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Loss of Function Variants in Sucrase-Isomaltase Improve Metabolic Health of Greenlanders

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The loss-of-function variant sucrase-isomaltase (SI) c.273_274delAG causes congenital sucrase-isomaltase deficiency (inability to break down and absorb sucrose and isomaltose), common in Arctic populations, and is associated with altered uptake and metabolism of dietary components, resulting in a healthier metabolic phenotype, researchers report in the April issue of Gastroenterology. The metabolic health affects appear to be mediated by decreased intestinal sucrose absorption and increased levels of circulating acetate. The authors propose that strategies to target SI might be developed for treatment of metabolic disorders.

BMI, body mass index; HO, homozygous for SI c.273_274delAG; HE, heterozygous; WT, not carriers of this variant; Sis-WT, wild-type mice; Sis-KO, mice with disruption of SIS gene

Ingested carbohydrates (starches and sugar) need to be broken down to monosaccharides in order to move across the intestinal epithelium and be taken up by the body. Carbohydrate digestion is initiated by α-amylases in the mouth and finishes in the small intestine via α-glucosidases, maltase-glucoamylase (MGAM), and SI. These digestive enzymes are targets of the anti-diabetic drugs acarbose, voglibose, and miglitol, which are believed to reduce the degradation of starch and sugars and thereby the amount of glucose absorbed into the blood.

Studying the naturally occurring genetic variations that disrupt functions of MGAM and SI could increase our understanding of the effects of targeting these enzymes. Deficiency of MGAM or SI has been linked to maldigestion and severe gastrointestinal symptoms in children. Congenital sucrase-isomaltase deficiency (CSID) is associated with diarrhea, abdominal pain, and bloating in children, but the effects on gastrointestinal and metabolic-health status in adults have not been reported. CSID is rare in most parts of the world, except in Arctic populations, where it has an estimated prevalence of 10%. The c.273-274delAG frameshift variant, predicted to cause loss of SI function, has an estimated frequency of 39% in the Greenland population.

Mette K. Andersen et al studied 6551 Greenlandic adults, some of whom are homozygous for this variant, to determine how loss of SI functions affects metabolic, gastrointestinal, and cardiovascular health. The authors also monitored food intake, body weight, and body composition in mice with disruption of the sucrase-isomaltase gene (SIS-knockout mice).

In 2 separate cohorts of Greenlandic adults, the frequencies of the SI c.273_274delAG variant were 14.2% (95% CI, 13.5%–15.1%) and 14.1% (95% CI, 12.8%–15.3%); the numbers of homozygous carriers were 99 and 34, respectively.

Andersen et al observed that homozygous carriers of the variant had a healthier metabolic profile than individuals heterozygous for or without the variant, including significantly lower body mass index (–2.0 kg/m2), body weight (–4.8 kg), fat percentage (–3.3%), fasting triglyceride (–0.27 mmol/L), and remnant cholesterol (–0.11 mmol/L). The variant was also associated high-density lipoprotein metabolism: homozygous individuals has significantly higher concentrations of very large high-density lipoprotein particles and significantly higher content of free cholesterol, cholesterol esters, total cholesterol, and total lipids as well as a nominally higher content of phospholipids.

The authors found significantly higher levels of polyunsaturated fatty acid, total omega-6 fatty acids, and linoleic acid, in homozygous carriers of the variant, as well as lower levels of monounsaturated fatty acids. Andersen et al found no significant associations between the variant and gastrointestinal symptoms or overall health perception. With respect to cardiovascular disease events, effect estimates indicated a lower risk of ischemic heart disease and heart failure in homozygous carriers (although statistically nonsignificant).

Loss of SI function seemed have greater effects on weight and levels of triglycerides than drugs that inhibit α-glucosidases (acarbose, voglibose, or miglitol), and effects equal to those of statins on triglyceride levels.

Further, the homozygous individuals had higher circulating levels of acetate and reduced sucrose uptake, but not lower calorie intake. It is not clear how loss of SI increases circulating acetate, a short-chain fatty acid (SCFA) produced by microbiota and mammalian cells. Acetate can be converted to acetyl-CoA and used in the tricarboxylic acid cycle, de novo lipogenesis, and histone modification. Andersen et al propose that acetate, bypassing liver metabolism, affects signaling in other organs to promote energy expenditure and control satiety, inflammation, or fat oxidation.

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 following sucrose gavage, and had lower plasma glucose levels in response to a sucrose-tolerance test. These effects disappeared when mice were fed just a high-fat diet, indicating the sucrose-specific benefits of the gene disruption. This mouse model will be useful to study the functions of SI and acetate production.

In an editorial that accompanies the article, Johnny Le and Cholsoon Jang say it will be important to determine whether acetate is the direct mediator of the observed health benefits, and to identify the microbiome species that produce these SFCAs in the SI-deficient mice and humans. A common SI missense variant (rs9290264), estimated to reduce the SI enzymatic activity by 35%, has been associated with lower abundance of the gut bacterial genus Parabacteroides, associated with changes in body weight and fat mass. Moreover, the altered high-density lipoprotein metabolism among homozygous carriers supports the health-promoting effects of removing cholesterol from extrahepatic tissues.

There are potential complications to therapeutic strategies to inhibit SI function. A common SI missense variant (rs9290264) was associated with increased risk of irritable bowel syndrome (IBS), and there is an increased prevalence of SI variants among patients with IBS. Andersen et al say that large studies with careful IBS phenotyping are needed to verify whether inhibition of SI will have adverse effects.

 

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Kristine Novak

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About The Author:

Dr. Kristine Novak

Dr. Kristine Novak

Dr. Kristine Novak is a science writer and editor based in San Francisco. She has extensive experience covering gastroenterology, hepatology, immunology, oncology, clinical, and biotechnology research discoveries.

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