The increased insulin sensitivity reduces plasma glucose levels due to increased glucose uptake, glucose disposal and decreased gluconeogenesis. Metformin belongs to the biguanide class of molecules, oral glucose-lowering drugs that increase insulin sensitivity rather than invoke altered insulin production. Metformin remains the primary candidate to promote glycaemic control in individuals with type 2 diabetes, yet its mechanism of action is still not understood. These findings suggest redox biology as a novel target to eliminate the renal complications associated with metformin treatment in individuals with impaired renal function. The results suggest that metformin directly alters the renal redox state, with elevated renal cytosolic redox states as well as decreased mitochondrial redox state. This study demonstrates that metformin-induced acute metabolic alterations in healthy kidneys favoured anaerobic metabolism at the expense of aerobic metabolism. Pyruvate oxidation was maintained in the diabetic rats, suggesting that the diabetic state abrogates metabolic reprogramming caused by metformin. Corresponding alterations to indices of mitochondrial, cytosolic and whole-cell redox potential were observed. In healthy rat kidneys, metformin increased lactate production and reduced mitochondrial pyruvate oxidation (decreased the 13C-bicarbonate/pyruvate ratio) within 30 min of administration. Metformin increased renal blood flow, but did not change total kidney oxygen consumption. Methodsĭiabetes was induced by intravenous injection of streptozotocin, and kidney metabolism in healthy and diabetic animals was investigated 4 weeks thereafter using hyperpolarised 13C-MRI, Clark-type electrodes and biochemical analysis. In this study, we investigated the acute metabolic and functional changes induced by metformin in the kidneys of both healthy and insulinopenic Wistar rats used as a model of diabetes. This inhibition alters cytosolic and mitochondrial reduction–oxidation (redox) potential, which has been reported to protect organ function in several disease states including diabetes. Metformin inhibits hepatic mitochondrial glycerol phosphate dehydrogenase, thereby increasing cytosolic lactate and suppressing gluconeogenesis flux in the liver.
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