Abstract
Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that loss of Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.
Highlights
Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes
In our study, we focused on the role of SLC16A13 in the liver for three reasons: First, the overall aim of the study is to investigate the potential role of SLC16A13 in human metabolic disease; second, human SLC16A13 expression is the highest in the liver, and third, the liver is crucial in glucose and lipid metabolism
Because the human SLC16A13 polymorphism is associated with type 2 diabetes (T2D), we speculated that SLC16A13 expression and/or protein function might be dysregulated in the context of metabolic disease independent of the known polymorphism
Summary
Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. We show that loss of Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease. We studied SLC16A13 expression in human and mouse tissue and generated gain- and loss-of-function models, including Slc16a13 knockout mice that were metabolically characterized in the context of dietinduced obesity
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