INS

Existing Annotations Review

Gene Description

Existing Annotations Review

Core Functions

Binds insulin receptor with high affinity to activate receptor tyrosine kinase signaling cascades regulating glucose homeostasis

Stimulates glucose uptake in muscle and adipose tissue through GLUT4 translocation via PI3K/AKT signaling

Suppresses hepatic glucose production through inhibition of gluconeogenesis and glycogenolysis via AKT-mediated FoxO1 inactivation

Promotes lipogenesis and inhibits lipolysis in adipose tissue through SREBP-1c activation and HSL inactivation

Stimulates protein synthesis and inhibits protein degradation through mTORC1 activation and FoxO1 suppression

References

Deep Research

Falcon

Perplexity

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GO Term	Evidence	Action	Reason
GO:0005158 insulin receptor binding	IBA GO_REF:0000033	ACCEPT	Summary: This annotation represents the core molecular function of insulin - specific binding to the insulin receptor. The deep research extensively documents insulin-receptor interactions, including the two-site binding model with site-1 (high affinity, Kd ~10-30 nM) formed by L1 domain and αCT domain, and site-2 (lower affinity). Structural studies have revealed the stepwise activation mechanism involving conformational transitions from Λ-shaped to Γ-shaped to T-shaped receptor states upon insulin binding. Reason: This is the primary and most specific molecular function term for insulin. The IBA evidence is well-supported by extensive structural and biochemical data showing insulin's high-affinity and specific binding to the insulin receptor. This annotation accurately captures the core molecular activity of the protein. Supporting Evidence: file:human/INS/INS-deep-research-perplexity.md Insulin binding to site-1, the primary insulin-binding site, is composed of the L1 domain of one α-subunit and the αCT domain of the adjacent α-subunit; insulin binds to this site with high affinity (Kd approximately 10-30 nanomolar) file:human/INS/INS-deep-research-perplexity.md The binding of insulin to its extracellular receptor leads to rapid and sequential autophosphorylation of multiple tyrosine residues distributed across different domains of the intracellular region file:human/INS/INS-deep-research-falcon.md Insulin acts mainly by binding INSR, which autophosphorylates and recruits adaptor proteins (IRS, Shc), bifurcating into
GO:0005179 hormone activity	IBA GO_REF:0000033	ACCEPT	Summary: Insulin functions as a peptide hormone secreted by pancreatic beta cells that acts systemically to regulate metabolism. This annotation correctly captures insulin's role as a signaling molecule that travels through the bloodstream to affect distant target tissues. Reason: This is an accurate but general annotation. While "insulin receptor binding" is more specific and informative, "hormone activity" is also correct and provides appropriate high-level classification of insulin's molecular function. Both terms are valid and complementary. Supporting Evidence: file:human/INS/INS-deep-research-perplexity.md Insulin functions as a 51-amino acid peptide hormone composed of two polypeptide chains linked by disulfide bonds, with the primary physiological role of regulating blood glucose homeostasis through complex signaling cascades PMID:38397072 Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone.
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: Insulin is secreted from pancreatic beta cells and functions in the extracellular space, where it travels through the bloodstream to reach target tissues. This is the primary location where mature insulin carries out its function as a hormone. Reason: This is the correct and most specific cellular component annotation for the location where mature insulin functions. Insulin is a secreted hormone that acts in the extracellular space. The IBA annotation is well-supported and represents the core functional location. Supporting Evidence: file:human/INS/INS-uniprot.txt SUBCELLULAR LOCATION: Secreted. file:human/INS/INS-deep-research-perplexity.md Insulin is secreted from pancreatic beta cells into the extracellular space in response to elevated blood glucose file:human/INS/INS-deep-research-falcon.md Plasma membrane/extracellular: Ca2+-triggered exocytosis releases insulin to circulation; insulin acts as a ligand for the insulin receptor in peripheral tissues.
