Adipokines regulate systemic insulin sensitivity in accordance to existing energy reserves.

Adipocyte-derived hormones, including adiponectin and leptin, regulate systemic insulin sensitivity in accordance to existing triglyceride reserves. Leptin levels reflect existing fat mass and the adipokine negatively regulates insulin action in adipose tissue. Adiponectin, on the other hand, preserves insulin sensitivity via transient increments of AMPK activity and its circulating levels seem to reflect the adipogenic capacity of adipose tissue. Because adiponectin and insulin synergize in their postprandial actions, it seems evident that inadequate adiponectin production causes systemic insulin resistance. As a consequence, compounds that either increase adiponectin production or mimic its actions can be considered as an efficient strategy for improving insulin sensitivity in type 2 diabetics. We have previously shown that troglitazone and metformin exert opposing actions on adiponectin production, indicating that combined use of troglitazone and metformin is a more efficient strategy as compared to metformin treatment. Here, we will provide additional arguments which stress the need for a fixed dose of troglitazone and metformin in order to preserve endogenous adiponectin production. Finally, after delineating critical nodes of insulin and adipokine crosstalk, putative pathways are proposed by which adiponectin and leptin cooperatively regulate systemic insulin sensitivity in accordance to existing fat mass. By amplifying insulin action downstream of PI3K, leptin exerts negative feedback on insulin signaling via mTOR-dependent pathways that target IRS-1 for serine phosphorylation and protein degradation. Adiponectin-mediated increments of AMPK activity, on the other hand, may attenuate mTOR signaling, leading to the preservation of insulin sensitivity in periods of increased nutrient availability. Considering that leptin and adiponectin are inversely associated with BMI, the proposed model provides a plausible explanation for the observation that leptin exerts strong negative feedback on systemic insulin sensitivity, while increasing PIP3 availability.