{"gene":"SLC5A1","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1992,"finding":"SGLT1 is a Na+/glucose cotransporter with a 12 membrane-spanning helical model; N-linked glycosylation at Asn248 is not required for function; Asp28 and Arg300 are essential residues for functional expression, with missense mutation D28N causing glucose-galactose malabsorption.","method":"cDNA cloning, expression in Xenopus oocytes, site-directed mutagenesis, electrophysiology","journal":"Acta physiologica Scandinavica. Supplementum","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in oocytes with mutagenesis, foundational structure-function paper","pmids":["1449065"],"is_preprint":false},{"year":1991,"finding":"SGLT1 mRNA and protein are expressed along the villus but not in crypts of rabbit small intestine; SGLT1 protein is restricted to the brush borders of mature enterocytes, increasing from crypt-villus junction to villus tip.","method":"In situ hybridization, immunocytochemistry","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — two orthogonal direct localization methods, replicated across intestinal regions","pmids":["1764071"],"is_preprint":false},{"year":1994,"finding":"The human SGLT1 gene comprises 15 exons spanning 72 kilobases on chromosome 22q11.2-qter; structure suggests evolutionary origin from a six-membrane-span ancestral precursor via gene duplication; missense mutation in exon 1 causes glucose/galactose malabsorption.","method":"Genomic cloning, restriction mapping, sequencing, chromosomal mapping in somatic cell hybrids","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — complete gene structure with functional mutation identification","pmids":["8195156"],"is_preprint":false},{"year":1997,"finding":"GLP-2 infusion in vivo induces trafficking of SGLT1 from an intracellular pool into the brush-border membrane within 60 minutes, producing a 3-fold increase in maximal transport rate; this effect is blocked by luminal brefeldin A or wortmannin, implicating phosphoinositol 3-kinase in the signaling pathway.","method":"Brush-border membrane vesicle isolation, kinetic analysis, sodium-dependent phloridzin binding, Western blotting, pharmacological inhibition in vivo","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (vesicle transport, phloridzin binding, Western blot, inhibitor studies) in single study","pmids":["9435650"],"is_preprint":false},{"year":1997,"finding":"SGLT1 is expressed in neurons of rabbit, pig, and human brain (pyramidal cells of cortex/hippocampus, Purkinje cells of cerebellum); neuronal SGLT1 can be upregulated during epileptic seizure as shown by increased [14C]AMG uptake persisting >1 day post-seizure.","method":"In situ hybridization, immunohistochemistry, Western blotting with synaptosomal membranes, autoradiography of radiolabeled SGLT1 substrate","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in multiple species including human","pmids":["9202297"],"is_preprint":false},{"year":1999,"finding":"Missense mutations G318R and A468V in SGLT1 cause glucose-galactose malabsorption by defective trafficking of mutant proteins from the endoplasmic reticulum to the plasma membrane; both mutant proteins are core-glycosylated and present in total cell protein but absent from the plasma membrane as shown by pre-steady-state current measurements.","method":"SSCP analysis, sequencing, Xenopus oocyte expression, radiotracer uptake, two-electrode voltage clamp, Western blotting, pre-steady-state current measurement","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in oocytes with multiple functional assays and trafficking localization","pmids":["10036327"],"is_preprint":false},{"year":2001,"finding":"SGLT1 cotransports water directly (264 water molecules per 2 Na+ and 1 sugar for human SGLT1; 424 for rabbit SGLT1) and also acts as a passive water channel; the cotransport is tightly coupled to sugar-induced current; coexpression with AQP1 enables near-instantaneous isotonic transport.","method":"Xenopus oocyte expression, electrophysiological voltage clamp, optical volume measurement","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with quantitative biophysical measurements of coupled water and ion transport","pmids":["11251046"],"is_preprint":false},{"year":2001,"finding":"HNF-1 binding to the minimal SGLT1 promoter (-66/+21 bp) is required for basal promoter function and glucose-induced transcriptional activation; site-directed mutagenesis of the HNF-1 motif eliminates basal promoter activity; HNF-1 abundance declines coordinately with SGLT1 during ruminant maturation and is restored by glucose infusion.","method":"Deletion analysis, site-directed mutagenesis, luciferase reporter assays, DNA mobility-shift assays, Northern blotting","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — promoter mutagenesis plus EMSA and in vivo correlation","pmids":["11606209"],"is_preprint":false},{"year":2002,"finding":"Vimentin is required for localization of SGLT1 in detergent-resistant membrane microdomains (lipid rafts); absence of vimentin in Vim-/- renal proximal tubular cells dramatically decreases SGLT1 protein in DRM and Na-glucose cotransport activity; disrupting rafts with methyl-β-cyclodextrin recapitulates the Vim-/- phenotype; cholesterol supplementation restores transport activity in Vim-/- cells.","method":"Primary culture from vimentin-null mice, detergent-resistant membrane fractionation, Na-glucose transport assay, cholesterol depletion/repletion","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — genetic KO combined with pharmacological and biochemical rescue experiments","pmids":["11865027"],"is_preprint":false},{"year":2002,"finding":"EGF stimulates translocation of SGLT1 from an internal microsomal pool into the brush border, increasing brush-border SGLT1 content and Vmax for glucose uptake; this effect requires actin polymerization and is abolished by cytochalasin D.","method":"Rabbit jejunal loop preparation, brush-border membrane vesicle Western blot, microsomal membrane Western blot, glucose kinetics, electron microscopy, pharmacological inhibition","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (membrane fractionation, kinetics, EM) in intact tissue","pmids":["9950820","12430982"],"is_preprint":false},{"year":2003,"finding":"In polarized Caco-2 cells, SGLT1 resides predominantly (~2:1 ratio) in intracellular compartments associated with microtubules rather than the apical membrane, representing a reserve pool; the intracellular pool is not simply newly synthesized protein (unchanged by cycloheximide); SGLT1 half-life is ~2.5 days.","method":"Free-flow electrophoresis fractionation, ELISA with epitope-specific antibodies, confocal microscopy, cycloheximide chase, metabolic labeling and immunoprecipitation","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal subcellular fractionation and imaging methods","pmids":["12773314"],"is_preprint":false},{"year":2004,"finding":"Nedd4-2 reduces SGLT1 activity; SGK1, SGK3, and PKB reverse Nedd4-2-mediated inhibition of SGLT1 by phosphorylating Nedd4-2; kinase-inactive mutants are without effect; deletion of SGK/PKB phosphorylation sites in Nedd4-2 blocks kinase effects on SGLT1.","method":"Xenopus oocyte co-expression, two-electrode voltage clamp (glucose-induced current), mutagenesis of Nedd4-2 phosphorylation sites, kinase phosphorylation assay","journal":"Obesity research","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in oocytes with mutagenesis of regulatory sites and kinase activity assay","pmids":["15166308"],"is_preprint":false},{"year":2008,"finding":"Sp1 and HNF1 transcription factors act synergistically at the rabbit SGLT1 promoter (within 196 bp upstream of transcription start site) to drive SGLT1 transcription; binding of both factors is reduced during chronic intestinal inflammation, contributing to decreased SGLT1 expression.","method":"SGLT1 promoter cloning, deletion analysis, reporter assays, mobility shift assays (EMSA), chromatin analysis","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1 — promoter mutagenesis, reporter assays, EMSA with functional correlation to disease model","pmids":["18339704"],"is_preprint":false},{"year":2010,"finding":"AMPK activation (constitutively active γR70Q-AMPK) enhances SGLT1 maximal transport rate without changing substrate affinity; AICAR, phenformin, and A-769662 increase SGLT1 protein abundance in the plasma membrane of Caco2 cells, suggesting AMPK promotes membrane translocation of SGLT1.","method":"Xenopus oocyte co-expression with AMPK constructs, dual electrode voltage clamp, confocal microscopy, Western blotting of membrane fractions of Caco2 cells","journal":"Molecular membrane biology","confidence":"High","confidence_rationale":"Tier 2 — oocyte reconstitution with kinase-dead controls plus cell-based membrane fractionation","pmids":["20334581"],"is_preprint":false},{"year":2011,"finding":"Homology modeling of hSGLT1 based on bacterial Na+ cotransporter structures, combined with mutagenesis of conserved gate and ligand-binding residues expressed in Xenopus oocytes, established that: (1) sugar and phlorizin share the same binding site; (2) F101 is involved in binding the phloretin moiety of phlorizin; (3) external Na+ opens the sugar-binding vestibule; (4) external gate residues are critical for efficient Na+/sugar cotransport stoichiometry.","method":"Homology modeling, site-directed mutagenesis, Xenopus oocyte expression, electrophysiology, SCAM (substituted-cysteine accessibility), phlorizin inhibition kinetics","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1 — structure-guided mutagenesis with multiple functional and accessibility assays","pmids":["22159082"],"is_preprint":false},{"year":2012,"finding":"Tau tubulin kinase 2 (TTBK2) increases SGLT1 membrane carrier protein abundance and electrogenic glucose transport capacity; this requires the full-length TTBK2 and its kinase activity, as truncated or kinase-dead mutants have no effect.","method":"Xenopus oocyte co-expression, dual electrode voltage clamp, kinase-dead and truncation mutants","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — oocyte reconstitution with kinase-dead controls; single lab, single expression system","pmids":["22814243"],"is_preprint":false},{"year":2011,"finding":"JAK2 (and the V617F gain-of-function mutant) increases SGLT1 maximal transport rate by enhancing carrier insertion into the plasma membrane (increased membrane protein abundance); kinase-inactive K882E-JAK2 has no effect; JAK2 inhibitor AG490 abrogates the stimulation.","method":"Xenopus oocyte co-expression, dual electrode voltage clamp, chemiluminescence membrane abundance assay, brefeldin A chase","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — oocyte reconstitution with kinase-dead control and inhibitor; single lab","pmids":["21406183"],"is_preprint":false},{"year":2015,"finding":"RS1 (RSC1A1) blocks exocytosis of SGLT1-containing vesicles from the Golgi via a phosphorylation-dependent mechanism in its RS1-Reg domain; glucose-dependent