Gene Mutation Reduces Glucose Uptake and Premature Mortality

A loss-of-function mutation in a gene in the digestive tract reduces glucose uptake from ingested food, which helps to protect the individual from diabetes, obesity, heart failure, and premature mortality from these disorders.

Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, effects related to intestinal glucose absorption have not been well characterized.


To shed light on these effects, investigators at Harvard University Medical School (Boston, MA, USA) conducted experiments designed to identify functional SGLT1 gene variants and characterize their clinical consequences.

Whole exome sequencing was performed on 8,478 participants in the ARIC (Atherosclerosis Risk in Communities) study. This study was a 25-year-long observational trial of atherosclerosis and cardiovascular risk factors in people living in four communities in the USA. In addition to genetic testing, the association of functional, nonsynonymous substitutions in SGLT1 with two-hour oral glucose tolerance test results was determined.

Results published in the October 9, 2018, issue of the Journal of the American College of Cardiology revealed that approximately 6% of the ARIC participants carried a mutation in SGLT-1 that caused limited impairment of glucose absorption. Individuals with this mutation had a lower incidence of type II diabetes, were less obese, had a lower incidence of heart failure, and had a lower mortality rate when compared to those without the mutation.

The investigators believe that reduced intestinal glucose uptake induced by the mutation may protect the individual from long-term cardiovascular and metabolic disorders, providing support for development of therapies that will target SGLT1 function to prevent and treat metabolic conditions.

"We are excited about this study because it helps clarify the link between what we eat, what we absorb, and our risk for disease. Knowing this opens the door to improved therapies for cardio-metabolic disease," said senior author Dr. Scott D. Solomon, professor of medicine at Harvard University Medical School. "This study is the first to fully evaluate the link between mutations in the gene mainly responsible for absorbing glucose in the gut--SGLT-1, or sodium glucose co-transporter-1--and cardio-metabolic disease."

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Harvard University Medical School