What's the best way to diagnose insulin resistance and hyperinsulinemia?

March 1, 2005

Whether you're trying to pinpoint one of the underlying mechanisms behind PCOS, detect diabetes in its preclinical stage, or work up a patient with metabolic syndrome, a more in-depth understanding of the various laboratory approaches to assess insulin function can only improve your diagnostic skills.

The American Diabetes Association (ADA) defines insulin resistance as an impaired metabolic response to either exogenous or endogenous insulin.1 Some researchers refer to it as a common pathologic state in which target cells fail to respond to ordinary levels of circulating insulin.2 But no matter how you define the hormonal defect, everyone agrees that it takes a heavy toll on American women, playing an important role in type 2 diabetes mellitus (DM), polycystic ovary syndrome (PCOS), metabolic syndrome, and coronary artery disease.

Resistance to this essential hormone may affect up to 25% of the general population,3 increasing the threat of cardiovascular disease, and affecting 50% to 70% of patients with PCOS.4 The degree of insulin sensitivity (or conversely, insulin resistance) varies within certain conditions. As you might expect, healthy, normal-weight persons are the most insulin sensitive, followed by obese persons with normoglycemia, first-degree relatives of patients with type 2 DM, women with PCOS, patients with impaired glucose tolerance, and obese patients with type 2 DM.5

In PCOS patients, several metabolic abnormalities have been described, but the most significant among these is insulin resistance and the compensatory hyperinsulinemia.6-10 Resistance to insulin in PCOS appears to result from an impaired action of insulin on glucose transport and antilipolysis in adipocytes, and possibly muscle, in the presence of normal insulin binding.11-13 The resulting compensatory hyperinsulinemia, in turn, leads to an exaggerated effect of insulin in other tissues that are normally less responsive, including the stimulation of androgen secretion by the ovarian theca cells.14,15 Insulin resistance underlies the androgenic features of the disorder and giving insulin-sensitizing drugs improves the clinical, endocrinologic, and metabolic features in many patients with PCOS.16-19 Finally, it's important to remember that while insulin resistance may occur independent of obesity, it is often worsened by it.20

Measuring insulin sensitivity and hyperinsulinemia Unfortunately, experts have yet to agree on the best or the simplest approach. There are two general ways to determine insulin sensitivity. One requires an intervention like IV glucose and insulin, which can directly evaluate the ability of insulin to dispose of glucose. The problem is these techniques are expensive, labor-intensive, potentially dangerous, and require specially-trained technicians.

The alternative is to assess insulin resistance or hyperinsulinemia by using surrogate measures like fasting values of glucose and insulin21 or to assess insulin, C-peptide, or glucose responses to a physiological glucose load, which is what the oral glucose tolerance test (OGTT) does. Fasting indexes and the OGTT are less complex to perform than direct measurements but still correlate reasonably well with the results of the more invasive studies.5

How do you directly measure insulin sensitivity? Although these three direct approaches are rarely used by physicians "in the trenches", they are still worth a brief overview.

The glucose clamp. The glucose clamp technique is considered the most accurate test available for the measurement of insulin action in vivo. During this procedure, patients are given a constant IV insulin infusion at a rate designed to maintain a selected plasma steady-state insulin level. At the same time plasma glucose concentration is maintained or "clamped" at the normal fasting level by using a variable IV dextrose infusion; thus, the expression euglycemic clamp.