Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance

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 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.

Identification of a Six-Gene SLC Family Signature With Prognostic Value in Patients With Lung Adenocarcinoma

“…The expression of SLC16A13 and SLC2A1 was higher in LUAD tissues and their expression was associated with a poorer prognosis, so these two genes might be oncogenic. SLC16A13 is a lactate transporter expressed at the plasma membrane and a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease ( Schumann et al, 2021 ), while its role in tumor needs to be further explored. SLC2A1 , also known as glucose transporter type 1 (GLUT1), is well characterized in cancer and is associated with tumor progression and metastasis ( Yan et al, 2015 ; Nagarajan et al, 2017 ; Xiao et al, 2018 ), including in LUAD where is has previously been shown to be upregulated and associated with poorer prognosis ( Guo et al, 2020 ).…”

New and Emerging Research on Solute Carrier and ATP Binding Cassette Transporters in Drug Discovery and Development: Outlook From the International Transporter Consortium

“…Beyond drug transporters, genetic variants in other transporters not generally involved in drug absorption or disposition have been associated with plasma levels of various endogenous solutes, including a number of amino acids, oligopeptides, neurotransmitters, and heavy metals 35–38 . Many of these solutes are not routinely measured in a clinical care setting and, therefore, cannot be used in observational studies.…”

“…37 Recently, follow-up studies have shown that the orphan transporter SLC16A13, which is located next to SLC16A11 on chromosome 17p13.1, is a lactate transporter and also plays a role in type 2 diabetes. 38 • Using knockout mice, riboflavin was identified as the major substrate of SLC22A14, which was an orphan at the time. 39 Detailed studies showed that riboflavin plays an important role in the testis and reduced uptake of riboflavin in male SLC22A14 knockout mice resulted in infertility.…”

“…110,[112][113][114] Beyond drug transporters, genetic variants in other transporters not generally involved in drug absorption or disposition have been associated with plasma levels of various endogenous solutes, including a number of amino acids, oligopeptides, neurotransmitters, and heavy metals. [35][36][37][38] Many of these solutes are not routinely measured in a clinical care setting and, therefore, cannot be used in observational studies. However, these solutes may serve as indicators of transporter activity or perturbations in transporter activity, for example, in the presence of prescription drugs to assess the effects of drugs on important micro and macro nutrient transporters.…”

“…Using GWAS for human disease and in particular associations of genetic polymorphisms in SLC16A11 with type 2 diabetes in Mexican subjects, 36 researchers identified pyruvate as a substrate of SLC16A11 explaining the mechanisms for the association with type 2 diabetes 37 . Recently, follow‐up studies have shown that the orphan transporter SLC16A13, which is located next to SLC16A11 on chromosome 17p13.1, is a lactate transporter and also plays a role in type 2 diabetes 38 Using knockout mice, riboflavin was identified as the major substrate of SLC22A14, which was an orphan at the time 39 .…”