Insulin Action and Its Disturbances in Disease - part 9 docx

480 INSULIN RESISTANCE, HYPERTENSION AND ENDOTHELIAL DYSFUNCTION 26. Vallance, P., Collier, J. and Moncada, S. (1989) Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet 2, 997–1000. 27. Yki-Jarvinen, H. and Utriainen, T. (1998) Insulin-induced vasodilatation: Physiology or pharmacology? Diabetologia 41, 369–379. 28. Ueda, S., Petrie, J. R., Cleland, S. J., Elliott, H. L. and Connell, J. M. C. (1998) The vasodilating effect of insulin is dependent on local glucose uptake: A double blind, placebo-controlled study. J Clin Endocrinol Metab 83, 2126–2131. 29. Cleland, S. J., Petrie, J. R., Ueda, S., Elliott, H. L. and Connell, J. M. C. (1999) Insulin- mediated vasodilation and glucose uptake are functionally linked in humans. Hypertension 33, 554–558. 30. Ueda, S., Petrie, J. R., Cleland, S. J., Elliott, H. L. and Connell, J. M. C. (1998) Insulin vasodilatation and the ‘arginine paradox’. Lancet 351, 959–960. 31. Zeng, G. and Quon, M. J. (1996) Insulin-stimulated production of nitric oxide is inhibited by Wortmannin: Direct measurement in vascular endothelial cells. J Clin Invest 98, 894–898. 32. Aljada, A. and Dandona, P. (2000) Effect of insulin on human aortic endothelial nitric oxide synthase. Metab Clin Exp 49, 147–150. 33. Kuboki, K., Jiang, Z Y., Takahara, N., Ha, S W., Igarashi, M., Yamauchi, T., Feener, E. P., Herbert, T. P., Rhodes, C. J. and King, G. L. (2000) Regulation of constitutive nitric oxide synthase gene expression in endothelial cells and in vivo. A specific vascular action of insulin. Circulation 101, 676–681. 34. Sobrevia, L., Nadal, A., Yudilevich, D. L. and Mann, G. E. (1996) Activation of L- arginine transport (system y+) and nitric oxide synthase by elevated glucose and insulin in human endothelial cells. J Physiol 490, 775–781. 35. Petrie, J. R., Ueda, S., Webb, D. J., Elliott, H. L. and Connell, J. M. C. (1996) Endothelial nitric oxide production and insulin sensitivity: A physiological link with implications for pathogenesis of cardiovascular disease. Circulation 93, 1331–1333. 36. Cleland, S. J., Petrie, J. R., Small, M., Elliott, H. L. and Connell, J. M. C. (2000) Insulin action is associated with endothelial function in hypertension and type 2 diabetes. Hypertension 35(1), 507–511. 37. Abe, H., Yamada, N., Kuwaki, T., Shimada, M., Osuga, J., Shionoiri, F., Yahagi, N., Kadowaki, T., Tamemoto, H., Ishibashi, S., Yazaki, Y. and Makuuchi, M. (1998) Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1. J Clin Invest 101, 1784–1788. 38. Jiang, Z. Y., Lin, Y W., Clemont, A., Feener, E. P., Hein, K. D., Igarashi, M., Yamauchi, T., White, M. F. and King, G. L. (1999) Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 104, 447–457. 39. Pinkney, J. H., Stehouwer, C. D. A., Coppack, S. W. and Yudkin, J. S. (1997) Endothe- lial dysfunction: Cause of the insulin resistance syndrome. Diabetes 46, S9–S13. 40. Baron, A. D. (1994) Hemodynamic actions of insulin. Am J Physiol – Endocrinol Metab 267, E187–E202. 41. Utriainen, T., Nuutila, P., Takala, T., Vicini, P., Ruotsalainen, Ronnemaa, T., Tolva- nen, T., Raitakari, M., Haaparanta, M., Kirvela, O., Cobelli, C. and Yki-Jarvinen, H. (1997) Intact insulin stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitus. J Clin Invest 100, 777–785. 42. Natali, A., Bonadonna, R., Santoro, D., Galvan, A. Q., Baldi, S., Frascerra, S., Palombo, C., Ghione, S. and Ferrannini, E. (1994) Insulin resistance and vasodilation in essential hypertension. Studies with adenosine. J Clin Invest 94, 1570–1576. REFERENCES 481 43. Nuutila, P., Raitakari, M., Laine, H., Kirvela, O., Takala, T., Utriainen, T., Makimat- tila, S., Pitkanen, O P., Ruotsalainen, U., Iida, H., Knuuti, J. and Yki-Jarvinen, H. (1996) Role of blood flow in regulating insulin-stimulated glucose uptake in humans: Stud- ies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography. J Clin Invest 97, 1741–1747. 44. Shankar, R. R., Wu, Y., Shen, H Q., Zhu, J S. and Baron, A. D. (2000) Mice with disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance. Diabetes 49, 684–687. 