Letter to the Editor: “Development and Risk Factors of Type 2 Diabetes in a Nationwide Population of Women With Polycystic Ovary Syndrome”

Letter to the Editor: “Development and Risk Factors of Type 2 Diabetes in a Nationwide... The article by Rubin et al. (1) is of great interest, because it clearly demonstrates the high risk of diabetes mellitus (DM) development in women with polycystic ovary syndrome (PCOS) compared with their healthy peers. Specifically, it was shown that DM occurrence is higher in women with PCOS, and, among other factors, increased body mass index (BMI) and insulin resistance (IR), but not age, are positively associated with this phenomenon. Additionally, the subjects who developed DM were significantly more obese than those who remained euglycemic. However, the percentage of lean women with PCOS who developed DM during the follow-up period is not provided, which is crucial information. Because the coexistence of B-cell dysfunction and IR is a prerequisite for DM occurrence, it is obvious that ameliorating IR will decrease the risk. Indeed, we have recently demonstrated in a cross-sectional study of 1345 women with PCOS that IR increases with aging only in obese and not in lean and overweight women with PCOS (2). Furthermore, in their long-term prospective study Gambineri et al. (3) reported that in lean women with PCOS the risk for DM development is comparable to that among their normal peers. Meanwhile, a critical analysis of the available studies shows that DM development risk is higher in obese women with PCOS than in their lean counterparts (Table 1) (4–12). Table 1. Evolution to Diabetes and Impaired Glucose Tolerance in PCOS, Available Literature Data Author, Year  n  BMI, kg/m2  Follow-Up, y  Evolution to Impaired Glucose Tolerance  Evolution to DM  Insulin Levels  Ehrmann, 1999  25  41  2.4  40%  N/A  N/A  Pasquali, 1999  21  32  10    N/A  Deterioration  Norman, 2001  67  35 to 41  6  9.3%  7.4%  N/A  27 to 28  0  0  N/A  Elting, 2001  34  24  15  N/A  2%  Stable  Legro, 2005  35  35  3  16%  N/A  Stable  Brown, 2011  172  26  2.6  0%  0%  Stable  82  26  5.5  0%  0%  Stable  Hudecova, 2011  84  ?  14  9.5%  8.3%  Ν/Α  Schmidt, 2011  35  27.1  21  0%  0%  Stable  Carmina, 2013  118  27  20  N/A  N/A  Stable  Rubin, 2017  1162  32.3  11.1  N/A  9/1000 person-years, OR 4  N/A  Rubin, 2017  18,477  N/A  11.1  N/A  8/1000 person-years, OR 4  N/A  Gambineri, 2012  249    16.9  Total group  39%  N/A  <25  Incidence rate × 100 person-years  0.25  N/A  25 to 30  0.63  N/A  >30  2.02  N/A  Author, Year  n  BMI, kg/m2  Follow-Up, y  Evolution to Impaired Glucose Tolerance  Evolution to DM  Insulin Levels  Ehrmann, 1999  25  41  2.4  40%  N/A  N/A  Pasquali, 1999  21  32  10    N/A  Deterioration  Norman, 2001  67  35 to 41  6  9.3%  7.4%  N/A  27 to 28  0  0  N/A  Elting, 2001  34  24  15  N/A  2%  Stable  Legro, 2005  35  35  3  16%  N/A  Stable  Brown, 2011  172  26  2.6  0%  0%  Stable  82  26  5.5  0%  0%  Stable  Hudecova, 2011  84  ?  14  9.5%  8.3%  Ν/Α  Schmidt, 2011  35  27.1  21  0%  0%  Stable  Carmina, 2013  118  27  20  N/A  N/A  Stable  Rubin, 2017  1162  32.3  11.1  N/A  9/1000 person-years, OR 4  N/A  Rubin, 2017  18,477  N/A  11.1  N/A  8/1000 person-years, OR 4  N/A  Gambineri, 2012  249    16.9  Total group  39%  N/A  <25  Incidence rate × 100 person-years  0.25  N/A  25 to 30  0.63  N/A  >30  2.02  N/A  Abbreviations: N/A, not applicable; OR, odds ratio. View Large It should be borne in mind that although lean women with PCOS have intrinsic IR, a cardinal characteristic of the syndrome, the degree of IR is comparable to that of their obese control peers (13). Hence, obesity per se could well be the critical risk factor for IR development, and it may be hypothesized that DM occurrence in women with PCOS is in fact an epiphenomenon due to an increased BMI, because obesity and PCOS usually coincide (14). Given that BMI and androgen excess are positively associated with IR and androgens decline through