Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Deep research on human insulin gene
Falcon deep research report on human INS (Edison Scientific Literature, May 2026)
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Preproinsulin matures via signal peptide cleavage in the ER lumen, proinsulin folding with three disulfide bonds, trafficking through Golgi/TGN, packaging into immature secretory granules, and proteolytic processing by PC1/3, PC2 and carboxypeptidase E to yield mature insulin and C-peptide.
"INS encodes preproinsulin, a single-chain precursor that enters the regulated secretory pathway. After co-translational targeting to the rough ER, the signal peptide is removed to generate proinsulin, which folds in the ER and forms three disulfide bonds. Proinsulin then traffics through the Golgi and is packaged into secretory granules, where endoproteolytic processing yields mature insulin and C-peptide."
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Mature insulin binds the insulin receptor (INSR) and activates two main downstream branches — PI3K→AKT (metabolic) and RAS→RAF→MEK→ERK (mitogenic).
"Insulin acts mainly by binding INSR, which autophosphorylates and recruits adaptor proteins (IRS, Shc), bifurcating into: PI3K→PIP3→AKT (metabolic branch): GLUT4 translocation, glycogen synthesis regulation via GSK3, mTOR-mediated protein synthesis, and transcriptional programs (e.g., FOXO regulation). RAS→RAF→MEK→ERK (MAPK) (mitogenic branch): growth/proliferation and gene-expression programs."
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Insulin biogenesis is coupled to β-cell ER folding capacity, redox state, ER Ca2+ homeostasis, and secretory trafficking; chronic hyperglycemia selectively suppresses translation of insulin and secretion-related mRNAs prior to global translational collapse.
"Its biosynthesis is tightly coupled to ER folding capacity, redox state, ER Ca2+ homeostasis, and secretory trafficking; recent 2023–2024 work clarifies how metabolism-driven redox buffering, chronic hyperglycemia-induced translational programs, and cargo condensation mechanisms can regulate or impair insulin production and secretion."
UniProt entry for human insulin
Condensation of the β-cell secretory granule luminal cargoes pro/insulin and ICA512 RESP18 homology domain.
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Proinsulin co-condenses with ICA512 RESP18HD at pH 6.8 to form micron-scale luminal condensates, suggesting proinsulin is an early driver of insulin secretory granule biogenesis via phase separation in the early secretory pathway.
"proinsulin is an early driver of insulin SG biogenesis, in a process in which its co-condensation with RESP18HD participates in their phase separation from other secretory proteins in transit through the same compartments but destined to other routes."
Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion.
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Chronic high glucose suppresses translation of insulin and of mRNAs required for secretory granule formation, exocytosis, and metabolism-coupled insulin secretion in β-cells, before induction of ER stress or global translational collapse.
"Before induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion."
Changes in Cells Associated with Insulin Resistance.
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Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells that regulates plasma glucose, fat, ketone body, and protein metabolism.
"Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue."
The Ailing β-Cell in Diabetes: Insights From a Trip to the ER: The 2023 Outstanding Scientific Achievement Award Lecture.
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SERCA-regulated ER calcium dynamics are required for normal proinsulin processing and trafficking in β-cells; disruption underlies β-cell stress in diabetes pathophysiology.
"a role for the sarcoendoplasmic reticulum calcium ATPase (SERCA) pump in the regulation of endoplasmic reticulum (ER) calcium, protein trafficking, and proinsulin processing within the β-cell."
A metabolic redox relay supports ER proinsulin export in pancreatic islet β cells.
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Glucose metabolism supplies reductive donors (NADPH, thioredoxin flux) that buffer ER redox; ER hyperoxidation delays proinsulin export and limits insulin granule formation.
"Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation. In this report, we identified glucose metabolism as a critical determinant in the redox homeostasis of the ER."
Molecular puzzle of insulin: structural assembly pathways and their role in diabetes.
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Preproinsulin synthesis begins in pancreatic β-cells with ER translocation and signal peptide cleavage; proinsulin folds in the ER, an environment optimized to support disulfide bond formation and minimize misfolding.
"Proinsulin foldability is optimized in the ER, an environment evolved to support the folding process and the formation of disulfide bonds while minimizing misfolding."
Structural consequences of the B5 histidine --> tyrosine mutation in human insulin characterized by X-ray crystallography and conformational analysis.
Bovine and human insulin activate CD8+-autoreactive CTL expressing both type 1 and type 2 cytokines in C57BL/6 mice.
PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis.
Insulin and glucocorticoids differentially regulate leptin transcription and secretion in brown adipocytes.
Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?
Regulation of the Akt/Glycogen synthase kinase-3 axis by insulin-like growth factor-II via activation of the human insulin receptor isoform-A.
Insulin signalling and the regulation of glucose and lipid metabolism.
Glucagon regulation of plasma ketone body concentration in human diabetes.
Insulin-dependent activation of endothelial nitric oxide synthase is impaired by O-linked glycosylation modification of signaling proteins in human coronary endothelial cells.
Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved.
Differential gene expression induced by insulin and insulin-like growth factor-II through the insulin receptor isoform A.
Insulin impairs endothelium-dependent vasodilation independent of insulin sensitivity or lipid profile.
Insulin stimulates glucose transport via nitric oxide/cyclic GMP pathway in human vascular smooth muscle cells.
Insulin decreases hepatic acute phase protein levels in severely burned children.
