Castracane VD, and RP Kauffman (Jan 1, 2003) Controlling PCOS, Part 1: Assessing insulin sensitivity. Contemporary OG/GYN

McAuley KA, Williams SM, Mann JI, Walker RJ, Lewis-Barned NJ, Temple LA, Duncan AW (2001) Diagnosing insulin resistance in the general population. Diabetes Care 24:460-464.

The concept of insulin resistance is relatively easy to understand, but determining precisely who is insulin resistant is more complicated. The relationship between glucose and insulin is quite complex and involves the interaction of many metabolic and regulatory factors. Normal insulin sensitivity varies widely and is influenced by age, ethnicity, and obesity. Simply put, not all people with impaired insulin sensitivity are necessarily suffering from a disorder, and pregnancy is a perfect example of this.

A World Health Organization consensus group recently concluded that the insulin sensitivity index (SI) of the lowest 25% of a general population can be considered insulin resistant. The European Group for the Study of Insulin Resistance took a more restricted view, defining insulin resistance as the SI of the lowest 10% of a non-obese, nondiabetic, normotensive Caucasian population. Richard Legro and his associates also used the SI of the lowest 10% of an obese, non-PCOS population to define insulin resistance. Ideally, we should be deriving the normal SI range from a population of women who are not obese, have regular menstrual cycles, are not suffering from hirsutism, and have normal circulating androgen levels.

**Choosing the best assessment technique**

The hyperinsulinemic-euglycemic clamp technique is the most scientifically sound technique for measuring insulin sensitivity, and it's against this standard that all other tests are usually compared. Because this and similar "clamp" techniques are expensive, time consuming, and labor intensive, they are not very practical in an office setting.

To overcome these obstacles, alternative tests have been developed, including the frequently sampled IV glucose tolerance test (FSIVGTT), insulin tolerance test (ITT), insulin sensitivity test (IST), and continuous infusion of glucose with model assessment (CIGMA). Unfortunately, all of these methods require IV access and multiple venipunctures, making them relatively impractical for office assessment. The oral glucose tolerance test (OGTT) does not require IV access but does involve several venipunctures and 2 to 4 hours of patient and technician time. Each of these tests has been shown to correlate reasonably well with dynamic clamp techniques.

**Clamp techniques and insulin infusion tests**

** Hyperinsulinemic-euglycemic clamp**. The gold standard for evaluating insulin sensitivity, this "clamp" technique requires a steady IV infusion of insulin to be administered in one arm. The serum glucose level is "clamped" at a normal fasting concentration by administering a variable IV glucose infusion in the other arm. Numerous blood samplings are then taken to monitor serum glucose so that a steady "fasting" level can be maintained. (In theory, the IV insulin infusion should completely suppress hepatic glucose production and not interfere with the test's ability to determine how sensitive target tissues are to the hormone.) The degree of insulin resistance should be inversely proportional to the glucose uptake by target tissues during the procedure. In other words, the less glucose that's taken up by tissues during the procedure, the more insulin resistant a patient is.

A variation of this technique, the hyperinsulinemic-hyperglycemic clamp provides a better measurement of pancreatic beta cell function but is less physiologic than the euglycemic technique.

** Insulin sensitivity test (IST)**. IST involves IV infusion of a defined glucose load and a fixed-rate infusion of insulin over approximately 3 hours. Somatostatin may be infused simultaneously to prevent insulin secretion, inhibit hepatic gluconeogenesis, and delay secretion of counter-regulatory hormones— particularly glucagon, growth hormone, cortisol, and catecholamines. Fewer blood samples are required for this test, compared to clamp techniques. The mean plasma glucose concentration over the last 30 minutes of the test reflects insulin sensitivity. Although lengthy, IST is less labor intensive than clamp techniques and the FSIVGTT.

* Insulin tolerance test (ITT)*. A simplified version of IST, ITT measures the decline in serum glucose after an IV bolus of regular insulin (0.1–0.5 U/kg) is administered. Several insulin and glucose levels are sampled over the following 15 minutes (depending on the protocol used). The ITT primarily measures insulin-stimulated uptake of glucose into skeletal muscle. Because this test is so brief, there's very little danger of counter-regulatory hormones interfering with its results.

IV access should be established for insulin injection, blood sampling, and for rapid administration of D50W should severe hypoglycemia occur. Normal values for women with PCOS have not been published to date, but normal ranges for insulin sensitivity in a general population have been published for persons with a body mass index below 30 kg/m2 and for obese subjects (BMI >30 kg/m2) at 0.026 to 0.085 mmol/L /minute and 0.012 to 0.017 mmol/L /minute respectively. These values reflect the rate of decline of log transformed glucose values.

**Taking the minimalist approach**

"Minimal" models require IV or oral administration of glucose only, unlike studies we discussed previously, which require IV insulin. Frequently sampled IV glucose tolerance tests (FSIVGTT). This method is less labor intensive than clamp techniques yet still requires as many as 25 blood samples over a 3-hour period, and a computer-assisted mathematical analysis. Several variations of the FSIVGTT have been published. One recently published study infused 0.3 g/kg of glucose over 1 minute, followed by tolbutamide 500 mg IV at 20 minutes into the glucose infusion. The SI was calculated by a computer-based program. Tolbutamide administration can also be used during FSIVGTT to augment endogenous insulin secretion and is particularly useful in women with diabetes.

** Continuous infusion of glucose with model assessment (CIGMA)**. Like ITT, CIGMA requires fewer venipunctures and is less laborious than clamp techniques. A constant IV glucose infusion is administered, and samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate SI. The results are reasonably compatible with clamp techniques; however, few laboratories have used CIGMA for insulin sensitivity testing in diabetic patients and there is no substantive data using the CIGMA technique in women with PCOS.

