A Human SGLT1 Variant Reduces Glucose and Calorie Uptake, thereby Lowering Disease Risk and Mortality

Researchers here report on a gene variant associated with reduced incidence of metabolic disease, type 2 diabetes, and heart disease. The mechanism of action is a reduced uptake of glucose (and thus calories) in the gut. The estimated effect size over decades of life based on the short term data gathered is large: a reduction of a third in mortality risk. That is sizable enough for me to think that the study needs replication before taking it at face value, but it is thought-provoking nonetheless.

One thing to consider while reading this paper is that gene variants of this nature may help to pin down the plausible scope of benefits that could result from beneficial alterations to gut microbial populations. Differences in these microbial populations is a more commonplace way in which glucose uptake and many other aspects of the interaction between diet and health can differ between individuals. It is an area of increasing research interest, though of course the potential benefits pale beside those that can be realized through rejuvenation biotechnologies after the SENS model.

After ingestion, complex carbohydrates are enzymatically broken down to produce monosaccharides (glucose, galactose, and fructose), which are absorbed in the small intestine and used as substrate for the body's metabolically active tissues. The sodium/glucose co-transporter (SGLT)-1 protein is a rate-limiting factor for absorption of glucose and galactose in the small intestine, and it uses transmembrane sodium gradients to drive the cellular uptake of these molecules. Loss-of-function mutations, including missense, nonsense, and frameshift mutations, of the SGLT1 gene result in impaired cellular glucose transport and cause glucose-galactose malabsorption (GGM), a severe genetic disorder.

Functional gene variants in SGLT1 associated with altered glucose metabolism in the general population have not been described. However, in the process of identifying causal mutations for GGM, SGLT1 gene variants that are associated with subtle abnormalities of glucose absorption in vivo have been identified; the importance of these variants, which do not result in GGM, is unknown. We hypothesized that rare or low-frequency variants in SGLT1 that are predicted to be damaging, but still preserve some of the protein's function, result in lower postprandial blood glucose levels by decreasing glucose uptake in the small intestine and thereby reduce overall caloric absorption.

Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%) had lower blood glucose and odds of impaired glucose tolerance than noncarriers. The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects and an external European-Finnish population sample of 6,784 subjects. Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in blood glucose via SGLT1 inhibition would be reduced prevalent obesity (odds ratio 0.43), incident diabetes (hazard ratio 0.58), heart failure (hazard ratio 0.53), and death (hazard ratio: 0.66).

Link: http://dx.doi.org/10.1016/j.jacc.2018.07.061


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