45. Hayashi, T., Wojtaszewski, J. F. P. and Goodyear, L. J. (1997) Exercise regulation of glucose transport in skeletal muscle. Am J Physiol – Endocrinol Metab 273, E1039–E1051. 46. Young, M. E., Radda, G. K. and Leighton, B. (1997) Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro. Biochem J 322, 223–228. 47. Collison, M., Glazier, A. M., Graham, D., Morton, J. J., Dominiczak, M. H., Ait- man, T. J., Connell, J. M., Gould, G. W. and Dominiczak, A. F. (2000) Cd36 and molec- ular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat. Diabetes 49, 2222–2226. 48. Williams, S. B., Cusco, J. A., Roddy, M A., Johnstone, M. T. and Creager, M. A. (1996) Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 27, 567–574. 49. Steinberg, H. O., Chaker, H., Leaming, R., Johnson, A., Brechtel, and Baron, A. D. (1996) Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 97, 2601–2610. 50. Hogikyan, R. V., Galecki, A. T., Pitt, B., Halter, J. B., Greene, D. A. and Supiano, M. A. (1998) Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity. J Clin Endocrinol Metab 83, 1946–1952. 51. Nitenberg, A., Paycha, F., Ledoux, S., Sachs, R., Attali, J R. and Valensi, P. (1998) Coronary artery responses to physiological stimuli are improved by deferoxamine but not by L-arginine in non-insulin-dependent diabetic patients with angiographically normal coronary arteries and no other risk factors. Circulation 97, 736–743. 52. Makimattila, B., Liu, M L., Vakkilainen, J., Schlenzka, A., Lahdenpera, S., Syvanne, M., Mantysaari, M., Summanen, P., Bergholm, R., Taskinen, M R. and Yki, Jarvinen, H. (1999) Impaired endothelium-dependent vasodilation in type 2 diabetes: Relation to LDL size, oxidized LDL, and antioxidants. Diabetes Care 22, 973–981. 53. Tooke, J. E. and Goh, K. L. (1999) Vascular function in Type 2 diabetes mellitus and pre-diabetes: The case for intrinsic endotheliopathy. Diabet Med 16, 710–715. 54. Caballero, A. E., Arora, S., Saouaf, R., Lim, S. C., Smakowski, P., Park, J. Y., King, G. L. L., Horton, E. S. and Veves, A. (1999) Microvascular and macrovas- cular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 48, 1856– 1862. 55. Valverde, A. M., Teruel, T., Navarro, P., Benito, M. and Lorenzo, M. (1998) Tumor necrosis factor-alpha causes insulin receptor substrate-2-mediated insulin resistance and inhibits insulin-induced adipogenesis in fetal brown adipocytes. Endocrinology 139, 1229–1238. 56. Feinstein, R., Kanety, H., Papa, M. Z., Lunenfeld, B. and Karasik, A. (1993) Tumor necrosis factor-alpha supresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. JBiolChem268, 26 055–26 058. 57. Halse, R., Pearson, S. L., McCormack, J. G., Yeaman, S. J. and Taylor, R. (2001) Effects of tumor necrosis factor-α on insulin action in cultured human muscle cells. Diabetes 50, 1102–1109. 482 INSULIN RESISTANCE, HYPERTENSION AND ENDOTHELIAL DYSFUNCTION 58. Wang, P., Ba, Z. E. and Chaudry, I. H. (1994) Administration of tumour necrosis factor-alpha in vivo depresses endothelium-dependent relaxation. Am J Physiol 266, H2535–H2541. 59. Ruan, H., Hacohen, N., Golub, T. R., Van Parijs, L. and Lodish, H. F. (2002) Tumor necrosis factor-α suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-κB activation by TNF-α is obligatory. Diabetes 51, 1319–1336. 60. Dandona, P., Aljada, A., Mohanty, P., Ghanim, H., Hamouda, W., Assian, E. and Ahmad, S. (2001) Insulin inhibits intranuclear nuclear factor κB and stimulates IκBin mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 86, 3257–3265. 61. Peraldi, P., Xu, M. and Spiegelman, B. M. (1997) Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J Clin Invest 100, 1863–1869. 62. Hundal, R. S., Petersen, K. F., Mayerson, A. B., Randhawa, P. S., Inzucchi, S., Shoel- son, S. E. and Shulman, G. I. (2002) Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest 109, 1321–1326. 63. Yuan, M., Konstantopoulos, N., Lee, J., Hansen, L., Li, Z. W., Karin, M. and Shoelson, S. E. (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293, 1673–1677. 