Insulin and SGK1 reduce the function of Na⁺/monocarboxylate transporter 1 (SMCT1/SLC5A8)

Abstract

SMCTs move several important fuel molecules that are involved in lipid, carbohydrate, and amino acid metabolism, but their regulation has been poorly studied. Insulin controls the translocation of several solutes that are involved in energetic cellular metabolism, including glucose. We studied the effect of insulin on the function of human SMCT1 expressed in Xenopus oocytes. The addition of insulin reduced α-keto-isocaproate (KIC)-dependent Na uptake by 29%. Consistent with this result, the coinjection of SMCT1 with SGK1 cRNA decreased the KIC-dependent Na uptake by 34%. The reduction of SMCT1 activity by SGK1 depends on its kinase activity, and it was observed that the coinjection of SMCT1 with S442D-SGK1 (a constitutively active mutant) decreased the KIC-dependent Na uptake by 50%. In contrast, an SMCT1 coinjection with K127M-SGK1 (an inactive mutant) had no effect on the KIC-dependent Na uptake. The decreasing SMCT1 function by insulin or SGK1 was corroborated by measuring [1-C]acetate uptake and the electric currents of SMCT1-injected oocytes. Previously, we found that SMCT2/Slc5a12-mRNA, but not SMCT1/Slc5a8-mRNA, is present in zebrafish pancreas (by in situ hybridization); however, SLC5a8 gene silencing was associated with the development of human pancreatic cancer. We confirmed that the mRNA and protein of both transporters were present in rat pancreas using RT-PCR with specific primers, Western blot analysis, and immunohistochemistry. Additionally, significant propionate-dependent Na uptake occurred in pancreatic islets and was reduced by insulin treatment. Our data indicate that human SMCT1 is regulated by insulin and SGK1 and that both SMCTs are present in the mammalian pancreas.

Sodium‐glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter‐organ crosstalk

“…Although SMCT 1 and 2 transport a wide variety of substrates in various tissues, few studies have explored the regulatory mechanism for SMCT 1 and 2 expression. Previously, TNF‐α and insulin treatment were reported to suppress SMCT1 expression in in vitro experiments . In this study, we observed that SMCT 1 and 2 expression increased in a low glucose condition or after inhibition of cellular glucose uptake by SGLT2i, pointing to an association with attenuated intracellular ER stress .…”

“…Previously, TNF-α and insulin treatment were reported to suppress SMCT1 expression in in vitro experiments. 58,59 In this study, we observed that SMCT 1 and 2 expression increased in a low glucose condition or after inhibition of cellular glucose uptake by SGLT2i, pointing to an association with attenuated intracellular ER stress. 44,45 Furthermore, the ER stress inhibitor PBA upregulated SMCT expression in renal proximal tubular cells, supporting the hypothesis of ER as a possible determinant of renal expression.…”

Sgk1

“…Both AKT (Berwick et al, 2004) and SGK1 (Seebohm et al, 2007) appear to be able to phosphorylate and activate PIKFYVE, thus regulating the localization and activity of diverse transporters, including the K + channel complex KCNQ1/KCNE1 (Seebohm et al, 2007), the Na + /monocarboxylate transporter SLC5A1 (Shojaiefard, Strutz-Seebohm, Tavare, Seebohm, & Lang, 2007), the creatine transporter SLC6A8 (Lopez-Barradas et al, 2016), the Ca 2+ -permeable cation channel TRPV6 (Sopjani et al, 2010), as well as the amino acid transporters EAAT2, -3, -4 (Gehring et al, 2009). In all these cases, experimental validation of the relative role and relevance of AKT and SGK1 is still lacking.…”

Sodium-coupled glucose transport, the SLC5 family, and therapeutically relevant inhibitors: from molecular discovery to clinical application

“…This suggests a possible role of SMCT1 in urate reabsorption in the kidney [167]. Another quite recent work showed the expression of both SMCT1 and SMCT2 in pancreas and also that SMCT1 function can be regulated by insulin [101].…”