{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC5A1, which encodes the sodium‐glucose cotransporter 1 (SGLT1), plays a critical role in active glucose uptake across multiple epithelia. In the kidney, although the bulk of filtered glucose reabsorption is mediated by its close homolog SGLT2, SGLT1 is responsible for reabsorbing residual glucose in the later segments of the proximal tubule, thereby contributing to overall glucose homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the intestine, SGLT1‐mediated glucose uptake is essential not only for nutrient absorption but also for cytoprotection against enterocyte apoptosis and barrier dysfunction induced by bacterial products, and its activity is modulated by external glucose concentrations and specific inhibitors such as phloridzin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Furthermore, beyond its classical roles in the gut and kidney, SGLT1 is expressed in the heart where it contributes to cardiomyocyte glucose uptake"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and its critical importance is underscored by mutations in SLC5A1 that cause glucose–galactose malabsorption, a life‐threatening neonatal disorder."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, altered SGLT1 expression has been implicated in various pathological contexts including enhanced glucose absorption in diabetes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", modulation by dietary polyphenols in the gut"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and aberrant expression in several cancers that in some cases correlates with prognosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": " Moreover, recent findings have extended the physiological relevance of SGLT1 to reproductive tissues where its expression influences endometrial glycogen storage and pregnancy outcomes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, extensive biophysical and structural studies have delineated key aspects of SGLT1 function. Investigations utilizing polarized intestinal cell models revealed that a substantial intracellular reserve of SGLT1 exists, which may be mobilized for regulated expression at the apical membrane."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Cryo‐electron microscopy and molecular dynamics simulations have provided insights into the architecture of SGLT1, uncovering the substrate binding and selectivity mechanisms that govern cotransport activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Functional reconstitution experiments and voltage‐jump analyses in heterologous expression systems further defined the kinetics of conformational transitions during the transport cycle"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", while analyses of intrinsic tryptophan fluorescence and cysteine‐targeted labeling have revealed critical disulfide interactions that influence transporter conformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSGLT1 function is subject to multifaceted regulation by cellular signaling pathways and interacting proteins. Activation of energy‐sensing kinases, such as AMPK, has been shown to promote the translocation of SGLT1 to the plasma membrane, thereby enhancing its activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " In parallel, the circadian clock component PER1 regulates SGLT1 transcription in renal proximal tubules, linking transporter expression to daily variations in sodium and glucose homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " Pharmacological inhibitors, including novel thioglycoside derivatives, competitively inhibit SGLT1 with distinct selectivity, providing a therapeutic avenue to modulate glucose absorption."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Endothelial studies have further implicated SGLT1 in mediating the uptake of bioactive compounds such as anthocyanins, which in turn influence cellular oxidative stress and mitochondrial function"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", while overexpression of regulatory proteins like MAP17 and viral oncoproteins (e.g. HPV E6) enhance SGLT1 expression in tumor cells, linking its activity to cancer cell survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "28"}]}, {"type": "t", "text": " Genetic studies have also identified variants in SLC5A1 that modulate its function and are associated with altered glucose handling and diabetic excursions, underscoring its clinical significance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": " Finally, additional evidence from tumor cell models indicates that SGLT1 upregulation supports intracellular glucose levels and may complement kinase‐independent activities of receptors such as IGF‐1R in sustaining cell viability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Charles S Hummel, Chuan Lu, Donald D F Loo, et al. 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