Plasma adiponectin consistently correlates positively with insulin sensitivity in normal human populations (1
), and we have previously established that this relationship also holds in almost all patients with severe insulin resistance, in whom adiponectin is extremely low (7
). Striking exceptions have proved to be patients with loss-of-function mutations in the insulin receptor, in whom plasma adiponectin is not only an order of magnitude higher than seen in other states of severe insulin resistance, but is also significantly higher than in the normal population (7
). We suggested that this discordance between high plasma adiponectin and extreme insulin resistance may be accounted for either by direct effects in adipocytes of the loss of insulin receptor function, or by the effects on adipose tissue development of severely impaired insulin receptor function in utero
and beyond (7
). Using type B insulin resistance as a model of acquired and reversible insulin receptor dysfunction in adult life, we now have established that dramatic hyperadiponectinaemia with loss of insulin receptor function is not dependent on receptor dysfunction during development, and moreover is reversible on restitution of receptor function. Our finding that the hyperadiponectinaemia in states of insulin receptor dysfunction is accounted for by a large preponderance of HMW multimers further accentuates the dissociation between plasma adiponectin and insulin sensitivity, as HMW adiponectin has been shown to correlate better with insulin sensitivity than total plasma adiponectin (1
). In contrast, the patients studied with idiopathic severe insulin resistance showed the same unexplained leftward shift in complex distribution that is seen in highly prevalent but milder insulin resistance.
The robust association of hypoadiponectinaemia with the earliest detectable stages of insulin resistance has raised the possibility that hypoadiponectinaemia may play a causal role in prevalent forms of insulin resistance. However the causal link in humans has yet to be established, and hyperadiponectinaemia in states of extreme insulin resistance due to insulin receptor dysfunction demonstrates that they may be entirely dissociated in some settings. Nevertheless this observation is not at odds with the notion of an aetiological role for hypoadiponectinaemia in other, more common, forms of insulin resistance: indeed, hypersecetion of adiponectin by adipocytes with a very proximal defect in insulin action could be regarded as an extreme compensatory response aimed at systemic insulin sensitization.
The mechanistic basis for this radical dissociation between insulin sensitivity and circulating adiponectin is unclear. It may in principle be accounted for by increased adiponectin secretion from adipocytes, by reduced clearance of circulating adiponectin, or by a combination of these. Several lines of evidence suggest that an effect on secretion is dominant: the 60% increase in plasma adiponectin reported in mice with adipose-specific deletion of the insulin receptor provides evidence that there is an adipocyte-specific role of the insulin receptor in determining plasma adiponectin levels in vivo
), while the shift in complex distribution towards HMW forms reported here, allied to previous demonstration that higher order adiponectin multimers do not interconvert in the circulation in vivo
), is also suggestive of a change in adipocyte secretory activity.
Hypersecretion of adiponectin from adipocytes with reduced or absent insulin receptor function could be attributable 1) to loss of direct suppression of adiponectin synthesis and secretion at a transcriptional or post transcriptional level by insulin receptor activation, or 2) to a more indirect effect mediated by changes in cellular metabolic or redox status in the absence or reduction of functional insulin receptor. A direct suppressive effect of insulin on adipocyte synthesis and secretion of adiponectin is generally not supported by studies in vitro
and ex vivo
to date (16
), however chronic insulin action in the context of a more physiological hormonal, nutritional and cellular milieu may elicit a different response. A longitudinal study of the development of insulin resistance in rhesus monkeys found no change in adipose tissue adiponectin mRNA despite low plasma adiponectin, suggesting that post transcriptional events may predominate (17
Hypersecretion of adiponectin could instead be related to the unrestrained catabolic mode of adipocytes with hypofunctional insulin receptors, consistent with the modestly elevated adiponectin seen in poorly controlled type 1 diabetes (13
). However the most physiological insulinopaenic catabolic state is fasting, and neither medium term fasting nor anorexia nervosa have consistently been shown to produce elevations in adiponectin (e.g. (20
)). A further possibility is that lack of insulin receptor function leads to elevated adiponectin through a reduction in intracellular reactive oxygen species (ROS), which have been shown to suppress adiponectin expression in vitro
and ex vivo
), and to be modulated by insulin receptor activity (24
This report attests to the utility of using human disease models such as T1DM (pure insulin deficiency) and INSR mutations or type B insulin resistance (isolated loss of INSR function with severe hyperinsulinaemia) to make novel observations of relevance to the biology of human insulin action in vivo.