GO:0050714 positive regulation of protein secretion	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: This annotation likely refers to insulin's effects on stimulating secretion of various proteins in target tissues, or possibly feedback effects on beta cell secretory processes. Reason: While insulin may have some effects on protein secretion in various tissues, this is not a primary or well-characterized core function of insulin. The primary functions are glucose homeostasis, metabolic regulation, and cell growth. This annotation represents a more peripheral effect and should be marked as non-core.
GO:0042593 glucose homeostasis	IBA GO_REF:0000033	ACCEPT	Summary: This is THE core biological process for insulin. Insulin's primary physiological role is maintaining blood glucose homeostasis through stimulation of glucose uptake, suppression of hepatic glucose production, and coordination of glucose storage as glycogen. Reason: This annotation captures the central and most important biological function of insulin. Extensive literature documents insulin's critical role in glucose homeostasis, and this is the primary reason insulin exists as a hormone. This is a core annotation that must be retained. Supporting Evidence: file:human/INS/INS-deep-research-perplexity.md The most physiologically important function of insulin is the stimulation of glucose uptake from the bloodstream into insulin-responsive tissues, particularly skeletal muscle and adipose tissue file:human/INS/INS-deep-research-perplexity.md Insulin potently suppresses hepatic glucose production through both direct actions on the liver and indirect actions mediated by effects on adipose tissue, muscle, and central nervous system signaling file:human/INS/INS-uniprot.txt Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. PMID:38397072 Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. file:human/INS/INS-deep-research-falcon.md Human INS (P01308) encodes a secreted peptide hormone precursor whose primary function is to produce mature insulin (A/B chains) that is stored in dense-core secretory granules and released in a glucose- and Ca2+-regulated manner from β-cells to maintain systemic metabolic homeostasis.
GO:0005179 hormone activity	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of IBA annotation above. Electronic annotation based on InterPro domains and keywords. Reason: This is a duplicate annotation (same term as line 2) but with different evidence code (IEA vs IBA). Both are correct. Duplicates are acceptable as they come from different evidence pipelines.
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: This is a more general parent term of "extracellular space" (GO:0005615). Both are correct but extracellular space is more specific. Reason: While "extracellular space" is more specific and preferred, this annotation is not wrong. It's a valid broader term. Having both the specific and general terms is acceptable in GO annotation practice.
GO:0006006 glucose metabolic process	IEA GO_REF:0000043	ACCEPT	Summary: Insulin regulates glucose metabolism broadly, including glucose uptake, glycolysis, glycogen synthesis, and suppression of gluconeogenesis. This is a valid but broad term. Reason: This is an accurate but general term. "Glucose homeostasis" is more specific to insulin's regulatory role, but "glucose metabolic process" is also correct as insulin affects multiple aspects of glucose metabolism. Both terms provide useful information at different levels of specificity. Supporting Evidence: file:human/INS/INS-deep-research-perplexity.md Once inside the cell, glucose is phosphorylated by hexokinase to glucose-6-phosphate, which is then retained in the cell and utilized for glycolysis or stored as glycogen file:human/INS/INS-uniprot.txt It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.
GO:1901701 cellular response to oxygen-containing compound	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: This is an extremely broad term that could apply to almost any cellular process. Insulin may technically be involved in responses to various oxygen-containing compounds, but this annotation is not informative about insulin's specific function. Reason: This term is far too general and non-specific to be useful for insulin annotation. While technically insulin signaling may involve responses to oxygen-containing compounds, this annotation doesn't capture any meaningful aspect of insulin's specific biological role. This represents computational over-annotation from ARBA.
