Type 2 diabetes (T2D) is one of the leading causes of morbidity and mortality worldwide, with some populations suffering higher risk. Latinos, for instance, develop T2D at a higher prevalence compared to non-Hispanic white populations. Genetic studies can identify regions in the genome, loci, which correlate with altered T2D risk in these specific populations. A recent genome wide association study in a Latino population identified T2D risk variants that span SLC16A11, a gene not previously connected to T2D. Following up on this finding, our group demonstrated that SLC16A11 is an H+-coupled monocarboxylate transporter, and that the T2D-associated variants disrupt SLC16A11 function via two mechanisms: (a) decreased expression and (b) reduced cell surface localization. In vitro knockdown of SLC16A11 in hepatocytes, to model the effect of the variants, leads to altered fatty acid and lipid metabolism. These findings are consistent with the metabolic profile seen in individuals with insulin resistance and T2D. Elucidating the regulatory mechanisms underlying SLC16A11 expression could be a key step in understanding its physiological importance and role in T2D pathophysiology. Research conducted in our lab indicates that wild-type SLC16A11 is expressed at low levels and rapidly degraded by the proteasome, suggesting that protein levels are tightly regulated. A proline to aspartic acid substitution (P2D) in the amino acid sequence of SLC16A11 was found to increase protein levels, an effect possibly mediated through N-terminal ubiquitination. We investigated this possible regulatory mechanism by comparing protein levels and stability of wild type and T2D risk SLC16A11, in the presence and absence of the P2D mutation. Identifying the mechanisms that regulate SLC16A11 expression and activity could illuminate the cellular roles of this poorly characterized transporter and shed light on how disruption of its function leads to increased diabetes risk.
PROJECT: Elucidating the regulatory mechanisms of SLC16A11, a Type 2 Diabetes associated gene
At the Broad Institute I was able to expand my skill set in a biomedical laboratory setting and enhance my critical thinking skills. Participating in the Broad Summer Research Program (BSRP) provided me with powerful tools and resources to succeed in biomedical research.