Clinical Interventions In The Management Of The Insulin Resistance Syndrome

On the basis of convincing clinical studies, it is no longer questioned that the -o insulin resistance syndrome is associated with an increased morbidity and mortal- |

ity. A more relevant question is whether improvement of insulin resistance with £

effective clinical interventions will decrease mortality and morbidity associated with the syndrome. Addressing the question will be problematic, as a clinically practical and reliable test to assess insulin resistance, or a way to serially measure clinical resistance with less invasive techniques for large-scale studies, is not well established (5). We do know, however, that there are a number of clinical a

& u interventions that increase insulin sensitivity. These interventions include a calorie-restricted diet, weight reduction, exercise, and pharmacological intervention with agents such as metformin and glitazones (5). Most clinicians will readily agree that, in those subjects who do comply, a calorie-restricted diet will markedly ameliorate insulin resistance. Insulin sensitivity, in these cases, is significantly increased very early after initiating the calorie-restricted diet and this reduction is observed even before significant weight loss has occurred. Clinically, a reduction in insulin resistance is reflected by an improvement in glycemic control or a marked decrease in the need for exogenous insulin or higher doses of oral antidiabetic medications to maintain glycemic control. It has also been firmly established that weight reduction over a longer time frame continues to improve insulin sensitivity. Should a patient not be able to lose weight, the most efficient means of preventing insulin resistance and worsening morbidity may be to avoid additional weight gain (5). A current controversy regarding nutritional recommendations for weight loss is whether caloric distribution among carbohydrates and the various fats is a critical parameter. A general consensus is that total calorie intake is the critical parameter responsible for the weight loss. However, others would argue that the distribution of calories is the key. Unfortunately, comparison trials evaluating such diets have not been done (5).

Exercise is an effective intervention in the management of the insulin-resistant syndrome, as vigorous exercise has been demonstrated to improve insulin sensitivity, even in elderly patients. Unfortunately, the effect on insulin sensitivity is known to diminish quickly (within 3 to 5 days) after stopping the exercise. Exercise should be considered a necessary adjunct to diet, as long-term exercise would result in little weight reduction unless caloric restriction is also part of the regimen.

Pharmacological treatment of insulin resistance is an area of active investigation. Two specific pharmacological approaches in the treatment of insulin resistance have been made available over the past several years. A class of compounds called biguanides, as represented by the agent metformin, has been available for a number of years and has a predominant effect of diminishing hepatic glucose production. The biguanides also have a moderate effect on skeletal muscle insulin resistance. On the other hand, drugs referred to as thiazolidinediones, represented by agents such as troglitazone, rosiglitazone, and pioglitazone, represent a class of drugs considered true insulin sensitizers, as insulin-stimulated glucose disposal -o is enhanced in insulin-sensitive tissues. Although both classes of drugs are currently available in the United States for treatment of the type 2 diabetic condition, £ neither class is approved to treat insulin resistance in the absence of the type 2 -g diabetic state.

Both classes of drugs have been postulated to be beneficial in either de- Ja laying or preventing the progression to type 2 diabetes. In particular, the Diabetes J

Prevention Program, sponsored by the National Institutes of Health, is designed a

& u to determine if any treatment (nutrition, exercise, or pharmacological) is effective in the primary prevention of type 2 diabetes in people who have been diagnosed with impaired glucose tolerance (13). As originally designed, there was to be a control group that employed intensive lifestyle changes to effect an approximately 7% reduction in body weight through caloric restriction and exercise. The second and third groups were to consist of pharmacological treatments to reduce insulin resistance, mainly metformin and troglitazone. The troglitazone arm was dropped from study due to an adverse event involving the liver. Because of the hepatic concern, troglitazone was removed from the market in March 2000.

It is not currently recommended that providers prescribe pharmacological treatment to their patients who are felt to be insulin resistant before the diagnosis is established for type 2 diabetes. Depending on the outcome of the current prevention trials, this may be a recommendation in the future. However, until the ongoing prevention trials are completed and the results made available, a non-pharmacological approach is probably the most reasonable option the clinician can offer to the patient in order to achieve a reduction in insulin resistance and prevent the development of type 2 diabetes. Appropriate candidates for such therapy include those who are centrally obese, have a strong family history of diabetes or gestational diabetes, demonstrate impaired fasting glucose on testing, or manifest other clinical symptoms associated with insulin resistance (e.g., hypertension, dyslipidemia).

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