64. Ventre, J., Doebber, T., Wu, M., MacNaul, K., Stevens, K., Pasparakis, M., Kollias, G. and Moller, D. E. (1997) Targeted disruption of the tumor necrosis factor-alpha gene: metabolic consequences in obese and nonobese mice. Diabetes 46, 1526–1531. 65. Ofei, F., Hurel, S., Newkirk, J., Sopwith, M. and Taylor, R. (1996) Effects of an engineered human anti-TNF-a antibody (CPD571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45, 881–885. 66. Stears, A. J. and Byrne, C. D. (2001) Adipocyte metabolism and the metabolic syndrome. Diabetes Obes Metab 3, 129–142. 67. Saltiel, A. R. and Kahn, R. C. (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806. 68. Shulman, G. I. (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106, 171–176. 69. Bermudez, E. A., Rifai, N., Buring, J., Manson, J. E. and Ridker, P. M. (2002) Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women. Arterioscleros Thrombos Vasc Biol 22, 1668–1673. 70. Han, T. S., Sattar, N., Williams, K., Gonzalez-Villalpando, C., Lean, M. E. J. and Haffner, S. M. (2002) Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care 25, 2016–2021. 71. Festa, A., D’Agostino, R., Tracy, R. P. and Haffner, S. M. (2002) Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. Diabetes 51, 1131–1137. 72. Bastard, J P., Maachi, J., Van Nhieu, J. T., Jardel, C., Brucker, E., Grimaldi, A., Robert, J J., Capeau, J. and Hainque, B. (2002) Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab 87, 2084–2089. 73. Mantzoros, C. S. (1999) The role of leptin in human obesity and disease: a review of current evidence. AnnInternMed130, 671–680. 74. Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S. and Goldstein, J. L. (1999) Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401, 73–76. REFERENCES 483 75. Steppan, C. M., Brown, E. J., Wright, C. M., Bhat, S., Banerjee, R. R., Dai, C. Y., Enders, G. H., Silberg, D. G., Wen, X., Wu, G. D. and Lazar, M. A. (2001) A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci USA 98, 502–506. 76. Nagaev, I. and Smith, U. (2001) Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun 285, 561–564. 77. Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., Ezaki, O., Akanuma, Y., Gavrilova, O., Vinson, C., Reitman, M. L., Kagechika, H., Shudo, K., Yoda, M., Nakano, Y., Tobe, K., Nagai, R., Kimura, S., Tomita, M., Froguel, P. and Kadowaki, T. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Med 7, 941–946. 78. Lindsay, R. S., Funahashi, T., Hanson, R. L., Matsuzawa, Y., Tanaka, S., Tataranni, P. A., Knowler, W. C. and Krakoff, J. (2002) Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 360, 57–8. 79. Adamczak, M., Wiecek, A., Funahashi, T., Chudek, J., Kokot, F. and Matsuzawa, Y. (2003) Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 16, 72–75. 80. Kumada, M., Kihara, S., Sumitsuji, S., Kawamoto, T., Matsumoto, S., Ouchi, N., Arita, Y., Okamoto, Y., Shimomura, I., Hiraoka, H., Nakamura, T., Funahashi, T. and Matsuzawa, Y. (2003) Osaka CAD Study Group. Coronary artery disease. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscleros Thrombos Vas cr Bio l 23, 85–9. 81. Steinberg, H. O., Tarshoby, M., Monestel, R., Hook, G., Cronin, J., Johnson, A., Bayazeed, B. and Baron, A. D. (1997) Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 100, 1230–1239. 82. deKreutzenberg, S. V., Crepaldi, C., Marchetto, S., Calo, L. and Tiengo, A. (2000) Plasma free fatty acids and endothelium-dependent vasodilation: Effect of chain-length and cyclooxygenase inhibition. J Clin Endocrinol Metab 85, 793–798. 83. Davda, R. K., Stepniakowski, K. T., Lu, G., Ullian, M. E., Goodfriend, T. L. and Egan, B. M. (1995) Oleic acid inhibits endothelial nitric oxide synthase by a protein kinase C-independent mechanism. Hypertension 26, 764–770. 84. Moller, D. E. (2001) New drug targets for type 2 diabetes and the metabolic syndrome. Nature 414, 821–827. 16 Insulin Resistance and Polycystic Ovary Syndrome Neus Potau 16.1 Introduction Polycystic ovary syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. In a broad sense PCOS may be considered to be synonymous with chronic unexplained hyperandrogenaemia, which accounts for approximately 95 per cent of hyperandrogenism in women. 