Drosophila transmembrane protein 214 (dTMEM214) regulates midgut glucose uptake and systemic glucose homeostasis

The availability of glucose transporter in the small intestine critically determines the capacity for glucose uptake and consequently systemic glucose homeostasis. Hence a better understanding of the physiological regulation of intestinal glucose transporter is pertinent. However, the molecular mechanisms that regulate sodium-glucose linked transporter 1 (SGLT1), the primary glucose transporter in the small intestine, remain incompletely un-derstood. Recently, the Drosophila SLC5A5 (dSLC5A5) has been found to exhibit properties consistent with a dietary glucose transporter in the Drosophila midgut, the equivalence of the mammalian small intestine. Hence, the fly midgut could serve as a suitable model system for the study of the in vivo molecular underpinnings of SGLT1 function. Here, we report the identification, through a genetic screen, of Drosophila transmembrane protein 214 (dTMEM214) that acts in the midgut enterocytes to regulate systemic glucose homeostasis and glucose up-take. We show that dTMEM214 resides in the apical membrane and cytoplasm of the midgut enterocytes, and that the proper subcellular distribution of dTMEM214 in the enterocytes is regulated by the Rab4 GTPase. As a cor-ollary, Rab4 loss-of-function phenocopies dTMEM214 loss-of-function in the midgut as shown by a decrease in enterocyte glucose uptake and an alteration in systemic glucose homeostasis. We further show that dTMEM214 regulates the apical membrane localization of dSLC5A5 in the enterocytes, thereby revealing dTMEM214 as a molecular regulator of glucose transporter in the midgut.

Automated summary

The availability of glucose transporter in the small intestine is crucial for glucose uptake and systemic glucose homeostasis. Research on the molecular mechanisms of sodium-glucose linked transporter 1 (SGLT1) regulation in the small intestine is incomplete. This study identified a gene called dTMEM214 that regulates glucose homeostasis and uptake in the midgut of Drosophila. dTMEM214 regulates the subcellular distribution of another protein, dSLC5A5, in the enterocytes, thereby acting as a molecular regulator of glucose transporter in the midgut.