Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

Abstract

BACKGROUND 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, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. RESULTS Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplo-type of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic condition/ns.

What does sodium‐glucose co‐transporter 1 inhibition add: Prospects for dual inhibition

“…The role of SGLT1 at many of these sites, as well as the consequences of SGLT1 inhibition, are poorly understood. A recent study, by using a Mendelian randomization strategy, showed that SGLT1 blockade should decrease the incidence of heart failure . Regarding the role of cardiac SGLT1, several mechanisms, including but not limited to, sodium influx replenishing adenosine triphosphate (ATP) stores, glycogen accumulation, generation of reactive oxygen species and toxic accumulation of calcium have been speculated to contribute to SGLT1's role in cardiac physiology and pathophysiology.…”

GutSelf: Interindividual Variability in the Processing of Dietary Compounds by the Human Gastrointestinal Tract

“…In the general population, the functional consequences of variants related to intestinal glucose absorption are uncharacterized. Seidelmann et al . therefore attempted to identify SGLT1 variants and to describe their clinical consequences.…”

“…therefore attempted to identify SGLT1 variants and to describe their clinical consequences. Seidelman et al . concluded that missense variants in SGLT1 protect from diet‐induced hyperglycemia in numerous populations.…”

Dextrose 10% Drink is Superior than Sodium Dextrose in Increasing Blood Glucose and Sprint Speed in Soccer Players: a Double-Blinded Randomized Crossover Trial Study

“…The slower mean increment of BG in the administration of sodium dextrose solution can be partly explained by the fact that SGLT-1 is a rate limiting pathway for enterocyte glucose absorption. SGLT-1 uses a transmembrane sodium gradient to carry out the cellular uptake (44). Such a situation may occur slower, considering the condition of soccer players is not in the actual match condition (45), suggesting lesser sodium loss through sweat perspiration that may give a result in a weaker sodium transmembrane gradient (46) (47).…”