of insulin sensitivity and their applicability in women with PCOS.
2.3. Prevalence of Insulin Resistance in PCOS
Approximately 50–70% of women with PCOS have some degree of insulin resistance (7), ranging from 20 to 95% (Table 2). Both obese and lean women with PCOS have been demonstrated to have some degree of insulin resistance (5). However, obese women with PCOS are more insulin resistant than either lean women with PCOS or obese, women without PCOS (5,11).
Some, but not all studies have reported a significant influence of ethnicity on the prevalence of insulin resistance in PCOS. In a study of 37 Mexican-American women and 65 Caucasian American women, all with PCOS, Kauffman et al. (12) reported that, using HOMA to estimate insulin sensitiv- ity, Mexican-American women were more insulin resistant than age- and weight-matched Caucasian women, with prevalences of insulin resistance of 73.1 vs 43.8%, respectively. In a controlled study of 36 women, Dunaif et al. (13) also found a higher prevalence of insulin resistance in Caribbean- Hispanic women with PCOS compared with Caucasian women.
Larger studies have not detected a significant influence of ethnicity on the presence of insulin resistance in PCOS. Carmina et al. (14) evaluated 75 women with PCOS—25 each from the United States, Italy, and Japan—and reported that insulin resistance, as measured by an ITT, was present similarly in all three groups of women, with a prevalence of 68–76% in the women. In a larger study of 267 women with PCOS and 50 ovulating controls, Carmina and Lobo (15) determined the preva- lence of insulin resistance to be approximately 80% using the homeostasis model assessment and quantitative assessment check indices and 65% using G:I ratios.
Similarly, Azziz and colleagues (16) recently observed a 64% prevalence of insulin resistance in 271 consecutive patients with PCOS using the homeostasis model assessment of insulin resistance (HOMA-IR) calculation to estimate insulin sensitivity, with no significant association between HOMA-IR and race among the black and white women with PCOS studied. They also reported that patients with insulin resistance were more obese, had greater degrees of android body fat, had higher serum androgen levels, and displayed more hirsutism and acne compared with their non-insulin- resistant counterparts.
In terms of the prevalence of insulin resistance in women with PCOS, studies have revealed that
the majority of, but not all, women with PCOS are insulin resistant.
Table 1 Methods of Measuring Insulin Sensitivity Correlation withSimple mathematicalInsulin resistance Testclamp techniqueiv access neededmodelcutoff in PCOSComments Hyperinsulinemic-euglycemic clampGold standardYesNoneNoneHyperglycemic version allows for best assessment of E-cell function Insulin tolerance test (ITT)GoodYesNoneNoneNumerous modifications Insulin sensitivity test (IST)GoodYesNoneNoneNumerous modifications Frequently sampled intravenousGoodYesNoneNoneNumerous modifications glucose tolerence test (FSIVGTT) Oral glucose tolerance test (OGTT)GoodNoG120/I120ⱕ1.0Modifications using this method include are under the curve (AUC) insulin and AUC glucose Fasting insulinGoodNoI0ⱖ20 whiteLoss of accuracy with hyperglycemia Fasting glucose:insulin ratioGoodNoG0/I0ⱖ23 Mexican-AmericanLoss of accuracy with hypergly- (G:I ratio)ⱕ4.5 whitecemia; different values in differ- ent ethnic groups Homeostatic model assessmentGoodNoIo x Go / 405ⱖ7.2 whiteUse 22.5 instead of 40.5 when (HOMA)ⱕ4.0 Mexican-Americanglucose expressed as mmol/L Quantitative insulin sensitivityGoodNo1/[10 g (I0) + 10 g (G0)]NoneApplicable to hyperglycemic check index (QUICKI)patients Adapted with permission from ref. 7.
