High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice
Objective: Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capa...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000080 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832576484889329664 |
|---|---|
| author | Eya Sellami Paulo Henrique Evangelista-Silva Caio Jordão Teixeira Khoudia Diop Patricia Mitchell Fernando Forato Anhê |
| author_facet | Eya Sellami Paulo Henrique Evangelista-Silva Caio Jordão Teixeira Khoudia Diop Patricia Mitchell Fernando Forato Anhê |
| author_sort | Eya Sellami |
| collection | DOAJ |
| description | Objective: Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capacity of luminal nutrients. While glucose is the primary dietary energy source absorbed in the gut, it is unknown whether excess fructose alters gut glucose sensing to impair blood glucose regulation and liver homeostasis. Methods: Mice were fed diets where carbohydrates were either entirely glucose (70 %Kcal) or glucose partially replaced with fructose (8.5 %Kcal). Glp2 receptor (Glp2r) was inhibited with Glp2 (3-33) injections. Glucose tolerance, insulin sensitivity, and gut glucose absorption were concomitantly assessed, and enteric sugar transporters and absorptive surface were quantified by RT-qPCR and histological analysis, respectively. Results: High fructose feeding led to impairment of blood glucose disposal, ectopic fat accumulation in the liver, and hepatic (but not muscle or adipose tissue) insulin resistance independent of changes in fat mass. This was accompanied by increased gut glucose absorption, which preceded glucose intolerance and liver steatosis. Fructose upregulated glucose transporters and enlarged the gut surface, but these effects were prevented by Glp2r inhibition. Blocking Glp2r prevented fructose-induced impairments in glucose disposal and hepatic lipid handling. Conclusion: Excess fructose impairs blood glucose and liver homeostasis by rewiring gut glucose sensing and exacerbating gut glucose absorption. Our findings are positioned to inform novel early diagnostic tools and treatments tailored to counter high fructose-induced metabolic derangements predisposing to T2D and MASLD. |
| format | Article |
| id | doaj-art-7d2e479fbb0746959c73ffaf0edf296d |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-7d2e479fbb0746959c73ffaf0edf296d2025-01-31T05:11:15ZengElsevierMolecular Metabolism2212-87782025-03-0193102101High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in miceEya Sellami0Paulo Henrique Evangelista-Silva1Caio Jordão Teixeira2Khoudia Diop3Patricia Mitchell4Fernando Forato Anhê5Québec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Medicine, Faculty of Medicine, Université Laval - 1050, Av. de la Médecine, Québec, QC, G1V 0A6, Canada; Institute of Nutrition and Functional Foods, Université Laval - 2440 Bd. Hochelaga, Québec, QC, G1V 0A6, CanadaQuébec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo – 1524, Av. Prof. Lineu Prestes, Sao Paulo, SP, 05508-000, BrazilQuébec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo – 1524, Av. Prof. Lineu Prestes, Sao Paulo, SP, 05508-000, BrazilQuébec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Institute of Nutrition and Functional Foods, Université Laval - 2440 Bd. Hochelaga, Québec, QC, G1V 0A6, CanadaQuébec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, CanadaQuébec Heart and Lung Institute Research Center, Université Laval - 2725, Ch. Sainte-Foy, Québec, QC, G1V 4G5, Canada; Department of Medicine, Faculty of Medicine, Université Laval - 1050, Av. de la Médecine, Québec, QC, G1V 0A6, Canada; Institute of Nutrition and Functional Foods, Université Laval - 2440 Bd. Hochelaga, Québec, QC, G1V 0A6, Canada; Corresponding author. Québec Heart and Lung Institute (IUCPQ), Université Laval, 2725, Ch. Sainte-Foy – office Y4225, Québec, QC, G1V 4G5, Canada.Objective: Increased fructose consumption contributes to type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), but the mechanisms are ill-defined. Gut nutrient sensing involves enterohormones like Glucagon-like peptide (Glp)2, which regulates the absorptive capacity of luminal nutrients. While glucose is the primary dietary energy source absorbed in the gut, it is unknown whether excess fructose alters gut glucose sensing to impair blood glucose regulation and liver homeostasis. Methods: Mice were fed diets where carbohydrates were either entirely glucose (70 %Kcal) or glucose partially replaced with fructose (8.5 %Kcal). Glp2 receptor (Glp2r) was inhibited with Glp2 (3-33) injections. Glucose tolerance, insulin sensitivity, and gut glucose absorption were concomitantly assessed, and enteric sugar transporters and absorptive surface were quantified by RT-qPCR and histological analysis, respectively. Results: High fructose feeding led to impairment of blood glucose disposal, ectopic fat accumulation in the liver, and hepatic (but not muscle or adipose tissue) insulin resistance independent of changes in fat mass. This was accompanied by increased gut glucose absorption, which preceded glucose intolerance and liver steatosis. Fructose upregulated glucose transporters and enlarged the gut surface, but these effects were prevented by Glp2r inhibition. Blocking Glp2r prevented fructose-induced impairments in glucose disposal and hepatic lipid handling. Conclusion: Excess fructose impairs blood glucose and liver homeostasis by rewiring gut glucose sensing and exacerbating gut glucose absorption. Our findings are positioned to inform novel early diagnostic tools and treatments tailored to counter high fructose-induced metabolic derangements predisposing to T2D and MASLD.http://www.sciencedirect.com/science/article/pii/S2212877825000080Glucagon-like peptide 2Glucagon-like peptide 2 receptorType 2 diabetesObesitySugar |
| spellingShingle | Eya Sellami Paulo Henrique Evangelista-Silva Caio Jordão Teixeira Khoudia Diop Patricia Mitchell Fernando Forato Anhê High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice Molecular Metabolism Glucagon-like peptide 2 Glucagon-like peptide 2 receptor Type 2 diabetes Obesity Sugar |
| title | High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice |
| title_full | High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice |
| title_fullStr | High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice |
| title_full_unstemmed | High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice |
| title_short | High fructose rewires gut glucose sensing via glucagon-like peptide 2 to impair metabolic regulation in mice |
| title_sort | high fructose rewires gut glucose sensing via glucagon like peptide 2 to impair metabolic regulation in mice |
| topic | Glucagon-like peptide 2 Glucagon-like peptide 2 receptor Type 2 diabetes Obesity Sugar |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000080 |
| work_keys_str_mv | AT eyasellami highfructoserewiresgutglucosesensingviaglucagonlikepeptide2toimpairmetabolicregulationinmice AT paulohenriqueevangelistasilva highfructoserewiresgutglucosesensingviaglucagonlikepeptide2toimpairmetabolicregulationinmice AT caiojordaoteixeira highfructoserewiresgutglucosesensingviaglucagonlikepeptide2toimpairmetabolicregulationinmice AT khoudiadiop highfructoserewiresgutglucosesensingviaglucagonlikepeptide2toimpairmetabolicregulationinmice AT patriciamitchell highfructoserewiresgutglucosesensingviaglucagonlikepeptide2toimpairmetabolicregulationinmice AT fernandoforatoanhe highfructoserewiresgutglucosesensingviaglucagonlikepeptide2toimpairmetabolicregulationinmice |