1 The most frequent forms of hyperandrogenism are premature pubarche (de- fined as the appearance of pubic hair before 8 years) in the pre-pubertal period and PCOS in the post-pubertal period, which affects approximately 5–10 per cent of women of reproductive age. 2 Insulin resistance and compensatory hyperinsulinaemia are prominent fea- tures of many women with PCOS. The aetiology of this condition is unknown, but recent evidence suggests that the principal underlying disorder is insulin resistance and that the resulting hyperinsulinaemia stimulates excess ovarian androgens. 3 Associated with insulin resistance, these women exhibit hyperlip- idaemia and have a high risk of type 2 diabetes and cardiovascular disease in later life. 4, 5 The new concept arising from the link with insulin resistance intro- duces a concept that not only has major implications for the health of affected women but also offers a potential for new treatments. Nowadays, the current treatment mainly with antiandrogens has been associ- ated with insulin sensitizers such as metformin or thiazolidinediones. The results obtained with these drugs seem to confirm their efficacy in reversing metabolic and ovarian abnormalities in these women and adolescent girls. Insulin Resistance. Edited by Sudhesh Kumar and Stephen O’Rahilly  2005 John Wiley & Sons, Ltd ISBN: 0-470-85008-6 486 INSULIN RESISTANCE AND POLYCYSTIC OVARY SYNDROME 16.2 Definition of polycystic ovary syndrome (PCOS) and diagnostic criteria PCOS is probably the most common endocrine disorder in women. Although not universally accepted, the 1990 point Conference of the National Institute of Health/National Institute of Child Health and Human Development established the diagnostic criteria on PCOS. PCOS is defined as a metabolic condition characterized by hyperandrogenism (hirsutism, acne, androgenic alopecia) and chronic anovulation (irregular menses with menses every 6 weeks to 6 months or amenorrhea) with the exclusion of spe- cific disorders, such as non-classical adrenal hyperplasia due to 21-hydroxylase deficiency, hyperprolactinaemia, androgen-secreting tumours and thyroid dis- eases. Thus, the most widely accepted definition of PCOS is the association of clinical and/or biochemical evidence of androgen excess with chronic anovulation (having excluded specific underlying disorders of the pituitary or adrenals). 6 This syndrome as a form of functional ovarian hyperandrogenism is a preva- lent disorder affecting approximately 5–10 per cent of reproductive women. 2 The prevalence of polycystic ovaries increases throughout puberty, reaching about 26 per cent by the age of 15. The prevalence of PCOS among teenage girls is not known but is clearly common. 7 Ethnic differences in the prevalence of PCOS have not been explored but not significant differences between white and black women in the USA have been observed. 2 Similar prevalence (6.8 and 6.5 per cent) was reported in two European countries. 8, 9 Insulin resistance, a common feature of PCOS, can be characterized as im- paired action of insulin in the uptake and metabolism of glucose. Impaired insulin action leads to elevated insulin levels, which causes a decrease in the synthesis of two important binding proteins: insulin-like growth factor binding protein (IGFBP1) and sex hormone binding globulin (SHBG). IGFBP1 binds IGF I and IGF II and SHBG binds to sex steroids, especially androgens. Obesity, which is seen in 50–65 per cent of PCOS patients, may increase the insulin resistance and hyperinsulinaemia. 3 Acanthosis nigricans, a dark and hyperpigmented hyperplasia of the skin typ- ically found at the nape of the neck and axila, is a marker of insulin resistance. Acanthosis nigricans is usually found in about 30 per cent of hyperandrogenic women. The triad of hyperandrogenism, insulin resistance and acanthosis nigri- cans (HAIR-AN) syndrome appears in a subgroup of patients with PCOS. 10 Chronically elevated luteinizing hormone (LH) and insulin resistance are two of the most common endocrine aberrations seen in PCOS. The genetic cause of high LH is not known. In vitro and in vivo evidence offers support that high LH and hyperinsulinemia work synergistically, causing ovarian growth, androgen production and ovarian cyst formation. 