VPS13C is ubiquitously expressed in mammals, with particularly high levels in pancreatic islets and β-cells (60, 67). The observations above have thus led us to hypothesize that VPS13C may play a role in the intracellular trafficking of insulin or other aspects of pancreatic β-cell function. To explore this possibility, we first determined the relationship between the possession of T2D risk alleles in humans and the expression of VPS13C, C2CD4A (C2 calcium-dependent domain 4A), and C2CD4B in human islets. Subsequently, we developed mice inactivated for Vps13c highly selectively in the β-cell by using the recently developed Ins1Cre deleter strain (33, 69). The latter is a knock-in model that avoids the complications associated with earlier insulin 2 promoter-dependent Cre's including recombination in the brain (77) and coexpression of human growth hormone (8). This approach reveals roles for Vps13c in the control of whole body glucose homeostasis, insulin secretion in vivo, and glucose-induced Ca2+ signal generation in the β-cell but suggests that C2CD4A may also contribute to disease risk.