Prevalence of Insulin Resistance in Women With Polycystic Ovary Syndrome
Study (ref.) Population Measure of insulin resistance Prevalence (%)
Dunaif et al., 1989 (5) Obese Euglycemic glucose clamp 26
Nonobese Euglycemic glucose clamp 60
Carmina et al., 1992 (14) U.S. Insulin tolerance test 76
Italy Insulin tolerance test 72
Japan Insulin tolerance test 68
Meirow et al., 1995 (48) Obese Glucose/insulin ratio 64
Nonobese Glucose/insulin ratio 20
Legro et al., 1998 (49) Obese, white Modified FSIVGTT 53
Kauffman et al., 2002 (12) U.S., all HOMA-IR 54.50
White HOMA-IR 43.80
Mexican-American HOMA-IR 73.10
Carmina and Lobo, 2004 (15) Italy, all HOMA-IR 77
QUICKI 79.20
Glucose/insulin ratio 65.40
Italy, obese HOMA-IR 95.30
QUICKI 95.30
Glucose/insulin ratio 76.70
DeUgarte et al., 2005 (16) Southeast U.S., all races HOMA-IR 64
FSIVGTT, frequently sampled intravenous glucose tolerance test; HOMA-IR, homeostatic model assessment for insulin resistance; QUICKI, quantitative insulin sensitivity check index.
2.4. Pathophysiology of Insulin Resistance in PCOS
Over the past decade, accumulating evidence has indicated that insulin resistance plays a major role in the pathogenesis of PCOS. Moreover, it has been hypothesized that the cellular defect that causes insulin resistance in PCOS may simultaneously result in increased ovarian androgen produc- tion. There is also emerging evidence that a form of insulin resistance present in PCOS may be intrinsic (and possibly unique) to the disorder, and that it is acquired only by women who are geneti- cally susceptible (17). The insulin resistance of PCOS is independent of obesity, metabolic abnor- malities, and sex hormone levels (17).
2.4.1. The Role of the Insulin Receptor and Hyperinsulinemia
The cause of insulin resistance in PCOS appears to be a postbinding defect in insulin receptor- mediated signal transduction (18). However, the exact nature of this defect remains largely unknown and is being explored. A subsequent chapter of this book elaborates on this concept in a summary of the molecular mechanisms of insulin resistance in PCOS.
The outcome of the postreceptor defect in insulin receptor-mediated signal transduction is periph- eral tissue resistance to insulin, which in turn results in higher insulin production and secretion from the pancreas. Insulin may then act both directly and indirectly to increase endogenous androgen levels via several mechanisms:
1. In the typical case of PCOS, insulin binds directly to insulin receptors in the ovary to increase ovarian androgen production by theca cells in response to LH stimulation (19).
2. If hyperinsulinemia is marked (as in rare syndromes of type A or B insulin resistance), extreme hyperinsulinemia may result in insulin “spillover” activation of ovarian insulin-like growth factor (IGF)- 1 receptors and thereby stimulate androgen production (20,21). In addition, atypical IGF receptor sub- types may be present in the ovary that have extremely high affinity for insulin binding (22).
3. Hyperinsulinemia inhibits synthesis of sex hormone-binding globulin by the liver, which leads to elevated levels of serum-free testosterone (17).
4. Hyperinsulinemia causes a decrease in secretion of IGF binding protein-1 in both the liver and the ovary, which in turn results in increased intraovarian bioavailability of IGF-1 and IGF-2 (23,24), two important regulators of ovarian follicular maturation and steroidogenesis (17,25).
Genetic defects have been implicated in the insulin signal transduction abnormality that leads to insulin resistance and hyperinsulinemia. Dunaif et al. reported genetic abnormalities in the regulation of insulin receptor phosphorylation, causing an increase in insulin-dependent serine phosphorylation and a decrease in insulin-dependent tyrosine phosphorylation (29). These abnormalities in insulin receptor phosphorylation result in reduced insulin responsiveness. Several polymorphisms have been identi- fied at the coding region of the insulin receptor gene in women with PCOS (30). However, most of these polymorphisms have also been demonstrated in normal subjects and do not appear to result in significant dysfunction of the insulin receptor (30). Extensive research is ongoing in locating major insulin receptor genetic defects and other insulin-related genetic defects that may cause the insulin resistance and hyperinsulinemia of PCOS.
