SEC16B is a novel regulator of glucose homeostasis

Genome-wide association studies (GWAS) have so far identified a large number of genetic loci associated with metabolic diseases. SEC16B, an endoplasmic reticulum (ER) export factor, has emerged as a strong candidate associated with obesity in multiple GWAS yet its physiological function on metabolism has not been characterized. Here, by using global Sec16b knockout mice, we show that loss of Sec16b gene causes glucose intolerance without an effect on body weight. At the cellular level, Sec16b loss damages the morphology of the ER and mitochondria in pancreatic ß cells. Mechanistically, Sec16b loss impairs insulin secretion via blocking intracellular Ca2+ influx via down-regulating cholinergic synapse signaling in ß cells. Moreover, dSec16 loss disrupts glucose homeostasis in Drosophila melanogaster, highlighting a core and evolutionarily conserved role of dSec16 in glucose homeostasis. Taken together, our study has for the first time established SEC16B as a conserved key regulator of metabolic heath across phyla. Overall design: Isolated pancreatic islets mRNA profiles of of 30 weeks old Sec16b+/+ and Sec16b-/- mice