phosphorylation of RS1-Reg disinhibits SGLT1 exocytosis after glucose ingestion; RS1-Reg-derived peptides can downregulate intestinal brush-border SGLT1 at high luminal glucose concentrations.","method":"Injection of RS1 fragments into Xenopus oocytes expressing SGLT1, uptake assay, phosphorylation site mutagenesis, cell-based vesicle release assays","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with domain mutagenesis and mechanistic dissection of Golgi exocytosis pathway","pmids":["26464324"],"is_preprint":false},{"year":2015,"finding":"Circadian clock protein PER1 transcriptionally regulates SGLT1 and NHE3 in renal proximal tubule cells; PER1 and CLOCK bind to SGLT1 and NHE3 promoters; blockade of PER1 nuclear entry decreases SGLT1 mRNA and protein (both membrane and intracellular) in mouse renal cortex and HK-2 cells.","method":"Pharmacological nuclear entry blockade, siRNA knockdown, ChIP assay, heterogeneous nuclear RNA analysis, immunoblotting of subcellular fractions, Na+-K+-ATPase activity","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 — ChIP, nuclear RNA, siRNA, pharmacological blockade across in vivo and in vitro models","pmids":["26377793"],"is_preprint":false},{"year":2016,"finding":"SGLT1 acts as an extremely efficient passive water channel with unitary water permeability (pf) similar to aquaporin-1; this pf is independent of glucose/Na+ presence, membrane voltage, or transport direction, indicating the water-impermeable occluded state is brief; passive osmotic flux through SGLT1 is orders of magnitude larger than any active water pumping.","method":"SGLT1 overexpression in MDCK monolayers, reconstitution into proteoliposomes, light scattering osmotic swelling assay, fluorescence correlation spectroscopy for protein abundance","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution in proteoliposomes plus cell monolayer, quantitative biophysical measurement","pmids":["26945065"],"is_preprint":false},{"year":2016,"finding":"Canagliflozin competitively inhibits both SGLT1 (Ki = 770.5 nM) and SGLT2 (Ki = 4.0 nM) from the extracellular side; patch-clamp experiments show inhibition is preferentially from the extracellular (not intracellular) face; 14C-canagliflozin is partially transported by SGLT2.","method":"Stable cell lines expressing human SGLT1/SGLT2, competitive inhibition kinetics, whole-cell patch-clamp, radiolabeled substrate transport","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods including patch-clamp and radiotracer with defined sidedness","pmids":["27189972"],"is_preprint":false},{"year":2019,"finding":"SGLT1 at the macula densa senses luminal glucose and upregulates NOS1 expression and activity, generating nitric oxide that blunts the tubuloglomerular feedback (TGF) response and promotes glomerular hyperfiltration; SGLT1 inhibitor KGA-2727 blocks this pathway; macula densa-specific NOS1 knockout abolishes the glucose-TGF-GFR axis.","method":"Microperfusion, micropuncture, renal clearance (FITC-inulin), macula densa-specific NOS1 KO mice, SGLT1 inhibitor KGA-2727","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO combined with pharmacological inhibition and direct functional measurements of TGF and GFR","pmids":["30867247"],"is_preprint":false},{"year":2019,"finding":"SGLT1 knockout in diabetic Akita mice attenuates diabetes-induced glomerular hyperfiltration, upregulation of macula densa NOS1 expression, kidney weight increase, glomerular enlargement, and albuminuria; SGLT1 mediates glucose-driven MD-NOS1 upregulation contributing to diabetic hyperfiltration.","method":"SGLT1 gene knockout in Akita diabetic mice, FITC-inulin GFR measurement, NOS1 immunostaining, kidney morphometry, albuminuria measurement","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 — clean KO in disease model with multiple defined phenotypic readouts, corroborates PMID 30867247","pmids":["31091127"],"is_preprint":false},{"year":2014,"finding":"Reduced constitutive nitric oxide (cNO) production inhibits SGLT1 activity by decreasing glucose affinity (Km shift) without changing Vmax; the mechanism involves altered N-linked glycosylation of SGLT1 via the cGMP/PKG signaling pathway; tunicamycin (glycosylation inhibitor) mimics the effect and reduces apparent SGLT1 molecular size from 75 kDa to 62 kDa.","method":"IEC-18 cells, transport kinetics, metabolic labeling and immunoprecipitation, PNGase-F deglycosylation, immunoblotting of luminal membranes","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution of PTM with multiple orthogonal methods linking cNO/cGMP/PKG to glycosylation to function","pmids":["24412219"],"is_preprint":false},{"year":2013,"finding":"EGFR physically associates with and stabilizes SGLT1 in cancer cells; the EGFR autophosphorylation region (978-1210 aa) is required for sufficient EGFR-SGLT1 interaction; this interaction is independent of EGFR tyrosine kinase activity and does not respond to EGF or TKIs; SGLT1 inhibition sensitizes prostate cancer cells to EGFR inhibitors.","method":"Co-immunoprecipitation, EGFR domain deletion constructs, pharmacological EGFR modulation, cell viability assays with SGLT1 inhibitor","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with domain deletion; interaction mechanism established but functional link partially pharmacological","pmids":["23765757"],"is_preprint":false},{"year":2019,"finding":"SGLT1 depletion in triple-negative breast cancer cells decreases phospho-EGFR levels and inhibits downstream AKT and ERK signaling; SGLT1 knockdown reduces cell growth in vitro and in vivo, establishing SGLT1 as required for EGFR pathway maintenance in TNBC.","method":"siRNA knockdown, Western blotting for phospho-EGFR/AKT/ERK, in vitro proliferation, in vivo xenograft","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined molecular pathway readout in vitro and in vivo; single lab","pmids":["31199048"],"is_preprint":false},{"year":2021,"finding":"PKCδ-phosphorylated EGFR (at Thr678) interacts with and stabilizes SGLT1 protein in TKI-resistant NSCLC cells; SGLT1 upregulation increases glucose uptake and confers acquired EGFR TKI resistance; SGLT1 blockade overcomes this resistance in vitro and in vivo.","method":"Co-immunoprecipitation, phosphorylation site identification, SGLT1 KD/inhibition in TKI-resistant cell lines, in vivo xenografts, glucose uptake assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with phosphorylation site identification plus functional in vivo rescue; single lab","pmids":["34155348"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of human SGLT1 in complex with its regulatory partner MAP17 bound to high-affinity inhibitor LX2761; LX2761 locks hSGLT1 in an outward-open conformation by wedging into the substrate-binding site and extracellular vestibule, blocking the putative water permeation pathway; conformational changes during outward-to-inward-open transitions are revealed.","method":"Cryo-EM structural determination of hSGLT1-MAP17 complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with inhibitor-bound state and mechanistic conformational analysis","pmids":["36307403"],"is_preprint":false},{"year":2008,"finding":"Capsaicin-sensitive vagal afferent fibers regulate posttranscriptional (but not transcriptional) control of intestinal SGLT1; total vagotomy or selective afferent deafferentation abolishes the diurnal rhythm in SGLT1 protein without affecting Sglt1 mRNA rhythm, and this is independent of the RS1 regulatory pathway.","method":"Selective capsaicin deafferentation vs. total vagotomy vs. sham surgery, quantitative PCR for Sglt1 and RS1 mRNA, immunoblotting at 6-h intervals","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic/surgical dissection with temporal protein vs. mRNA measurements; single lab","pmids":["18308853"],"is_preprint":false},{"year":2015,"finding":"Reduction of SGLT1 expression in the ventromedial hypothalamus (VMH) by shRNA augments glucagon and epinephrine counterregulatory responses to hypoglycemia and increases hepatic glucose production; VMH SGLT1 knockdown also improves impaired counterregulatory responses in recurrently hypoglycemic and diabetic rats.","method":"AAV-shRNA bilateral VMH microinjection, hypoglycemic clamp, hormone measurements, tritiated glucose kinetics","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — region-specific gene KD with defined physiological readouts in multiple disease models","pmids":["26130763"],"is_preprint":false},{"year":2020,"finding":"HNF1α directly activates the Slc5a1 (SGLT1) promoter in pancreatic α-cells; HNF1α deficiency reduces SGLT1 expression in islets; SGLT1 inhibition suppresses low-glucose-stimulated glucagon secretion in islets and αTC1-6 cells, and SGLT1 inhibition has no additional effect in HNF1α-deficient cells, placing SGLT1 downstream of HNF1α in glucagon secretion.","method":"Hnf1a knockout mice, luciferase promoter assay, islet glucagon secretion assay, SGLT1 inhibitor in αTC1-6 cells and isolated islets, gene expression analysis","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (KO) + promoter assay + pharmacological inhibition with specific phenotypic readout","pmids":["32711050"],"is_preprint":false},{"year":2021,"finding":"Mouse and human hearts express a truncated slc5a1 transcript lacking transmembrane domains and residues involved in glucose and sodium binding; SGLT1 knockout mice (lacking exon 1) show no difference in cardiac glucose uptake under basal, insulin-stimulated, or hyperglycemic conditions; high-dose phlorizin inhibits cardiac glucose uptake by a GLUT (not SGLT1)-dependent mechanism.","method":"SGLT1 exon-1 knockout mice, isolated cardiomyocyte glucose uptake assay, in vivo micro-PET, phlorizin dose-response, transcript variant sequencing","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 1-2 — clean KO model with multiple functional assays plus molecular characterization of novel transcript variant","pmids":["33416451"],"is_preprint":false},{"year":2017,"finding":"Upper small intestinal glucose sensing triggers an SGLT1-dependent pathway to lower hepatic glucose production in rodents; high-fat diet reduces SGLT1 expression and glucose sensing in the upper small intestine; metformin restores SGLT1 expression and glucose sensing; microbiota transplant from metformin-treated rats upregulates SGLT1 and restores glucose sensing.","method":"Upper small intestinal cannulation/infusion in rats, glucose production measurement, Western blotting for SGLT1, microbiota transplantation","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and microbiota manipulation with pathway placement; SGLT1 role inferred from expression changes and pharmacological blockade rather than clean KO","pmids":["29056513"],"is_preprint":false},{"year":2019,"finding":"Gene deletion of SGLT1 in mice subjected to renal ischemia-reperfusion injury does not affect the initial injury but improves kidney recovery (lower plasma creatinine, higher GFR, reduced tubular injury score, lesser fibrosis markers) compared with wild-type, identifying SGLT1 activity in