Polycystic ovary syndrome: How are obesity and insulin resistance involved?

• direct infusion of IV glucose and/or insulin
• indirect assessment using surrogate markers (such as fasting glucose and insulin, or C-peptide, and oral glucose tolerance test [OGTT]).

Direct infusion of IV glucose or insulin reveals how insulin disposes of glucose from the blood stream; however, this method is expensive, time consuming, and potentially dangerous due to possible hypoglycemia. Indirect assessments are less complex to perform and correlate reasonably well with the results of the more invasive direct measures.

Direct infusion of glucose and insulin

The hyperinsulinemic euglycemic clamp is the gold standard, but drawbacks relegate it to medical research only. This method measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. Numerous blood samplings (every 5 to 10 minutes) are taken to monitor serum glucose so that a steady “fasting” level can be maintained. The degree of insulin resistance is measured by the amount of glucose that is taken up by tissues during the procedure.^11-14

The “clamp” technique is the most scientifically sound method for measuring insulin sensitivity, and it’s the standard against which all other tests are usually compared. Because the clamp technique is expensive, time consuming (about 2 hours), and labor intensive, however, it is not practical and is rarely performed in clinical care. It is primarily used in medical research.

Frequently sampled IV glucose tolerance tests: “minimal model.” The frequently sampled IV glucose tolerance test estimates insulin sensitivity through a computer-based mathematical analysis of the glucose-insulin dynamics. Though this test still requires 11 to 34 blood samples over a 3-hour period, it is less labor intensive than the clamp technique. However, in contrast to the clamp, it does not distinguish between peripheral and hepatic glucose utilization.¹⁵

Direct infusion of insulin

Insulin sensitivity test. This test involves IV infusion of a set glucose load and a fixed-rate infusion of insulin over approximately 3 hours. The mean plasma glucose concentration over the last 30 minutes of the test reflects insulin sensitivity. Although lengthy, the insulin sensitivity test is less labor intensive and requires fewer blood samples than the clamp technique.¹⁶

Insulin tolerance test. This test is a simplified version of the insulin sensitivity test, as it measures the decline in serum glucose after an IV bolus of insulin is administered. Several insulin and glucose levels are sampled over the following 15 minutes. In contrast to the clamp and the minimal model, the insulin tolerance test primarily measures insulin-stimulated uptake of glucose into skeletal muscle, and insulin sensitivity values reflect the rate of decline of log transformed glucose values.¹⁷

Direct infusion of glucose

Continuous infusion of glucose with model assessment. This method utilizes a constant IV glucose infusion; samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate insulin sensitivity. The results are correlated with clamp techniques; however, few laboratories have used this continuous-infusion method for insulin sensitivity testing in women with PCOS.¹⁸

Unfortunately, all of these methods require IV access and multiple venipunctures, making them relatively impractical for office assessment. To overcome these obstacles, alternative tests have been developed including fasting methods and the OGTT, the latter of which does not require IV access and does correlate reasonably well with dynamic clamp techniques.

Fasting methods

Fasting insulin. The measurement of fasting serum insulin is simple and inexpensive. Generally, a fasting level of 30 μU/mL indicates greater insulin resistance in a diabetic individual than in a normoglycemic patient. However, fasting insulin levels may be in the “normal” range in up to 40% of PCOS patients who have impaired glucose tolerance diagnosed by the OGTT. It has been suggested by some investigators that a fasting insulin greater than 20 μU/mL in white women and greater than 23 μU/mL in Mexican-American women probably indicates insulin resistance in women with PCOS. Some have also advocated averaging two or three readings to account for day-to-day variability.^19-21

Fasting plasma glucose. This is a simple blood test taken after 8 hours of fasting. Fasting plasma glucose (FPG) levels are considered normal up to 100 mg/dL (or 5.5 mmol/L). Levels between 100 and 125 mg/dL (5.5 to 7.0 mmol/L) are considered impaired fasting glucose or prediabetes. These levels are considered to be risk factors for DM and its complications. DM is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher. A “normal” result on the FPG test is not always reliable. Repeat testing with the OGTT is recommended if risk factors are suggestive for the presence of DM or a prediabetic condition.