Contribution of SGLT1 in cardiac glucose transport

Abstract

Sodium-glucose transporter 1 (SGLT1) is the major SGLT isoform expressed in the heart. Under baseline condition, its absence does not affect heart function and structure. Using the pharmacological SGLT1 inhibitor, phlorizin, several data suggested that SGLT1 could contribute to overall glucose transport under physiological as well as under pathological conditions, i.e. in the ischemic heart. However, SGL1 role in glucose transport has never been formerly demonstrated. This study aimed to evaluate, in physiological and pathological conditions, the consequence of SGLT1 transporter invalidation on cardiomyocyte glucose uptake. Glucose uptake was measured in isolated cardiomyocytes using 2,3[H]-glucose and 3[H]-2-deoxyglucose. SGLT1 contribution was evaluated by pharmacologic (phlorizin) and genetic means (KO mice). GLUT transporters expression was examined by RT-qPCR and Western Blot. Under basal and hyperglycemic conditions as well as under insulin or oligomycin stimulation, glucose uptake was similar in SGLT1 + / + and SGLT1 − / − cardiomyocytes. We verified that SGLT1 absence was not compensated by an increase in GLUT1 or GLUT4 expression. Phlorizin inhibited insulin-stimulated glucose transport in a dose dependent manner, leading to its complete inhibition at high concentration (1 mM). However, this effect was independent of SGLT1 as phlorizin impact on glucose transport was similar in SGLT1 + / + and SGLT1 − / − cardiomyocytes. Furthermore, the phlorizin-induced glucose uptake inhibition was not explained by any change on insulin signaling or GLUT4 translocation, suggesting that phlorizin directly affected the GLUTs facilitated glucose transporters. Phlorizin effect on glucose transport does not involve SGLT1 but rather a direct effect on GLUTs. We also demonstrated that SGLT1 does not significantly contribute to glucose uptake in the cardiomyocyte in physiological and pathological conditions.