the late proximal tubule as deleterious during recovery.","method":"Sglt1 gene knockout mice, bilateral renal ischemia-reperfusion, FITC-sinistrin GFR, plasma creatinine, urinary KIM-1, renal mRNA markers, histological scoring","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 2 — clean gene KO with multiple defined phenotypic and molecular readouts","pmids":["30995111"],"is_preprint":false},{"year":2014,"finding":"Incretin (GIP and GLP-1) secretion in response to intestinal glucose is abolished in SGLT1-deficient mice but not GLUT2-deficient mice, demonstrating that SGLT1 is the primary mediator of glucose-induced incretin secretion; SGLT1-deficient mice also show drastically reduced tissue retention of radiolabeled glucose throughout the small intestine.","method":"SGLT1-KO and GLUT2-KO mouse glucose gavage, radiotracer glucose tissue retention, plasma GIP, GLP-1, insulin measurements, apical membrane Western blotting","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — two transgenic KO models with multiple hormonal and tracer readouts, replicated across intestinal segments","pmids":["24587162"],"is_preprint":false},{"year":2009,"finding":"Diabetes increases SGLT1 mRNA expression in parotid and submandibular salivary glands and increases SGLT1 protein in the luminal membrane of ductal cells, which enhances water reabsorption from primary saliva and contributes to reduced salivary flow; insulin treatment reverses all alterations.","method":"Streptozotocin diabetic rat model, qRT-PCR, immunohistochemistry, salivary flow measurement, insulin reversal","journal":"The Journal of membrane biology","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative mRNA, localization by IHC, functional readout, pharmacological reversal; single lab","pmids":["19238474"],"is_preprint":false},{"year":2011,"finding":"High-starch/low-fat diet induction of SGLT1 gene expression in rat jejunum is associated with histone H3K4 mono-, di-, and trimethylation and binding of the histone acetyltransferase GCN5 at SGLT1 promoter/enhancer and transcribed regions, but not with H3K9/H4K20 methylation or HP1 binding.","method":"Chromatin immunoprecipitation (ChIP) with anti-methylated histone antibodies and anti-GCN5, quantitative PCR of precipitated chromatin, diet intervention","journal":"Journal of nutritional science and vitaminology / Nutrition","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP with multiple histone marks at SGLT1 locus; single lab, no direct mutagenesis of sites","pmids":["21697636","25592016"],"is_preprint":false}],"current_model":"SGLT1 (SLC5A1) is a 12-transmembrane-helix Na+/glucose cotransporter that drives secondary active glucose (and galactose) uptake across apical membranes of intestinal enterocytes, renal proximal tubule S3 segments, and macula densa cells using the Na+ electrochemical gradient; it simultaneously cotransports water (~264 molecules per transport cycle) and passively channels water; its plasma-membrane abundance is dynamically regulated by trafficking from an intracellular Golgi/microtubule-associated reserve pool via multiple kinases (SGK1/3, PKB, AMPK, JAK2, TTBK2) acting partly through phosphorylation of the ubiquitin ligase Nedd4-2 and the Golgi regulatory protein RS1, by EGF- and GLP-2-stimulated actin-dependent vesicle insertion, and by circadian clock proteins (PER1, CLOCK) at the transcriptional level; at the macula densa, SGLT1-mediated glucose sensing upregulates NOS1-derived NO to blunt tubuloglomerular feedback and promote glomerular hyperfiltration in diabetes; in cancer cells, SGLT1 physically interacts with EGFR (requiring the EGFR autophosphorylation domain) to stabilize glucose uptake and support survival signaling; the cryo-EM structure of hSGLT1–MAP17 with inhibitor LX2761 reveals an outward-open, inhibitor-occluded conformation explaining competitive blockade of the substrate-binding vestibule."},"narrative":{"teleology":[{"year":1991,"claim":"Establishing where SGLT1 operates: prior to tissue-level localization it was unclear which cell types and membrane domains express the transporter; in situ hybridization and immunocytochemistry showed SGLT1 is restricted to the brush-border membrane of mature villus enterocytes, establishing its polarized apical distribution.","evidence":"In situ hybridization and immunocytochemistry on rabbit small intestine sections","pmids":["1764071"],"confidence":"High","gaps":["Protein trafficking pathway from biosynthesis to brush border not addressed","Expression in non-intestinal tissues not examined"]},{"year":1992,"claim":"Defining the transport mechanism and disease-causing residues: cDNA expression in oocytes established SGLT1 as a 12-transmembrane-helix Na⁺/glucose cotransporter and identified D28 and R300 as essential residues, with D28N causing glucose–galactose malabsorption — the first direct genotype-to-phenotype link.","evidence":"cDNA cloning, Xenopus oocyte expression, site-directed mutagenesis, electrophysiology","pmids":["1449065"],"confidence":"High","gaps":["Three-dimensional structure unknown","Stoichiometry of Na⁺:glucose coupling not resolved at atomic level"]},{"year":1994,"claim":"Gene architecture revealed: the complete 15-exon, 72-kb gene on 22q11.2 was characterized, suggesting an evolutionary origin by internal duplication of a 6-TM precursor and locating additional GGM-causing mutations.","evidence":"Genomic cloning, restriction mapping, sequencing, somatic cell hybrid chromosomal mapping","pmids":["8195156"],"confidence":"High","gaps":["Regulatory elements beyond the coding region not characterized","Promoter elements not defined"]},{"year":1997,"claim":"Two key contextual expansions: (1) GLP-2 was shown to rapidly recruit SGLT1 from an intracellular reserve pool to the brush border via PI3K-dependent trafficking, establishing that membrane insertion — not transcription — acutely controls transport capacity; (2) neuronal SGLT1 expression was documented in brain with upregulation during seizure.","evidence":"Brush-border membrane vesicle isolation with phlorizin binding and inhibitor studies in vivo; immunohistochemistry and autoradiography across species","pmids":["9435650","9202297"],"confidence":"High","gaps":["Identity of the intracellular compartment not determined","Neuronal SGLT1 functional role not defined beyond expression"]},{"year":1999,"claim":"Trafficking as the disease mechanism: GGM-causing mutations G318R and A468V produce core-glycosylated protein trapped in the ER, showing that loss-of-function results from failed plasma membrane delivery rather than protein instability.","evidence":"Oocyte expression with pre-steady-state current measurement, Western blot, radiotracer uptake","pmids":["10036327"],"confidence":"High","gaps":["ER quality control machinery involved not identified","Whether pharmacological chaperones can rescue trafficking not tested"]},{"year":2001,"claim":"Two fundamental properties clarified: (1) SGLT1 cotransports ~264 water molecules per sugar cycle and also acts as a passive water channel, quantifying its role in intestinal fluid absorption; (2) HNF-1 binding at the minimal promoter is required for basal and glucose-induced SGLT1 transcription.","evidence":"Oocyte volume measurements with electrophysiology; promoter deletion/mutagenesis with EMSA and reporter assays","pmids":["11251046","11606209"],"confidence":"High","gaps":["Structural basis of the water pathway unknown","HNF-1 interplay with other transcription factors not resolved"]},{"year":2002,"claim":"Membrane-domain and cytoskeletal requirements defined: vimentin was shown to be necessary for SGLT1 localization in lipid rafts and full transport activity, and EGF was found to stimulate actin-dependent SGLT1 insertion into the brush border, establishing cytoskeletal control of surface delivery.","evidence":"Vimentin-null mouse proximal tubular cells with raft fractionation and cholesterol rescue; rabbit jejunal loop with cytochalasin D inhibition","pmids":["11865027","12430982"],"confidence":"High","gaps":["Direct vimentin–SGLT1 physical interaction not demonstrated","Actin remodeling signaling intermediates downstream of EGF not identified"]},{"year":2003,"claim":"The intracellular reserve pool was quantified: in polarized Caco-2 cells, ~2/3 of SGLT1 resides in a stable microtubule-associated intracellular compartment with a 2.5-day half-life, confirming regulated trafficking rather than de novo synthesis as the rapid-response mechanism.","evidence":"Free-flow electrophoresis fractionation, ELISA, confocal microscopy, cycloheximide chase","pmids":["12773314"],"confidence":"High","gaps":["Molecular identity of the intracellular compartment (recycling endosome vs. Golgi-derived) not resolved","Signals triggering release from the pool not identified"]},{"year":2004,"claim":"Kinase–ubiquitin ligase regulatory axis identified: SGK1, SGK3, and PKB were shown to stimulate SGLT1 by phosphorylating and inactivating the ubiquitin ligase Nedd4-2, providing a molecular mechanism for hormonal upregulation of surface SGLT1.","evidence":"Oocyte coexpression with kinase-dead and Nedd4-2 phosphosite mutants, two-electrode voltage clamp","pmids":["15166308"],"confidence":"High","gaps":["Direct ubiquitination of SGLT1 by Nedd4-2 not demonstrated","In vivo relevance of this axis in intestine or kidney not confirmed"]},{"year":2008,"claim":"Transcriptional and post-transcriptional regulation layers distinguished: Sp1/HNF1 synergy at the promoter was shown to drive transcription (reduced in inflammation), while capsaicin-sensitive vagal afferents were found to regulate SGLT1 protein rhythmicity post-transcriptionally without affecting mRNA, revealing dual-layer control.","evidence":"Promoter mutagenesis with EMSA; selective vagal deafferentation vs. total vagotomy with temporal protein/mRNA profiling","pmids":["18339704","18308853"],"confidence":"High","gaps":["Post-transcriptional mechanism downstream of vagal afferents (translation vs. stability) unresolved","Identity of vagal neurotransmitter acting on SGLT1 not known"]},{"year":2010,"claim":"AMPK added to the kinase repertoire: constitutively active AMPK increased SGLT1 Vmax by promoting membrane insertion, linking cellular energy sensing to glucose absorption capacity.","evidence":"Oocyte coexpression with AMPK constructs, voltage clamp; Caco-2 membrane fractionation with AMPK activators","pmids":["20334581"],"confidence":"High","gaps":["Whether AMPK acts through Nedd4-2 or an independent pathway not determined","Physiological stimulus activating AMPK in enterocytes not identified"]},{"year":2011,"claim":"Structure–function of the substrate-binding vestibule resolved: homology modeling guided mutagenesis showed sugar and phlorizin share the same binding site, F101 contacts the phloretin moiety, and external Na⁺ opens the vestibule gate, explaining the alternating-access mechanism.","evidence":"Homology modeling, SCAM, site-directed mutagenesis in oocytes, electrophysiology, phlorizin kinetics","pmids":["22159082"],"confidence":"High","gaps":["No