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

Abstract

Sodium glucose transporters (SGLTs) belong to the mammalian solute carrier family SLC5. This family includes 12 different members in human that mediate the transport of sugars, vitamins, amino acids, or smaller organic ions such as choline. The SLC5 family belongs to the sodium symporter family (SSS), which encompasses transporters from all kingdoms of life. It furthermore shares similarity to the structural fold of the APC (amino acid-polyamine-organocation) transporter family. Three decades after the first molecular identification of the intestinal Na +-glucose cotransporter SGLT1 by expression cloning, many new discoveries have evolved, from mechanistic analysis to molecular genetics, structural biology, drug discovery, and clinical applications. All of these advances have greatly influenced physiology and medicine. While SGLT1 is essential for fast absorption of glucose and galactose in the intestine, the expression of SGLT2 is largely confined to the early part of the kidney proximal tubules, where it reabsorbs the bulk part of filtered glucose. SGLT2 has been successfully exploited by the pharmaceutical industry to develop effective new drugs for the treatment of diabetic patients. These SGLT2 inhibitors, termed gliflozins, also exhibit favorable nephroprotective effects and likely also cardioprotective effects. In addition, given the recent finding that SGLT2 is also expressed in tumors of pancreas and prostate and in glioblastoma, this opens the door to potential new therapeutic strategies for cancer treatment by specifically targeting SGLT2. Likewise, further discoveries related to the functional association of other SGLTs of the SLC5 family to human pathologies will open the door to potential new therapeutic strategies. We furthermore hope that the herein summarized information about the physiological roles of SGLTs and the therapeutic benefits of the gliflozins will be useful for our readers to better understand the molecular basis of the beneficial effects of these inhibitors, also in the context of the tubuloglomerular feedback (TGF), and the renin-angiotensin system (RAS). The detailed mechanisms underlying the clinical benefits of SGLT2 inhibition by gliflozins still warrant further investigation that may serve as a basis for future drug development.

Novel biallelic variants expand the SLC5A6-related phenotypic spectrum

“…The sodium (Na + ):multivitamin transporter (SMVT) is a member of the sodium:solute symporter (SSS) family, a group of membrane proteins mediating the transport of the respective solute(s) by using the sodium gradient. SMVT is encoded by SLC5A6 and forms together with other members of the SSS family the solute carrier family 5 (SLC5) [ 1 ]. SMVT is required for the Na + -dependent uptake of the water-soluble vitamins pantothenic acid (vitamin B5) and biotin (vitamin B7), the vitamin-like substance α-lipoic acid, and iodide [ 2 – 5 ].…”

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

“…Sodium–glucose cotransporter (SGLT) belongs to the solute carrier five gene family, which transports glucose against a concentration gradient in an energy-consuming manner and plays an important role in the active transport of glucose ( Wood and Trayhurn, 2003 ; Sano et al, 2020 ). Sodium–glucose cotransporter 1 (SGLT1) is expressed in various human tissues and organs, including the intestine, lung, heart, skeletal muscle, and kidney ( Gyimesi et al, 2020 ). SGLT1 is essential for the quick absorption of glucose and galactose in the intestine, and increases in SGLT1 protein expression cause interstitial fibrosis and cardiac remodeling in mice ( Ramratnam et al, 2014 ).…”

Glucose Transporters as a Target for Anticancer Therapy

“…An increased level of SGLTs is also used by cancer cells to enhance their glucose uptake. Sodium-dependent glucose cotransporters may also be a target therapy in anticancer therapeutic strategies [105]. Like in the case of GLUT proteins, inhibitors of SGLTs may be used as a strategy in cancer treatment [106][107][108].…”