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

Year: 2024

Type: article

Abstract: 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 Ca 2+ -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 Ca 2+ 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 biogenesis. However, humans with T2D demonstrate decreased Golgi Cab45G localization and increased granule Cab45G localization 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.

Source: iScience

DOI: 10.1016/j.isci.2024.111719

Institutions: The University of Sydney, University of Washington, University of Denver, The University of Melbourne, St Vincent's Hospital Melbourne, Yale University

Language: English

Topic: Pancreatic function and diabetes

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,150

Funders: University of Sydney, State Government of Victoria, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Institute of General Medical Sciences

Awards: G6292354501, The preferential release of young insulin secretory granules., G7276536445, G9000056602, G9000267603

OpenAlex ID: W4405915182