Clinical Review

Sizing up insulin resistance—one treatment doesn’t fit all

OBG Manag. 2005 April;17(4):70-80

There is no single best intervention for all women. It depends on the severity of glucose intolerance and metabolic abnormality in each patient.

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References

1. Lord JM, Flight IH, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ. 2003;327:951-953.

2. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

3. Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998;19:491-503.

4. Modan M, Harris MI, Halkin H. Evaluation of WHO and NDDG criteria for impaired glucose tolerance. Results from two national samples. Diabetes. 1989;38:1630-1635.

5. Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

6. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.

7. American College of Obstetricians and Gynecologists. Practice Bulletin #41: Polycystic Ovary Syndrome. Washington, DC: ACOG; December 2002. Obstet Gynecol. 2002;100:1389-1402.

8. Bloomgarden ZT. American Association of Clinical Endocrinologists (AACE) Consensus Conference on the Insulin Resistance Syndrome: 25-26 August 2002, Washington, DC. Diabetes Care. 2003;26:933-939.

9. Lindstrom J, Louheranta A, Mannelin M, et al. The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care. 2003;26:3230-6.

10. Laaksonen DE, Niskanen L, Lakka HM, Lakka TA, Uusitupa M. Epidemiology and treatment of the metabolic syndrome. Ann Med. 2004;36:332-346.

11. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The Decode Study Group. European Diabetes Epidemiology Group. Diabetes epidemiology: collaborative analysis of diagnostic criteria in Europe. Lancet. 1999;354:617-621.

12. Legro RS, Kunselman AR, Dodson WC, Dunaif A. 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. 1999;84:165-169.

13. 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;22:141-146.

14. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab. 2004;90:66-71.

15. Talbott EO, Zborowski JV, Sutton-Tyrrell K, McHugh-Pemu KP, Guzick DS. Cardiovascular risk in women with polycystic ovary syndrome. Obstet Gynecol Clin North Am. 2001;28:111-133.

16. Chasen-Taber L, Willett WC, Stampfer MJ, et al. A prospective study of oral contraceptives and NIDDM among US women. Diabetes Care. 1997;20:330-335.

17. Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril. 2004;82:421-429.

18. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose–response trial. Am J Med. Dec. 1997;103:491-497.

19. Elter K, Imir G, Durmusoglu F. Clinical, endocrine and metabolic effects of metformin added to ethinyl estradiol-cyproterone acetate in non-obese women with polycystic ovarian syndrome: a randomized controlled study. Hum Reprod. 2002;17:1729-1737.

20. Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993;42:1663-1672.

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IN THIS ARTICLE

Is PCOS a way station on the road to diabetes?

Treatment algorithm based on 4 degrees of insulin resistance

How to code PCOS-related exams and tests

Fast Track

Intensive lifestyle modification reduces the risk of diabetes by 58%, versus 29% for drugs

Monitor treatment by measuring waist circumference, as well as BP, fasting lipids, and glucose tolerance

Because many payers do not reimburse for routine screening, indicate that these tests are to screen for a suspected condition

2,000 mg metformin daily in 2 divided doses may improve glycemic values more effectively than 850 mg twice a day

Insulin resistance. Some clinicians take it for granted, assuming every woman with polycystic ovary syndrome (PCOS) has it and treating her the same as every other patient with the syndrome.

Admittedly, some evidence supports this approach. For example, a recent meta-analysis¹ demonstrated that metformin improves ovulation and, in conjunction with clomiphene citrate, boosts pregnancy rates. That may be rationale enough to use the drug routinely for ovulatory-related infertility in women with PCOS.

But for the rest of our PCOS patients, measuring the degree of insulin resistance—by assessing the patient for metabolic syndrome and glucose intolerance—can yield a reasonably accurate view of long-term risk, as well as the optimal intervention for a given patient.

More good news: Effective treatment does exist, including lifestyle modification and pharmacologic therapy. And lest we assume drugs are the strongest medicine, consider this: Intensive lifestyle intervention reduces the risk of diabetes by as much as 58%—about twice the efficacy of medication.²

While many small reports implicate insulin resistance or hyperinsulinemia in a variety of reproductive disorders and even endometrial cancer, the quality and quantity of that evidence pale in comparison with data showing it can cause type 2 diabetes.³ Anything we can do to slow the progression is bound to benefit the patient and, in the long run, help prevent cardiovascular disease as well.

How to identify insulin resistance

The best way is to assess the patient for metabolic syndrome (TABLE) and then measure the 2-hour glucose level after a 75-g oral glucose load. The World Health Organization criterion for impaired glucose tolerance (IGT) after this test is a plasma glucose level of 140–199 mg/dL.⁴

TABLE

Is it metabolic syndrome or not?

3 or more risk factors make the diagnosis
RISK FACTOR	CUTOFF
Abdominal obesity (waist circumference)	>88 cm (>35 in)
Triglycerides	150 mg/dL
HDL cholesterol
Blood pressure	130/85 mm Hg
Fasting and/or 2-hour glucose from a 75-g oral glucose tolerance test	110–126 mg/dL* and/or 2-hour glucose level of 140–199 mg/dL^†
HDL = high-density lipoprotein
*As recommended by the Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
†As recommended by ACOG and AACE

Limitations of other tests

The problem with traditional research tests such as euglycemic clamp studies and intravenous glucose/insulin tolerance tests is that they are invasive, labor intensive, time-consuming, and require a skilled team to perform—all of which translate into a poor clinical test. And among the limitations of the homeostatic models devised to replace them—which use fasting glucose and insulin levels as surrogate measures of these dynamic tests—is poor sensitivity in patients with IGT.

These models also have shifting cutoff levels in different studies in different populations.

Clinical parameters are more practical

Rather than rely on these traditional and homeostatic tests, some experts focus on validated clinical parameters. For example, the Third Report of the National Cholesterol Education Program Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP-III) defined metabolic syndrome using biometric and biochemical measures of centripetal obesity, hypertension, fasting hyperglycemia, and dyslipidemia (TABLE).⁵

Metabolic syndrome is closely related to insulin resistance syndrome, or syndrome X, which is characterized by dyslipidemia (depressed high-density lipoprotein [HDL] cholesterol and elevated triglycerides), hypertension, and glucose intolerance.⁶

Other groups such as ACOG⁷ and the American Association of Clinical Endocrinologists⁸ recommend adding a modified glucose tolerance test to the fasting blood tests used to identify metabolic syndrome.

Although a 2-hour glucose level after dynamic challenge does not test insulin sensitivity, it is more likely to identify a pathological relationship between insulin sensitivity and compensatory insulin secretion—one that is less detectable using fasting measures of glucose and insulin. One reason: In most women with IGT, fasting glucose levels are in the normal range. Thus, the fasting test alone would provide little discriminatory information.

Why glucose intolerance is important

Impaired glucose tolerance is a strong risk factor for diabetes, and recent studies show it is possible to delay progression to diabetes in women with IGT using lifestyle and, when appropriate, pharmacotherapy.^2,9,10 IGT also identifies excess risk for mortality, especially in women.¹¹ This is important because in obese women with PCOS, IGT approaches 40%.^12-14 And the incidence of type 2 diabetes among women with PCOS is 11.9%, compared with only 1.4% in healthy controls.¹⁵