Discussion
Relationship between obesity and insulin resistance
The results of the current, population-based study provide additional insight into the relationship between obesity and insulin resistance and are reasonably similar to the only published study in which this relationship has been evaluated in a large number of individuals using a specific method to determine insulin-mediated glucose disposal. In addition to supporting previous results' and that differences in weight modulate insulin action, the data presented provide a quantitative estimate of the role of obesity in regulating insulin-mediated glucose disposal. The relationship between BMI and SSPG shown in and indicates that only approximately 22% of the variability in SSPG concentration (r2) in this healthy volunteer population can be attributed to differences in BMI, an estimate that is consistent with the report of the European Group for the Study of Insulin Resistance (EGIR). This group quantified insulin action in 1,146 nondiabetic, normotensive individuals with the euglycemic, hyperinsulinemic clamp, and it also defined insulin resistance as the value of insulin-mediated glucose disposal in the lowest 10% of the normal weight population (BMI <25.0 kg/m2). With this criterion they found 26% of the obese individuals (BMI > 29.0 kg/m2) to be insulin-resistant. This estimate is similar to our finding that only 25% of our population in the upper tertile of insulin resistance had a BMI >30.0 kg/m2. Similar quantitative estimates of the magnitude of the relationship between obesity and insulin resistance can be found in a case-control study involving both Pima Indians and Caucasians in which approximately 25% of the variability in insulin action could be ascribed to differences in body weight. Because these studies excluded patients with diabetes and/or hypertension, syndromes known to be both more common in obese individuals and associated with impaired insulin action independent of obesity (, the estimates of the relationship between obesity and insulin resistance are applicable only to individuals without any disease known to affect insulin action.
One important caveat that must be made as to our estimate of the magnitude of the relationship between obesity and insulin-mediated glucose disposal is the use of BMI as the measure of obesity. This decision was based upon our attempt to relate our findings to the NHANES III results, but it should be noted that the conclusions of the EGIR investigators was independent of the estimates of obesity used in that “neither the waist circumference, nor the waist-to-hip ratio, indices of body fat distribution, was related to insulin sensitivity after adjustment for age, gender, and BMI.”
Relationship between obesity, insulin resistance, and type 2 diabetes
The results of this study provide relevant information concerning the link between obesity and insulin resistance and the development of type 2 diabetes. Several prospective studies have shown that degree of insulin resistance and/or hyperinsulinemia are strong predictors of type 2 diabetes in normal glucose tolerant individuals and It is obvious from that, at any given BMI, the most insulin-resistant tertile had plasma insulin concentrations that were three to four times higher than those in the most insulin-sensitive tertile. It should also be noted that the individuals in the most insulin-resistant tertile were also the most glucose intolerant, a change that also increases their risk of developing type 2 diabetes Based upon these considerations, it can be concluded that overweight/obese individuals are not at equal risk to develop type 2 diabetes, and those in the lowest insulin-resistant tertile are at less risk of developing type 2 diabetes than an insulin-resistant individual of any weight.
Relationship between obesity, insulin resistance, and CHD
The results presented also provide considerable insight into the relationship between obesity, insulin resistance, and CHD risk. Insulin resistance and/or compensatory hyperinsulinemia have been shown to predict CHD in nondiabetics , although it is not clear if this is a direct effect or secondary to the risk factors present in these individuals The metabolic abnormalities most closely related to insulin resistance are hyperinsulinemia, some degree of glucose intolerance, hypertriglyceridemia, and a low HDL cholesterol concentration , changes that have been shown to increase CHD risk and . In our study we have demonstrated that, for a given level of obesity, these metabolic abnormalities are clearly accentuated in the most insulin-resistant tertile . Thus, whether it is insulin resistance, per se, or its most common manifestations that increase CHD risk in insulin-resistant individuals, these changes are not present in obese individuals who are insulin-sensitive.
Conclusions
The results presented have reaffirmed the fact that the greater the BMI, the more insulin-resistant the individual. At the same time our results show that overweight/obese individuals can be insulin-sensitive and that normal weight subjects can be insulin-resistant. In addition, we have differentiated between the relative impact of overweight/obesity and insulin resistance on CHD risk factors, demonstrating that insulin resistance at any given BMI accentuates the risks of both type 2 diabetes and CHD. Implications of these findings are self-evident; the most intensive efforts to reduce risk of type 2 diabetes and CHD in overweight/obese individuals should be focused on those individuals who are also insulin-resistant.
References
1 Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord 1998;22:39–47.2 K.M. West and J.M. Kalbfleisch, Influence of nutritional factors on prevalence of diabetes. Diabetes, 20 (1971), pp. 99–108. | )
3 R.J. Havlik, H.B. Hubert, R.R. Fabsitz and M. Feinleib, Weight and hypertension. Ann Intern Med, 98 (1983), pp. 855–859. | )
4 the European Group for the Study of Insulin Resistance (EGIR), E. Ferrannini, A. Natali, P. Bell, P. Cavallo-Perin, N. Lalic and G. Mingrone, Insulin resistance and hypersecretion in obesity. J Clin Invest, 100 (1997), pp. 1166–1173. | )
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