GO:0005515 protein binding	IPI PMID:17051221 Structures of human insulin-degrading enzyme reveal a new su...	MODIFY	Summary: This annotation is based on physical interaction with insulin-degrading enzyme (IDE). While technically correct, "protein binding" is uninformative. The more specific term "protease binding" is annotated separately for this interaction. Reason: Generic "protein binding" annotations should be replaced with more specific binding terms when available. In this case, since insulin binds to IDE (a protease), the annotation "protease binding" (GO:0002020) already exists and is more informative. However, the primary binding partner is the insulin receptor, so "insulin receptor binding" is most important. Proposed replacements: protease binding Supporting Evidence: PMID:17051221 Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
GO:0005515 protein binding	IPI PMID:23302862 How insulin engages its primary binding site on the insulin ...	MODIFY	Summary: This annotation is based on interaction with insulin receptor (INSR). This is the most important molecular interaction for insulin, but "protein binding" is too general. Reason: This interaction with insulin receptor should be annotated with the specific term "insulin receptor binding" (GO:0005158) which already exists in the annotation set, rather than the generic "protein binding" term. Proposed replacements: insulin receptor binding Supporting Evidence: PMID:23302862 How insulin engages its primary binding site on the insulin receptor.
GO:0005515 protein binding	IPI PMID:29512653 Structure of the insulin receptor-insulin complex by single-...	MODIFY	Summary: This is another annotation for insulin-insulin receptor interaction based on cryo-EM structure determination. Same issue as above - too generic. Reason: Should use "insulin receptor binding" (GO:0005158) instead of generic "protein binding". Proposed replacements: insulin receptor binding Supporting Evidence: PMID:29512653 Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	ACCEPT	Summary: This is from a large-scale binary protein interactome study. Multiple different binding partners detected, but all use generic "protein binding" term. Reason: For high-throughput interactome studies where specific binding functions haven't been characterized, "protein binding" is acceptable. These annotations document physical interactions even if more specific functional terms aren't yet available. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome.
GO:0005515 protein binding	IPI PMID:9388210 Inhibition of insulin receptor activation by insulin-like gr...	ACCEPT	Summary: Interaction with insulin-like growth factor binding proteins (IGFBPs) that can inhibit insulin receptor activation. Reason: Without a more specific term for IGFBP binding available in GO, "protein binding" is acceptable for documenting this interaction. This interaction has functional significance for insulin receptor signaling. Supporting Evidence: PMID:9388210 Inhibition of insulin receptor activation by insulin-like growth factor binding proteins.
GO:0005515 protein binding	IPI PMID:9773776 Megalin is an endocytic receptor for insulin.	ACCEPT	Summary: Interaction with megalin, an endocytic receptor that can internalize insulin. Reason: This documents a specific interaction with megalin that is relevant for insulin clearance and degradation. Without a more specific GO term available, "protein binding" is acceptable. Supporting Evidence: PMID:9773776 Megalin is an endocytic receptor for insulin.
GO:0042802 identical protein binding	IPI PMID:10508408 Structural consequences of the B5 histidine --> tyrosine mut...	ACCEPT	Summary: This and the following 7 annotations document insulin's ability to form dimers and higher-order oligomers (hexamers). This is important for insulin storage in secretory granules as zinc-insulin hexamers. Reason: Insulin oligomerization is a well-established and functionally important property. Insulin forms dimers and zinc-stabilized hexamers that are the storage form in pancreatic beta cells. Multiple independent studies support this annotation. Supporting Evidence: file:human/INS/INS-deep-research-perplexity.md Insulin possesses a histidine residue at position B10 that coordinates zinc ions, enabling the formation of zinc-stabilized hexamers through a toroidal geometry in which two zinc ions coordinate the B10 histidine residues of three insulin dimers file:human/INS/INS-deep-research-perplexity.md These zinc-insulin hexamers represent the predominant storage form of insulin within pancreatic beta cell secretory granules PMID:10508408 Structural consequences of the B5 histidine --> tyrosine mutation in human insulin characterized by X-ray crystallography and conformational analysis.
