Adiponectin and leptin in human severe insulin resistance – Diagnostic utility and biological insights

There is an intimate interplay between systemic insulin action and the actions of the adipocyte-derived proteins leptin and adiponectin. Concordant findings in humans and rodents demonstrate that leptin gates critical physiological functions to the prevailing nutritional state, however the physiological functions of adiponectin are less convincingly established. Murine evidence suggests that adiponectin can exert insulin-sensitising effects, plasma concentrations of adiponectin in humans correlate in most populations with insulin sensitivity, and increasingly strong evidence suggests an association between common genetic variation around the adiponectin gene and diabetes. However rare and severe genetic variants lowering adiponectin levels have not been convincingly associated with insulin resistance, and the discordant and sometimes extreme hyperadiponectinaemia seen in patients with severe insulin resistance due to loss of insulin receptor function poses a challenge to the widely held view that low adiponectin in humans plays a role in causing prevalent insulin resistance. The mechanism underlying this phenomenon remains to be elucidated, but the best available evidence implicates increased production of adiponectin in states of insulin receptor dysfunction, attributable at least in part to increased transcription of the ADIPOQ gene. Further investigation of the cellular basis of insulin receptoropathy-related hyperadiponectinaemia may shine further light on the human pathobiology of this most abundant and enigmatic product of adipose tissue.

► Leptin plays a critical role in hypothalamic energy sensing and insulin resistance.
► There are no examples of complete genetic adiponectin deficiency in humans.
► Adiponectin levels correlate negatively with common forms of insulin resistance.
► Plasma adiponectin is elevated in patients with insulin receptor dysfunction.
► Understanding this phenomenon may yield important insights into adiponectin regulation.