Key result
Carrying functional SGLT1 missense mutations is linked to ~29% lower odds of impaired glucose tolerance.
Why the study?
Does carrying functional missense variants in SGLT1 improve glucose tolerance and reduce cardiometabolic risk in the general population?
Observational (n=15,262)
Yes
Does carrying functional missense variants in SGLT1 improve glucose tolerance and reduce cardiometabolic risk in the general population?
Answers are grounded in this paper and cite their sources.
Functionally damaging missense variants in SGLT1 are associated with improved glucose tolerance and a lower estimated long-term risk of cardiometabolic outcomes, supporting SGLT1 inhibition as a therapeutic target.
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 haplotype 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 conditions.
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Seidelmann et al. (2018) conducted an observational in Impaired glucose tolerance and cardiometabolic risk (n=15,262). SGLT1 missense mutation haplotype (Asn51Ser, Ala411Thr, His615Gln) vs. Noncarriers was evaluated on Impaired glucose tolerance (OR 0.71, 95% CI 0.59-0.86). Carriers of a functional SGLT1 missense mutation haplotype had lower odds of impaired glucose tolerance compared to noncarriers (OR 0.71; 95% CI 0.59-0.86).
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