Genetic Variation in Sugar Metabolism Confers a Protective Metabolic Profile

See “Loss of sucrase-isomaltase function increases acetate levels and improves metabolic health in Greenlandic cohorts,” by Andersen MK, Skotte L, Jørsboe E, et al, on page 1171. See “Loss of sucrase-isomaltase function increases acetate levels and improves metabolic health in Greenlandic cohorts,” by Andersen MK, Skotte L, Jørsboe E, et al, on page 1171. The disaccharide, sucrose, and its components, glucose and fructose, compose a large portion of the modern diet. Excessive intake of sucrose is linked to many metabolic diseases such as obesity, diabetes, fatty liver, and cardiovascular disease.1Imamura F. O’Connor L. Ye Z. et al.Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction.BMJ. 2015; h3576Google Scholar, 2Green A.K. Jacques P.F. Rogers G. et al.Sugar-sweetened beverages and prevalence of the metabolically abnormal phenotype in the Framingham Heart Study.Obesity. 2014; 22: E157-E163Google Scholar, 3Sánchez-Lozada L.G. Mu W. Roncal C. et al.Comparison of free fructose and glucose to sucrose in the ability to cause fatty liver.Eur J Nutr. 2010; 49: 1-9Google Scholar In this issue of Gastroenterology, Andersen et al4Andersen M.K. Skotte L. Jørsboe E. et al.Loss of sucrase-isomaltase function increases acetate levels and improves metabolic health in Greenlandic cohorts.Gastroenterology. 2022; 162: 1171-1182Abstract Full Text Full Text PDF Scopus (1) Google Scholar document the adult clinical outcomes of a naturally occurring genetic mutation in an arctic population that causes dysfunctional sucrose breakdown and confers healthy anthropometric and metabolic profiles. Once sucrose is taken up from the diet, it is broken down into glucose and fructose by sucrase-isomaltase (SI), an enzyme located on the brush border of the small intestine.5Miller D. Crane R.K. The digestive function of the epithelium of the small intestine.Biochim Biophys Acta. 1961; 52: 293-298Google Scholar Most glucose bypasses intestinal and hepatic metabolism and distributes throughout the body, but fructose is catabolized rapidly by the intestine and the liver before reaching the systemic circulation.6Jang C. Hui S. Lu W. et al.The small intestine converts dietary fructose into glucose and organic acids.Cell Metab. 2018; 27: 351-361.e3Google Scholar Although their metabolism is distinct, both glucose and fructose can contribute to excessive energy intake and insulin resistance, leading to obesity and diabetes. Accordingly, to inhibit glucose absorption for diabetes treatment, modern medicine has developed therapeutics such as acarbose that blocks intestinal enzymes (eg, alpha-glucosidase) to prevent the digestion of complex carbohydrates into glucose.7Chiasson J.-L. Josse R.G. Gomis R. et al.Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.Lancet. 2002; 359: 2072-2077Google Scholar However, no drug has been developed to block the absorption of fructose generated from sucrose breakdown. Interestingly, there exist in the human population natural defects in sucrose digestion. It was first reported in 1972, a Greenland population with a high prevalence (approximately 14%) of dysfunctional sucrose metabolism.8McNair A. Gudmand-Høyer E. Jarnum S. et al.Sucrose malabsorption in Greenland.Br Med J. 1972; 2: 19-21Google Scholar Later, it was to be identified a common founder frameshift mutation (c.273_274delAG ) in the SI gene.9Marcadier J.L. Boland M. Scott C.R. et al.Congenital sucrase–isomaltase deficiency: identification of a common Inuit founder mutation.Can Med Assoc J. 2015; 187: 102-107Google Scholar This mutation led to a total loss in SI protein in homozygote individuals, and pediatric clinical studies reported that patients fed sucrose-rich foods were afflicted with gastrointestinal symptoms, diarrhea, and abdominal pain.10Treem W.R. Congenital sucrase-isomaltase deficiency.J Pediatr Gastroenterol Nutr. 1995; 21: 1-14Google Scholar However, because most studies have focused on the pediatric demographic, Andersen et al sought to understand the health of the adult population. This study surveying an impressive number (6551) of Greenland adults holds great implications in understanding how these biochemical pathways when altered may impact long-term health, providing avenues for targeting SI as novel therapeutics. The authors measured a wide variety of health parameters and circulating metabolites, finding that individuals with the homozygous mutation showed a significantly lower body mass index, body weight, and fat percentage. The serum lipid panel displayed decreased low-density lipoprotein cholesterol and increased high-density lipoprotein cholesterol, increased unsaturated fatty acids, and decreased triglycerides. Then, the authors sought to uncover possible variables that may explain the healthier metabolic profile of the homozygote population. They focused on 2 observed measures on the (1) decreased sucrose intake and (2) increased serum acetate levels. Intuitively, consuming less sucrose would be consistent with an improved metabolic profile. However, when they controlled for this variable, anthropometric measures remained significantly different, indicating that these protective benefits could be independent of decreased sucrose intake. In contrast, when they controlled for acetate serum levels, the anthropometric measures became nonsignificant. Acetate, a short-chain fatty acid (SCFA), can be produced by microbiota or by mammalian cells.11Cummings J.H. Pomare E.W. Branch W.J. et al.Short chain fatty acids in human large intestine, portal, hepatic and venous blood.Gut. 1987; 28: 1221-1227Google Scholar,12Knowles S.E. Jarrett I.G. Filsell O.H. et al.Production and utilization of acetate in mammals.Biochem J. 1974; 142: 401-411Google Scholar Acetate can be converted to acetyl-CoA for many biological processes: tricarboxylic acid cycle, de novo lipogenesis, or histone modification.13Henry R.A. Kuo Y.