experimental high-resolution structure yet","Conformational dynamics during the transport cycle not directly observed"]},{"year":2013,"claim":"An unexpected kinase-independent EGFR interaction discovered: EGFR physically associates with SGLT1 in cancer cells via the EGFR autophosphorylation domain (978-1210), stabilizing SGLT1 independent of EGFR kinase activity, linking glucose uptake to oncogenic signaling.","evidence":"Co-immunoprecipitation with EGFR domain deletion constructs, pharmacological EGFR modulation, cell viability assays","pmids":["23765757"],"confidence":"Medium","gaps":["Reciprocal SGLT1 domain mapping not performed","Whether the interaction is direct or mediated by an adaptor unknown","Single-lab finding"]},{"year":2014,"claim":"Two physiological roles clarified: (1) SGLT1, but not GLUT2, is the obligate sensor for glucose-induced incretin (GIP and GLP-1) secretion in vivo; (2) constitutive NO regulates SGLT1 glucose affinity via cGMP/PKG-dependent N-linked glycosylation, adding a post-translational control layer.","evidence":"SGLT1-KO vs. GLUT2-KO mice with glucose gavage and incretin measurements; IEC-18 transport kinetics with PNGase-F deglycosylation and metabolic labeling","pmids":["24587162","24412219"],"confidence":"High","gaps":["Which enteroendocrine cell populations require SGLT1 not resolved at single-cell level","Specific glycosylation sites regulated by NO not identified"]},{"year":2015,"claim":"Multiple regulatory nodes refined: RS1 (RSC1A1) was identified as a Golgi gatekeeper whose phosphorylation-dependent release permits SGLT1 vesicle exocytosis after glucose ingestion; PER1/CLOCK were shown to bind SGLT1 promoters driving circadian transcription in renal tubule; VMH-specific SGLT1 knockdown enhanced counterregulatory responses to hypoglycemia.","evidence":"RS1 domain injection in oocytes with phosphosite mutagenesis; ChIP for PER1/CLOCK on SGLT1 promoter with siRNA and nuclear entry blockade; AAV-shRNA VMH injection with hypoglycemic clamp","pmids":["26464324","26377793","26130763"],"confidence":"High","gaps":["RS1 phosphorylation kinase identity not established in vivo","Whether PER1 effect on SGLT1 is direct or through intermediate regulators not excluded","Central SGLT1 mechanism of glucose sensing unresolved"]},{"year":2016,"claim":"Water permeation quantified at single-molecule level: reconstituted SGLT1 has unitary water permeability comparable to AQP1, independent of substrate or voltage, establishing that passive osmotic water flux far exceeds any coupled water transport.","evidence":"SGLT1 reconstitution into proteoliposomes, MDCK monolayer expression, light-scattering osmotic assay, fluorescence correlation spectroscopy","pmids":["26945065"],"confidence":"High","gaps":["Structural pathway for water through SGLT1 not identified","Physiological contribution of SGLT1 water permeation vs. aquaporins not quantified in vivo"]},{"year":2019,"claim":"Macula densa glucose sensing mechanism established: SGLT1 at the macula densa senses luminal glucose and upregulates NOS1, generating NO that blunts tubuloglomerular feedback; SGLT1-KO in diabetic mice attenuated hyperfiltration, glomerular hypertrophy, and albuminuria, directly implicating SGLT1 in diabetic kidney disease pathogenesis.","evidence":"Microperfusion/micropuncture with SGLT1 inhibitor KGA-2727, macula densa-specific NOS1-KO; SGLT1-KO in Akita diabetic mice with GFR, morphometry, albuminuria","pmids":["30867247","31091127"],"confidence":"High","gaps":["Signal transduction from SGLT1-mediated glucose entry to NOS1 transcription not fully delineated","Whether SGLT1 blockade is renoprotective in human diabetes not tested"]},{"year":2020,"claim":"HNF1α–SGLT1 axis extended to pancreatic α-cells: HNF1α directly activates the Slc5a1 promoter in α-cells, and SGLT1 inhibition suppresses low-glucose-stimulated glucagon secretion, placing SGLT1 downstream of HNF1α in the glucagon secretory pathway.","evidence":"Hnf1a-KO mice, luciferase promoter assay, islet glucagon secretion assay with SGLT1 inhibitor","pmids":["32711050"],"confidence":"High","gaps":["Mechanism by which SGLT1-mediated Na⁺/glucose entry triggers glucagon exocytosis not resolved","Relevance to HNF1α-MODY phenotype not established"]},{"year":2021,"claim":"Cardiac SGLT1 re-evaluated: the heart expresses a truncated SLC5A1 transcript lacking key transmembrane/binding domains, and SGLT1-KO mice show no cardiac glucose uptake defect, challenging earlier claims of functional cardiac SGLT1.","evidence":"SGLT1 exon-1 KO mice, isolated cardiomyocyte uptake, micro-PET, transcript sequencing","pmids":["33416451"],"confidence":"High","gaps":["Whether the truncated transcript has any non-transport function not addressed","Applicability to human heart not confirmed"]},{"year":2022,"claim":"Atomic-resolution mechanism achieved: the cryo-EM structure of hSGLT1–MAP17 with inhibitor LX2761 revealed an outward-open conformation where the inhibitor occludes the substrate-binding vestibule and water pathway, providing a structural framework for the alternating-access transport cycle and competitive inhibitor design.","evidence":"Cryo-EM structural determination of hSGLT1–MAP17 complex","pmids":["36307403"],"confidence":"High","gaps":["Inward-open and occluded-state structures not yet determined experimentally","Structural basis of water permeation pathway not fully resolved","MAP17 functional role in transport cycle unclear"]},{"year":null,"claim":"Key unresolved questions include: the complete set of experimental structures across the transport cycle (inward-open, occluded states); the structural basis for simultaneous water permeation; whether direct Nedd4-2-mediated ubiquitination of SGLT1 occurs; the signal transduction pathway linking SGLT1-mediated glucose entry at the macula densa to NOS1 transcriptional upregulation; and the in vivo relevance of the SGLT1–EGFR interaction in cancer.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Full transport-cycle structural coverage lacking","Water permeation pathway unresolved structurally","In vivo ubiquitination of SGLT1 by Nedd4-2 not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,6,14,20,27]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[21,22,34]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,5,9,10,13,27]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,10,17]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,6,14,20,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,13,16,21,22]},{"term_id":"R-HSA-8963743","term_label":"Digestion and absorption","supporting_discovery_ids":[1,34]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,5,9,10,17]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[18,28]}],"complexes":["SGLT1–MAP17"],"partners":["MAP17","NEDD4L","SGK1","EGFR","RSC1A1","HNF1A","VIM","PER1"],"other_free_text":[]},"mechanistic_narrative":"SLC5A1 encodes SGLT1, a Na⁺/glucose cotransporter that harnesses the inward Na⁺ electrochemical gradient to drive secondary active uptake of glucose and galactose across the apical membrane of intestinal enterocytes, renal proximal tubule S3 segments, macula densa cells, and certain neurons, while simultaneously functioning as a high-capacity passive water channel [PMID:1449065, PMID:11251046, PMID:26945065]. Plasma-membrane abundance of SGLT1 is rate-limiting and dynamically controlled: a large intracellular microtubule-associated reserve pool undergoes regulated exocytic insertion in response to GLP-2, EGF, and multiple kinases (SGK1/3, PKB, AMPK, JAK2) that converge on the ubiquitin ligase Nedd4-2 and the Golgi gatekeeper RS1, while transcription is driven by HNF1α/Sp1 and modulated by the circadian clock proteins PER1/CLOCK [PMID:9435650, PMID:15166308, PMID:26464324, PMID:26377793, PMID:12773314]. SGLT1-mediated glucose sensing at the macula densa upregulates NOS1-derived nitric oxide to attenuate tubuloglomerular feedback, a mechanism that drives glomerular hyperfiltration in diabetes, and in the intestine SGLT1 is the obligate sensor for glucose-induced GIP and GLP-1 incretin secretion [PMID:30867247, PMID:31091127, PMID:24587162]. Loss-of-function missense mutations (e.g., D28N, G318R, A468V) that impair trafficking to the plasma membrane cause autosomal recessive glucose–galactose malabsorption [PMID:1449065, PMID:10036327]."},"prefetch_data":{"uniprot":{"accession":"P13866","full_name":"Sodium/glucose cotransporter 1","aliases":["High affinity sodium-glucose cotransporter","Solute carrier family 5 member 1"],"length_aa":664,"mass_kda":73.5,"function":"Electrogenic Na(+)-coupled sugar symporter that actively transports D-glucose or D-galactose at the plasma membrane, with a Na(+) to sugar coupling ratio of 2:1. Transporter activity is driven by a transmembrane Na(+) electrochemical gradient set by the Na(+)/K(+) pump (PubMed:20980548, PubMed:34880492, PubMed:35077764, PubMed:8563765, PubMed:37217492). Has a primary role in the transport of dietary monosaccharides from enterocytes to blood. Responsible for the absorption of D-glucose or D-galactose across the apical brush-border membrane of enterocytes, whereas basolateral exit is provided by GLUT2. Additionally, functions as a D-glucose sensor in enteroendocrine cells, triggering the secretion of the incretins GCG and GIP that control food intake and energy homeostasis (By similarity) (PubMed:8563765). Together with SGLT2, functions in reabsorption of D-glucose from glomerular filtrate, playing a nonredundant role in the S3 segment of the proximal tubules (By similarity). Transports D-glucose into endometrial epithelial cells, controlling glycogen synthesis and nutritional support for the embryo as well as the decidual transformation of endometrium prior to conception (PubMed:28974690). Acts as a water channel enabling passive water transport across the plasma membrane in response to the osmotic gradient created upon sugar and Na(+) uptake. Has high water conductivity, comparable to aquaporins, and therefore is expected to play an important role in transepithelial water permeability, especially in the small intestine","subcellular_location":"Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/P13866/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC5A1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC5A1","total_profiled":1310},"omim":[{"mim_id":"620216","title":"SOLUTE CARRIER FAMILY 5 (SODIUM/GLUCOSE COTRANSPORTER), MEMBER 9; SLC5A9","url":"https://www.omim.org/entry/620216"},{"mim_id":"615778","title":"CLAUDIN 15; CLDN15","url":"https://www.omim.org/entry/615778"},{"mim_id":"610238","title":"SOLUTE CARRIER FAMILY 5 (SODIUM/GLUCOSE COTRANSPORTER), MEMBER 11; SLC5A11","url":"https://www.omim.org/entry/610238"},{"mim_id":"606824","title":"GLUCOSE/GALACTOSE MALABSORPTION; GGM","url":"https://www.omim.org/entry/606824"},{"mim_id":"603252","title":"FORKHEAD BOX L1; FOXL1","url":"https://www.omim.org/entry/603252"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":497.5}],"url":"https://www.proteinatlas.org/search/SLC5A1"},"hgnc":{"alias_symbol":["D22S675","NAGT","SGLT-1"],"prev_symbol":["SGLT1"]},"alphafold":{"accession":"P13866","domains":[{"cath_id":"1.20.1730.10","chopping":"65-442_453-575_639-664","consensus_level":"high","plddt":90.2443,"start":65,"end":664}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P13866","model_url":"https://alphafold.ebi.ac.uk/files/AF-P13866-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P13866-F1-predicted_aligned_error_v6.png","plddt_mean":84.