The view that overweight and obese persons are at increased risk for type 2 diabetes, hypertension, and coronary heart disease as a result of insulin resistance is supported by results from prospective intervention studies indicating that improved insulin sensitivity and the associated metabolic benefits are limited to persons defined as being insulin resistant before losing weight (7-10). For example, in a 12-month study of weight loss (10) in overweight persons classified as being either insulin resistant (high triglyceride and low high-density lipoprotein [HDL] cholesterol concentrations) or insulin sensitive (low triglyceride and high HDL cholesterol concentrations), a weight loss–associated decrease in plasma insulin concentration and an improvement in dyslipidemia were confined to the insulin-resistant group.

Evidence that not all overweight and obese persons are insulin resistant (5-10) and that the metabolic benefits from weight loss are predominantly seen in those who are defined as being insulin resistant before losing weight [7-10] suggests that strategies to overcome the untoward health-related effect of overweight and obesity become more focused. A decision to begin treatment efforts by stratifying overweight and obese persons by their degree of insulin resistance and to emphasize disease risk reduction rather than simple weight loss requires 1) the ability to recognize the appropriate subpopulation of obese persons in a relatively straightforward manner and 2) evidence that weight loss in this selected group will be of clinical benefit.

Identifying Overweight Persons Who Are Insulin Resistant

The importance of identifying insulin-resistant persons to be the focus of weight-loss programs is supported by the results of two prospective studies that measured insulin-mediated glucose disposal. The studies found that persons in the upper tertile of insulin-mediated glucose disposal—that is, the most insulin-resistant persons—were at a statistically significantly increased risk for developing type 2 diabetes, coronary heart disease, or hypertension (11, 12). Another prospective study (3) showed that when insulin was used as a surrogate measure of insulin resistance, all three syndromes developed to a substantially greater degree in the 25% of the population with the highest insulin levels. Directly quantifying insulin-mediated glucose disposal is not clinically practical, and plasma insulin measurements are not standardized. However, once focus is shifted to the downstream consequences of insulin resistance and hyperinsulinemia, the task becomes simpler. A BMI greater than 25.0 kg/m² is currently used to define being overweight; a BMI greater than 30.0 kg/m² merits the designation of obese. Based on these definitions, it would be prudent to evaluate any person with a BMI greater than 25.0 kg/m² for the manifestations of insulin resistance. Persons with a BMI greater than 27.0 kg/m² are considered to be at such great risk that antiobesity drugs approved by the U.S. Food and Drug Administration can be prescribed. These persons certainly require risk factor evaluation. In the presence of a family history of type 2 diabetes, hypertension, or coronary heart disease, identifying risk factors is even more imperative.

There are no unequivocal cut-points for identifying overweight persons most likely to be at increased risk for type 2 diabetes, coronary heart disease, and hypertension. However, several simple measurements described in the following sections can provide considerable clinical insight.

Dyslipidemia

People who are insulin resistant have a characteristic atherogenic lipoprotein profile, including a high plasma triglyceride and a low HDL cholesterol concentration (1, 2, 13), a shift in the diameter of the low-density lipoprotein (LDL) particles (14), and an increase in the postprandial accumulation of remnant lipoproteins (15, 16). Although LDL particle diameter and postprandial lipemia cannot be routinely determined, plasma triglyceride and HDL cholesterol concentrations are measured by reasonably well-standardized methods. Plasma triglyceride concentrations will usually be greater than 1.7 mmol/L (>150 mg/dL) (1, 2) in insulin-resistant persons; when this level is exceeded, LDL particles become smaller and denser (17) and the postprandial accumulation of remnant lipoproteins becomes accentuated (16). Thus, once the plasma triglyceride concentration exceeds 1.7 mmol/L (150 mg/dL), three of the four atherogenic lipoprotein abnormalities associated with insulin resistance are probably present. A low HDL cholesterol concentration is the fourth lipoprotein abnormality in insulin-resistant and hyperinsulinemic persons; a value less than 1.04 (<40 mg/dL) is associated with both the insulin resistance syndrome (1, 2) and increased risk for coronary heart disease (18). Thus, overweight persons with a triglyceride concentration greater than 1.70 mmol/L (>150 mg/dL) and an HDL cholesterol concentration less than 1.04 mmol/L (<40 mg/dL) are almost certainly insulin resistant to the degree that predicts substantial clinical benefit with weight loss.

