Abstract
Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D.
Highlights
Pancreatic islet β-cells maintain whole animal nutrient status via release of the glucoregulatory hormone, insulin, which is stored in dense-core secretory granules throughout the β-cell cytoplasm (Figure 1A)
Following oxidative protein folding in the Endoplasmic Reticulum (ER), proinsulin is trafficked into the Golgi, where it is packaged with other regulated secretory cargo, such as the processing hormones, prohormone convertase 1/3 (PC1/3), prohormone convertase 2 (PC2), and carboxypeptidase E (CPE), into the budding secretory granule [7,83]
adenosine triphosphate (ATP) and other metabolic signals generated by glucose oxidation directly trigger and amplify insulin granule exocytosis through membrane depolarization and insulin granule recruitment [48–50]
Summary
Pancreatic islet β-cells maintain whole animal nutrient status via release of the glucoregulatory hormone, insulin, which is stored in dense-core secretory granules throughout the β-cell cytoplasm (Figure 1A). While growing evidence supports a direct role for metabolic regulation of insulin expression, including INS gene transcription and preproinsulin mRNA translation, the mechanisms governing how metabolic signals impact ER and Golgi functions are less well-established, yet these organelles define the β-cell’s capacity for insulin granule production [24–28]. Human and rodent βity) and environmental stresses (ER and mitochondrial stress) likely contribute to β-cell cells have an exceptional ability for secretory adaptations that modify insulin production in T2D, yet how these events directly impact the β-cell’s secretory program are indecline response to either nutrient deprivation or excess [12,18,24,25]. This adaptive plasticity not well understood [29,30]. Genetic predisposition (reduced secretory capacity) and environmental stresses (ER and mitochondrial stress) likely contribute to β-cell decline in
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