Modulation of the gut-brain axis through selective inhibition of the sodium-glucose cotransporter type 1: physiological and therapeutic implications
DOI:
https://doi.org/10.18203/2320-6012.ijrms20262193Keywords:
Gut-brain axis, SGLT1, GLP-1, Peptide YY, Satiety, Metabolic therapyAbstract
The sodium-glucose cotransporter type 1 (SGLT1) is fundamental in intestinal glucose absorption. Its selective inhibition modulates the gut-brain axis by increasing carbohydrate delivery to the distal ileum, which stimulates the secretion of incretins such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) by enteroendocrine L-cells. Objectives were to analyze the physiological bases and clinical evidence of gut-brain axis modulation through SGLT1 inhibition, as well as its therapeutic implications. Systematic literature review (2019-2026) in PubMed, Scopus, and Cochrane regarding SGLT1 kinetics, incretin release, postprandial glycemic control, and the safety profile of selective and dual inhibitors. Intestinal SGLT1 inhibition delays glucose absorption, triggering a sustained endogenous release of GLP-1 and PYY. This afferent signaling, mediated by the vagus nerve to hypothalamic centers, promotes early satiety. Clinically, inhibitors like sotagliflozin demonstrate efficacy in reducing postprandial hyperglycemia and inducing weight loss. The gastrointestinal safety profile is associated with controlled malabsorption that favorably modifies microbiota composition. SGLT1 inhibition represents a comprehensive therapeutic approach. By activating the physiological pathways of the gut-brain axis, it offers significant benefits in metabolic control, positioning itself as a promising strategy for diabetes and obesity management.
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References
Drucker DJ. The Cardiovascular Biology of Glucagon-like Peptide-1. Cell Metab. 2016;24(1):15-30. DOI: https://doi.org/10.1016/j.cmet.2016.06.009
Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell. 2019;154(2):274-84. DOI: https://doi.org/10.1016/j.cell.2013.07.004
Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2021;91(2):733-94. DOI: https://doi.org/10.1152/physrev.00055.2009
Song P, Onishi A, Koepsell H, Vallon V. Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin Ther Targets. 2022;20(9):1109-25. DOI: https://doi.org/10.1517/14728222.2016.1168808
Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2017;87(4):1409-39. DOI: https://doi.org/10.1152/physrev.00034.2006
Buse JB, Garg SK, Rosenstock J, Bailey TS, Banks P, Bode BW, et al. Sotagliflozin in Combination With Optimized Insulin Therapy in Adults With Type 1 Diabetes: The North American inTandem1 Study. Diabetes Care. 2018;41(9):1970-80. DOI: https://doi.org/10.2337/dc18-0343
Danne T, Cariou B, Banks P, St L O'Rourke K. HbA1c and Hypoglycemia Reductions at 24 and 52 Weeks With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: The European inTandem2 Study. Diabetes Care. 2018;41(9):1981-90. DOI: https://doi.org/10.2337/dc18-0342
Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N Engl J Med. 2021;384(2):129-39. DOI: https://doi.org/10.1056/NEJMoa2030186
Nauck MA, Meier JJ. The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 2023;4(6):525-36. DOI: https://doi.org/10.1016/S2213-8587(15)00482-9
Rosenstock J, Cefalu WT, Lapuerta P, Zambrowicz B, Ogbaa I, Banks P, et al. Greater efficacy of dual SGLT1/2 inhibition with sotagliflozin in type 2 diabetes with severe hyperglycemia. Diabetologia. 2022;65(3):472-83.
Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2020;124(2):499-508. DOI: https://doi.org/10.1172/JCI72227
Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, et al. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther. 2019;92(2):158-69. DOI: https://doi.org/10.1038/clpt.2012.58
Batterham RL, Bloom SR. The gut hormone peptide YY regulates appetite. Ann N Y Acad Sci. 2018;994:162-8. DOI: https://doi.org/10.1111/j.1749-6632.2003.tb03176.x
Powell DR, Smith M, Greer J, Harris A, Zhao S, DaCosta C, et al. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J Pharmacol Exp Ther. 2020;345(2):250-9. DOI: https://doi.org/10.1124/jpet.113.203364
Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2022;8(12):728-42. DOI: https://doi.org/10.1038/nrendo.2012.140
Cefalu WT, McGuire DK, Garza D. Gastrointestinal safety profile of dual SGLT1/2 inhibitors: A meta-analysis of phase 3 trials. Diabetes Obes Metab. 2023;25(4):1012-21.
