Hypoadiponectinemia--cause or consequence of human "insulin resistance"?

CONTEXT: Adiponectin is a highly abundant plasma protein synthesized nearly exclusively in adipose tissue from the ADIPOQ gene. It has excited intense interest because of robust correlation of its circulating levels with indices of insulin resistance (IR) and risk of type 2 diabetes, and their unusual inverse relationship with fat mass. It has been suggested that pharmacological strategies aimed at augmenting adiponectin levels or action may generate novel insulin-sensitizing drugs. EVIDENCE ACQUISITION: Relevant publications were identified by searching PubMed, with secondary searches of their bibliographies. EVIDENCE SYNTHESIS: Rodent studies suggest that adiponectin exerts a direct insulin-sensitizing effect on the liver, consistent with a role in the pathogenesis of prevalent forms of IR and its sequelae. However, the complex higher-order structure of adiponectin and inconsistent reports regarding its putative receptors have complicated efforts to understand the mechanistic basis of this. No proof yet exists that adiponectin modulates insulin sensitivity in humans, and genetic, biochemical, and physiological evidence suggests that low adiponectin levels may be a consequence of IR with compensatory hyperinsulinemia. This suggests that there may be a bidirectional relationship between IR and hypoadiponectinemia in humans.
CONCLUSIONS: The relationship between adiponectin and insulin action in humans is more complex than often suggested. Further investigation of the direction of causality in this relationship, allied to studies of the cellular mechanisms involved, will be central to improving understanding of the physiological role of this enigmatic protein, and to efforts to exploit it for therapeutic benefit.