Dapagliflozin Aggravates Renal Injury via Promoting Gluconeogenesis in db/db Mice.
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.
['Jia|Yingli|Y|', 'He|Jinzhao|J|', 'Wang|Liang|L|', 'Su|Limin|L|', 'Lei|Lei|L|', 'Huang|Wei|W|', 'Geng|Xiaoqiang|X|', 'Zhang|Shun|S|', 'Meng|Xiaolu|X|', 'Zhou|Hong|H|', 'Yang|Baoxue|B|']
D000818:Animals D019540:Area Under Curve D001559:Benzhydryl Compounds D001786:Blood Glucose D001806:Blood Urea Nitrogen D001835:Body Weight D003404:Creatinine D003921:Diabetes Mellitus, Experimental D005943:Gluconeogenesis D005947:Glucose D005951:Glucose Tolerance Test D005960:Glucosides D007328:Insulin D007668:Kidney D007687:Kidney Tubules, Proximal D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008820:Mice, Obese D046529:Microscopy, Electron, Transmission D012372:ROC Curve D015398:Signal Transduction
Type 2 diabetes mellitus Diabetic nephropathy Glucose homeostasis Gluconeogenic key enzymes SGLT2 inhibitor