D'Alessio D. The role of dysregulated glucagon secretion in type 2 diabetes. Diabetes Obes Metab. 2021;13(1):126-32. DOI: https://doi.org/10.1111/j.1463-1326.2011.01449.x
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. DOI: https://doi.org/10.1136/bmj.n71
Cani PD, Van Hul M, Lefort C, Depommier C, Rastelli M, Everard A. Microbial regulation of organismal energy homeostasis. Nat Metab. 2019;1(1):34-46. DOI: https://doi.org/10.1038/s42255-018-0017-4
Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell. 2020;165(6):1332-45. DOI: https://doi.org/10.1016/j.cell.2016.05.041
Gribble FM, Reimann F. Enteroendocrine Cells: Chemosensors in the Intestinal Epithelium. Annu Rev Physiol. 2016;78:277-99. DOI: https://doi.org/10.1146/annurev-physiol-021115-105439
Seeley RJ, Chambers AP, Sandoval DA. The role of gut adaptation in the profound effects of bariatric surgery on obesity and type 2 diabetes. Cell Metab. 2021;21(3):369-78. DOI: https://doi.org/10.1016/j.cmet.2015.01.001
Sandoval DA, D'Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015;95(2):513-48. DOI: https://doi.org/10.1152/physrev.00013.2014
Richards P, Parker HE, Adriaenssens AE, Hodgson JM, Cork SC, Trapp S, et al. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes. 2019;63(4):1224-33. DOI: https://doi.org/10.2337/db13-1440
Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R885-95. DOI: https://doi.org/10.1152/ajpregu.00520.2015
Müller TD, Finan B, Bloom SR, D'Alessio D, Tschöp MH. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72-130. DOI: https://doi.org/10.1016/j.molmet.2019.09.010
DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11-26. DOI: https://doi.org/10.1038/nrneph.2016.170
Schwartz MW, Seeley RJ, Zeltser LM, Drewnowski A, Ravussin E, Redman LM, et al. Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocr Rev. 2017;38(4):267-96. DOI: https://doi.org/10.1210/er.2017-00111
Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2022;506(7488):284-93.
Blundell JE, Halford JC. Regulation of nutrient supply: the brain and appetite control. Proc Nutr Soc. 2018;53(2):407-18. DOI: https://doi.org/10.1079/PNS19940046
Pitt B, Bhatt DL, Szarek M, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin and Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure. J Am Coll Cardiol. 2021;77(16):2040-1.
Scheen AJ. Gastrointestinal safety of SGLT-2 inhibitors and dual SGLT-1/2 inhibitors. Expert Opin Drug Saf. 2023;22(1):45-58.
Röder PV, Wu B, Liu Y, Han W. Pancreatic regulation of glucose homeostasis. Exp Mol Med. 2016;48(3):e219. DOI: https://doi.org/10.1038/emm.2016.6
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2016;444(7122):1027-31. DOI: https://doi.org/10.1038/nature05414
Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes. 2022;61(2):364-71. DOI: https://doi.org/10.2337/db11-1019
Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, et al. The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun. 2018;4:1829. DOI: https://doi.org/10.1038/ncomms2852
Vrieze A, Van Nood E, Holleman F, Salojärvi J, Kootte RS, Bartelsman JF, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2021;143(4):913-6.e7. DOI: https://doi.org/10.1053/j.gastro.2012.06.031
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31-9. DOI: https://doi.org/10.1016/S0140-6736(18)32590-X
Davies MJ, Aroda VR, Collins BS, Gabbay RA, Green J, Maruthur NM, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753-86. DOI: https://doi.org/10.2337/dci22-0034
Seidelmann SB, Feofanova E, Yu B, Franceschini N, Clish CB, Kuusisto J, et al. Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk. J Am Coll Cardiol. 2018;72(15):1763-73. DOI: https://doi.org/10.1016/j.jacc.2018.07.061