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.

Keywords: ER function; Golgi; beta-cell function; glutathione; granule trafficking; insulin granule; insulin secretion; proinsulin; secretory granule biogenesis.

Figure 1

Insulin is stored in dense-core secretory granules. Transmission electron micrographs of mouse β-cells depicting dense-core secretory granules (A) or a single insulin secretory granule from a human β-cell (B). Crystal structure of hexameric insulin with central Zn²⁺ ions in gray (C) coordinated by histidine (A10) side chains (D). (C,D) Paired insulin dimers within the hexamer are colored separately for visual clarity. Lavender or green denote the A chains; purple or green denote the B chains. Images were created using Mol* of 2INS from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) [14,15].

Figure 2

Nutrient metabolism supports β-cell function. Multiple stages of insulin production and secretion are regulated by mitochondrial metabolism through the generation of signaling molecules, adenosine triphosphate (ATP), tricarboxylic acid (TCA) cycle intermediates, and reducing equivalents. Long-term (>12 h) glucose stimulation can enhance INS expression through transcription and preproinsulin mRNA stability. Acute (<4 h) glucose stimulation can activate preproinsulin mRNA translation as well as support proinsulin folding in the ER by supplying reducing equivalents, such as glutathione. In addition, glucose can facilitate insulin granule assembly and export from the Golgi. Finally, glucose-derived signals can trigger plasma membrane depolarization and promote insulin granule fusion and insulin exocytosis. Images were created using Biorender.

Figure 3

Proinsulin structure. Structure of proinsulin highlighting the disulfide bonds between the A and B chains (A7-B7, A20-B19) and within the A chain (A6-A11), which are necessary for proper folding. Structure is colorized to highlight the following features: blue is the B chain; red is the A chain; green, yellow, and orange denotes C-peptide region. Images were created using Mol* of 2KQP from the RCSB PDB [15,98].

Figure 4

Proinsulin disulfide bond formation requires a redox shuttle. Isomerization of proinsulin disulfide bonds occurs through a metabolism-driven redox shuttle, involving NADPH/NADP+, glutathione (GSH/GSSG), and protein disulfide isomerases (PDIs). This process is necessary to correct mispaired cysteine residues that may lead to the formation of intermolecular disulfide bonds between proinsulin molecules. Upon proper folding and structural stabilization via the correct disulfide bonds, proinsulin exits from the ER and continues through the secretory pathway. SH denotes a free sulfhydryl in cysteine side chain; S-S denotes oxidized cystines in the disulfide bond. Images were created using Biorender.

Figure 5

VGF is an intrinsically disordered protein. (A) Disordered regions of human VGF were identified using the VL-XT algorithm in PONDR. (B) Predicted folded structure of VGF was generated using AlphaFold [154,155]. Disordered regions lack secondary structure.

Figure 6

Proinsulin granule export from the TGN. Granin proteins self-assemble into multimeric macromolecular structures, which selectively capture proinsulin and other secretory granule cargo through a process referred to as liquid phase separation. As the condensate coalesces, granin proteins interact with the Golgi membrane at cholesterol-rich lipid rafts. SPCA1-mediated Ca²⁺ influx drives oligomerization of Cab45 and further condensation of granin-proinsulin complexes. Following nutrient stimulation or other signals, disruption of Cab45 oligomers through FAM20C-mediated phosphorylation promotes proinsulin vesicle budding and exit from the TGN. Images were created using Biorender.