| Process/Function | Key molecular steps | Key molecules/enzymes | Subcellular localization | Evidence/source (short cite with year) |
|---|---|---|---|---|
| Preproinsulin synthesis and ER targeting | INS is translated as a 110-aa preproinsulin; N-terminal signal peptide directs cotranslational translocation into ER, where signal peptide is cleaved to form proinsulin | Signal peptide, SRP/translocon, signal peptidase | Rough ER / ER lumen of pancreatic β-cells | Ayan 2023; Urbaniak 2025 (pqac-00000003, pqac-00000002) |
| Proinsulin folding and disulfide bond formation | Proinsulin folds in ER and forms three essential disulfide bonds; misfolded molecules are retained/degraded, linking folding efficiency to insulin output | PDI, ER oxidoreductases, chaperones (e.g., BiP/GRP78, GRP94) | ER lumen | Urbaniak 2025; Rohli 2024 (pqac-00000001, pqac-00000012) |
| Metabolic support for proinsulin export | Mitochondrial metabolism supplies reductive power needed to maintain ER redox; ER hyperoxidation delays proinsulin export and reduces granule biogenesis | NADPH, thioredoxin system, mitochondrial metabolism, ERO1/PDI network | ER linked to mitochondrial metabolic pathways | Rohli 2024 (pqac-00000012, pqac-00000026) |
| ER stress and trafficking control | Chronic ER Ca2+ defects impair convertase maturation, proinsulin trafficking, and increase proinsulin/insulin ratio; altered ER→Golgi trafficking contributes to β-cell dysfunction | SERCA2, PC1/3, PC2, ER Ca2+ handling machinery | ER, cis-Golgi, intermediate secretory compartments | Evans-Molina 2024 (pqac-00000014, pqac-00000024) |
| Golgi trafficking and granule maturation | Folded proinsulin exits ER, traffics through Golgi/TGN, and is packaged into immature secretory granules for maturation | COPII machinery, Golgi sorting factors, Zn2+, Ca2+ | Golgi, trans-Golgi network, immature granules | Urbaniak 2025; Ayan 2023 (pqac-00000005, pqac-00000003) |
| Proteolytic processing to mature insulin | Proinsulin is cleaved at B-chain/C-peptide and C-peptide/A-chain junctions; dibasic residues are removed to yield mature disulfide-linked insulin A and B chains plus C-peptide | PC1/3, PC2, carboxypeptidase E/CPE | Immature/maturing secretory granules | Szablewski 2024; Ayan 2023; Urbaniak 2025 (pqac-00000004, pqac-00000003, pqac-00000005) |
| Secretory granule condensation/biogenesis | Proinsulin has intrinsic self-condensation tendency; co-condensation with ICA512 RESP18HD may help segregate cargo and drive early secretory granule formation | Proinsulin/insulin, ICA512 RESP18HD | Early secretory pathway / nascent secretory granules | Toledo 2023 (pqac-00000031) |
| Glucose-stimulated insulin secretion (triggering phase) | Glucose metabolism raises ATP, closes KATP channels, depolarizes membrane, opens voltage-gated Ca2+ channels, and triggers exocytosis of readily releasable granules | GLUT1/2, glucokinase, KATP channels, VDCCs, Ca2+ | Plasma membrane, cytosol, docked insulin granules | Dalle 2024; Szablewski 2024 (pqac-00000015, pqac-00000009) |
| Biphasic/amplified secretion | First phase releases pre-docked granules; second phase recruits reserve granules via metabolic coupling factors and cytoskeletal remodeling | Cdc42, Rac1, NAD(P)H/NADPH, PLC/PKC, cAMP | Cortical actin network, cytoplasm, plasma membrane | Szablewski 2024; Dalle 2024 (pqac-00000009, pqac-00000015) |
| Translational adaptation and glucose toxicity | Acute glucose enhances translation of proinsulin and secretion-related proteins; sustained hyperglycemia selectively suppresses translation of insulin, granule biogenesis, exocytosis, and coupling-factor mRNAs before global translational collapse | Insulin mRNA 5′UTR regulatory elements, secretion-pathway mRNAs | Cytosol/ribosomes with downstream effects on ER-granule pathway | Cheruiyot 2024 (pqac-00000025) |
| Endocrine signaling function after secretion | Mature insulin is released to circulation, dissociates to active monomers, binds insulin receptor, and activates metabolic and mitogenic signaling pathways | Insulin, INSR, IRS proteins, PI3K-AKT, MAPK | Extracellular space; target-cell plasma membrane and cytosol | Ayan 2023; Dalle 2024 (pqac-00000003, pqac-00000016) |


*Table: This table summarizes the core functional annotation of human INS/insulin from biosynthesis through secretion and downstream signaling. It integrates recent mechanistic and review evidence across subcellular compartments, highlighting the molecules and enzymes most relevant to precise functional interpretation.*