Although both a high triglyceride and a low HDL cholesterol concentration have been identified as risk factors for coronary heart disease (18, 19), the ratio of their plasma concentrations may be an even more useful predictor. Thus, the observation (20) that the triglyceride-to-HDL cholesterol concentration ratio was as powerful a predictor of coronary heart disease as the more conventional ratios of LDL cholesterol to HDL cholesterol or total cholesterol to HDL cholesterol is supported by evidence that the risk for ischemic heart disease was much greater when the "conventional" risk factors (high LDL cholesterol concentration, hypertension, smoking, and physical inactivity) were associated with a high triglyceride-to-HDL cholesterol concentration ratio (21). Evidence also shows that the untoward effects of these four conventional risk factors were substantially attenuated in persons with a low triglyceride-to-HDL cholesterol ratio.

Hypertension

Because only about 50% of hypertensive patients are insulin resistant and hyperinsulinemic (22), the presence or absence of hypertension is not as powerful a predictor of insulin resistance as is a high triglyceride and low HDL cholesterol concentration. However, patients with high blood pressure who are at greatest risk for coronary heart disease have the characteristic lipoprotein profile of the insulin resistance syndrome (23, 24). A high triglyceride (>1.70 mmol/L [>150 mg/dL]) and a low HDL cholesterol (<1.04 mmol/L [<40 mg/dL]) concentration in an overweight person with hypertension identifies a person who is both insulin resistant and at greatly increased risk for coronary heart disease and one who needs intensive intervention.

Glucose Intolerance

Although insulin resistance is the basic defect in patients with type 2 diabetes, most insulin-resistant persons can maintain the degree of compensatory hyperinsulinemia needed to prevent gross decompensation of glucose homeostasis. In patients with a normal fasting plasma glucose concentration (<6.11 mmol/L [<110 mg/dL]), a plasma glucose concentration 120 minutes after a 75-g oral glucose load greater than 11.1 mmol/L (200 mg/dL) is diagnostic of type 2 diabetes; a value of 7.77 to 11.1 mmol/L (140 to 200 mg/dL) indicates impaired glucose tolerance (25). In both instances, it is highly probable that the glucose intolerance will be associated with insulin resistance, hyperinsulinemia, and the atherogenic lipoprotein profile characteristic of the insulin resistance syndrome.

Fasting plasma glucose concentration is a less sensitive guide to the presence or absence of insulin resistance, and a "normal" fasting plasma glucose concentration (<6.11 mmol/L [<110 mg/dL]) does not mean that a person is insulin sensitive. A fasting plasma glucose concentration greater than 6.99 mmol/L (>126 mg/dL) is diagnostic of type 2 diabetes (25) and almost certainly identifies an insulin-resistant person. Patients with a fasting plasma glucose concentration between 6.11 and 6.99 mmol/L (110 and 126 mg/dL) are classified as having impaired fasting glucose and are also likely to be insulin resistant and hyperinsulinemic.

Clustering of Abnormalities

The most characteristic abnormality in insulin-resistant and hyperinsulinemic persons is a high triglyceride and a low HDL cholesterol concentration; their presence is a strong indicator that a person is insulin resistant and hyperinsulinemic (1, 2, 13). Hypertension and impaired fasting glucose are less sensitive indicators of insulin resistance, but either abnormality, when present in patients with the characteristic dyslipidemia of insulin resistance, greatly increases the likelihood that insulin resistance is present. More important, these changes tend to occur together (1, 2), and it has been estimated that approximately 25% of the U.S. population has three or more of the following abnormalities: excess weight, high triglyceride or low HDL cholesterol concentration, hypertension, or impaired fasting glucose (26).

