Angptl4 does not control hyperglucagonemia or α-cell hyperplasia following glucagon receptor inhibition

Significance Glucagon supports glucose homeostasis by stimulating hepatic glucose output. Inhibition of glucagon signaling has drawn much attention because of potential implications for diabetes treatment. It is well established that inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion and expansion of pancreatic α-cell mass. It was recently proposed that Angptl4, an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance, links glucagon receptor inhibition to α-cell proliferation. Here we confirm that Angptl4 is a powerful regulator of plasma triglycerides, but not of hyperglucagonemia or α-cell hyperplasia. We observed an increase in plasma amino acids in humans following administration of a glucagon receptor-blocking antibody, confirming preclinical findings indicate that amino acids mediate the compensatory α-cell response.