Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice
Open Access
- 23 February 2018
- journal article
- research article
- Published by S. Karger AG in Cellular Physiology and Biochemistry
- Vol. 45 (5), 1747-1758
- https://doi.org/10.1159/000487783
Abstract
Background/Aims: A sodium-glucose co-transporter-2 inhibitor dapagliflozin is widely used for lowering blood glucose and its usage is limited in type 2 diabetes mellitus patients with moderate renal impairment. As its effect on kidney function is discrepant and complicated, the aim of this study is to determine the effect of dapagliflozin on the progression of diabetic nephropathy and related mechanisms. Methods: Twelve-week-old male C57BL/6 wild-type and db/db mice were treated with vehicle or 1 mg/kg dapagliflozin for 12 weeks. Body weight, blood glucose, insulin tolerance, glucose tolerance, pyruvate tolerance and 24-hour urine were measured every 4 weeks. At 24 weeks of age, renal function was evaluated by blood urea nitrogen level, creatinine clearance, urine output, urinary albumin excretion, Periodic Acid-Schiff staining, Masson’s trichrome staining and electron microscopy. Changes in insulin signaling and gluconeogenic key regulatory enzymes were detected using Western blot analysis. Results: Dapagliflozin did not alleviate but instead aggravated diabetic nephropathy manifesting as increased levels of microalbuminuria, blood urea nitrogen, and glomerular and tubular damage in db/db mice. Despite adequate glycemic control by dapagliflozin, urinary glucose excretion increased after administration before 24 weeks of age and was likely associated with renal impairment. Increased urinary glucose excretion was mainly derived from the disturbance of glucose homeostasis with elevated hepatic and renal gluconeogenesis induced by dapagliflozin. Although it had no effect on insulin sensitivity and glucose tolerance, dapagliflozin further induced the expression of gluconeogenic key rate-limiting enzymes through increasing the expression levels of FoxO1 in the kidney and liver. Conclusion: These experimental results indicate that dapagliflozin aggravates diabetes mellitus-induced kidney injury, mostly through increasing gluconeogenesis.This publication has 25 references indexed in Scilit:
- Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose productionJCI Insight, 2014
- Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trialThe Lancet Diabetes & Endocrinology, 2014
- Transcriptional regulators of hepatic gluconeogenesisArchives of Pharmacal Research, 2013
- Chronic high glucose downregulates mitochondrial calpain 10 and contributes to renal cell death and diabetes-induced renal injuryKidney International, 2012
- A novel approach to control hyperglycemia in type 2 diabetes: Sodium glucose co-transport (SGLT) inhibitors. Systematic review and meta-analysis of randomized trialsAnnals of Medicine, 2011
- The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKDJournal of the American Society of Nephrology, 2010
- Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implicationsDiabetic Medicine, 2010
- From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes MellitusDiabetes, 2009
- High glucose initiates calpain-induced necrosis before apoptosis in LLC-PK1 cellsKidney International, 2007
- Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interactionNature, 2003