GO:0042802 identical protein binding	IPI PMID:17472440 A helical structural nucleus is the primary elongating unit ...	ACCEPT	Summary: Study on insulin amyloid fibril formation, another form of insulin self-association. Reason: While amyloid formation is pathological rather than physiological, it does represent insulin-insulin binding. The annotation is technically correct. Supporting Evidence: PMID:17472440 A helical structural nucleus is the primary elongating unit of insulin amyloid fibrils.
GO:0042802 identical protein binding	IPI PMID:20738396 Structural features of proinsulin C-peptide oligomeric and a...	ACCEPT	Summary: Structural study of proinsulin C-peptide oligomerization. Note this is about C-peptide, not mature insulin. Reason: C-peptide is part of the proinsulin precursor, and this annotation applies to the full-length preproinsulin/proinsulin forms that are present during biosynthesis. Supporting Evidence: PMID:20738396 2010 Aug 3. Structural features of proinsulin C-peptide oligomeric and amyloid states.
GO:0042802 identical protein binding	IPI PMID:22854022 SERF protein is a direct modifier of amyloid fiber assembly.	ACCEPT	Summary: Study on SERF protein as modifier of amyloid fiber assembly involving insulin. Reason: Documents insulin self-association in context of amyloid formation. Supporting Evidence: PMID:22854022 2012 Jul 26. SERF protein is a direct modifier of amyloid fiber assembly.
GO:0042802 identical protein binding	IPI PMID:23106816 Insulin solubility transitions by pH-dependent interactions ...	ACCEPT	Summary: Study on insulin solubility transitions involving interactions with C-peptide. Reason: Documents insulin oligomerization behavior. Supporting Evidence: PMID:23106816 Insulin solubility transitions by pH-dependent interactions with proinsulin C-peptide.
GO:0042802 identical protein binding	IPI PMID:23416304 Amino acid sequence determinants in self-assembly of insulin...	ACCEPT	Summary: Study on amino acid determinants in insulin amyloid superstructures. Reason: Documents insulin self-assembly properties. Supporting Evidence: PMID:23416304 2013 Feb 14. Amino acid sequence determinants in self-assembly of insulin chiral amyloid superstructures: role of C-terminus of B-chain in association of fibrils.
GO:0042802 identical protein binding	IPI PMID:23510797 Peptides that form β-sheets on hydrophobic surfaces accelera...	ACCEPT	Summary: Study on surface-induced insulin amyloidal aggregation. Reason: Documents insulin oligomerization. Supporting Evidence: PMID:23510797 2013 Mar 16. Peptides that form β-sheets on hydrophobic surfaces accelerate surface-induced insulin amyloidal aggregation.
GO:0042802 identical protein binding	IPI PMID:8844841 A novel complex of a phenolic derivative with insulin: struc...	ACCEPT	Summary: Structural study of insulin complexes related to T→R transition. Reason: Documents functional insulin oligomerization relevant to hexamer formation. Supporting Evidence: PMID:8844841 A novel complex of a phenolic derivative with insulin: structural features related to the T-->R transition.
GO:0008286 insulin receptor signaling pathway	IDA PMID:8702995 Akt, a pleckstrin homology domain containing kinase, is acti...	ACCEPT	Summary: This study demonstrated that insulin activates Akt (PKB) kinase primarily through phosphorylation, establishing insulin's role in the PI3K/Akt signaling cascade. Reason: This is a core biological process annotation for insulin. Activation of the insulin receptor signaling pathway is the primary mechanism by which insulin exerts its effects on glucose homeostasis and metabolism. Well-supported by extensive literature. Supporting Evidence: file:human/INS/INS-deep-research-perplexity.md The binding of insulin to its extracellular receptor leads to rapid and sequential autophosphorylation of multiple tyrosine residues distributed across different domains of the intracellular region file:human/INS/INS-deep-research-perplexity.md The phosphatidylinositol 3-kinase (PI3K) pathway represents the primary route through which insulin exerts its metabolic effects PMID:8702995 Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. file:human/INS/INS-deep-research-falcon.md PI3K→PIP3→AKT (metabolic branch): GLUT4 translocation, glycogen synthesis regulation via GSK3, mTOR-mediated protein synthesis, and transcriptional programs (e.g., FOXO regulation).
