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Luseogliflozin, a SGLT2 Inhibitor, Does Not Affect Glucose Uptake International Journal of Molecular Sciences Article Luseogliflozin, a SGLT2 Inhibitor, Does Not Affect Glucose Uptake Kinetics in Renal Proximal Tubules of Live Mice Anqi Zhang, Daisuke Nakano *, Wararat Kittikulsuth , Yuka Yamashita and Akira Nishiyama Department of Pharmacology, Kagawa University, Takamatsu 760-8521, Kagawa, Japan; [email protected] (A.Z.); [email protected] (W.K.); [email protected] (Y.Y.); [email protected] (A.N.) * Correspondence: [email protected]; Tel.: +81-(878)-912-125 Abstract: Proximal tubules (PTs) take up most of the glucose in the glomerular filtrate and return it to peritubular capillary blood. Sodium-glucose cotransporter 2 (SGLT2) at the apical membrane takes up glucose into the cell. Glucose then flows across the cells and is transported to the interstitium via glucose transporter 2 (GLUT2) at the basolateral membrane. However, glucose transport under SGLT2 inhibition remains poorly understood. In this study, we evaluated the dynamics of a fluores- cent glucose analog, 2-NBDG, in the PTs of live mice treated with or without the SGLT2 inhibitor, luseogliflozin. We employed real-time multiphoton microscopy, in which insulin enhanced 2-NBDG uptake in skeletal muscle. Influx and efflux of 2-NBDG in PT cells were compared under hypo-, normo-, and hyperglycemic conditions. Luseogliflozin did not exert significant effects on glucose influx parameters under any level of blood glucose. Our results suggest that blood glucose level per se does not alter glucose influx or efflux kinetics in PTs. In conclusion, neither SGLT2 inhibition nor Citation: Zhang, A.; Nakano, D.; blood glucose level affect glucose uptake kinetics in PTs. The former was because of glucose influx Kittikulsuth, W.; Yamashita, Y.; through basolateral GLUT2, which is an established bidirectional transporter. Nishiyama, A. Luseogliflozin, a SGLT2 Inhibitor, Does Not Affect Keywords: glucose handling; proximal tubules; intravital imaging Glucose Uptake Kinetics in Renal Proximal Tubules of Live Mice. Int. J. Mol. Sci. 2021, 22, 8169. https:// doi.org/10.3390/ijms22158169 1. Introduction In modern life, owing to improvements in living conditions and enrichment of food Academic Editor: types, excessive energy intake has created new challenges that threaten the health of Anastasios Lymperopoulos individuals. These challenges include diabetes. Accordingly, treatment and prevention of diabetes are becoming increasingly important. Inhibitors of sodium-glucose cotransporter Received: 2 June 2021 2 (SGLT2) act via a mechanism that is different from that of other antihyperglycemic drugs Accepted: 23 July 2021 Published: 29 July 2021 for reducing blood glucose levels. Furthermore, compared with other antihyperglycemic drugs, there is increasing evidence that SGLT2 inhibitors reduce the risk of cardiorenal- Publisher’s Note: MDPI stays neutral vascular events [1,2]. Therefore, there is high demand for knowledge on how SGLT2 with regard to jurisdictional claims in inhibitors confer favorable effects. published maps and institutional affil- Large amounts of glucose are reabsorbed in the convoluted segment of the proximal iations. tubules. SGLT2, expressed on brush border membranes, transports sodium and glucose from the tubular lumen into the cells. SGLT2 inhibitors reduce glucose uptake in proximal tubule cells, which increases glucose excretion in urine, thereby reducing blood glucose levels under hyperglycemic conditions. It is believed that glucose taken up through SGLT2 flows across the cells and is transported to the interstitium. Glucose transporter 2 (GLUT2), Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. expressed in the basement membrane, transports glucose from the intracellular space to This article is an open access article interstitial fluid. distributed under the terms and GLUT2 is an important glucose transporter and is widely distributed in various organs conditions of the Creative Commons and tissues, such as the liver, intestine, kidney, pancreatic islet β-cells, and central nervous Attribution (CC BY) license (https:// system [3]. Additionally, GLUT2 facilitates bidirectional glucose transport [4]. When the creativecommons.org/licenses/by/ blood glucose level is high, blood glucose passes through GLUT2 expressed in the liver 4.0/). and is stored as glycogen. When the blood glucose level is low, the liver promotes glycogen Int. J. Mol. Sci. 2021, 22, 8169. https://doi.org/10.3390/ijms22158169 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 11 Int. J. Mol. Sci. 2021, 22, 8169 2 of 11 the liver and is stored as glycogen. When the blood glucose level is low, the liver promotes glycogen decomposition to glucose and provides glucose to the blood through GLUT2 [5]. In the kidney, GLUT2 is coexpressed with SGLT2 [6]. In our previous study using intravi- decomposition to glucose and provides glucose to the blood through GLUT2 [5]. In the tal imaging at a subcellular spatial resolution, we found that GLUT2 downregulation dra- kidney, GLUT2 is coexpressed with SGLT2 [6]. In our previous study using intravital imag- matically reduced glucose uptake into the proximal tubules of mice treated with luseogli- ing at a subcellular spatial resolution, we found that GLUT2 downregulation dramatically flozin, a SGLT2 inhibitor [7]. This observation suggested the potential for glucose uptake reduced glucose uptake into the proximal tubules of mice treated with luseogliflozin, a by GLUT2 in the kidney under the influence of SGLT2 inhibitors. This prompted our in- SGLT2 inhibitor [7]. This observation suggested the potential for glucose uptake by GLUT2 interest the kidneyin determining under the whether influence SGLT2 of SGLT2 inhibition inhibitors. using This luseogliflozin prompted our affects interest glucose in deter- up- miningtake dynamics whether in SGLT2 the proximal inhibition tubule using cells luseogliflozin of live mice. affects We also glucose evaluated uptake proximal dynamics tubule in theglucose proximal uptake tubule dynamics cells of with live and mice. without We also luse evaluatedogliflozin proximal under different tubule glucose levels of uptake blood dynamicsglucose. We with used and fluorescent without luseogliflozin glucose analog unders 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4- different levels of blood glucose. We used fluorescentyl) amino]-D-glucose glucose analogs (2-NBDG) 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) in vivo and 2-deoxyglucose in vitro to amino]-D-glucose visualize glucose (2-NBDG)dynamics. in vivo and 2-deoxyglucose in vitro to visualize glucose dynamics. 2.2. ResultsResults 2.1.2.1. InIn VivoVivo AnalysisAnalysis ofof GlucoseGlucose DynamicsDynamics inin SkeletalSkeletal MuscleMuscle UsingUsing MultiphotonMultiphoton ImagingImaging WeWe firstfirst confirmedconfirmed thethe reliabilityreliability ofof ourour inin vivovivoimaging imaging systemsystem byby measuringmeasuring thethe insulin-acceleratedinsulin-accelerated 2-NBDG 2-NBDG uptake uptake in in skeletal skeletal muscle. muscle. InsulinInsulin waswas intravenouslyintravenously injected injected 55 minmin beforebefore 2-NBDG2-NBDG administration. The focal plane plane was was selected selected based based on on the the autofluo- autoflu- orescencerescence of of skeletal skeletal muscle, muscle, which which was was excited excited at ata wavelength a wavelength of of860 860 nm nm (Figure (Figure 1A).1A). As Asshown shown in inFigure Figure 1B,1B, insulin insulin time-dependentl time-dependentlyy increased 2-NBDG-derived2-NBDG-derived fluorescence fluorescence (green)(green) in in skeletal skeletal muscle muscle (Figure (Figure1B). 1B). The The result result supports supports the the reliability reliability of our of our multiphoton multipho- imagington imaging system system for for visualization visualization of inof vivoin vivoglucose glucose dynamics dynamics by by using using the the fluorescent fluorescent glucoseglucose analog,analog, 2-NBDG.2-NBDG. FigureFigure 1.1. IntravitalIntravital imagingimaging forfor skeletalskeletal musclemuscle glucoseglucose uptake.uptake. ((AA)) ProtocolProtocol forfor the the skeletal skeletal muscle muscle experiment.experiment. InsulinInsulin waswas injected injected 5 5 min min before before injection injection of of the the fluorescent fluorescent glucose glucose analog, analog, 2-deoxy-2- 2-deoxy- 2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose (2-NBDG). We observed skeletal muscle of [(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose (2-NBDG). We observed skeletal muscle of the the medial thigh of mice, and the focal plane was selected based on autofluorescence from muscle medial thigh of mice, and the focal plane was selected based on autofluorescence from muscle fibers fibers (blue). (B) Representative in vivo images of 2-NBDG (green) uptake in mouse skeletal muscle (blue).before (andB) Representative after 2-NBDG ininjection vivo images (n = 4). of Scale 2-NBDG bar = (green) 80 µm. uptake in mouse skeletal muscle before and after 2-NBDG injection (n = 4). Scale bar = 80 µm. Int. J. Mol. Sci. 2021, 22, 8169 3 of 11 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 11 2.2. Analysis of Glucose Dynamics in Proximal Tubules of Live Animals Next, we evaluated 2-NBDG uptake in the kidneys of live mice. We injected luseogliflozin 2.2. Analysis of Glucose Dynamics in Proximal Tubules of Live Animals intraperitoneally 90 min before 2-NBDG administration [8]. In some mice, insulin was Next, we evaluated 2-NBDG uptake
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