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

2型糖尿病是世界范围内日益流行的健康威胁。尽管有现代治疗，糖尿病相关的死亡率比未受影响的个体高2-3倍。因此，更深入的认识和更有效的治疗是临床迫切需要的。SLC16A11基因编码丙酮酸和乳酸等单羧酸的质膜转运蛋白，在患者全基因组关联研究中显示与2型糖尿病的发展密切相关。具体来说，该基因的单倍型导致SLC16A11和2型糖尿病的表达减少。原代肝细胞中SLC16A11的下调导致甘油三酯和二酰基甘油的积累，这是胰岛素抵抗的介质。相反，我们自己的研究表明，在人slc16a11过表达的HEK细胞中，从头脂肪生成显著减少。然而，SLC16A11如何与脂质代谢改变相关，以及SLC16A11功能紊乱时，哪些生化、细胞和生理机制导致2型糖尿病尚不清楚。在初步研究中，我们能够证明SLC16A11在人和小鼠肝脏中有强烈的表达，并且在小鼠和患者中，NALFD、胰岛素抵抗和T2D存在时，肝脏mRNA的表达显著降低。这些数据支持了SLC16A11与非酒精性脂肪性肝病和胰岛素抵抗的发展，从而与2型糖尿病有关的观点。因此，我们假设SLC16A11通过影响单羧酸盐（如乳酸和丙酮酸）的转运，从而促进非酒精性脂肪性肝病和胰岛素抵抗的发展，这些单羧酸盐作为脂质代谢的底物，从而降低胰岛素敏感性。在此建议下，我们的目标是通过使用已经生成的过表达SLC16A11的HEK细胞，通过内流和外排实验来确定SLC16A11转运体的底物。此外，我们将利用同样使用CRISPR / Cas9产生的SLC16A11敲除小鼠，首次在体内表征SLC16A11缺失的代谢效应，这些小鼠也在纯合状态下存活。在这些基因敲除小鼠的帮助下，我们将进一步研究aav8介导的SLC16A11在肝脏中的重新表达是否可以挽救肝脏表型。最后，SLC16A11在患者肝脏和脂肪组织中的表达将与代谢综合征不同成分的存在相关。我们的数据将首次揭示候选基因SLC16A11是如何导致2型糖尿病的，以及“靶向SLC16A11（通过增强其功能）作为T2D潜在治疗方法的承诺是否得以实现”。

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‘.