Normal and defective pathways in biogenesis and maintenance of the insulin storage pool
Ming Liu, … , Ling Qi, Peter Arvan
Ming Liu, … , Ling Qi, Peter Arvan
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e142240. https://doi.org/10.1172/JCI142240.
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Normal and defective pathways in biogenesis and maintenance of the insulin storage pool

Abstract

Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β cell identity), or β cell dedifferentiation, or β cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for β cell failure in type 1 diabetes.

Authors

Ming Liu, Yumeng Huang, Xiaoxi Xu, Xin Li, Maroof Alam, Anoop Arunagiri, Leena Haataja, Li Ding, Shusen Wang, Pamela Itkin-Ansari, Randal J. Kaufman, Billy Tsai, Ling Qi, Peter Arvan

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Figure 2

β Cell phenotypes of defective insulin production and storage.

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β Cell phenotypes of defective insulin production and storage. β Cell dy...
β Cell dysfunction may begin many years before diagnosis of diabetes, and progressive deterioration of β cell function represents the natural history of T2D. In healthy, well-differentiated and well-compensated β cells (left), the synthesis of proinsulin (green) and its folding and processing are homeostatically regulated to meet metabolic demand in order to maintain the biogenesis of insulin (red), which is stored in granules for insulin secretion. Well before end-stage β cell failure, proinsulin biosynthesis may be actively ongoing even in β cells that no longer maintain an insulin storage pool (middle). β Cell degranulation appears (by immunofluorescence analysis of insulin content) as a loss of β cell identity. As the disease progresses further (right), there is also a diminution of proinsulin biosynthesis in addition to the loss of insulin storage. This schematic figure shows individual β cells for clarity, but given the heterogeneity of islet β cells, these representations should be viewed not as a fixed stage for all β cells in the population, but rather as the phenotype for a prevailing portion of islet β cells across the pancreas during disease progression. β Cell death is not shown in the figure, but this is also a relevant consideration in many forms of diabetes.