time, it appears that if women with PCOS do not become obese, they are likely to have a better metabolic profile during their reproductive years. Accordingly, we should not label all women with PCOS as being at high risk for DM, but only those who remain obese through the years. Last but not least, one of the major tasks of the caring physician should be to persistently encourage a healthy lifestyle and weight reduction to minimize DM risk and gain better metabolic control. Acknowledgments Disclosure Summary: The author has nothing to disclose. Abbreviations: BMI body mass index DM diabetes mellitus IR insulin resistance PCOS polycystic ovary syndrome. References 1. Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and risk factors of type 2 diabetes in a nationwide population of women with polycystic ovary syndrome. J Clin Endocrinol Metab . 2017; 102( 10): 3848– 3857. Google Scholar CrossRef Search ADS PubMed  2. Livadas S, Kollias A, Panidis D, Diamanti-Kandarakis E. Diverse impacts of aging on insulin resistance in lean and obese women with polycystic ovary syndrome: evidence from 1345 women with the syndrome. Eur J Endocrinol . 2014; 171( 3): 301– 309. Google Scholar CrossRef Search ADS PubMed  3. Gambineri A, Patton L, Altieri P, Pagotto U, Pizzi C, Manzoli L, Pasquali R. Polycystic ovary syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study. Diabetes . 2012; 61( 9): 2369– 2374. Google Scholar CrossRef Search ADS PubMed  4. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care . 1999; 22( 1): 141– 146. Google Scholar CrossRef Search ADS PubMed  5. Pasquali R, Gambineri A, Anconetani B, Vicennati V, Colitta D, Caramelli E, Casimirri F, Morselli-Labate AM. The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clin Endocrinol (Oxf) . 1999; 50( 4): 517– 527. Google Scholar CrossRef Search ADS PubMed  6. Norman RJ, Masters L, Milner CR, Wang JX, Davies MJ. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum Reprod . 2001; 16( 9): 1995– 1998. Google Scholar CrossRef Search ADS PubMed  7. Elting MW, Korsen TJ, Bezemer PD, Schoemaker J. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod . 2001; 16( 3): 555– 560. Google Scholar CrossRef Search ADS   8. Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab . 2005; 90( 6): 3236– 3242. Google Scholar CrossRef Search ADS PubMed  9. Brown ZA, Louwers YV, Fong SL, Valkenburg O, Birnie E, de Jong FH, Fauser BC, Laven JS. The phenotype of polycystic ovary syndrome ameliorates with aging. Fertil Steril . 2011; 96( 5): 1259– 1265. Google Scholar CrossRef Search ADS PubMed  10. Hudecova M, Holte J, Olovsson M, Larsson A, Berne C, Poromaa IS. Diabetes and impaired glucose tolerance in patients with polycystic ovary syndrome—a long term follow-up. Hum Reprod . 2011; 26( 6): 1462– 1468. Google Scholar CrossRef Search ADS PubMed  11. Schmidt J, Landin-Wilhelmsen K, Brännström M, Dahlgren E. Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab . 2011; 96( 12): 3794– 3803. Google Scholar CrossRef Search ADS PubMed  12. Carmina E, Campagna AM, Lobo RA. Emergence of ovulatory cycles with aging in women with polycystic ovary syndrome (PCOS) alters the trajectory of cardiovascular and metabolic risk factors. Hum Reprod . 2013; 28( 8): 2245– 2252. Google Scholar CrossRef Search ADS PubMed  13. Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, Teede HJ. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp. Hum Reprod . 2013; 28( 3): 777– 784. Google Scholar CrossRef Search ADS PubMed  14. Alvarez-Blasco F, Botella-Carretero JI, San Millán JL, Escobar-Morreale HF. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med . 2006; 166( 19): 2081– 2086. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Letter to the Editor: “Development and Risk Factors of Type 2 Diabetes in a Nationwide Population of Women With Polycystic Ovary Syndrome”

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Oxford University Press
Copyright
Copyright © 2018 Endocrine Society
ISSN
0021-972X
eISSN
1945-7197
D.O.I.