GO:0048018 receptor ligand activity	IDA PMID:8702995 Akt, a pleckstrin homology domain containing kinase, is acti...	ACCEPT	Summary: This is a general term indicating that insulin functions as a ligand for its receptor. This is accurate but less specific than "insulin receptor binding". Reason: This is a valid molecular function term that correctly describes insulin as a receptor ligand. While "insulin receptor binding" is more specific, both terms are appropriate and provide complementary information. Supporting Evidence: PMID:8702995 Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation.
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IDA PMID:8702995 Akt, a pleckstrin homology domain containing kinase, is acti...	ACCEPT	Summary: This annotation captures one of the two major signaling cascades activated by insulin - the PI3K/Akt pathway, which mediates most metabolic effects including glucose uptake, glycogen synthesis, and protein synthesis. Reason: This is a core signaling pathway for insulin and represents one of the most important mechanisms by which insulin regulates glucose homeostasis. Well-documented in the literature. Supporting Evidence: file:human/INS/INS-deep-research-perplexity.md The phosphatidylinositol 3-kinase (PI3K) pathway represents the primary route through which insulin exerts its metabolic effects, particularly regarding glucose homeostasis, glycogen synthesis, and protein synthesis file:human/INS/INS-deep-research-perplexity.md Once activated, AKT phosphorylates numerous downstream substrates that collectively mediate the metabolic effects of insulin PMID:8702995 Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. file:human/INS/INS-deep-research-falcon.md PI3K→PIP3→AKT (metabolic branch): GLUT4 translocation, glycogen synthesis regulation via GSK3, mTOR-mediated protein synthesis, and transcriptional programs (e.g., FOXO regulation).
GO:0005179 hormone activity	NAS PMID:14986111 Impaired binding of insulin to erythrocyte membrane receptor...	ACCEPT	Summary: Another instance of the hormone activity annotation, this time with NAS evidence code. Reason: Duplicate of earlier annotations but with different evidence. This is acceptable. Supporting Evidence: PMID:14986111 Impaired binding of insulin to erythrocyte membrane receptor and the activation of nitric oxide synthase by the hormone in human breast cancer.
GO:0005615 extracellular space	IDA PMID:9667398 Familial hyperproinsulinaemia due to a mutation substituting...	ACCEPT	Summary: Direct experimental evidence for insulin localization in extracellular space. Reason: This provides experimental (IDA) evidence for the cellular component annotation, complementing the IBA annotation. Supporting Evidence: PMID:9667398 Familial hyperproinsulinaemia due to a mutation substituting histidine for arginine at position 65 in proinsulin: identification of the mutation by restriction enzyme mapping.
GO:0008286 insulin receptor signaling pathway	IDA PMID:15792832 Insulin and nitric oxide stimulates glucose transport in hum...	ACCEPT	Summary: Study on insulin and nitric oxide stimulation of glucose transport in human placenta. Reason: Multiple independent experimental confirmations of insulin's role in the insulin receptor signaling pathway are valuable and support the core annotation. Supporting Evidence: PMID:15792832 2005 Jan 27. Insulin and nitric oxide stimulates glucose transport in human placenta.
GO:0008286 insulin receptor signaling pathway	IGI PMID:19727662 Extracellular PBEF/NAMPT/visfatin activates pro-inflammatory...	UNDECIDED	Summary: The GOA reference for this annotation is PMID:19727662, which is in fact a NAMPT/visfatin paper on vascular smooth muscle cells, not an insulin paper (verified during PR #764 round-2 review). The annotation itself (insulin → insulin receptor signaling pathway) is correct in principle but the cited evidence does not actually support it; cannot validate without a correct PMID. Reason: Original GOA reference (PMID:19727662) is misattributed — it is a NAMPT paper, not an insulin paper. Action retained as UNDECIDED until GOA supplies (or curator identifies) a correctly-attributed reference for IGI evidence of INS in insulin receptor signaling. Note: the broader insulin receptor signaling pathway annotation remains amply supported elsewhere in this review by other valid references. Supporting Evidence: PMID:19727662 2009 Aug 29. Extracellular PBEF/NAMPT/visfatin activates pro-inflammatory signalling in human vascular smooth muscle cells through nicotinamide phosphoribosyltransferase activity.
