The processing, maturation, and secretion of
insulin are under precise regulation, and dysregulation causes profound defects in
glucose handling, leading to diabetes. Tmem30a is the β subunit of the
phosphatidylserine (PS) flippase, which maintains the membrane asymmetric distribution of PS. Tmem30a regulates cell survival and the localization of subcellular structures and is thus critical to the normal function of multiple physiological systems. Here, we show that conditional knockout of Tmem30a specifically in pancreatic islet β cells leads to
obesity,
hyperglycemia,
glucose intolerance,
hyperinsulinemia, and
insulin resistance in mice, due to insufficient
insulin release. Moreover, we reveal that Tmem30a plays an essential role in
clathrin-mediated vesicle transport between the trans Golgi network (TGN) and the plasma membrane (PM), which comprises immature secretory granule (ISG) budding at the TGN. We also find that Tmem30a deficiency impairs
clathrin-mediated vesicle budding and thus blocks both
insulin maturation in ISGs and the transport of
glucose-sensing Glut2 to the PM. Collectively, these disruptions compromise both insulin secretion and
glucose sensitivity, thus contributing to impairments in
glucose-stimulated insulin secretion. Taken together, our data demonstrate an important role of Tmem30a in
insulin maturation and
glucose metabolic homeostasis and suggest the importance of membrane
phospholipid distribution in metabolic disorders.