10.1210/jc.2017-02051
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Abstract

The article by Rubin et al. (1) is of great interest, because it clearly demonstrates the high risk of diabetes mellitus (DM) development in women with polycystic ovary syndrome (PCOS) compared with their healthy peers. Specifically, it was shown that DM occurrence is higher in women with PCOS, and, among other factors, increased body mass index (BMI) and insulin resistance (IR), but not age, are positively associated with this phenomenon. Additionally, the subjects who developed DM were significantly more obese than those who remained euglycemic. However, the percentage of lean women with PCOS who developed DM during the follow-up period is not provided, which is crucial information. Because the coexistence of B-cell dysfunction and IR is a prerequisite for DM occurrence, it is obvious that ameliorating IR will decrease the risk. Indeed, we have recently demonstrated in a cross-sectional study of 1345 women with PCOS that IR increases with aging only in obese and not in lean and overweight women with PCOS (2). Furthermore, in their long-term prospective study Gambineri et al. (3) reported that in lean women with PCOS the risk for DM development is comparable to that among their normal peers. Meanwhile, a critical analysis of the available studies shows that DM development risk is higher in obese women with PCOS than in their lean counterparts (Table 1) (4–12). Table 1. Evolution to Diabetes and Impaired Glucose Tolerance in PCOS, Available Literature Data Author, Year  n  BMI, kg/m2  Follow-Up, y  Evolution to Impaired Glucose Tolerance  Evolution to DM  Insulin Levels  Ehrmann, 1999  25  41  2.4  40%  N/A  N/A  Pasquali, 1999  21  32  10    N/A  Deterioration  Norman, 2001  67  35 to 41  6  9.3%  7.4%  N/A  27 to 28  0  0  N/A  Elting, 2001  34  24  15  N/A  2%  Stable  Legro, 2005  35  35  3  16%  N/A  Stable  Brown, 2011  172  26  2.6  0%  0%  Stable  82  26  5.5  0%  0%  Stable  Hudecova, 2011  84  ?  14  9.5%  8.3%  Ν/Α  Schmidt, 2011  35  27.1  21  0%  0%  Stable  Carmina, 2013  118  27  20  N/A  N/A  Stable  Rubin, 2017  1162  32.3  11.1  N/A  9/1000 person-years, OR 4  N/A  Rubin, 2017  18,477  N/A  11.1  N/A  8/1000 person-years, OR 4  N/A  Gambineri, 2012  249    16.9  Total group  39%  N/A  <25  Incidence rate × 100 person-years  0.25  N/A  25 to 30  0.63  N/A  >30  2.02  N/A  Author, Year  n  BMI, kg/m2  Follow-Up, y  Evolution to Impaired Glucose Tolerance  Evolution to DM  Insulin Levels  Ehrmann, 1999  25  41  2.4  40%  N/A  N/A  Pasquali, 1999  21  32  10    N/A  Deterioration  Norman, 2001  67  35 to 41  6  9.3%  7.4%  N/A  27 to 28  0  0  N/A  Elting, 2001  34  24  15  N/A  2%  Stable  Legro, 2005  35  35  3  16%  N/A  Stable  Brown, 2011  172  26  2.6  0%  0%  Stable  82  26  5.5  0%  0%  Stable  Hudecova, 2011  84  ?  14  9.5%  8.3%  Ν/Α  Schmidt, 2011  35  27.1  21  0%  0%  Stable  Carmina, 2013  118  27  20  N/A  N/A  Stable  Rubin, 2017  1162  32.3  11.1  N/A  9/1000 person-years, OR 4  N/A  Rubin, 2017  18,477  N/A  11.1  N/A  8/1000 person-years, OR 4  N/A  Gambineri, 2012  249    16.9  Total group  39%  N/A  <25  Incidence rate × 100 person-years  0.25  N/A  25 to 30  0.63  N/A  >30  2.02  N/A  Abbreviations: N/A, not applicable; OR, odds ratio. View Large It should be borne in mind that although lean women with PCOS have intrinsic IR, a cardinal characteristic of the syndrome, the degree of IR is comparable to that of their obese control peers (13). Hence, obesity per se could well be the critical risk factor for IR development, and it may be hypothesized that DM occurrence in women with PCOS is in fact an epiphenomenon due to an increased BMI, because obesity and PCOS usually coincide (14). Given that BMI and androgen excess are positively associated with IR and androgens decline through time, it appears that if women with PCOS do not become obese, they are likely to have a better metabolic profile during their reproductive years. Accordingly, we should not label all women with PCOS as being at high risk for DM, but only those who remain obese through the years. Last but not least, one of the major tasks of the caring physician should be to persistently encourage a healthy lifestyle and weight reduction to minimize DM risk and gain better metabolic control. Acknowledgments Disclosure Summary: The author has nothing to disclose. Abbreviations: BMI body mass index DM diabetes mellitus IR insulin resistance PCOS polycystic ovary syndrome. References 1. Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and risk factors of type 2 diabetes in a nationwide population of women with polycystic ovary syndrome. J Clin Endocrinol Metab . 2017; 102( 10): 3848– 3857. Google Scholar CrossRef Search ADS PubMed  2. Livadas S, Kollias A, Panidis D, Diamanti-Kandarakis E. Diverse impacts of aging on insulin resistance in lean and obese women with polycystic ovary syndrome: evidence from 1345 women with the syndrome. Eur J Endocrinol . 2014; 171( 3): 301– 309. Google Scholar CrossRef Search ADS PubMed  3. Gambineri A, Patton L, Altieri P, Pagotto U, Pizzi C, Manzoli L, Pasquali R. Polycystic ovary syndrome is a risk factor for type 2 diabetes: results from a long-term prospective study. Diabetes . 2012; 61( 9): 2369– 2374. Google Scholar CrossRef Search ADS PubMed  4. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care . 1999; 22( 1): 141– 146. Google Scholar CrossRef Search ADS PubMed  5. Pasquali R, Gambineri A, Anconetani B, Vicennati V, Colitta D, Caramelli E, Casimirri F, Morselli-Labate AM. The natural history of the metabolic syndrome in young women with the polycystic ovary syndrome and the effect of long-term oestrogen-progestagen treatment. Clin Endocrinol (Oxf) . 1999; 50( 4): 517– 527. Google Scholar CrossRef Search ADS PubMed  6. Norman RJ, Masters L, Milner CR, Wang JX, Davies MJ. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum Reprod . 2001; 16( 9): 1995– 1998. Google Scholar CrossRef Search ADS PubMed  7. Elting MW, Korsen TJ, Bezemer PD, Schoemaker J. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod . 2001; 16( 3): 555– 560. Google Scholar CrossRef Search ADS   8. Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab . 2005; 90( 6): 3236– 3242. Google Scholar CrossRef Search ADS PubMed  9. Brown ZA, Louwers YV, Fong SL, Valkenburg O, Birnie E, de Jong FH, Fauser BC, Laven JS. The phenotype of polycystic ovary syndrome ameliorates with aging. Fertil Steril . 2011; 96( 5): 1259– 1265. Google Scholar CrossRef Search ADS PubMed  10. Hudecova M, Holte J, Olovsson M, Larsson A, Berne C, Poromaa IS. Diabetes and impaired glucose tolerance in patients with polycystic ovary syndrome—a long term follow-up. Hum Reprod . 2011; 26( 6): 1462– 1468. Google Scholar CrossRef Search ADS PubMed  11. Schmidt J, Landin-Wilhelmsen K, Brännström M, Dahlgren E. Cardiovascular disease and risk factors in PCOS women of postmenopausal age: a 21-year controlled follow-up study. J Clin Endocrinol Metab . 2011; 96( 12): 3794– 3803. Google Scholar CrossRef Search ADS PubMed  12. Carmina E, Campagna AM, Lobo RA. Emergence of ovulatory cycles with aging in women with polycystic ovary syndrome (PCOS) alters the trajectory of cardiovascular and metabolic risk factors. Hum Reprod . 2013; 28( 8): 2245– 2252. Google Scholar CrossRef Search ADS PubMed  13. Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, Teede HJ. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp. Hum Reprod . 2013; 28( 3): 777– 784. Google Scholar CrossRef Search ADS PubMed  14. Alvarez-Blasco F, Botella-Carretero JI, San Millán JL, Escobar-Morreale HF. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med . 2006; 166( 19): 2081– 2086. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 Endocrine Society

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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Jan 1, 2018

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