#ExpBio - More Medulla Please

Apr 24 2017 Published by under [Medicine&Pharma], ExpBio 2017

Structure of Metformin

Newly diagnosed patients with type 2 diabetes generally start the drug metformin. Through a number of metabolic effects, this medication improves hyperglycemia. Over time, most drugs prove to have effects other than those initially identified. Metformin seems beneficial to the kidney, but how does that happen?

Once again we will ponder medullary hypoxia. In yesterday's post, the hypoxia occurred acutely, during heart surgery; now, we will address chronic hypoxia due to diabetes.

In this study, rats were made diabetic with streptozotocin. Some were treated with metformin. After approximately 1 month, kidney function and oxygenation in the cortex and medulla were measured under anesthesia. Cortical and medullary tissue were studied for mitochondrial function.

Metformin did not prevent elevation of glomerular filtration rate, a known phenomenon of diabetes. While oxygenation, measured as the partial pressure of O2, was lowered in both the cortex and medulla of control animals, metformin improved oxygenation in the medulla of diabetic animals.

Diabetes also promotes oxidative stress in the kidney. As a defense against this, the mitochondria become less efficient. An uncoupling protein (UCP2) allows respiration to continue but without ATP formation. In the present study, uncoupled respiration doubled in the medulla in diabetic animals, while metformin treatment returned this parameter to normal.

Metformin increases medullary oxygenation in animals, perhaps via inhibiting UCP2. More study is needed to characterize this effect and what it means for diabetic kidney disease. It also points out our ignorance of the medulla on the clinical side of things. When we biopsy a kidney, we examine the cortex. Our attention has been so focused on the glomeruli and the tubules surrounding them that we may be missing the real action.

ABSTRACT

Metformin†Normalises†Medullary†Hypoxia†in†The†Diabetic†Rat†Kidney

Michael Christensen1, Tomas Schiffer2, Rikke Nørregaard1, Fredrik Palm2. 1Aarhus University, Aarhus N, Denmark, 2Uppsala University, Uppsala, Sweden

Background

Metformin is the first choice treatment of type 2 diabetes where it can lower the level of blood glucose by inhibiting hepatic gluconeogenesis and increase cellular glucose uptake. Besides the effect on blood glucose metformin has also shown protective effects in several renal diseases including diabetic nephropathy. The development of hypoxia in the kidney is suggested to be an important driving force for the development of diabetic nephropathy and we therefore wanted to investigate how metformin affects the oxygenation levels and mitochondrial function in the diabetic kidney.

Methods

Sprague Dawley rats were injected with streptozotocin (STZ) (50 mg/kg) and when rats were diabetic, metformin (250 mg/kg) was administrated in the drinking water. Rats were prepared for In†Vivo†measurements 25-30 days after STZ injection. Rats were anesthetized, placed on a heating pad, tracheotomized and a catheter was placed in the left femoral vein for infusion of Ringer solution containing H-inulin and Paraaminohippurate. The left femoral artery was catheterized for blood pressure measurements and blood sampling. The left kidney was exposed by a subcostal flank incision, immobilized in a plastic cup and catheters were placed in the left ureter as well as bladder for collection of urine. Intrarenal pO2 was measured in kidney cortex and medulla by oxygen microsensors. To assess mitochondrial function, mitochondria were isolated from kidney cortex and medulla and analyzed by highresolution respirometry (Oroboros, O2K)

Important findings

Diabetic rats showed increased glomerular filtration rate (GFR), which was not affected by metformin treatment. PO2 was lower both in the outer medulla as well as cortex in the diabetic animals. Metformin treatment elevated PO2 in the outer medulla both in the control animals as well as in the diabetic animals. Isolated mitochondria from the outer medulla of diabetic rats showed a significantly higher GDP dependent respiration which was normalized by metformin treatment indicating inhibition of uncoupling protein 2 (UCP2) activity.

Conclusion

Metformin increases PO2 in the outer medulla both in control and diabetic animals, this could in part be mediated by inhibition of UCP2.

 

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