1 Figure 16.1 shows the multiple factors that can contribute to the development of PCOS. DEFINITION OF POLYCYSTIC OVARY SYNDROME (PCOS) 487 INSULIN OBESITY INSULIN RESISTANCE PITUITARY LH ACTH ADRENAL GLANS P 450c17 ANDROGENS DHEAS PCOS OVARY P 450c17 ANDROGENS TESTOSTERONE ANDROSTENEDIONE AND FOLLICLE ARREST ANOVULATION OTHER FACTORS Genes Puberty Premature pubarche Low birthweight IGFI Figure 16.1 Development of PCOS and the multiple factors that affect steroid dysregu- lation. Synergic role of insulin, LH and IGFI in androgen production. Other factors such as genes or functional abnormalities in prenatal, childhood or pubertal periods must be considered The diagnosis of polycystic ovary syndrome is usually made on the basis of a combination of clinical and biochemical criteria (Table 16.1). The degree of hirsutism can be assessed by the Ferriman–Gallwey score, a simple, semiquantitative method for recording the distribution and severity of excess body hair. 11 The classic anatomical pattern of polycystic ovaries can be identified by ultrasound assessment as increased number of subcapsular follicular cysts and increased intervening stroma. 12 These ultrasound features are consistent with, but not essential for, the diagnosis of the syndrome. 13 Serum levels of testosterone and androstenedione are usually increased. DHEAS dehydroepiandrosterone sul- fate levels are increased by up to 50 per cent in women with PCOS. Elevated free testosterone activity, defined by the free androgen index, represents the most sensitive biochemical marker supporting the diagnosis. Prolactin is usually 488 INSULIN RESISTANCE AND POLYCYSTIC OVARY SYNDROME Table 16.1 Clinical and biochemical evaluation of PCOS Menstrual disturbances Ferriman–Gallwey score Clinical Pelvic ultrasonography Obesity (BMI) Testosterone, androstenedione, DHEAS SHBG Biochemical FSH, LH, prolactin Fasting glucose and insulin OGTT Test GnRH agonist (nafarelin, leuprolide acetate) Dexamethasona suppression normal, although it has been reported that approximately 15 per cent of PCOS patients have mild elevations. 14 No single test is diagnostic of the syndrome, but choice should be guided by clinical presentation. Serum LH levels are typically elevated in PCOS but up to 50 per cent of the young women with other clinical and biochemical features of the syndrome may have normal serum LH levels. Measurement of LH is therefore of limited diagnostic value; it is quite specific that raised LH and normal FSH essentially occur only in PCOS, but this is not very sensitive. 1 To assess insulin resistance with compensatory hyperinsulinism, fasting blood glucose and insulin could be useful and simple to detect a primary abnormal- ity. With a standard oral glucose tolerance test, a hyperinsulinaemic response, impaired glucose tolerance or type 2 diabetes could be documented. The abnormal response of 17 α-hydroxyprogesterone after an agonist ana- logue of gonadotrophin-releasing hormone (GnRH) challenge has been described in women and adolescents. 15, 16 Short-term leuprolide acetate (500 µgsc)isa reliable tool for identification of the ovary source of hyperandrogenaemia. The response was considered supranormal if the peak plasma 17 α-hydroxyprogester- one 24 h postestimulation was greater than 4.75 nmol/l (160 ng/dl). 