biostudies-literatureGermanos MState Government of VictoriaNHMRCNational Institutes of HealthUniversity of SydneyNIGMS NIH HHS111719https://www.ebi.ac.uk/biostudies/studies/S-EPMC11787600biostudies-literatureUnknown28(2)In type 2 diabetes (T2D), the rate of insulin secretory granule biogenesis can limit insulin secretion from pancreatic β-cells. Using rat insulinoma INS1 β-cells, we show that the soluble Ca²⁺-binding/trafficking protein, Cab45G, serves as a non-essential chaperone for insulin granule biogenesis. In β-cells, Cab45G is stored within a <i>cis</i>-Golgi reservoir. Cab45G deletion dysregulates Ca²⁺ homeostasis and leads to secretory abnormality, but insulin granule biogenesis remains intact. Increasing Cab45G biosynthesis leads to anterograde trafficking into insulin granules, stimulating their production. Using human donor islets, we identify increased anterograde Cab45G trafficking in obese humans with and without T2D, consistent with the heightened demand for granule biScienceCab45G trafficking through the insulin secretory pathway is altered in human type 2 diabetes.PMC11787600GNT1139828R35 GM149293R01 GM121481Needham EJGermanos MNaghiloo SMasler DThomas HYeoman CAilion MWilson ADiaz-Vegas AThorn PLarance MTaper MAsensio Cvan der Kraan AGTong Jvon Blume JKebede MAAn YLoudovaris TYau BCattin-Ortola JSun KfalseCab45G trafficking through the insulin secretory pathway is altered in human type 2 diabetes.In type 2 diabetes (T2D), the rate of insulin secretory granule biogenesis can limit insulin secretion from pancreatic β-cells. Using rat insulinoma INS1 β-cells, we show that the soluble Ca²⁺-binding/trafficking protein, Cab45G, serves as a non-essential chaperone for insulin granule biogenesis. In β-cells, Cab45G is stored within a <i>cis</i>-Golgi reservoir. Cab45G deletion dysregulates Ca²⁺ homeostasis and leads to secretory abnormality, but insulin granule biogenesis remains intact. Increasing Cab45G biosynthesis leads to anterograde trafficking into insulin granules, stimulating their production. Using human donor islets, we identify increased anterograde Cab45G trafficking in obese humans with and without T2D, consistent with the heightened demand for granule b2025-01-01T00:00:00Z2025 Feb2026-06-01T10:27:36.091Z2025-04-19T16:25:28.297ZS-EPMC117876003989802410.1016/j.isci.2024.111719