Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

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.

ER Redox Homeostasis Regulates Proinsulin Trafficking and Insulin Granule Formation in the Pancreatic Islet β-Cell

“…Thus failing mitochondrial function may not only limit ATP production for exocytosis, but also directly contribute to ER hyperoxidation via an insufficient supply of reducing equivalents and increased generation of reactive oxygen species, such as hydrogen peroxide. 56 In further support of this, we show that Eb treatment can modestly improve GSIS in a cell culture model of β-cell dysfunction; however additional studies are needed to confirm these findings in human models. Future studies may investigate the links between mitochondrial dysfunction and ER redox status as a possible mechanism contributing to secretory defects in T2D.…”

From Isles of Königsberg to Islets of Langerhans: Examining the Function of the Endocrine Pancreas Through Network Science

“…These intracellular signaling steps interact with each other and are finely tuned by additional physiological, pathological, and pharmacological triggering and amplifying factors ( 133 , 141 , 262 , 263 ). The [Ca 2+ ] IC signal itself is determined by a number of upstream processes that include glucose entry, cellular and mitochondrial metabolism, and electrical responses leading to action potential-dependent Ca 2+ entry and an interplay with intracellular buffering and storage mechanisms ( 216 , 261 , 264 ). It is important to note that Ca 2+ is not just an indicator of cellular activity but is indeed a key mediator for downstream processes required for insulin secretion itself ( 265 ), where a glucose-stimulated uptake of Ca 2+ ( 266 ) triggers the fusion of insulin granules with the cell plasma membrane to elicit insulin release by exocytosis ( 267 – 269 ).…”

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

“…During the postnatal period, the endocrine pancreas expands to reach an appropriate adult β cell mass, and the insulin-secreting cells finalize their functional maturation [ 5 , 6 , 7 ]. Multiple signaling pathways orchestrate the proliferation and functional maturation of β cells and are vital to ensuring adequate insulin requirements in adulthood with the transition from infant to adult nutrition [ 8 ]. Early postnatal nutrition is currently the focus of diabetes research, as inappropriate nutrition early in life poses a risk for developing diabetes in adulthood, which can affect the β cells of the offspring even over two generations [ 7 ].…”