Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts
BACKGROUND & AIMS: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointesti...
Published in: | Gastroenterology |
---|---|
Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
2022
|
Subjects: | |
Online Access: | https://portal.findresearcher.sdu.dk/da/publications/a0e191ac-a57d-4c2c-b7c9-ad9eb27deedd https://doi.org/10.1053/j.gastro.2021.12.236 https://findresearcher.sdu.dk/ws/files/202400420/PIIS0016508521040658.pdf |
id |
ftsydanskunivpub:oai:sdu.dk:publications/a0e191ac-a57d-4c2c-b7c9-ad9eb27deedd |
---|---|
record_format |
openpolar |
spelling |
ftsydanskunivpub:oai:sdu.dk:publications/a0e191ac-a57d-4c2c-b7c9-ad9eb27deedd 2024-04-28T08:12:00+00:00 Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts Andersen, Mette K Skotte, Line Jørsboe, Emil Polito, Ryan Stæger, Frederik F Aldiss, Peter Hanghøj, Kristian Waples, Ryan K Santander, Cindy G Grarup, Niels Dahl-Petersen, Inger K Diaz, Lars J Overvad, Maria Senftleber, Ninna K Søborg, Bolette Larsen, Christina V L Lemoine, Clara Pedersen, Oluf Feenstra, Bjarke Bjerregaard, Peter Melbye, Mads Jørgensen, Marit E Færgeman, Nils J Koch, Anders Moritz, Thomas Gillum, Matthew P Moltke, Ida Hansen, Torben Albrechtsen, Anders 2022-04 application/pdf https://portal.findresearcher.sdu.dk/da/publications/a0e191ac-a57d-4c2c-b7c9-ad9eb27deedd https://doi.org/10.1053/j.gastro.2021.12.236 https://findresearcher.sdu.dk/ws/files/202400420/PIIS0016508521040658.pdf eng eng https://portal.findresearcher.sdu.dk/da/publications/a0e191ac-a57d-4c2c-b7c9-ad9eb27deedd info:eu-repo/semantics/openAccess Andersen , M K , Skotte , L , Jørsboe , E , Polito , R , Stæger , F F , Aldiss , P , Hanghøj , K , Waples , R K , Santander , C G , Grarup , N , Dahl-Petersen , I K , Diaz , L J , Overvad , M , Senftleber , N K , Søborg , B , Larsen , C V L , Lemoine , C , Pedersen , O , Feenstra , B , Bjerregaard , P , Melbye , M , Jørgensen , M E , Færgeman , N J , Koch , A , Moritz , T , Gillum , M P , Moltke , I , Hansen , T & Albrechtsen , A 2022 , ' Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts ' , Gastroenterology , vol. 162 , no. 4 , pp. 1171-1182.e3 . https://doi.org/10.1053/j.gastro.2021.12.236 Drug Target Genetics Loss of Function Metabolic Health Sucrase-Isomaltase article 2022 ftsydanskunivpub https://doi.org/10.1053/j.gastro.2021.12.236 2024-04-10T14:42:12Z BACKGROUND & AIMS: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency. METHODS: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings. RESULTS: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (β [standard error], -2.0 [0.5] kg/m 2 P = 3.1 × 10 -5 ), body weight (-4.8 [1.4] kg; P = 5.1 × 10 -4 ), fat percentage (-3.3% [1.0%]; P = 3.7 × 10 -4 ), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10 -6 ), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10 -5 ). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (β [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10 -26 ), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test. CONCLUSIONS: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate. Article in Journal/Newspaper Arctic greenlandic University of Southern Denmark Research Portal Gastroenterology 162 4 1171 1182.e3 |
institution |
Open Polar |
collection |
University of Southern Denmark Research Portal |
op_collection_id |
ftsydanskunivpub |
language |
English |
topic |
Drug Target Genetics Loss of Function Metabolic Health Sucrase-Isomaltase |
spellingShingle |
Drug Target Genetics Loss of Function Metabolic Health Sucrase-Isomaltase Andersen, Mette K Skotte, Line Jørsboe, Emil Polito, Ryan Stæger, Frederik F Aldiss, Peter Hanghøj, Kristian Waples, Ryan K Santander, Cindy G Grarup, Niels Dahl-Petersen, Inger K Diaz, Lars J Overvad, Maria Senftleber, Ninna K Søborg, Bolette Larsen, Christina V L Lemoine, Clara Pedersen, Oluf Feenstra, Bjarke Bjerregaard, Peter Melbye, Mads Jørgensen, Marit E Færgeman, Nils J Koch, Anders Moritz, Thomas Gillum, Matthew P Moltke, Ida Hansen, Torben Albrechtsen, Anders Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts |
topic_facet |
Drug Target Genetics Loss of Function Metabolic Health Sucrase-Isomaltase |
description |
BACKGROUND & AIMS: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency. METHODS: The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings. RESULTS: Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (β [standard error], -2.0 [0.5] kg/m 2 P = 3.1 × 10 -5 ), body weight (-4.8 [1.4] kg; P = 5.1 × 10 -4 ), fat percentage (-3.3% [1.0%]; P = 3.7 × 10 -4 ), fasting triglyceride (-0.27 [0.07] mmol/L; P = 2.3 × 10 -6 ), and remnant cholesterol (-0.11 [0.03] mmol/L; P = 4.2 × 10 -5 ). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (β [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10 -26 ), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test. CONCLUSIONS: These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate. |
format |
Article in Journal/Newspaper |
author |
Andersen, Mette K Skotte, Line Jørsboe, Emil Polito, Ryan Stæger, Frederik F Aldiss, Peter Hanghøj, Kristian Waples, Ryan K Santander, Cindy G Grarup, Niels Dahl-Petersen, Inger K Diaz, Lars J Overvad, Maria Senftleber, Ninna K Søborg, Bolette Larsen, Christina V L Lemoine, Clara Pedersen, Oluf Feenstra, Bjarke Bjerregaard, Peter Melbye, Mads Jørgensen, Marit E Færgeman, Nils J Koch, Anders Moritz, Thomas Gillum, Matthew P Moltke, Ida Hansen, Torben Albrechtsen, Anders |
author_facet |
Andersen, Mette K Skotte, Line Jørsboe, Emil Polito, Ryan Stæger, Frederik F Aldiss, Peter Hanghøj, Kristian Waples, Ryan K Santander, Cindy G Grarup, Niels Dahl-Petersen, Inger K Diaz, Lars J Overvad, Maria Senftleber, Ninna K Søborg, Bolette Larsen, Christina V L Lemoine, Clara Pedersen, Oluf Feenstra, Bjarke Bjerregaard, Peter Melbye, Mads Jørgensen, Marit E Færgeman, Nils J Koch, Anders Moritz, Thomas Gillum, Matthew P Moltke, Ida Hansen, Torben Albrechtsen, Anders |
author_sort |
Andersen, Mette K |
title |
Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts |
title_short |
Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts |
title_full |
Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts |
title_fullStr |
Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts |
title_full_unstemmed |
Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts |
title_sort |
loss of sucrase-isomaltase function increases acetate levels and improves metabolic health in greenlandic cohorts |
publishDate |
2022 |
url |
https://portal.findresearcher.sdu.dk/da/publications/a0e191ac-a57d-4c2c-b7c9-ad9eb27deedd https://doi.org/10.1053/j.gastro.2021.12.236 https://findresearcher.sdu.dk/ws/files/202400420/PIIS0016508521040658.pdf |
genre |
Arctic greenlandic |
genre_facet |
Arctic greenlandic |
op_source |
Andersen , M K , Skotte , L , Jørsboe , E , Polito , R , Stæger , F F , Aldiss , P , Hanghøj , K , Waples , R K , Santander , C G , Grarup , N , Dahl-Petersen , I K , Diaz , L J , Overvad , M , Senftleber , N K , Søborg , B , Larsen , C V L , Lemoine , C , Pedersen , O , Feenstra , B , Bjerregaard , P , Melbye , M , Jørgensen , M E , Færgeman , N J , Koch , A , Moritz , T , Gillum , M P , Moltke , I , Hansen , T & Albrechtsen , A 2022 , ' Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic Cohorts ' , Gastroenterology , vol. 162 , no. 4 , pp. 1171-1182.e3 . https://doi.org/10.1053/j.gastro.2021.12.236 |
op_relation |
https://portal.findresearcher.sdu.dk/da/publications/a0e191ac-a57d-4c2c-b7c9-ad9eb27deedd |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.1053/j.gastro.2021.12.236 |
container_title |
Gastroenterology |
container_volume |
162 |
container_issue |
4 |
container_start_page |
1171 |
op_container_end_page |
1182.e3 |
_version_ |
1797579100751134720 |