Metformin and kidney protection: a letter to editor on recent findings (original) (raw)
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Medical principles and practice : international journal of the Kuwait University, Health Science Centre, 2015
The anti-diabetic and oral hypoglycaemic agent metformin, first used clinically in 1958, is today the first choice or 'gold standard' drug for the treatment of type 2 diabetes and polycystic ovary disease. Of particular importance for the treatment of diabetes, metformin affords protection against diabetes-induced vascular disease. In addition, retrospective analyses suggest that treatment with metformin provides therapeutic benefits to patients with several forms of cancer. Despite almost 60 years of clinical use, the precise cellular mode(s) of action of metformin remains controversial. A direct or indirect role of adenosine monophosphate (AMP)-activated protein kinase (AMPK), the fuel gauge of the cell, has been inferred in many studies, with evidence that activation of AMPK may result from a mild inhibitory effect of metformin on mitochondrial complex 1, which in turn would raise AMP and activate AMPK. Discrepancies, however, between the concentrations of metformin used ...
Chemico-Biological Interactions, 2011
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion and/or action. One of the most important complications of this metabolic disease is diabetic nephropathy. Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Recent studies have established that metformin, an oral hypoglycemic drug, possesses antioxidant effects. However, whether metformin can protect against diabetic nephropathy has not been reported before. The overall objectives of the present study are to elucidate the potential nephroprotective effect of metformin in a rat diabetic nephropathy model and explore the exact underlying mechanism(s) involved. The effect of metformin on the biochemical changes associated with hyperglycemia induced by streptozotocin was investigated in rat kidney tissues. In addition, energy nucleotides (AMP and ATP), and Acetyl-CoA in the kidney homogenates and mitochondria, and the mRNA expression of oxidative stress and pro-inflammatory mediators were assessed. Our results showed that treatment of normoglycemic rats with metformin caused significant increase in ATP, Acetyl-CoA, and CoA-SH contents in kidney homogenates and mitochondria along with profound decrease in AMP level. On the other hand, treatment of diabetic nephropathy rats with metformin normalized all biochemical changes and the energy status in kidney tissues. At the transcriptional levels, metformin treatment caused significant restoration in diabetic nephropathyinduced oxidative stress mRNA levels, particularly GSTa, NQO1, and CAT genes, whereas inhibited TNF-a and IL-6 pro-inflammatory genes. Our data lend further credence for the contribution of metformin in the nephroprotective effect in addition to its well known hypoglycemic action.
The Effect of Metformin in Diabetic and Non-Diabetic Rats with Experimentally-Induced Chronic Kidney Disease, 2021
This work aimed to investigate whether treatment with the antidiabetic drug metformin would affect adenine-induced chronic kidney disease (CKD) in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Rats were randomly divided into eight groups, and given either normal feed, or feed mixed with adenine (0.25% w/w, for five weeks) to induce CKD. Some of these groups were also simultaneously treated orally with metformin (200 mg/kg/day). Rats given adenine showed the typical signs of CKD that included detrimental changes in several physiological and traditional and novel biochemical biomarkers in plasma urine and kidney homogenates such as albumin/creatinine ratio, N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, 8-isoprostane, adiponectin, cystatin C, as well as plasma urea, creatinine, uric acid, indoxyl sulfate, calcium, and phosphorus. Several indices of inflammation and oxidative stress, and renal nuclear factor-κB and nuclear factor erythroid 2-related factor 2 levels were also measured. Histopathologically, adenine caused renal tubular necrosis and fibrosis. The activation of the intracellular mitogen-activated protein kinase signaling pathway was inhibited in the groups that received metformin and STZ together, with or without adenine induced-CKD. Induction of diabetes worsened most of the actions induced by adenine. Metformin significantly ameliorated the renal actions induced by adenine and STZ when these were given singly, and more so when given together. The results suggest that metformin can be a useful drug in attenuating the progression of CKD in both diabetic and non-diabetic rats.
