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, 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.