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC5A1","jax_strain_url":"https://www.jax.org/strain/search?query=SLC5A1"},"sequence":{"accession":"P13866","fasta_url":"https://rest.uniprot.org/uniprotkb/P13866.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P13866/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P13866"}},"corpus_meta":[{"pmid":"24587162","id":"PMC_24587162","title":"The 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Supplementum\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in oocytes with mutagenesis, foundational structure-function paper\",\n      \"pmids\": [\"1449065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"SGLT1 mRNA and protein are expressed along the villus but not in crypts of rabbit small intestine; SGLT1 protein is restricted to the brush borders of mature enterocytes, increasing from crypt-villus junction to villus tip.\",\n      \"method\": \"In situ hybridization, immunocytochemistry\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal direct localization methods, replicated across intestinal regions\",\n      \"pmids\": [\"1764071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human SGLT1 gene comprises 15 exons spanning 72 kilobases on chromosome 22q11.2-qter; structure suggests evolutionary origin from a six-membrane-span ancestral precursor via gene duplication; missense mutation in exon 1 causes glucose/galactose malabsorption.\",\n      \"method\": \"Genomic cloning, restriction mapping, sequencing, chromosomal mapping in somatic cell hybrids\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete gene structure with functional mutation identification\",\n      \"pmids\": [\"8195156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"GLP-2 infusion in vivo induces trafficking of SGLT1 from an intracellular pool into the brush-border membrane within 60 minutes, producing a 3-fold increase in maximal transport rate; this effect is blocked by luminal brefeldin A or wortmannin, implicating phosphoinositol 3-kinase in the signaling pathway.\",\n      \"method\": \"Brush-border membrane vesicle isolation, kinetic analysis, sodium-dependent phloridzin binding, Western blotting, pharmacological inhibition in vivo\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (vesicle transport, phloridzin binding, Western blot, inhibitor studies) in single study\",\n      \"pmids\": [\"9435650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SGLT1 is expressed in neurons of rabbit, pig, and human brain (pyramidal cells of cortex/hippocampus, Purkinje cells of cerebellum); neuronal SGLT1 can be upregulated during epileptic seizure as shown by increased [14C]AMG uptake persisting >1 day post-seizure.\",\n      \"method\": \"In situ hybridization, immunohistochemistry, Western blotting with synaptosomal membranes, autoradiography of radiolabeled SGLT1 substrate\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in multiple species including human\",\n      \"pmids\": [\"9202297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Missense mutations G318R and A468V in SGLT1 cause glucose-galactose malabsorption by defective trafficking of mutant proteins from the endoplasmic reticulum to the plasma membrane; both mutant proteins are core-glycosylated and present in total cell protein but absent from the plasma membrane as shown by pre-steady-state current measurements.\",\n      \"method\": \"SSCP analysis, sequencing, Xenopus oocyte expression, radiotracer uptake, two-electrode voltage clamp, Western blotting, pre-steady-state current measurement\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in oocytes with multiple functional assays and trafficking localization\",\n      \"pmids\": [\"10036327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SGLT1 cotransports water directly (264 water molecules per 2 Na+ and 1 sugar for human SGLT1; 424 for rabbit SGLT1) and also acts as a passive water channel; the cotransport is tightly coupled to sugar-induced current; coexpression with AQP1 enables near-instantaneous isotonic transport.\",\n      \"method\": \"Xenopus oocyte expression, electrophysiological voltage clamp, optical volume measurement\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with quantitative biophysical measurements of coupled water and ion transport\",\n      \"pmids\": [\"11251046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HNF-1 binding to the minimal SGLT1 promoter (-66/+21 bp) is required for basal promoter function and glucose-induced transcriptional activation; site-directed mutagenesis of the HNF-1 motif eliminates basal promoter activity; HNF-1 abundance declines coordinately with SGLT1 during ruminant maturation and is restored by glucose infusion.\",\n      \"method\": \"Deletion analysis, site-directed mutagenesis, luciferase reporter assays, DNA mobility-shift assays, Northern blotting\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — promoter mutagenesis plus EMSA and in vivo correlation\",\n      \"pmids\": [\"11606209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Vimentin is required for localization of SGLT1 in detergent-resistant membrane microdomains (lipid rafts); absence of vimentin in Vim-/- renal proximal tubular cells dramatically decreases SGLT1 protein in DRM and Na-glucose cotransport activity; disrupting rafts with methyl-β-cyclodextrin recapitulates the Vim-/- phenotype; cholesterol supplementation restores transport activity in Vim-/- cells.\",\n      \"method\": \"Primary culture from vimentin-null mice, detergent-resistant membrane fractionation, Na-glucose transport assay, cholesterol depletion/repletion\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO combined with pharmacological and biochemical rescue experiments\",\n      \"pmids\": [\"11865027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"EGF stimulates translocation of SGLT1 from an internal microsomal pool into the brush border, increasing brush-border SGLT1 content and Vmax for glucose uptake; this effect requires actin polymerization and is abolished by cytochalasin D.\",\n      \"method\": \"Rabbit jejunal loop preparation, brush-border membrane vesicle Western blot, microsomal membrane Western blot, glucose kinetics, electron microscopy, pharmacological inhibition\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (membrane fractionation, kinetics, EM) in intact tissue\",\n      \"pmids\": [\"9950820\", \"12430982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In polarized Caco-2 cells, SGLT1 resides predominantly (~2:1 ratio) in intracellular compartments associated with microtubules rather than the apical membrane, representing a reserve pool; the intracellular pool is not simply newly synthesized protein (unchanged by cycloheximide); SGLT1 half-life is ~2.5 days.\",\n      \"method\": \"Free-flow electrophoresis fractionation, ELISA with epitope-specific antibodies, confocal microscopy, cycloheximide chase, metabolic labeling and immunoprecipitation\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal subcellular fractionation and imaging methods\",\n      \"pmids\": [\"12773314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nedd4-2 reduces SGLT1 activity; SGK1, SGK3, and PKB reverse Nedd4-2-mediated inhibition of SGLT1 by phosphorylating Nedd4-2; kinase-inactive mutants are without effect; deletion of SGK/PKB phosphorylation sites in Nedd4-2 blocks kinase effects on SGLT1.\",\n      \"method\": \"Xenopus oocyte co-expression, two-electrode voltage clamp (glucose-induced current), mutagenesis of Nedd4-2 phosphorylation sites, kinase phosphorylation assay\",\n      \"journal\": \"Obesity research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in oocytes with mutagenesis of regulatory sites and kinase activity assay\",\n      \"pmids\": [\"15166308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sp1 and HNF1 transcription factors act synergistically at the rabbit SGLT1 promoter (within 196 bp upstream of transcription start site) to drive SGLT1 transcription; binding of both factors is reduced during chronic intestinal inflammation, contributing to decreased SGLT1 expression.\",\n      \"method\": \"SGLT1 promoter cloning, deletion analysis, reporter assays, mobility shift assays (EMSA), chromatin analysis\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — promoter mutagenesis, reporter assays, EMSA with functional correlation to disease model\",\n      \"pmids\": [\"18339704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AMPK activation (constitutively active γR70Q-AMPK) enhances SGLT1 maximal transport rate without changing substrate affinity; AICAR, phenformin, and A-769662 increase SGLT1 protein abundance in the plasma membrane of Caco2 cells, suggesting AMPK promotes membrane translocation of SGLT1.\",\n      \"method\": \"Xenopus oocyte co-expression with AMPK constructs, dual electrode voltage clamp, confocal microscopy, Western blotting of membrane fractions of Caco2 cells\",\n      \"journal\": \"Molecular membrane biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — oocyte reconstitution with kinase-dead controls plus cell-based membrane fractionation\",\n      \"pmids\": [\"20334581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Homology modeling of hSGLT1 based on bacterial Na+ cotransporter structures, combined with mutagenesis of conserved gate and ligand-binding residues expressed in Xenopus oocytes, established that: (1) sugar and phlorizin share the same binding site; (2) F101 is involved in binding the phloretin moiety of phlorizin; (3) external Na+ opens the sugar-binding vestibule; (4) external gate residues are critical for efficient Na+/sugar cotransport stoichiometry.\",\n      \"method\": \"Homology modeling, site-directed mutagenesis, Xenopus oocyte expression, electrophysiology, SCAM (substituted-cysteine accessibility), phlorizin inhibition kinetics\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis with multiple functional and accessibility assays\",\n      \"pmids\": [\"22159082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tau tubulin kinase 2 (TTBK2) increases SGLT1 membrane carrier protein abundance and electrogenic glucose transport capacity; this requires the full-length TTBK2 and its kinase activity, as truncated or kinase-dead mutants have no effect.\",\n      \"method\": \"Xenopus oocyte co-expression, dual electrode voltage clamp, kinase-dead and truncation mutants\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — oocyte reconstitution with kinase-dead controls; single lab, single expression system\",\n      \"pmids\": [\"22814243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JAK2 (and the V617F gain-of-function mutant) increases SGLT1 maximal transport rate by enhancing carrier insertion into the plasma membrane (increased membrane protein abundance); kinase-inactive K882E-JAK2 has no effect; JAK2 inhibitor AG490 abrogates the stimulation.