16 Hyperandrogenism in PCOS may therefore represent an intrinsic abnormality of ovarian theca-interstitial cell function. This conclusion is supported by clinical studies suggesting that the ovary is the primary abnormality site. The response observed in women with PCOS in the above mentioned test (GnRH agonist) could not be explained on the basis of LH hyper-responsiveness. Women with PCOS given an hCG challenge test produce more androstenedione and 17 α-hydroxyprogesterone than normal subjects and this difference remains evident after suppression of endogenous LH secretion by GnRH. 17, 18 As many hyperandrogenic anovulatory women have significantly increased ovarian steroidogenic responses to stimulation with GnRH analogues, Rosenfield and colleagues have coined the term ‘functional ovarian hyperandrogenism,’ as an alternative to PCOS. 19 HYPERANDROGENISM AND HYPERINSULINISM 489 16.3 Hyperandrogenism and hyperinsulinism The earliest description of ‘diabete des femmes a barbe’ pointed out the rela- tionship between androgen excess in women and disturbances in carbohydrate metabolism. 20 The coexistence of severe insulin resistance and acanthosis nigri- cans in three lean adolescent women confirmed the association between hyper- androgenism and hyperinsulinism. 21 Insulin resistance associated with PCOS was also reported some years later by Chang and colleagues in 1983. 22 This resistance, which is independent of obesity, causes hyperinsulinaemia 23 and more than 50 per cent of the obese women with PCOS are insulin resistant compared with age and weight-matched controls. 24 Hyperinsulinaemia is shown to be a characteristic finding in women with ovarian androgen excess, even in the absence of diabetes. Nowadays, it has become evident that insulin resistance is a cardinal feature of PCOS that could serve as the pathogenic link between hyperandrogenism and hyperinsulinism. Because insulin resistance is related to many manifestations of PCOS, there tends to be substantial overlap between the PCOS phenotype and the so-called ‘metabolic syndrome’ or ‘syndrome X’: obesity, glucose intolerance, hyperten- sion, macrovascular disease and dyslipidaemia, which are seen in both syn- dromes. Figure 16.2 shows the metabolic and endocrine disorders associated with PCOS and insulin resistance. It is generally accepted that women with PCOS are predisposed to type 2 diabetes and that the development of diabetes cannot be attributed solely to the obesity that typically accompanies PCOS. The prevalence of impaired glucose tolerance in PCOS is between 30 and 40 per cent and that of type 2 diabetes is between 5 and 10 per cent. 4, 5 These prevalences approximate those in Pima indians, who have one of the highest rates of diabetes in the world. In addition, suggesting some genetic risk factor in this process, most women and adolescents with PCOS have a family history of type 2 diabetes. 25, 26 Elevated serum androgens may at times cause mild insulin resistance but it is unlikely that the insulin resistance of PCOS occurs as a result of hyperandrogen- ism. 27 Insulin resistance persists in women with PCOS in whom both ovaries have been removed surgically or in women whose ovarian androgen produc- tion has been suppressed with the use of long-acting gonadotrophin-releasing hormone (GnRH) agonist. 1 Pre-pubertal women with acanthosis nigricans are hyperinsulinaemic, yet ele- vated serum androgen levels do not appear until several years following the diagnosis of insulin resistance. In the same way, some women with point muta- tions in the insulin receptor gene causing hyperinsulinaemic insulin resistance have been shown to have PCOS. Collectively, the genetic syndromes of severe insulin resistance secondary to mutations in the insulin receptor gene (leprechau- nism, Rabson–Mendenhall syndrome and type A insulin resistance syndrome) have a common phenotype characterized by hyperandrogenism, insulin resis- tance with hyperinsulinism and acanthosis nigricans. These observations support [...]