A Cab for Insulin: Characterising Cab45 in Pancreatic β-Cells

Abstract

The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the blood. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules, and these specialised organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin into the circulation. At this point in time, the mechanisms that govern the generation of insulin secretory granules are poorly defined. This is pertinent to understanding the molecular pathogenesis of type 2 diabetes, where a reduced population and/or compromised quality of secretory granules can contribute to the failure of β-cells to release enough insulin for the control of circulating glucose. Recently, a soluble 45 kDa Ca2+-binding protein that localises to the Golgi apparatus, Cab45, has emerged as a promising candidate that could contribute to the initial stages of secretory granule biogenesis. In the constitutively secreting HeLa cell line, Cab45 sorts secretory cargo into vesicles from the Golgi apparatus. Its mode of action can be described as an aggregative mechanism that has preference for certain cargo, providing a means by which large volumes of protein can be directed through specific trafficking routes. This is a suitable mechanism for a cell such as the β-cell, which dedicates much of its energy to synthesising insulin and other secretory cargoes, but manages to consistently traffic this cargo with high accuracy. Presented here is the first investigation of Cab45 function in cell models that participate in regulated secretion. Cab45 expression is invariably correlated to β-cell function in both humans and in animal models of type 2 diabetes, and its experimental depletion impairs the function of all models that have been studied.