Type 2 Diabetes-Associated Variants Disrupt Function of SLC16A11

Abstract

Type 2 Diabetes (T2D) affects individuals of Mexican and Latin American descent at twice the rate seen in populations of European descent. Recently a risk haplotype in SLC16A11 that explains ~20% of the increased T2D prevalence in Mexico was identified. Here, through genetic fine-mapping, we define a reduced set of tightly-linked common variants likely to contain the causal allele(s). In this thesis, I demonstrate that variants on the T2D-associated haplotype have two distinct effects: (1) decreased expression of the SLC16A11 gene in human liver and (2) missense changes in the SLC16A11 protein that disrupt a key interaction with the chaperone basigin, thereby reducing plasma membrane localization and ultimately protein activity. Both independent mechanisms reduce SLC16A11 function, and together suggest that SLC16A11 is the causal gene. To gain insight into how disruption of SLC16A11 impacts T2D risk, we investigate this previously uncharacterized transporter and categorize SLC16A11 as a proton-coupled monocarboxylate transporter. I characterize the impact of perturbing SLC16A11 on the metabolism of primary human hepatocytes and find that steady state metabolite levels of acylcarnitines, diacylglycerols, and triacylglycerols are altered as a result of SLC16A11 knock-down. In addition, we generated Slc16a11 CRISPR-Cas9 knockout mouse models. In short-term studies in these knockout mice, we found increased triacylglycerols levels in liver and serum. Our metabolic studies indicate that perturbing SLC16A11 alters lipids implicated in insulin resistance and T2D. Taken together, this thesis suggests that targeting SLC16A11 has the potential for meaningful therapeutic impact, and in particular that increasing SLC16A11 function could be beneficial for T2D.