... fasting glucose and insulin include the homeostasis model assessment (HOMA),40 fasting insulin resistance index (FIRI),41 fasting glucose insulin ratio,24 and quantitative insulin sensitivity check index (QUICKI)42 and others Determining the fasting glucose insulin ratio could be a good screening test in that it is simple, quick and relatively inexpensive to obtain a single blood sample, and it has been... none of the insulin- sensitizing drugs have Food and Drug Administration (FDA) approval for use in PCOS, hirsutism or hyperandrogenism with insulin resistance Considering that women with PCOS may have insulin resistance secondary to a deficiency of D-chiro-inositol-containing phosphoglycans that mediate insulin action, the administration of this substance could improve insulin sensitivity According to this... Effects of serine kinase inhibitors and IR activators J Clin Endocrinol Metab 87, 4088–4 093 32 Nobels, F and Dewailley, D ( 199 2) Puberty and polycystic ovary syndrome: The insulin/ insulin-like growth factor hypothesis Fertil Steril 58, 655–663 33 Potau, N., Ib´ nez, L., Riqu´ , S and Carrascosa, A ( 199 7) Pubertal changes in insulin a˜ e secretion and peripheral insulin sensitivity Horm Res 48, 2 19 226 34... and Pugeat, M e ( 199 5) Effect of diet and metformin administration on sex hormone-binding globulin, androgens, and insulin in hirsute and obese women J Clin Endocrinol Metab 80, 2057–2062 92 Nestler, J E and Jakubowicz, D J ( 199 6) Decreases in ovarian cytochrome P450c17 activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome N Engl J Med 335, 617–623 93 ... a decrease in insulin sensitivity. 79, 33 The insulin resistance during puberty is restricted to peripheral glucose metabolism and is associated with concomitant increases in growth hormone and insulinlike growth factor (IGFI) secretion and a decrease in IGFBP1 and SHBG concentrations.80 The hyperinsulinaemia and increased IGFI activity during puberty have been proposed as inducing factors in the development... Bergman, R N., Prager, R., Volund, A and Olefsky, J M ( 198 7) Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp J Clin Invest 79, 790 –800 37 Tritos, N A and Mantzoros, C S ( 199 8) Syndromes of severe insulin resistance J Clin Endocrinol Metab 83, 3025–3030 38 Cederholm, J and Wibell, L ( 199 0) Insulin release and peripheral sensitivity at... test must be interpreted in the context of plasma glucose levels, because the presence of any degree of hyperglycaemia 492 INSULIN RESISTANCE AND POLYCYSTIC OVARY SYNDROME suggests the existence of defects in insulin secretion, which invalidates the degree of insulinaemia as an index of insulin resistance Fasting insulin levels above 50–70 µU/ml or insulin peak in post-oral-glucose challenge above... & Sons, Ltd ISBN: 0-4 7 0-8 500 8-6 512 SYNDROMES OF SEVERE INSULIN RESISTANCE (SSIRs) plasma insulin While no formal criteria for severe insulin resistance are widely accepted, a fasting insulin level >150 pmol/l and/ or a post-glucose-load insulin level of >1500 pmol/l indicate a marked degree of insulin resistance However it should be noted that such levels are not infrequently seen in patients with morbid... and acquired syndromes of severe insulin resistance Finally, we will consider therapeutic options in these conditions 17.2 General biochemical and clinical features of severe insulin resistance Compensatory hyperinsulinaemia and disturbed glucose metabolism Primary defects in insulin s ability to exert its normal actions in muscle, liver and fat are associated with a compensatory increase in insulin. .. state in which a given concentration of insulin elicits a subnormal biological response While insulin has several metabolic and mitogenic actions, insulin resistance is usually defined in terms of an impairment in insulin s ability to lower plasma glucose, an action it performs through stimulating glucose uptake into muscle and fat and suppressing the hepatic production of glucose Although insulin resistance . and Lorenzo, M. ( 199 8) Tumor necrosis factor-alpha causes insulin receptor substrate-2-mediated insulin resistance and inhibits insulin- induced adipogenesis in fetal brown adipocytes. Endocrinology. J. R., Cleland, S. J., Elliott, H. L. and Connell, J. M. C. ( 199 8) Insulin vasodilatation and the ‘arginine paradox’. Lancet 351, 95 9 96 0. 31. Zeng, G. and Quon, M. J. ( 199 6) Insulin- stimulated. (HOMA), 40 fasting insulin resistance index (FIRI), 41 fasting glucose insulin ratio, 24 and quantitative insulin sensitivity check index (QUICKI) 42 and others. Determining the fasting glucose insulin ratio