Christensen 2018 Diabetes Metab Res Rev
|Christensen M, Schiffer TA, Gustafsson H, Krag SP, Nørregaard R, Palm F (2018) Metformin attenuates renal medullary hypoxia in diabetic nephropathy through uncoupling protein-2 inhibition. Diabetes Metab Res Rev 21:e3091.|
Abstract: To examine the effect of the hypoglycemic drug metformin on oxygen metabolism and mitochondrial function, in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis.
Sprague Dawley rats were injected with streptozotocin (STZ) (50 mg/kg) and when stable started on metformin treatment (250 mg/kg) in the drinking water. Rats were prepared for In Vivo measurements 25-30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport were estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analyzed by high-resolution respirometry and superoxide production was evaluated using electron paramagnetic resonance.
Insulinopenic rats chronically treated with metformin for four weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats.
Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK.
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Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Diabetes
Organism: Rat Tissue;cell: Kidney Preparation: Isolated mitochondria
Coupling state: LEAK, OXPHOS Pathway: N, NS HRR: Oxygraph-2k
Labels, 2018-10, Metformin