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What makes SGLT2 inhibition so effective in lowering blood glucose in diabetes? (689.5)
Author(s) -
Gerasimova Maria,
Rose Michael,
Koepsell Hermann,
Masuda Takahiro,
Mayoux Eric,
Thomson Scott,
Rieg Timo,
Vallon Volker
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.689.5
Subject(s) - empagliflozin , medicine , renal glucose reabsorption , endocrinology , tubuloglomerular feedback , gluconeogenesis , phosphoenolpyruvate carboxykinase , diabetes mellitus , chemistry , type 2 diabetes , renal function , biochemistry , metabolism , enzyme
Studies in knockout mice indicated that, in euglycemia, the sodium glucose cotransporters SGLT2 and SGLT1 reabsorb 97 and 3% of filtered glucose, respectively. The SGLT1 contribution is enhanced to 40‐50% during genetic or pharmacologic SGLT2 inhibition. Here we show that the SGLT2 inhibitor empagliflozin (in diet for 15 weeks; 60‐80 mg/kg/d) strongly lowered blood glucose (BG) in type 1 diabetic Akita mice (means of 187‐237 vs. 517‐535 mg/dl in vehicle group; n=10‐13/group). In steady‐state, empagliflozin did not increase urinary glucose/creatinine ratios in Akita, indicating the reduction in filtered glucose (due to lowering BG and preventing glomerular hyperfiltration [determined in awake mice by FITC‐inulin plasma kinetics; GFR means of 255 vs. 397 µl/min]) balanced the inhibition of glucose reabsorption. Akita‐diabetes, empagliflozin alone, and Akita+empagliflozin similarly increased renal membrane SGLT2 expression (by 38‐56%) but reduced the expression of SGLT1 (by 33‐37%) vs vehicle‐treated wild‐type mice (WT). Phosphoenolpyruvate carboxykinase (PEPCK) is a principal gluconeogenic enzyme and regulated by gene transcription. Renal PEPCK mRNA expression was elevated by 60% in Akita versus WT mice and normalized by empagliflozin. All mentioned differences were statistically significant. We conclude that the diabetes‐induced changes in renal SGLT2/SGLT1 expression facilitate the blood glucose lowering potential of SGLT2 inhibition by upregulating the target protein and downregulating compensating SGLT1 (the latter is also observed in mice lacking SGLT2 and prevents excessive glucose uptake in late proximal tubule). In addition, SGLT2 inhibition may attenuate diabetes‐induced renal gluconeogenesis. Grant Funding Source : Supported by NIH grants R01DK56248, R01HL94728, P30DK079337