TBC1D30 regulates proinsulin and insulin secretion and is the target of a genomic association signal for proinsulin – published online 10/03/2025

Victoria A. Parsons, Swarooparani Vadlamudi, Kayleigh M. Voos, Abigail E. Rohy, Anne H. Moxley, Maren E. Cannon, Jonathan D. Rosen, Christine A. Mills, Laura E. Herring, K. Alaine Broadaway, Damaris N. Lorenzo & Karen L. Mohlke

Before mature insulin is secreted from the pancreatic beta cell, it must first be converted from its precursor, proinsulin. Typically, this process is efficient, and less than 10% of the secreted insulin circulates as proinsulin. Changes in plasma proinsulin levels can predict risk of type 2 diabetes and indicate beta cell dysfunction. Genome-wide association studies have identified genetic variants associated with plasma proinsulin levels but identifying the genes and variants driving these associations remains challenging. In this issue, Parsons et al (https://doi.org/10.1007/s00125-025-06391-w) investigate a proinsulin genetic association signal at the gene TBC1D30, which encodes a putative Rab GTPase-activating protein that may affect vesicle trafficking. The authors report that genome editing of TBC1D30’s sequence in insulinoma cells and gene knockdown in human islets altered proinsulin and insulin secretion. The authors conclude that TBC1D30 plays a role in insulin secretion and is likely the affected gene underlying the association signal.

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