2.4.2. The Role of Obesity
Obesity may also contribute to the insulin resistance of PCOS. However, it has been suggested that it is the distribution of fat, rather than the mere presence of obesity or increased body mass index, that is mainly significant (31). Regardless of ethnicity, most overweight women with PCOS have central, or android (visceral), obesity, resulting in a waist-to-hip ratio greater than 0.85 (32). Visceral adiposity is known to be metabolically active and is more highly associated with hyperinsulinemia than subcutaneous fat (33). Of note, 70% of lean women with PCOS also have an android distribution of fat (34).
The mechanism(s) by which increased visceral adipose tissue results in hyperinsulinemia are not well understood. Altered lipolysis in visceral fat cells appears to result in increased free fatty acids that drain via the portal vein to the liver and subsequently affect the secretion, metabolism, and peripheral actions of insulin (35). Notably, defects in visceral adipose cell lipolysis have been dem- onstrated even in non-obese women with PCOS (36). Insulin resistance in central obesity can also be associated with tumor necrosis factor (TNF)-D and leptin, both produced from adipose tissue (35).
Both TNF-D and leptin are involved in mediating serine phosphorylation of insulin receptor sub- strate-1, which interferes with the action of both insulin and IGF-1. TNF-D has also been reported to inhibit insulin signaling through peroxisome proliferators-activated receptor-J.
2.5. Complications of Insulin Resistance in PCOS
Because of its association with insulin resistance, PCOS can lead to several metabolic complica- tions. The metabolic syndrome has been reported to occur at an increased overall prevalence rate of 43–47% in women with PCOS (37–39) compared with the 24% prevalence rate in US women (40).
Studies have shown that atherosclerosis is more prevalent in women with PCOS (5). Women with PCOS are also at risk for developing gestational diabetes and type 2 diabetes mellitus (DM) (41,42).
In women with PCOS, there is a reported prevalence of 30–40% of glucose intolerance (43) and prevalence of 5–10% of type 2 diabetes (44). In addition, women with PCOS have a 5- to 10-fold increased rate of conversion from impaired glucose tolerance to type 2 DM (44,45). A recent study revealed that women with PCOS and baseline normal glucose tolerance have a 16% conversion rate per year to type 2 DM (46).
Other long-term risks resulting from insulin resistance include hypertension, atherogenic dyslip-
idemia, hypercoagulability, and vascular endothelial dysfunction, all risk factors for cardiovascular
cardial infarction, with increased cardiovascular risk independent of obesity (47).
3. CONCLUSION
Insulin resistance with compensatory hyperinsulinemia occurs in the majority of women with PCOS, both obese and lean. This hormone abnormality contributes to the hyperandrogenism and chronic anovulation characteristic of PCOS. The pathophysiology of insulin resistance in PCOS is related in part to a postbinding defect in insulin receptor-mediated signal transduction, but the cause of this defect remains unknown. Nevertheless, because of insulin resistance, women with PCOS are at risk for several long-term metabolic complications, most notably type 2 DM and cardiovascular disease.
4. FUTURE AVENUES OF INVESTIGATION
Much is still unknown about the pathogenesis of insulin resistance and hyperinsulinism in PCOS.
Future avenues of investigation include identification of genetic defects that might lead to the insulin resistance present in PCOS and further delineation of the cellular and molecular pathways that result in insulin resistance and hyperinsulinemia. In addition, investigation is needed to determine why some tissues, such as skeletal muscle, are insulin resistant whereas other tissues, particularly the ovaries, remain sensitive to the effects of insulin in PCOS.
KEY POINTS
• Approximately 50–70% of women with PCOS have some degree of insulin resistance that is independent of weight.
• The pathogenesis of insulin resistance in PCOS appears to involve a postbinding receptor defect in insulin receptor-mediated signal transduction, which in turn results in higher insulin secretion from the pancreas.
• Because of its association with insulin resistance, PCOS can lead to several metabolic complications, including type 2 DM, dyslipidemia, hypertension, and cardiovascular disease.
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