Sizing up insulin resistance—one treatment doesn’t fit all
There is no single best intervention for all women. It depends on the severity of glucose intolerance and metabolic abnormality in each patient.
In type 2 diabetes, as well as polycystic ovary syndrome (PCOS), a main component is peripheral insulin resistance,20 although women with PCOS have somewhat better beta cell function than diabetic women, with initial hypersecretion and compensation. Over time, dysfunction develops, leading to inadequate insulin secretion, beta cell exhaustion, fasting hyperglycemia, and frank type 2 diabetes.
Just what is insulin resistance?
Insulin is the primary anabolic hormone in the body, acting in diverse ways in different tissues. Yet insulin resistance is usually defined as a single action: decreased insulin-mediated glucose uptake by peripheral tissues (largest utilizer: skeletal muscle).
Most research tests, such as euglycemic clamp studies, focus on glucose uptake—or its disappearance from the circulation—during dynamic challenge tests. The higher the glucose uptake, the greater the insulin sensitivity and the lower the eventual risk of developing diabetes.
Signs of insulin resistance in PCOS patients
In women with PCOS, the picture is complicated by selective tissue sensitivity to insulin and/or selective actions within tissues that are either sensitive (adrenal or ovary) or resistant (skeletal muscle) to insulin.21
Women with PCOS are profoundly resistant to insulin at the level of skeletal muscle, where 85% to 90% of insulin is utilized. This is comparable to the resistance in women with type 2 diabetes.22
In the target tissues of women with PCOS, compensatory hyperinsulinemia is thought to create aberrant states, suggesting that these tissues are differentially responsive to insulin’s action. For instance, hyperinsulinemia drives excess ovarian and adrenal androgen production, stimulates the proliferation of the piloseba-ceous unit (worsening acne and hirsutism), and suppresses hepatic sex hormone binding globulin production, thus increasing the bioavailable androgen load.
Insulin resistance is not always a disorder
Determining precisely who is insulin-resistant, and assigning clinical cutoffs, are complicated tasks. We lack standardized assays for insulin, and results vary from lab to lab. Normal insulin sensitivity varies widely and is influenced by age, gender, ethnicity, diet, and obesity. Simply put, not all people with impaired insulin sensitivity are necessarily suffering from a disorder. Pregnancy, a temporary condition of markedly diminished insulin sensitivity, is one example.
Thus, establishing limits for normal degrees of insulin sensitivity is arbitrary; often the bottom 10% to 25% of a population is labeled “insulin-resistant.”
Managing impaired glucose tolerance
Diet and exercise double risk reduction
In a recent trial by the Diabetes Prevention Program Research Group, which offers excellent guidelines for intervention,2 both metformin and lifestyle intervention reduced diabetes risk, although lifestyle was far more effective (58% reduction versus 29%).
That trial randomized 3,234 men and women with IGT to 3 treatments: conventional lifestyle recommendations, intensive and active lifestyle intervention, or insulin sensitization with metformin.
Intensive lifestyle intervention involved a case manager to ensure compliance with the study’s goals: at least a 7% loss in body weight maintained over the life of the study, and at least 150 minutes of exercise weekly. Exercise was key. Individuals who complied with intensive lifestyle intervention exercised an average of 6 hours weekly over the 4 years of the trial. The other groups exercised on average less than 2 hours weekly.
For metabolic abnormalities, start with lifestyle
With this information, it is possible to devise an algorithm for women with PCOS, depending on their degree of metabolic abnormality (FIGURE).
All individuals—even those taking medication—should be counseled about the importance of a healthy lifestyle, including staying physically active and quitting smoking. In addition:
- In women with metabolic syndrome, intensive lifestyle intervention is warranted, preferably supervised (ie, by a registered dietician and exercise trainer). This may involve out-of-pocket expense, but expert advice in these areas requires a professional. Obese, metabolically challenged women should also avoid overstrenuous exercise programs.
- Impaired glucose tolerance arouses further concern; insulin sensitization with metformin may be appropriate.
- If type 2 diabetes is diagnosed, repeat the blood tests to confirm the diagnosis and then evaluate the patient for sequelae and refer her for more intensive management.
If metabolic syndrome progresses, or if individual parameters change for the worse, additional therapy may be warranted, such as altering the dose or the choice of insulin sensitizer.
Guidelines into action
SUZANNE’S CASE
Suzanne is a 32-year-old mother of twins who presents with PCOS at a new-patient appointment, seeking advice about longterm care. She has a history of irregular menses; she conceived her twins on clomiphene 6 years ago, and now is being treated with an oral contraceptive (OC) containing 30 μg ethinyl estradiol, which she has taken for 4 years. She does not desire fertility.