GO:0043123 positive regulation of canonical NF-kappaB signal transduction	IDA PMID:19727662 Extracellular PBEF/NAMPT/visfatin activates pro-inflammatory...	UNDECIDED	Summary: The GOA reference for this annotation is PMID:19727662, which is in fact a NAMPT/visfatin paper, not an insulin paper (verified during PR #764 round-2 review). Cannot validate the IDA evidence for INS → NF-kappaB signaling on the cited reference alone. Reason: Original GOA reference (PMID:19727662) is misattributed — it is a NAMPT paper studying vascular smooth muscle cells, not an insulin paper. While insulin may activate NF-kappaB in some contexts, this specific annotation cannot be evaluated until a correct reference is supplied. Supporting Evidence: PMID:19727662 2009 Aug 29. Extracellular PBEF/NAMPT/visfatin activates pro-inflammatory signalling in human vascular smooth muscle cells through nicotinamide phosphoribosyltransferase activity.
GO:0005179 hormone activity	IMP PMID:381941 A structurally abnormal insulin causing human diabetes.	ACCEPT	Summary: Classic study on structurally abnormal insulin causing diabetes, demonstrating hormone function. Reason: Another instance with experimental evidence (IMP) for hormone activity. Supporting Evidence: PMID:381941 A structurally abnormal insulin causing human diabetes.
GO:0008286 insulin receptor signaling pathway	IDA PMID:20455999 A novel domain of caveolin-2 that controls nuclear targeting...	ACCEPT	Summary: Study on caveolin-2 regulation of insulin-specific ERK activation. Reason: Additional experimental support for insulin receptor signaling pathway. Supporting Evidence: PMID:20455999 A novel domain of caveolin-2 that controls nuclear targeting: regulation of insulin-specific ERK activation and nuclear translocation by caveolin-2.
GO:0008286 insulin receptor signaling pathway	IMP PMID:14615391 Insulin stimulates glucose transport via nitric oxide/cyclic...	ACCEPT	Summary: Study showing insulin stimulates glucose transport via NO/cGMP pathway. Reason: Experimental evidence for insulin receptor signaling, though this highlights the NO/cGMP branch. Supporting Evidence: PMID:14615391 Insulin stimulates glucose transport via nitric oxide/cyclic GMP pathway in human vascular smooth muscle cells.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-6809006	ACCEPT	Summary: Proinsulin passes through the Golgi apparatus during its trafficking from ER to secretory granules. Reason: This is an accurate annotation for the biosynthetic trafficking of proinsulin through the secretory pathway. While not the final functional location, this represents an important intermediate location during insulin biogenesis in beta cells. Supporting Evidence: file:human/INS/INS-deep-research-falcon.md Golgi/TGN: trafficking and packaging into immature secretory granules.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-6809010	ACCEPT	Summary: Duplicate Golgi membrane annotation from different Reactome reaction. Reason: Multiple Reactome reactions document proinsulin trafficking through Golgi.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-6809011	ACCEPT	Summary: Another Golgi membrane annotation from Reactome. Reason: Additional Reactome support for Golgi localization.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-264997	ACCEPT	Summary: Proinsulin enters the ER lumen after translocation and undergoes disulfide bond formation there. Reason: This is an accurate annotation for an early stage of insulin biosynthesis. Preproinsulin is translocated into the ER lumen where it is processed to proinsulin and undergoes critical folding and disulfide bond formation. Supporting Evidence: file:human/INS/INS-deep-research-perplexity.md Following translocation into the ER lumen, preproinsulin undergoes signal peptide cleavage to generate proinsulin, the 86-amino acid single-chain precursor of insulin file:human/INS/INS-deep-research-perplexity.md The ER environment is specifically optimized to facilitate this disulfide bond formation through multiple specialized mechanisms PMID:40052150 Proinsulin foldability is optimized in the ER, an environment evolved to support the folding process and the formation of disulfide bonds while minimizing misfolding. PMID:38935435 Hyperoxidation of the ER delays proinsulin export and limits the proinsulin supply available for insulin granule formation.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-265010	ACCEPT	Summary: Another ER lumen annotation from Reactome pathway. Reason: Additional Reactome support for ER localization.
GO:0005796 Golgi lumen	TAS Reactome:R-HSA-264976	ACCEPT	Summary: Proinsulin travels through the Golgi lumen and binds zinc and calcium there. Reason: Accurate annotation for proinsulin trafficking. The Golgi lumen is where proinsulin binds zinc and calcium ions, which are important for subsequent crystal formation in secretory granules.