\",\n      \"method\": \"Xenopus oocyte co-expression, dual electrode voltage clamp, chemiluminescence membrane abundance assay, brefeldin A chase\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — oocyte reconstitution with kinase-dead control and inhibitor; single lab\",\n      \"pmids\": [\"21406183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RS1 (RSC1A1) blocks exocytosis of SGLT1-containing vesicles from the Golgi via a phosphorylation-dependent mechanism in its RS1-Reg domain; glucose-dependent phosphorylation of RS1-Reg disinhibits SGLT1 exocytosis after glucose ingestion; RS1-Reg-derived peptides can downregulate intestinal brush-border SGLT1 at high luminal glucose concentrations.\",\n      \"method\": \"Injection of RS1 fragments into Xenopus oocytes expressing SGLT1, uptake assay, phosphorylation site mutagenesis, cell-based vesicle release assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with domain mutagenesis and mechanistic dissection of Golgi exocytosis pathway\",\n      \"pmids\": [\"26464324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Circadian clock protein PER1 transcriptionally regulates SGLT1 and NHE3 in renal proximal tubule cells; PER1 and CLOCK bind to SGLT1 and NHE3 promoters; blockade of PER1 nuclear entry decreases SGLT1 mRNA and protein (both membrane and intracellular) in mouse renal cortex and HK-2 cells.\",\n      \"method\": \"Pharmacological nuclear entry blockade, siRNA knockdown, ChIP assay, heterogeneous nuclear RNA analysis, immunoblotting of subcellular fractions, Na+-K+-ATPase activity\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, nuclear RNA, siRNA, pharmacological blockade across in vivo and in vitro models\",\n      \"pmids\": [\"26377793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SGLT1 acts as an extremely efficient passive water channel with unitary water permeability (pf) similar to aquaporin-1; this pf is independent of glucose/Na+ presence, membrane voltage, or transport direction, indicating the water-impermeable occluded state is brief; passive osmotic flux through SGLT1 is orders of magnitude larger than any active water pumping.\",\n      \"method\": \"SGLT1 overexpression in MDCK monolayers, reconstitution into proteoliposomes, light scattering osmotic swelling assay, fluorescence correlation spectroscopy for protein abundance\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in proteoliposomes plus cell monolayer, quantitative biophysical measurement\",\n      \"pmids\": [\"26945065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Canagliflozin competitively inhibits both SGLT1 (Ki = 770.5 nM) and SGLT2 (Ki = 4.0 nM) from the extracellular side; patch-clamp experiments show inhibition is preferentially from the extracellular (not intracellular) face; 14C-canagliflozin is partially transported by SGLT2.\",\n      \"method\": \"Stable cell lines expressing human SGLT1/SGLT2, competitive inhibition kinetics, whole-cell patch-clamp, radiolabeled substrate transport\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods including patch-clamp and radiotracer with defined sidedness\",\n      \"pmids\": [\"27189972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGLT1 at the macula densa senses luminal glucose and upregulates NOS1 expression and activity, generating nitric oxide that blunts the tubuloglomerular feedback (TGF) response and promotes glomerular hyperfiltration; SGLT1 inhibitor KGA-2727 blocks this pathway; macula densa-specific NOS1 knockout abolishes the glucose-TGF-GFR axis.\",\n      \"method\": \"Microperfusion, micropuncture, renal clearance (FITC-inulin), macula densa-specific NOS1 KO mice, SGLT1 inhibitor KGA-2727\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO combined with pharmacological inhibition and direct functional measurements of TGF and GFR\",\n      \"pmids\": [\"30867247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGLT1 knockout in diabetic Akita mice attenuates diabetes-induced glomerular hyperfiltration, upregulation of macula densa NOS1 expression, kidney weight increase, glomerular enlargement, and albuminuria; SGLT1 mediates glucose-driven MD-NOS1 upregulation contributing to diabetic hyperfiltration.\",\n      \"method\": \"SGLT1 gene knockout in Akita diabetic mice, FITC-inulin GFR measurement, NOS1 immunostaining, kidney morphometry, albuminuria measurement\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO in disease model with multiple defined phenotypic readouts, corroborates PMID 30867247\",\n      \"pmids\": [\"31091127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Reduced constitutive nitric oxide (cNO) production inhibits SGLT1 activity by decreasing glucose affinity (Km shift) without changing Vmax; the mechanism involves altered N-linked glycosylation of SGLT1 via the cGMP/PKG signaling pathway; tunicamycin (glycosylation inhibitor) mimics the effect and reduces apparent SGLT1 molecular size from 75 kDa to 62 kDa.\",\n      \"method\": \"IEC-18 cells, transport kinetics, metabolic labeling and immunoprecipitation, PNGase-F deglycosylation, immunoblotting of luminal membranes\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution of PTM with multiple orthogonal methods linking cNO/cGMP/PKG to glycosylation to function\",\n      \"pmids\": [\"24412219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EGFR physically associates with and stabilizes SGLT1 in cancer cells; the EGFR autophosphorylation region (978-1210 aa) is required for sufficient EGFR-SGLT1 interaction; this interaction is independent of EGFR tyrosine kinase activity and does not respond to EGF or TKIs; SGLT1 inhibition sensitizes prostate cancer cells to EGFR inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, EGFR domain deletion constructs, pharmacological EGFR modulation, cell viability assays with SGLT1 inhibitor\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with domain deletion; interaction mechanism established but functional link partially pharmacological\",\n      \"pmids\": [\"23765757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGLT1 depletion in triple-negative breast cancer cells decreases phospho-EGFR levels and inhibits downstream AKT and ERK signaling; SGLT1 knockdown reduces cell growth in vitro and in vivo, establishing SGLT1 as required for EGFR pathway maintenance in TNBC.\",\n      \"method\": \"siRNA knockdown, Western blotting for phospho-EGFR/AKT/ERK, in vitro proliferation, in vivo xenograft\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined molecular pathway readout in vitro and in vivo; single lab\",\n      \"pmids\": [\"31199048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKCδ-phosphorylated EGFR (at Thr678) interacts with and stabilizes SGLT1 protein in TKI-resistant NSCLC cells; SGLT1 upregulation increases glucose uptake and confers acquired EGFR TKI resistance; SGLT1 blockade overcomes this resistance in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation site identification, SGLT1 KD/inhibition in TKI-resistant cell lines, in vivo xenografts, glucose uptake assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with phosphorylation site identification plus functional in vivo rescue; single lab\",\n      \"pmids\": [\"34155348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of human SGLT1 in complex with its regulatory partner MAP17 bound to high-affinity inhibitor LX2761; LX2761 locks hSGLT1 in an outward-open conformation by wedging into the substrate-binding site and extracellular vestibule, blocking the putative water permeation pathway; conformational changes during outward-to-inward-open transitions are revealed.\",\n      \"method\": \"Cryo-EM structural determination of hSGLT1-MAP17 complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with inhibitor-bound state and mechanistic conformational analysis\",\n      \"pmids\": [\"36307403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Capsaicin-sensitive vagal afferent fibers regulate posttranscriptional (but not transcriptional) control of intestinal SGLT1; total vagotomy or selective afferent deafferentation abolishes the diurnal rhythm in SGLT1 protein without affecting Sglt1 mRNA rhythm, and this is independent of the RS1 regulatory pathway.\",\n      \"method\": \"Selective capsaicin deafferentation vs. total vagotomy vs. sham surgery, quantitative PCR for Sglt1 and RS1 mRNA, immunoblotting at 6-h intervals\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic/surgical dissection with temporal protein vs. mRNA measurements; single lab\",\n      \"pmids\": [\"18308853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Reduction of SGLT1 expression in the ventromedial hypothalamus (VMH) by shRNA augments glucagon and epinephrine counterregulatory responses to hypoglycemia and increases hepatic glucose production; VMH SGLT1 knockdown also improves impaired counterregulatory responses in recurrently hypoglycemic and diabetic rats.\",\n      \"method\": \"AAV-shRNA bilateral VMH microinjection, hypoglycemic clamp, hormone measurements, tritiated glucose kinetics\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — region-specific gene KD with defined physiological readouts in multiple disease models\",\n      \"pmids\": [\"26130763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HNF1α directly activates the Slc5a1 (SGLT1) promoter in pancreatic α-cells; HNF1α deficiency reduces SGLT1 expression in islets; SGLT1 inhibition suppresses low-glucose-stimulated glucagon secretion in islets and αTC1-6 cells, and SGLT1 inhibition has no additional effect in HNF1α-deficient cells, placing SGLT1 downstream of HNF1α in glucagon secretion.\",\n      \"method\": \"Hnf1a knockout mice, luciferase promoter assay, islet glucagon secretion assay, SGLT1 inhibitor in αTC1-6 cells and isolated islets, gene expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (KO) + promoter assay + pharmacological inhibition with specific phenotypic readout\",\n      \"pmids\": [\"32711050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mouse and human hearts express a truncated slc5a1 transcript lacking transmembrane domains and residues involved in glucose and sodium binding; SGLT1 knockout mice (lacking exon 1) show no difference in cardiac glucose uptake under basal, insulin-stimulated, or hyperglycemic conditions; high-dose phlorizin inhibits cardiac glucose uptake by a GLUT (not SGLT1)-dependent mechanism.