Gastroenterology. 2021 Dec 13;S0016-5085(21)04065-8. doi:10.1053/j.gastro.2021.12.236.Online ahead of print.

Mette K Andersen ¹, Line Skotte ², Emil Jørsboe ³, Ryan Polito ¹, Frederik F Stæger ⁴, Peter Aldiss ¹, Kristian Hanghøj ⁴, Ryan K Waples ⁴, Cindy G Santander ⁴, Niels Grarup ¹, Inger K Dahl-Petersen ⁵, Lars J Diaz ⁶, Maria Overvad ⁶, Ninna K Senftleber ⁷, Bolette Søborg ², Christina V L Larsen ⁸, Clara Lemoine ¹, Oluf Pedersen ¹, Bjarke Feenstra ², Peter Bjerregaard ⁹, Mads Melbye ¹⁰, Marit E Jørgensen ¹¹, Nils J Færgeman ¹², Anders Koch ¹³, Thomas Moritz ¹, Matthew P Gillum ¹, Ida Moltke ¹⁴, Torben Hansen ¹⁵, Anders Albrechtsen ¹⁶

Author information

¹Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

²Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

³Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

⁴Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

⁵National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark.

⁶Steno Diabetes Center Copenhagen, Gentofte, Denmark.

⁷Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark.

⁸National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland.

⁹National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.

¹⁰Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

¹¹National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark; Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland.

¹²Department of Biochemistry and Molecular Biology, Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark.

¹³Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; Greenland Centre for Health Research, University of Greenland, Nuuk, Greenland; Department of Infectious Diseases, Rigshospitalet University Hospital, Copenhagen, Denmark.

¹⁴Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark. Electronic address: ida@binf.ku.dk.

¹⁵Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark. Electronic address: torben.hansen@sund.ku.dk.

¹⁶Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark. Electronic address: albrecht@binf.ku.dk.

Abstract

Background & aims: The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, an inability to breakdown and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms, when dietary sucrose is introduced. Here we aimed to describe the health of adults with sucrase-isomaltase deficiency.

Methods: Association between c.273_274delAG and phenotypes related to metabolic health was assessed in two cohorts of Greenlandic adults (N=4,922 and N=1,629). A sucrase-isomaltase knock-out (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 BMI (β (SE), -2.0 kg/m² (0.5), P=3.1x10^-5), body weight (-4.8 kg (1.4), P=5.1x10^-4), fat percentage (-3.3% (1.0), P=3.7x10^-4), fasting triglyceride (-0.27 mmol/L (0.07), P=2.3x10^-6), and remnant cholesterol (-0.11 mmol/L (0.03), P=4.2x10^-5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (0.056 mmol/L (0.002), P=2.1x10^-26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which compared to 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.