GDF15 is a Critical Renostat in the Defense Against Hypoglycemia

Episodic hypoglycemia is one of the best honed, evolutionary conserved phenomena in biology, because of the constant feast-fast cycles that have characterized most of history. The counterregulatory response to hypoglycemia, mobilizing substrate stores to produce glucose, is the primary adaptive mechanism to enable survival. Catecholamines and glucagon have long been considered the key hypoglycemia counterregulatory hormones, but here we identify a new hypoglycemia counterregulatory factor. We employed the insulin tolerance test (ITT) and hyperinsulinemic-hypoglycemic clamp to mimic the two common settings in which hypoglycemia can occur in patients: postprandial insulin overdose and elevated basal insulin administration, respectively. We found that Growth Differentiation Factor 15 (GDF15) production is induced in the S3 segment of the renal proximal tubules and its release increases hepatic gluconeogenesis by increasing intrahepatic lipolysis in a beta-adrenergic receptor-2 (Adrb2)-dependent manner. In addition, mice exposed to recurrent hypoglycemia and patients with T1D exhibit impaired GDF15 production in the setting of hypoglycemia. These data demonstrate that GDF15 acts acutely as a gluco-counterregulatory hormone and identify a critical role for kidney-derived GDF15 in glucose homeostasis under physiological and pathophysiological conditions.