\",\n      \"method\": \"SGLT1 exon-1 knockout mice, isolated cardiomyocyte glucose uptake assay, in vivo micro-PET, phlorizin dose-response, transcript variant sequencing\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean KO model with multiple functional assays plus molecular characterization of novel transcript variant\",\n      \"pmids\": [\"33416451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Upper small intestinal glucose sensing triggers an SGLT1-dependent pathway to lower hepatic glucose production in rodents; high-fat diet reduces SGLT1 expression and glucose sensing in the upper small intestine; metformin restores SGLT1 expression and glucose sensing; microbiota transplant from metformin-treated rats upregulates SGLT1 and restores glucose sensing.\",\n      \"method\": \"Upper small intestinal cannulation/infusion in rats, glucose production measurement, Western blotting for SGLT1, microbiota transplantation\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and microbiota manipulation with pathway placement; SGLT1 role inferred from expression changes and pharmacological blockade rather than clean KO\",\n      \"pmids\": [\"29056513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Gene deletion of SGLT1 in mice subjected to renal ischemia-reperfusion injury does not affect the initial injury but improves kidney recovery (lower plasma creatinine, higher GFR, reduced tubular injury score, lesser fibrosis markers) compared with wild-type, identifying SGLT1 activity in the late proximal tubule as deleterious during recovery.\",\n      \"method\": \"Sglt1 gene knockout mice, bilateral renal ischemia-reperfusion, FITC-sinistrin GFR, plasma creatinine, urinary KIM-1, renal mRNA markers, histological scoring\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gene KO with multiple defined phenotypic and molecular readouts\",\n      \"pmids\": [\"30995111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Incretin (GIP and GLP-1) secretion in response to intestinal glucose is abolished in SGLT1-deficient mice but not GLUT2-deficient mice, demonstrating that SGLT1 is the primary mediator of glucose-induced incretin secretion; SGLT1-deficient mice also show drastically reduced tissue retention of radiolabeled glucose throughout the small intestine.\",\n      \"method\": \"SGLT1-KO and GLUT2-KO mouse glucose gavage, radiotracer glucose tissue retention, plasma GIP, GLP-1, insulin measurements, apical membrane Western blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two transgenic KO models with multiple hormonal and tracer readouts, replicated across intestinal segments\",\n      \"pmids\": [\"24587162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Diabetes increases SGLT1 mRNA expression in parotid and submandibular salivary glands and increases SGLT1 protein in the luminal membrane of ductal cells, which enhances water reabsorption from primary saliva and contributes to reduced salivary flow; insulin treatment reverses all alterations.\",\n      \"method\": \"Streptozotocin diabetic rat model, qRT-PCR, immunohistochemistry, salivary flow measurement, insulin reversal\",\n      \"journal\": \"The Journal of membrane biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative mRNA, localization by IHC, functional readout, pharmacological reversal; single lab\",\n      \"pmids\": [\"19238474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"High-starch/low-fat diet induction of SGLT1 gene expression in rat jejunum is associated with histone H3K4 mono-, di-, and trimethylation and binding of the histone acetyltransferase GCN5 at SGLT1 promoter/enhancer and transcribed regions, but not with H3K9/H4K20 methylation or HP1 binding.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) with anti-methylated histone antibodies and anti-GCN5, quantitative PCR of precipitated chromatin, diet intervention\",\n      \"journal\": \"Journal of nutritional science and vitaminology / Nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with multiple histone marks at SGLT1 locus; single lab, no direct mutagenesis of sites\",\n      \"pmids\": [\"21697636\", \"25592016\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SGLT1 (SLC5A1) is a 12-transmembrane-helix Na+/glucose cotransporter that drives secondary active glucose (and galactose) uptake across apical membranes of intestinal enterocytes, renal proximal tubule S3 segments, and macula densa cells using the Na+ electrochemical gradient; it simultaneously cotransports water (~264 molecules per transport cycle) and passively channels water; its plasma-membrane abundance is dynamically regulated by trafficking from an intracellular Golgi/microtubule-associated reserve pool via multiple kinases (SGK1/3, PKB, AMPK, JAK2, TTBK2) acting partly through phosphorylation of the ubiquitin ligase Nedd4-2 and the Golgi regulatory protein RS1, by EGF- and GLP-2-stimulated actin-dependent vesicle insertion, and by circadian clock proteins (PER1, CLOCK) at the transcriptional level; at the macula densa, SGLT1-mediated glucose sensing upregulates NOS1-derived NO to blunt tubuloglomerular feedback and promote glomerular hyperfiltration in diabetes; in cancer cells, SGLT1 physically interacts with EGFR (requiring the EGFR autophosphorylation domain) to stabilize glucose uptake and support survival signaling; the cryo-EM structure of hSGLT1–MAP17 with inhibitor LX2761 reveals an outward-open, inhibitor-occluded conformation explaining competitive blockade of the substrate-binding vestibule.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLC5A1 encodes SGLT1, a Na⁺/glucose cotransporter that harnesses the inward Na⁺ electrochemical gradient to drive secondary active uptake of glucose and galactose across the apical membrane of intestinal enterocytes, renal proximal tubule S3 segments, macula densa cells, and certain neurons, while simultaneously functioning as a high-capacity passive water channel [PMID:1449065, PMID:11251046, PMID:26945065]. Plasma-membrane abundance of SGLT1 is rate-limiting and dynamically controlled: a large intracellular microtubule-associated reserve pool undergoes regulated exocytic insertion in response to GLP-2, EGF, and multiple kinases (SGK1/3, PKB, AMPK, JAK2) that converge on the ubiquitin ligase Nedd4-2 and the Golgi gatekeeper RS1, while transcription is driven by HNF1α/Sp1 and modulated by the circadian clock proteins PER1/CLOCK [PMID:9435650, PMID:15166308, PMID:26464324, PMID:26377793, PMID:12773314]. SGLT1-mediated glucose sensing at the macula densa upregulates NOS1-derived nitric oxide to attenuate tubuloglomerular feedback, a mechanism that drives glomerular hyperfiltration in diabetes, and in the intestine SGLT1 is the obligate sensor for glucose-induced GIP and GLP-1 incretin secretion [PMID:30867247, PMID:31091127, PMID:24587162]. Loss-of-function missense mutations (e.g., D28N, G318R, A468V) that impair trafficking to the plasma membrane cause autosomal recessive glucose–galactose malabsorption [PMID:1449065, PMID:10036327].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing where SGLT1 operates: prior to tissue-level localization it was unclear which cell types and membrane domains express the transporter; in situ hybridization and immunocytochemistry showed SGLT1 is restricted to the brush-border membrane of mature villus enterocytes, establishing its polarized apical distribution.\",\n      \"evidence\": \"In situ hybridization and immunocytochemistry on rabbit small intestine sections\",\n      \"pmids\": [\"1764071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein trafficking pathway from biosynthesis to brush border not addressed\", \"Expression in non-intestinal tissues not examined\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Defining the transport mechanism and disease-causing residues: cDNA expression in oocytes established SGLT1 as a 12-transmembrane-helix Na⁺/glucose cotransporter and identified D28 and R300 as essential residues, with D28N causing glucose–galactose malabsorption — the first direct genotype-to-phenotype link.\",\n      \"evidence\": \"cDNA cloning, Xenopus oocyte expression, site-directed mutagenesis, electrophysiology\",\n      \"pmids\": [\"1449065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Three-dimensional structure unknown\", \"Stoichiometry of Na⁺:glucose coupling not resolved at atomic level\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Gene architecture revealed: the complete 15-exon, 72-kb gene on 22q11.2 was characterized, suggesting an evolutionary origin by internal duplication of a 6-TM precursor and locating additional GGM-causing mutations.\",\n      \"evidence\": \"Genomic cloning, restriction mapping, sequencing, somatic cell hybrid chromosomal mapping\",\n      \"pmids\": [\"8195156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulatory elements beyond the coding region not characterized\", \"Promoter elements not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Two key contextual expansions: (1) GLP-2 was shown to rapidly recruit SGLT1 from an intracellular reserve pool to the brush border via PI3K-dependent trafficking, establishing that membrane insertion — not transcription — acutely controls transport capacity; (2) neuronal SGLT1 expression was documented in brain with upregulation during seizure.\",\n      \"evidence\": \"Brush-border membrane vesicle isolation with phlorizin binding and inhibitor studies in vivo; immunohistochemistry and autoradiography across species\",\n      \"pmids\": [\"9435650\", \"9202297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the intracellular compartment not determined\", \"Neuronal SGLT1 functional role not defined beyond expression\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Trafficking as the disease mechanism: GGM-causing mutations G318R and A468V produce core-glycosylated protein trapped in the ER, showing that loss-of-function results from failed plasma membrane delivery rather than protein instability.\",\n      \"evidence\": \"Oocyte expression with pre-steady-state current measurement, Western blot, radiotracer uptake\",\n      \"pmids\": [\"10036327\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ER quality control machinery involved not identified\", \"Whether pharmacological chaperones can rescue trafficking not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Two fundamental properties clarified: (1) SGLT1 cotransports ~264 water molecules per sugar cycle and also acts as a passive water channel, quantifying its role in intestinal fluid absorption; (2) HNF-1 binding at the minimal promoter is required for basal and glucose-induced SGLT1 transcription.\",\n      \"evidence\": \"Oocyte volume measurements with electrophysiology; promoter deletion/mutagenesis with EMSA and reporter assays\",\n      \"pmids\": [\"11251046\", \"11606209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the water pathway unknown\", \"HNF-1 interplay with other transcription factors not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Membrane-domain and cytoskeletal requirements defined: vimentin was shown to be necessary for SGLT1 localization in lipid rafts and full transport activity, and EGF was found to stimulate actin-dependent SGLT1 insertion into the brush border, establishing cytoskeletal control of surface delivery.