Functional imaging of pharmacological action of SGLT2 inhibitor ipragliflozin via PET imaging using ¹¹C‐MDG

Abstract

Sodium‐dependent glucose cotransporter 2 (SGLT2) is a pharmacological target of type 2 diabetes mellitus. The aim of this study was to noninvasively visualize the pharmacological action of a selective SGLT2 inhibitor ipragliflozin in the kidney using positron emission tomography (PET) imaging with 11C‐methyl‐d‐glucoside (11C‐MDG), an SGLT‐specific radio‐labeled substrate. PET imaging with 11C‐MDG in vehicle‐treated rats demonstrated that intravenously injected 11C‐MDG substantially accumulated in the renal cortex, reflecting that the compound was reabsorbed by SGLTs. In contrast, ipragliflozin‐treated rats showed significantly lower uptake of 11C‐MDG in renal cortex in a dose‐related manner, suggesting that ipragliflozin inhibited the renal reabsorption of 11C‐MDG. This method of visualizing the mode of action of an SGLT2 inhibitor in vivo has demonstrated the drug's mechanism in reducing renal glucose reabsorption in kidney in living animals.

Effect of Insulin on Proximal Tubules Handling of Glucose: A Systematic Review

“…Studies in knockout mice for SGLT2 or SGLT1 or SGLT2 plus SGLT1 have demonstrated that SGLT2 reabsorbs 80% to 90% glucose of the glomerular filtrate while SGLT1 reabsorbs the remaining 10-20% [71]. However, under acute [72] or chronic [73] SGLT2 inhibition or in SGLT2 knockout mice [73,74], a compensatory increase in SGLT1-mediated glucose transport explains 40-50% of its fractional reabsorption. This is observed early, even in the first hour of SGLT2 inhibition in murine models [72].…”

“…However, under acute [72] or chronic [73] SGLT2 inhibition or in SGLT2 knockout mice [73,74], a compensatory increase in SGLT1-mediated glucose transport explains 40-50% of its fractional reabsorption. This is observed early, even in the first hour of SGLT2 inhibition in murine models [72]. SGLT1 vicariance justifies the maintenance of until 50% of the normal fractional glucose reabsorption during selective SGLT2 inhibition in humans [75][76][77].…”

Oral administration of linoleic acid immediately before glucose load ameliorates postprandial hyperglycemia

“…LA decreased the postprandial glucose level in the portal vein 15 min after glucose load ( Figure 2A ), so LA might inhibit glucose uptake via SGLT1 in the small intestine. α-MDG is a selective substrate of SGLTs ( Mitsuoka et al, 2016 ), and phlorizin is an antagonist of SGLT1 and SGLT2 ( Niederberger et al, 2020 ). CACO-2 cells from DSMZ were previously shown to efficiently express SGLT1, and α-MDG uptake in CACO-2 cells from DSMZ was at maximum efficiency 13 or more days after seeding ( Steffansen et al, 2017 ).…”

Current Use and Complementary Value of Combining in Vivo Imaging Modalities to Understand the Renoprotective Effects of Sodium-Glucose Cotransporter-2 Inhibitors at a Tissue Level

“…a-Methyl-4-[ 18 F]-fluoro-4-deoxy-D-glucopyranoside is a high affinity SGLT1-substrate, a medium affinity SGLT2-substrate and a very low affinity GLUT-substrate, whereas 4-deoxy-4-[ 18 F]-fluoro-D-glucose is substrate for both GLUTs and SGLTs ( Sala-Rabanal et al, 2016 ). Mitsuoka et al used the SGLT1 and SGLT2-specific substrate [ 11 C]-methyl-d-glucoside to show an ipragliflozin-dose-related inhibition of [ 11 C]-methyl-d-glucoside reabsorption ( Mitsuoka et al, 2016 ). This shows that radiolabeled substrates can quantitate the glucose blocking potential of SGLT2i, but the individual contribution of SGLT1 and SGLT2 cannot be distinguished.…”