Discrimination Between Obesity and Insulin Resistance in the Relationship With Adiponectin

Fahim Abbasi; James W. Chu; Cindy Lamendola; Tracey McLaughlin; John Hayden; Gerald M. Reaven; Peter D. Reaven


Diabetes. 2004;53(3) 

In This Article


It is apparent from these studies of obese and nonobese individuals that adiponectin levels are more tightly linked with insulin concentrations and insulin resistance than degree of obesity. Obese insulin-sensitive subjects had higher adiponectin levels than the obese insulin-resistant subjects, despite the fact that weight and BMI were equal in both groups of obese subjects. Similarly, adiponectin levels in nonobese insulin-sensitive subjects were elevated compared with those of the nonobese subjects who were classified as insulin resistant. Thus, within each category of obesity, stratification by insulin sensitivity status proved a useful indicator of adiponectin concentration. Moreover, when adiponectin levels were plotted against BMI (Fig. 2A), it was evident that adiponectin levels in insulin-resistant subjects were uniformly low, regardless of the obesity status of the individual subjects. These results demonstrate a clear and significant relationship between insulin resistance and plasma adiponectin concentrations.

Regression analyses provided further evidence of a relatively robust relationship between insulin resistance or insulin levels and adiponectin. In contrast, weight, BMI, and waist circumference were less strongly related to adiponectin. Several prior studies[1,2] have also reported that insulin resistance is closely related to adiponectin levels, even after adjusting for measures of obesity. The present data extend the findings of these studies by providing a rather striking example of an obesity-independent association of insulin resistance with adiponectin levels. The observation that plasma insulin concentrations were associated with both adiponectin levels and insulin resistance raised the possibility that part of the association between these latter two variables may be explained through their mutual relationships with insulin. More specifically, plasma insulin concentrations are well recognized to be elevated in insulin-resistant nondiabetic individuals,[22,23,24] and there is evidence that insulin may have direct effects on adiponectin concentrations. Adiponectin message and protein expression have been shown to be sensitive to insulin concentrations in vitro,[15,26,27] and elevation of plasma insulin levels during hyperinsulinemic clamps has induced falls in adiponectin levels in both obese and nonobese subjects.[16,28] It is therefore conceivable that the higher levels of insulin in insulin-resistant subjects may downregulate levels of adiponectin, as suggested by the data in Fig. 3. A similar role for insulin in the regulation of proteins secreted from fat cells has been previously described for the adipokine, leptin.[29,30] However, the close relationship between insulin resistance and compensatory hyperinsulinemia, coupled with the standardized regression coefficients showing that both insulin levels and insulin resistance status were strongly related to adiponectin, makes it difficult to determine whether insulin resistance or hyperinsulinemia is most closely linked to adiponectin concentration.

It should be emphasized that our results are not necessarily in conflict with previous reports[8,9,10,11] that adiponectin concentrations are inversely correlated with the degree of adiposity. However, our study design permitted us to demonstrate that adiponectin concentrations are related to the degree of insulin resistance/hyperinsulinemia independent of weight, BMI, or waist circumference. On the other hand, our reliance on BMI and waist circumference as measures of obesity may have limited detection of subtle effects of adiposity on plasma adiponectin concentrations. However, our findings are consistent with reports from prior studies[1,2] indicating that adiponectin levels are related to measures of insulin resistance independent of visceral adiposity. On the other hand, we cannot exclude the possibility that differences in degree of adiposity and/or fat distribution, if measured more precisely, might also modulate adiponectin concentrations. Although these data are in agreement with recent suggestions that individuals with obesity and insulin resistance may be predisposed to develop more cardiovascular risk factors than those with obesity alone,[13,31] this does not imply that obesity without insulin resistance is benign.

Finally, although our results document an association between insulin resistance and insulin levels with plasma adiponectin concentrations, they also provide some indication that adiponectin levels can also be disassociated from insulin resistance. For example, there was extensive overlap of adiponectin levels between insulin-sensitive and insulin-resistant subjects, and levels of adiponectin in several insulin-sensitive individuals were among the lowest measured in our population. There are other reported instances of disassociation between adiponectin levels and insulin resistance. For example, increases in adiponectin levels do not accompany exercise training-associated improvements in insulin resistance or fitness.[8,32] Similarly, although large reductions in weight resulting from gastric partition surgery are associated with moderate elevations in adiponectin levels,[10] a more typical weight loss program utilizing simple caloric restriction does not appear to alter adiponectin levels.[33] Yet, both methods of weight loss lead to substantial improvements in insulin action.[10,33]

These data point out that the relationship between adiponectin and insulin resistance is probably not one of direct cause and effect in all instances. It is possible that in some situations their inverse relationship may be mediated in part by insulin levels, by other hormones such as catecholamines or androgens,[15,16,34] by proinflammatory cytokines,[17,35] by medications,[16,17] or possibly by changes in clearance of adiponectin. Although our data indicated a less robust relationship of adiponectin with obesity, some or all of these factors may also be influenced by the extent and location of obesity. Additionally, the molecular mechanisms modulating insulin resistance may vary between individuals and in different circumstances (e.g., obesity and exercise), and thus the relevance of adiponectin in these situations may also vary. An alternative explanation may be related to the different forms of adiponectin and its receptors now identified in animals and humans and the possibility that the biological action of adiponectin may differ among these structural variants and isoforms.[36,37] The results of the current study do not permit us to choose between these alternate explanations, but do indicate that sorting out the relationship between adiponectin and insulin resistance may be more complex than initially thought.


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