\",\n      \"evidence\": \"Vimentin-null mouse proximal tubular cells with raft fractionation and cholesterol rescue; rabbit jejunal loop with cytochalasin D inhibition\",\n      \"pmids\": [\"11865027\", \"12430982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vimentin–SGLT1 physical interaction not demonstrated\", \"Actin remodeling signaling intermediates downstream of EGF not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The intracellular reserve pool was quantified: in polarized Caco-2 cells, ~2/3 of SGLT1 resides in a stable microtubule-associated intracellular compartment with a 2.5-day half-life, confirming regulated trafficking rather than de novo synthesis as the rapid-response mechanism.\",\n      \"evidence\": \"Free-flow electrophoresis fractionation, ELISA, confocal microscopy, cycloheximide chase\",\n      \"pmids\": [\"12773314\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the intracellular compartment (recycling endosome vs. Golgi-derived) not resolved\", \"Signals triggering release from the pool not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Kinase–ubiquitin ligase regulatory axis identified: SGK1, SGK3, and PKB were shown to stimulate SGLT1 by phosphorylating and inactivating the ubiquitin ligase Nedd4-2, providing a molecular mechanism for hormonal upregulation of surface SGLT1.\",\n      \"evidence\": \"Oocyte coexpression with kinase-dead and Nedd4-2 phosphosite mutants, two-electrode voltage clamp\",\n      \"pmids\": [\"15166308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitination of SGLT1 by Nedd4-2 not demonstrated\", \"In vivo relevance of this axis in intestine or kidney not confirmed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Transcriptional and post-transcriptional regulation layers distinguished: Sp1/HNF1 synergy at the promoter was shown to drive transcription (reduced in inflammation), while capsaicin-sensitive vagal afferents were found to regulate SGLT1 protein rhythmicity post-transcriptionally without affecting mRNA, revealing dual-layer control.\",\n      \"evidence\": \"Promoter mutagenesis with EMSA; selective vagal deafferentation vs. total vagotomy with temporal protein/mRNA profiling\",\n      \"pmids\": [\"18339704\", \"18308853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-transcriptional mechanism downstream of vagal afferents (translation vs. stability) unresolved\", \"Identity of vagal neurotransmitter acting on SGLT1 not known\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"AMPK added to the kinase repertoire: constitutively active AMPK increased SGLT1 Vmax by promoting membrane insertion, linking cellular energy sensing to glucose absorption capacity.\",\n      \"evidence\": \"Oocyte coexpression with AMPK constructs, voltage clamp; Caco-2 membrane fractionation with AMPK activators\",\n      \"pmids\": [\"20334581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AMPK acts through Nedd4-2 or an independent pathway not determined\", \"Physiological stimulus activating AMPK in enterocytes not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Structure–function of the substrate-binding vestibule resolved: homology modeling guided mutagenesis showed sugar and phlorizin share the same binding site, F101 contacts the phloretin moiety, and external Na⁺ opens the vestibule gate, explaining the alternating-access mechanism.\",\n      \"evidence\": \"Homology modeling, SCAM, site-directed mutagenesis in oocytes, electrophysiology, phlorizin kinetics\",\n      \"pmids\": [\"22159082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental high-resolution structure yet\", \"Conformational dynamics during the transport cycle not directly observed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"An unexpected kinase-independent EGFR interaction discovered: EGFR physically associates with SGLT1 in cancer cells via the EGFR autophosphorylation domain (978-1210), stabilizing SGLT1 independent of EGFR kinase activity, linking glucose uptake to oncogenic signaling.\",\n      \"evidence\": \"Co-immunoprecipitation with EGFR domain deletion constructs, pharmacological EGFR modulation, cell viability assays\",\n      \"pmids\": [\"23765757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal SGLT1 domain mapping not performed\", \"Whether the interaction is direct or mediated by an adaptor unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two physiological roles clarified: (1) SGLT1, but not GLUT2, is the obligate sensor for glucose-induced incretin (GIP and GLP-1) secretion in vivo; (2) constitutive NO regulates SGLT1 glucose affinity via cGMP/PKG-dependent N-linked glycosylation, adding a post-translational control layer.\",\n      \"evidence\": \"SGLT1-KO vs. GLUT2-KO mice with glucose gavage and incretin measurements; IEC-18 transport kinetics with PNGase-F deglycosylation and metabolic labeling\",\n      \"pmids\": [\"24587162\", \"24412219\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which enteroendocrine cell populations require SGLT1 not resolved at single-cell level\", \"Specific glycosylation sites regulated by NO not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Multiple regulatory nodes refined: RS1 (RSC1A1) was identified as a Golgi gatekeeper whose phosphorylation-dependent release permits SGLT1 vesicle exocytosis after glucose ingestion; PER1/CLOCK were shown to bind SGLT1 promoters driving circadian transcription in renal tubule; VMH-specific SGLT1 knockdown enhanced counterregulatory responses to hypoglycemia.\",\n      \"evidence\": \"RS1 domain injection in oocytes with phosphosite mutagenesis; ChIP for PER1/CLOCK on SGLT1 promoter with siRNA and nuclear entry blockade; AAV-shRNA VMH injection with hypoglycemic clamp\",\n      \"pmids\": [\"26464324\", \"26377793\", \"26130763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RS1 phosphorylation kinase identity not established in vivo\", \"Whether PER1 effect on SGLT1 is direct or through intermediate regulators not excluded\", \"Central SGLT1 mechanism of glucose sensing unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Water permeation quantified at single-molecule level: reconstituted SGLT1 has unitary water permeability comparable to AQP1, independent of substrate or voltage, establishing that passive osmotic water flux far exceeds any coupled water transport.\",\n      \"evidence\": \"SGLT1 reconstitution into proteoliposomes, MDCK monolayer expression, light-scattering osmotic assay, fluorescence correlation spectroscopy\",\n      \"pmids\": [\"26945065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural pathway for water through SGLT1 not identified\", \"Physiological contribution of SGLT1 water permeation vs. aquaporins not quantified in vivo\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Macula densa glucose sensing mechanism established: SGLT1 at the macula densa senses luminal glucose and upregulates NOS1, generating NO that blunts tubuloglomerular feedback; SGLT1-KO in diabetic mice attenuated hyperfiltration, glomerular hypertrophy, and albuminuria, directly implicating SGLT1 in diabetic kidney disease pathogenesis.\",\n      \"evidence\": \"Microperfusion/micropuncture with SGLT1 inhibitor KGA-2727, macula densa-specific NOS1-KO; SGLT1-KO in Akita diabetic mice with GFR, morphometry, albuminuria\",\n      \"pmids\": [\"30867247\", \"31091127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transduction from SGLT1-mediated glucose entry to NOS1 transcription not fully delineated\", \"Whether SGLT1 blockade is renoprotective in human diabetes not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"HNF1α–SGLT1 axis extended to pancreatic α-cells: HNF1α directly activates the Slc5a1 promoter in α-cells, and SGLT1 inhibition suppresses low-glucose-stimulated glucagon secretion, placing SGLT1 downstream of HNF1α in the glucagon secretory pathway.\",\n      \"evidence\": \"Hnf1a-KO mice, luciferase promoter assay, islet glucagon secretion assay with SGLT1 inhibitor\",\n      \"pmids\": [\"32711050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SGLT1-mediated Na⁺/glucose entry triggers glucagon exocytosis not resolved\", \"Relevance to HNF1α-MODY phenotype not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cardiac SGLT1 re-evaluated: the heart expresses a truncated SLC5A1 transcript lacking key transmembrane/binding domains, and SGLT1-KO mice show no cardiac glucose uptake defect, challenging earlier claims of functional cardiac SGLT1.\",\n      \"evidence\": \"SGLT1 exon-1 KO mice, isolated cardiomyocyte uptake, micro-PET, transcript sequencing\",\n      \"pmids\": [\"33416451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the truncated transcript has any non-transport function not addressed\", \"Applicability to human heart not confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Atomic-resolution mechanism achieved: the cryo-EM structure of hSGLT1–MAP17 with inhibitor LX2761 revealed an outward-open conformation where the inhibitor occludes the substrate-binding vestibule and water pathway, providing a structural framework for the alternating-access transport cycle and competitive inhibitor design.\",\n      \"evidence\": \"Cryo-EM structural determination of hSGLT1–MAP17 complex\",\n      \"pmids\": [\"36307403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inward-open and occluded-state structures not yet determined experimentally\", \"Structural basis of water permeation pathway not fully resolved\", \"MAP17 functional role in transport cycle unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the complete set of experimental structures across the transport cycle (inward-open, occluded states); the structural basis for simultaneous water permeation; whether direct Nedd4-2-mediated ubiquitination of SGLT1 occurs; the signal transduction pathway linking SGLT1-mediated glucose entry at the macula densa to NOS1 transcriptional upregulation; and the in vivo relevance of the SGLT1–EGFR interaction in cancer.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full transport-cycle structural coverage lacking\", \"Water permeation pathway unresolved structurally\", \"In vivo ubiquitination of SGLT1 by Nedd4-2 not demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 6, 14, 20, 27]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [21, 22, 34]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 5, 9, 10, 13, 27]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 10, 17]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 6, 14, 20, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 13, 16, 21, 22]},\n      {\"term_id\": \"R-HSA-8963743\", \"supporting_discovery_ids\": [1, 34]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 5, 9, 10, 17]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [18, 28]}\n    ],\n    \"complexes\": [\n      \"SGLT1–MAP17\"\n    ],\n    \"partners\": [\n      \"MAP17\",\n      \"NEDD4L\",\n      \"SGK1\",\n      \"EGFR\",\n      \"RSC1A1\",\n      \"HNF1A\",\n      \"VIM\",\n      \"PER1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}