-M. Bhattacharjee V. et al.Changing the selectivity of p300 by acetyl-CoA modulation of histone acetylation.ACS Chem Biol. 2015; 10: 146-156Google Scholar, 14Fujino T. Kondo J. Ishikawa M. et al.Acetyl-CoA synthetase 2, a mitochondrial matrix enzyme involved in the oxidation of acetate.J Biol Chem. 2001; 276: 11420-11426Google Scholar, 15Howard B.V. Howard W.J. Bailey J.M. Acetyl coenzyme A synthetase and the regulation of lipid synthesis from acetate in cultured cells.J Biol Chem. 1974; 249: 7912-7921Google Scholar Interestingly, acetate can have both a positive and negative role. Acetate supplementation in a heart failure mouse model conferred protective effects.16Marques F.Z. Nelson E. Chu P.-Y. et al.High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice.Circulation. 2017; 135: 964-977Google Scholar In contrast, excessive acetate production by the gut microbiota contributes to the development of fatty liver or obesity.17Zhao S. Jang C. Liu J. et al.Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate.Nature. 2020; 579: 586-591Google Scholar,18Perry R.J. Peng L. Barry N.A. et al.Acetate mediates a microbiome-brain-β-cell axis to promote metabolic syndrome.Nature. 2016; 534: 213-217Google Scholar Among these and other studies depicting the protective or harmful effects of acetate, where do the findings from Andersen et al play? Given the high acetate levels in the homozygote systemic circulation, the authors hypothesize that acetate bypassing liver metabolism may serve protective roles through affecting signaling in other organs. Such an effect may involve the promotion of energy expenditure and control of satiety, inflammation, or fat oxidation.19Canfora E.E. van der Beek C.M. Jocken J.W.E. et al.Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial.Sci Rep. 2017; 7: 2360Google Scholar To further understand the mechanism, Andersen et al developed a mouse model for SI deficiency. This mouse model (Sis-KO mice) recapitulated the metabolic profile of SI-deficient patients, namely, leaner body mass on a sucrose-containing diet despite similar calorie intake. These effects disappeared when mice were fed just a high-fat diet, suggesting a sucrose-specific benefit. Upon sucrose gavage, Sis-KO mice showed increased acetate levels in systemic blood, reminiscent of the human homozygote population. Thus, this mouse model will be useful to further study acetate use and signaling in various organs to understand how they contribute to protection. There are several remaining questions. What are the mechanisms and target organs behind acetate-mediated protection (Figure 1)? Given the well-established protective roles of other SCFAs (propionate and butyrate),19Canfora E.E. van der Beek C.M. Jocken J.W.E. et al.Colonic infusions of short-chain fatty acid mixtures promote energy metabolism in overweight/obese men: a randomized crossover trial.Sci Rep. 2017; 7: 2360Google Scholar is acetate the real mediator of the observed health benefits? What are the microbiome species that produce SCFAs in SI-deficient mice or human populations? Is targeting SI feasible for treating metabolic diseases and what are the potential side effects? How are the health outcomes when these human cohorts age? At the moment, there is no significance in the first incidences of cardiovascular disease, yet protection may become more apparent as the cohort ages and cardiovascular risks increase. A more immediate study would be to use the Sis-KO mice model for inducible diseases such as diabetes or aging to understand how the protective benefits modulate disease and improve outcomes. These authors provide an important continued study on a population with genetic mutation whose early childhood presentation has been well-documented, yet adult health studies remain lacking. Even more, they have developed a mouse model valuable for future study. Finally, their findings provide implications for understanding other genetic variations in the global population, which may confer health advantages to inform the development of novel therapeutics. Loss of Sucrase-Isomaltase Function Increases Acetate Levels and Improves Metabolic Health in Greenlandic CohortsGastroenterologyVol. 162Issue 4PreviewA sucrase-isomaltase loss-of-function variant was associated with a markedly healthier metabolic profile in Greenlandic adults, suggesting that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health. Full-Text PDF Open Access