A causal role of the carboxylic acid transporter SLC16A11 in the pathogenesis of type 2 diabetes?

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Type 2 diabetes is an epidemically growing health threat all over the world. Despite modern therapies, diabetes associated mortality is 2-3 times higher compared to non-affected individuals. Therefore, a deeper understanding and more efficient therapies are an urgent clinical need. The SLC16A11 gene, which encodes a plasma-membrane transporter for monocarboxylates such as pyruvate and lactate, shows a strong association with the development of type 2 diabetes in genome-wide association studies in patients. Specifically, a haplotype in the gene leads to reduced expression of SLC16A11 and type 2 diabetes. The knockdown of SLC16A11 in primary hepatocytes results in the accumulation of triglycerides and diacylglycerols, mediators of insulin resistance. Conversely, our own studies show that de novo lipogenesis is significantly reduced in human SLC16A11-overexpressing HEK cells. However, it is not yet known how SLC16A11 is associated with altered lipid metabolism and which biochemical, cellular and physiological mechanisms lead to type 2 diabetes when SLC16A11 function is disturbed. In preliminary studies, we were able to demonstrate that SLC16A11 is strongly expressed in human and murine liver, and that hepatic mRNA expression is significantly reduced in the presence of NALFD, insulin resistance and T2D in mice and patients. These data support the idea that SLC16A11 is associated with the development of non-alcoholic fatty liver disease and insulin resistance, and thus, type 2 diabetes. Therefore, we hypothesize that SLC16A11 contributes to the development of non-alcoholic fatty liver disease and insulin resistance by affecting the transport of monocarboxylates such as lactate and pyruvate, which serve as substrates for lipid metabolism and thus reduce insulin sensitivity. With this proposal, we aim at determining the substrates of the SLC16A11 transporter by in- and efflux experiments using the already generated SLC16A11 overexpressing HEK cells. In addition, using SLC16A11 knockout mice, which we also generated using CRISPR / Cas9 and which are viable also in the homozygous state, we will characterize the metabolic effect of the lack of SLC16A11 for the first time in vivo. With the help of these knockout mice, we will further investigate, whether the hepatic phenotype can be rescued by AAV8-mediated re-expression of SLC16A11 in the liver. Finally, SLC16A11 expression in liver and adipose tissue of patients will be associated with the presence of different components of the metabolic syndrome. Our data will provide first insight how the candidate gene SLC16A11 leads to type 2 diabetes and if the ‘the promise of targeting SLC16A11 [by enhancing its function] as a potential therapy for T2D is to be fulfilled‘.