Benefits of Weight Loss in Insulin-Resistant Overweight Persons

After overweight persons are identified as insulin resistant and at increased risk for type 2 diabetes, coronary heart disease, and hypertension, what is the evidence that weight loss will be of benefit? The response to this question requires a distinction between prevention and treatment.

Prevention

Although essentially no information is available on the ability of weight loss to prevent coronary heart disease or hypertension, several prospective studies show that weight loss can prevent progression to type 2 diabetes in persons with less severe degrees of glucose intolerance (27-30). However, because these studies included increased physical activity as part of the intervention, it is not clear how much of the benefit was derived from weight loss and how much was from the increase in physical activity.

Treatment

Much evidence shows that weight loss can improve insulin action, decrease circulating insulin concentrations, decrease blood pressure in hypertensive persons, and lead to better glycemic control in patients with type 2 diabetes. All of this information cannot be reviewed here; however, I discuss some of the evidence that shows the benefits of weight loss on dyslipidemia, glucose metabolism, and blood pressure in insulin-dependent persons.

Dyslipidemia

Evidence published 28 years ago demonstrated that weight loss in obese persons was associated with decreases in insulin resistance, hyperinsulinemia, and hypertriglyceridemia (4). More recently, studies showed that these beneficial effects of weight loss were confined to overweight persons who were insulin resistant before losing weight (7-10), and there were no or minimal beneficial effects in persons classified as being insulin sensitive (10).

Glucose Tolerance

Most patients with type 2 diabetes are insulin resistant (1, 2, 31), and weight loss has been shown to improve glycemic control in these patients (32, 33). In nondiabetic persons, daylong plasma glucose concentrations (which were slightly but statistically higher in insulin-resistant than in insulin-sensitive obese persons) (9, 34), decreased after weight loss in overweight persons who were insulin resistant; their plasma glucose values became similar to those of the insulin-sensitive persons. Daylong circulating insulin concentrations were approximately twice as high in insulin-resistant overweight persons as in weight-matched insulin-sensitive overweight persons (9, 34); both hyperinsulinemia and insulin resistance decreased substantially with weight loss in insulin-resistant persons, whereas no change occurred in overweight persons who were insulin sensitive.

Hypertension

In 1978, weight loss was shown to reduce blood pressure in hypertensive patients (35). A more recent article suggested that the improvement in blood pressure after weight loss in obese adolescents was related to the associated changes in insulin sensitivity (36). A study of adults with hypertension reached a similar conclusion, with a highly significant relationship between the improvement in insulin sensitivity and the decrease in blood pressure (37).

Conclusion

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Being overweight substantially increases morbidity and mortality from various diseases. In addition to type 2 diabetes, coronary heart disease, and hypertension, overweight and obesity increase the risk for gallbladder disease, respiratory function disorders, and cancer (38). Although obesity is associated with many diseases, fewer than 50% of interviewed physicians routinely counseled overweight persons about weight loss (39). There is an enormous gap between what is known about the untoward effects of overweight and obesity and what is being done. Substantial evidence shows that insulin-resistant and hyperinsulinemic persons are at increased risk for type 2 diabetes, coronary heart disease, and hypertension. Although there is less evidence for a relation between obesity and cancer, they may be linked via insulin resistance and hyperinsulinemia (21).

Although a different approach may not solve all of the health-related problems associated with obesity, a useful beginning might be recognizing the fact that not all obese persons are at equal risk and then identifying those at highest risk—persons with insulin resistance and hyperinsulinemia. Relatively simple measures are available that can identify the subset of overweight and obese persons who are insulin resistant and hyperinsulinemic. The clinical benefit of weight loss in these persons is well established. The next step would be to direct intense effort toward weight control in these persons who are most in need of losing weight. Because weight loss is so difficult to achieve, it would be unfortunate if efforts were diluted by failure to focus on those who will benefit the most. In this context, the recent publication by the National Heart, Lung and Blood Institute, titled "The Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," may be helpful.