Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms

Abstract

SUMMARY Type 2 Diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ~20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly-linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function, and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter, and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D.

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…Instead, several members have been shown to depend on the association with a highly glycosylated ancillary protein for correct targeting and functional expression at the plasma membrane. MCT1, MCT3, MCT4,3 MCT11,5 and MCT126 were demonstrated to preferably interact with the transmembrane glycoprotein CD147, also known as basigin or EMMPRIN, whereas MCT2 has been shown to form a complex with a closely related glycoprotein gp70, known as embigin 3. Both basigin and embigin belong to the immunoglobulin superfamily and consist of a single transmembrane domain and two to three extracellular immunoglobulin domains depending on the splice variant 3.…”

“…MCT11 has recently been shown to mediate H + ‐coupled transport of pyruvate, indicating similar substrate specificities as MCT1–MCT4; however, transport of other monocarboxylates was not tested. Thus, other endogenous or exogenous substrates of MCT11 have not been identified by now 5. Human MCT5, MCT13, and MCT14 remain orphan transporters with yet unknown functions and substrate specificities.…”

“…A study investigating Mexican families with children <18 years with T2DM found a link between a SLC16A11 variant (rs13342232) and early onset of the disease 57. Evidence supporting the assumption that SLC16A11 is a causal gene contributing to T2DM pathogenesis was just recently provided on a functional level 5. The risk haplotype has been demonstrated to dose‐dependently decrease SLC16A11 gene expression in the liver and disturb the interaction of MCT11 with CD147, reducing the functional expression at the plasma membrane.…”

“…The risk haplotype has been demonstrated to dose‐dependently decrease SLC16A11 gene expression in the liver and disturb the interaction of MCT11 with CD147, reducing the functional expression at the plasma membrane. Knockdown of MCT11/ SLC16A11 in in vitro experiments using primary human hepatocytes led to an increase in acylcarnitines, diacylglycerols, and triacylglycerols i.e., changes in fatty acid and lipid metabolism consistent with those observed in insulin resistance and T2DM 5. Therefore, more detailed investigations of exact mechanisms and further systematic characterization of the transporter is needed.…”

Precision medicine in diabetes: an opportunity for clinical translation

“…34 A recent functional study demonstrated that lower levels of monocarboxylate transporter 11 (the protein encoded by SLC16A11) in the plasma membrane of primary human hepatocytes are associated with T2D-relevant changes in fatty acid and lipid metabolism. 56 Though the mechanism of action is incompletely understood, therapies targeting this monocarboxylate transporter and enhancing its function in hepatocytes may be particularly effective in people whose risk of developing T2D is driven by this disrupted mechanism. 57 In another example, a missense polymorphism in HNF1A (MAF of 2% in Mexicans with T2D) increases the risk of T2D fivefold.…”