Nonetheless, detailed analysis of glucose- and KCl-induced Ca2+ dynamics did provide evidence for alterations at the level of secretory granule behavior, which may play a role to impair insulin secretion in vivo. Importantly, islets from male βVps13cKO mice maintained on RC or on HFD responded normally with insulin secretion in response to either glucose or high KCl (Fig. 8), consistent with mild, and late-onset, glucose intolerance in these animals. Glucose-induced Ca2+ increases were nonetheless significantly delayed in the KO animals (Fig. 10). By contrast, when fed on RC, islets from female βVps13cKO mice displayed a significant enhancement in glucose-stimulated Ca2+ increases vs. islets from control littermates (Fig. 11A), whereas GSIS was unaltered (and tended to be decreased in response to KCl), as mentioned above. These observations suggest that the Ca2+ responsiveness of the secretory machinery to intracellular Ca2+ increases may be diminished in female βVps13cKO mice, perhaps reflecting changes in the number of fusion-competent secretory granules, as reported after manipulation of the GWAS gene TCF7L2 (81) or the microRNA miR124 (4) and might suggest a common mode of action of genes affecting T2D risk. Finally, it is possible, given that proinsulin levels were elevated in carriers of risk alleles, that prohormone processing is altered after Vps13c inactivation (67). To investigate this hypothesis, we measured random-fed insulin and proinsulin concentrations in RC-fed mice. No differences were seen in either insulin or proinsulin plasma concentrations, nor was the insulin/proinsulin ratio different between controls and KO mice (Fig. 13).