Cab45G trafficking through the insulin secretory pathway is altered in human type 2 diabetes

Journal article

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 cis-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 and humans with T2D, consistent with the heightened demand for granule biogenesis. However, in humans with T2D, Cab45G localizes to a larger proportion of insulin granules compared to those without T2D. Our study provides the first insight into Cab45G function in specialized secretory cells and opens avenues of investigation into mechanisms associated with β-cell compensation and failure.

Authors: Germanos, M; Yau, B; Taper, M; Yeoman, C; Wilson, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Cell Press
• Journal: iScience
• Volume: 28
• Issue: 2
• Article number: 111719
• Publication date: 2024-12-30
• Acceptance date: 2024-12-28
• DOI: 10.1016/j.isci.2024.111719
• EISSN: 2589-0042
• Language: English