ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 12.4 | DOI: 10.1530/ey.15.12.4

Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA


To read the full abstract: Cell 2017;170:199-212 e20

T2DM has a disproportionate impact on persons of Latin American descent. GWAS in Mexican and other Latin American samples identified a haplotype containing four missense SNPs, all in SLC16A11, that were much more common in individuals with Native American ancestry than in east Asian, European and African samples. The association was stronger in younger, leaner people with T2DM.5 Individuals who carry the risk haplotype develop T2DM two years earlier, on average, and generally at a lower BMI than non-carriers. People who inherited copies from both parents are about 50% more likely to have diabetes than non-carriers.

The human SLC16 gene family comprises 14 members. The family is also known as the monocarboxylate transporter (MCT) family since the first members to be identified were the proteins responsible for the proton-linked transport of important monocarboxylate metabolites such as pyruvate, L-lactate and ketone bodies across the plasma membrane, as well as a high affinity thyroid hormone transporter (MCT8) and an aromatic amino acid transporter. The SLC16 family members are involved in a wide range of metabolic pathways including energy metabolism of the brain, skeletal muscle, heart and tumor cells; gluconeogenesis, T-lymphocyte activation, bowel metabolism, spermatogenesis, pancreatic β-cell malfunction, thyroid hormone metabolism, and drug transport.

Here, Rusu et al. uncovered two distinct mechanisms by which SLC16A11 variants disrupt the gene’s function in liver cells. Some genetic variations in SLC16A11 simply decrease its expression in the liver. Other variants disrupt its interaction with Basigin - a chaperone glycoprotein that plays an important role in targeting the monocarboxylate transporters of SLC16A11 to the plasma membrane. The disruption changes the location of SLC16A11 within the cell and affects cellular fatty acid and lipid metabolism in the liver. The findings suggest that reviving SLC16A11 function may be beneficial for treating T2DM, thus opening new avenues in the search for therapeutics.

5. The STDC. Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature 2014; 506(7486): 97-101.

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