* Oral glucose tolerance test (OGTT)*. OGTT, a mainstay in the diagnosis of impaired glucose tolerance (IGT) and diabetes mellitus in pregnant and nonpregnant women, may be used to assess insulin sensitivity as well. Because no IV access is needed, OGTT is better suited for assessment of large populations than the other techniques we outlined. A modified OGTT that uses a 75- or 100-g glucose load and measures glucose and insulin at various intervals over 2 to 4 hours has been used in clinical studies.

Like other minimal approaches to diagnosis, OGTT provides information on beta cell secretion and peripheral insulin action, and various mathematical equations have been used to provide an SI value. Insulin sensitivity has been assessed by calculating insulin area under the curve (AUCinsulin), AUCglucose/AUCinsulin, and by an insulin sensitivity index (ISI) that applies only the glucose and insulin values from 0 and 120 minutes into a complex mathematical formula.

A 2-hour G/I ratio has also been reported to give a reasonably accurate SI, with a ratio of <1.0 suggestive of insulin resistance in a PCOS population. Insulin resistance has also been assessed qualitatively if one or more insulin values exceed an upper limit of normal at appropriate intervals.

Researchers have compared various methods for assessing insulin sensitivity in type 2 diabetics using the OGTT and found good correlations between AUCinsulin, insulin level at 120 minutes (I120), and the steady state plasma glucose concentrations derived from a modified ITT.27 OGTT provides a better assessment for impaired glucose tolerance and diabetes mellitus than fasting techniques because these patients may have normal fasting glucose values despite abnormal 2-hour levels.

**Fasting methods for assessing insulin sensitivity**

As mentioned before, the search for uncomplicated and inexpensive quantitative tools to evaluate insulin sensitivity has led to development of fasting state (homeostatic) assessments. These tests are based on fasting glucose and fasting insulin, and use straightforward mathematical calculations to assess insulin sensitivity and beta cell function. Several homeostatic approaches have been developed in recent years, each with its merits and deficiencies. One of the weaknesses of these models is that they assume the relationship between glucose and insulin is linear when in fact it's parabolic.

** Fasting insulin (I0)**. Fasting serum insulin is an inexpensive assay, and does not require any mathematical calculations. A fasting insulin >20 µU/mL in Caucasian women12, 21 and >23 µU/mL in Mexican-American women12 probably indicates insulin resistance in women with PCOS. At least one researcher has advocated averaging two or three readings to account for day-to-day variability.

Although I0 is less variable than other fasting procedures in normoglycemic patients, clinicians must still interpret results cautiously. A fasting level of 30 µU/mL indicates greater insulin resistance in a diabetic individual than in a normoglycemic patient since a similar basal insulin level would not proportionately suppress glucose in a diabetic patient as well as in the normal subject. Remember that insulin sensitivity is the ability of the hormone to reduce serum glucose. If fasting glucose is high—for example, in a patient with impaired glucose tolerance—that may indicate a diminished effect from circulating insulin (or in severe cases of insulin resistance, diminished quantity of the hormone). Hence I0 should not be used in glucose-intolerant or diabetic patients.

** Glucose/insulin ratio (G/I ratio)**. The G/I ratio has become very popular since its first description in 1998 as an accurate index of insulin sensitivity in women with PCOS. The ratio of glucose to insulin is easily calculated, with lower values depicting higher degrees of insulin resistance. A G/I ratio of less than 4.5 has been shown to be sensitive (95%) and specific (84%) for insulin resistance in a group of women with PCOS, when compared to a control group.

** Homeostatic model assessment (HOMA)**. HOMA has been widely employed in clinical research to assess insulin sensitivity. Rather than using fasting insulin or a G/I ratio, the product of the fasting values of glucose (expressed as mg/dL) and insulin (expressed as µU/mL) is divided by a constant:

I0 x G0

__________

405

The constant 405 should be replaced by 22.5 if glucose is expressed in S.I. units. Unlike I0 and the G/I ratio, the HOMA calculation compensates for fasting hyperglycemia. Also keep in mind that HOMA and I0 values increase in the insulin-resistant patient while the G/I ratio decreases. The HOMA value correlates well with clamp techniques and has been frequently used to assess changes in insulin sensitivity after treatment.16 HOMA has also been used to study insulin resistance among PCOS patients of differing ethnic origins.

** Quantitative insulin sensitivity check index (QUICKI)**. Like HOMA, QUICKI can be applied to normoglycemic and hyperglycemic patients. It is derived by calculating the inverse of the sum of logarithmically expressed values of fasting glucose and insulin:

1

__________

[log(I0) + log(G0)]

Many investigators believe that QUICKI is superior to HOMA as a way of determining insulin sensitivity, although the two values correlate well. As the SI decreases, QUICKI values increase.

* McCauley et al. (2001) Score for measuring the Insulin Sensitivity Index.* The ISI is calculated for fat-free body mass by dividing the glucose disposal rate (M - mg/kg/min) by the average plasma insulin concentration over the final 60 minutes of the 120 minute test. An ISI of

ISI = exp[3.29 - 0.25*ln(I0) - 0.22*ln(BMI) - 0.28*ln(TG)]

ISI = exp[2.63 - 0.28*ln(I0) - 0.31*ln(TG)]

In comparisons with the euglycemic insulin clamp technique the first formula (with BMI) has a specificity of 0.82 and a sensitivity of 0.63 for determining ISI. The second forumula (without BMI) has a specificity of 0.84 and a sensitivity of 0.62.