Insulin induces the release of vasodilator compounds from platelets by a nitric oxide-G kinase-VAMP-3-dependent pathway.
Impaired binding of insulin to erythrocyte membrane receptor and the activation of nitric oxide synthase by the hormone in human breast cancer.
Intravenous insulin decreases protein breakdown in infants on extracorporeal membrane oxygenation.
Insulin activates vascular endothelial growth factor in vascular smooth muscle cells: influence of nitric oxide and of insulin resistance.
Insulin decreases the secretion of apoB-100 from hepatic HepG2 cells but does not decrease the secretion of apoB-48 from intestinal CaCo-2 cells.
Insulin and nitric oxide stimulates glucose transport in human placenta.
Neuroprotection of insulin against oxidative stress-induced apoptosis in cultured retinal neurons: involvement of phosphoinositide 3-kinase/Akt signal pathway.
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
Activation of the insulin receptor by insulin and a synthetic peptide leads to divergent metabolic and mitogenic signaling and responses.
Milk intake and feeding behavior in the first week of life and its relationship to cord blood ghrelin, leptin, and insulin concentrations.
Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers.
Extracellular PBEF/NAMPT/visfatin activates pro-inflammatory signalling in human vascular smooth muscle cells through nicotinamide phosphoribosyltransferase activity.
In vitro degradation of insulin-like peptide 3 by insulin-degrading enzyme.
A novel domain of caveolin-2 that controls nuclear targeting: regulation of insulin-specific ERK activation and nuclear translocation by caveolin-2.
Structural features of proinsulin C-peptide oligomeric and amyloid states.
SERF protein is a direct modifier of amyloid fiber assembly.
Insulin solubility transitions by pH-dependent interactions with proinsulin C-peptide.
How insulin engages its primary binding site on the insulin receptor.
Amino acid sequence determinants in self-assembly of insulin chiral amyloid superstructures: role of C-terminus of B-chain in association of fibrils.
Peptides that form β-sheets on hydrophobic surfaces accelerate surface-induced insulin amyloidal aggregation.
Resistin in dairy cows: plasma concentrations during early lactation, expression and potential role in adipose tissue.
Saturated fatty acid-induced miR-195 impairs insulin signaling and glycogen metabolism in HepG2 cells.
Glucose tolerance is associated with differential expression of microRNAs in skeletal muscle: results from studies of twins with and without type 2 diabetes.
Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis.
MicroRNA 7 Impairs Insulin Signaling and Regulates Aβ Levels through Posttranscriptional Regulation of the Insulin Receptor Substrate 2, Insulin Receptor, Insulin-Degrading Enzyme, and Liver X Receptor Pathway.
A reference map of the human binary protein interactome.
Insulin stimulates atypical protein kinase C-mediated phosphorylation of the neuronal adaptor FE65 to potentiate neurite outgrowth by activating ARF6-Rac1 signaling.
A structurally abnormal insulin causing human diabetes.
Binding of human, porcine and bovine insulin to insulin receptors from human brain, muscle and adipocytes and to expressed recombinant alternatively spliced insulin receptor isoforms.
Insulin and IGF-1 increase mitogenesis and glucose metabolism in the multiple myeloma cell line, RPMI 8226.
Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity.
Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation.
A novel complex of a phenolic derivative with insulin: structural features related to the T-->R transition.
Insulin-induced activation of NADPH-dependent H2O2 generation in human adipocyte plasma membranes is mediated by Galphai2.
Inhibition of insulin receptor activation by insulin-like growth factor binding proteins.
Effects of insulin on wound healing.
Familial hyperproinsulinaemia due to a mutation substituting histidine for arginine at position 65 in proinsulin: identification of the mutation by restriction enzyme mapping.
Megalin is an endocytic receptor for insulin.
Binding of Grb10 to the insulin receptor
Proinsulin binds zinc and calcium forming Proinsulin:zinc:calcium
P4HB mediates disulfide bond formation in Proinsulin
Proinsulin translocates from the endoplasmic reticulum to the Golgi
Proinsulin:Zinc:Calcium complex translocates to immature secretory granule
ARFGAP, cargo, v-SNAREs and p24 proteins bind nascent COPI complex
ARFGAPs stimulate ARF GTPase activity
ERGIC-to-Golgi vesicles bind dynein:dynactin
Vesicle is tethered through binding GOLGA2:GORASP1, GOLGB1 and the COG complex
cis-Golgi t-SNAREs bind YKT6 on tethered vesicle
Binding of IRS to insulin receptor
Dissociation of IRS-P from insulin receptor
Autophosphorylation of insulin receptor
Insulin binds the insulin receptor
Internalisation of the insulin receptor
Dissociation of insulin from insulin receptor
Binding of SHC1 to insulin receptor
Dissociation of p-Y427-SHC1 from insulin receptor
Amyloid fibrils have additional components
Amyloid precursor proteins form ordered fibrils
Pcsk1 (rat) cleaves human proinsulin to yield Insulin(25-56) and Insulin(57-110)
Carboxypeptidase E (rat Carboxypeptidase H) cleaves Insulin(25-56) to yield Insulin(25-54)
Pcsk2 (rat) cleaves human Insulin(57-110) to yield Insulin(90-110) and C-peptide (Insulin(57-89))
Carboxypeptidase E (rat Carboxypeptidase H) cleaves C-peptide (Insulin(57-89)) to yield C-peptide (Insulin(57-87))