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Metformin does not prevent glucose intolerance but improves renal function and reduces oxidative stress in type 1 diabetes CHRISTINE DRIVER 207503523 2015 The financial assistance of the National Research Foundation (NRF) towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at, are those of the author and are not necessarily to be attributed to the NRF i Metformin does not prevent glucose intolerance but improves renal function and reduces oxidative stress in type 1 diabetes By CHRISTINE DRIVER 207503523 Submitted in partial fulfilment of the requirements for the award of the degree of MASTER OF PHARMACY (PHARMACOLOGY)
Journal of Nephropathology, 2017
Background: Oxidative stress and impaired antioxidant capacity in diabetes are associated with diabetic nephropathy. Metformin, as an adjunct to insulin could decrease oxidative stress and may therefore improve renal function in type 1 diabetes (T1D). Objectives: To investigate the effects of metformin as adds-on therapy to insulin on renal dysfunction in T1D. Materials and Methods: Male Sprague-Dawley rats (230-250 g) were divided into 5 groups (n =7). Rats in groups A and B were orally treated with 3.0 mL/kg body weight (BW) of distilled water, while those in groups C and D were treated with insulin (4.0 U/kg BW bid) or oral metformin (250 mg/kg BW), respectively. Group E rats were similarly treated with both metformin and insulin. Groups BE were rendered diabetic by intraperitoneal injections of 65 mg/kg BW of streptozotocin. Fasting blood glucose concentrations and glucose tolerance tests were done. The animals were sacrificed by halothane overdose after 56 days, blood taken by cardiac puncture and kidneys excised and stored at-80°C for further analysis. Results: Untreated diabetic rats exhibited significant weight loss, increased polydipsia and polyuria, impaired glucose tolerance, electrolyte retention, reduced creatinine clearance and urea excretion and increased oxidative stress compared to controls, respectively. However, these were reversed by treatment with metformin and insulin. Conclusions: Metformin does not improve glycemic control in TID but exerts renoprotective effects by reducing oxidative stress in the presence of insulin. Metformin should therefore be considered for adjunct therapy with insulin in TID.
International journal of molecular medicine, 2013
Metabolic syndrome is characterized by insulin resistance, dyslipidemia and hypertension. These metabolic changes contribute to the development of obesity-induced kidney injury. AMP-activated protein kinase (AMPK) is a ubiquitous enzyme that is involved in the cellular metabolic response to metabolic stress. Metformin, an AMPK activator, has been reported to exert a protective effect against non-alcoholic steatohepatitis. However, little is known about its role in the pathogenesis of obesity-induced renal injury. The aim of this study was to investigate the effects of metformin on high-fat diet (HFD)-induced kidney injury. Obesity was induced by HFD (60% of total calories from fat, 20% protein and 20% carbohydrates) in 6-week-old C57BL/6 mice. Mice were fed HFD plus 0.5% metformin. The effects of metformin on HFD-induced renal injury were evaluated by determining metabolic parameters, serum adipokine levels and renal AMPK/acetyl-CoA carboxylase (ACC) activities, as well as a histolo...
Nigerian Journal of Basic and Applied Sciences, 2018
Persistent hyperglycaemia results in complications in diabetes mellitus (DM) and metformin is the baseline drug used in diabetic management. The effect of metformin on fasting blood glucose (FBG), homogenized kidney tissue malondialdehyde (MDA), protein carbonyl (PCO), total antioxidant capacity (TAC) and histology in streptozotocin-induced diabetic rats were investigated. Eighteen Sprague Dawley rats were assigned into three groups (n= 6 rats per group i.e. A; negative control on distilled water, B; positive control on distilled water and C; on 100 mg/kg/day metformin groups. Diabetes mellitus (DM) was induced using streptozotocin 65 mg/kg intraperitoneally and treatments were given daily by oral gavage for 3 weeks. Plasma fasting blood glucose (FBG), kidney tissue oxidative stress markers and histology were determined. The results showed that FBG, MDA, and PCO levels were significantly higher in B group compared to A group, and lower in C group compared to B. The TAC level was significantly lower in B compared to A and higher in C compared to B group of rats. Histological study showed improvement in kidney histology in all treatments, however, kidney weight did not differ. The results suggest that, metformin reduces oxidative stress in streptozotocin-induced diabetic rats possibly through its antihyperglycaemic effect.
Metformin Protects against Podocyte Injury in Diabetic Kidney Disease
Pharmaceuticals, 2020
Metformin is the most commonly prescribed drug for treating type 2 diabetes mellitus (T2D). Its mechanisms of action have been under extensive investigation, revealing that it has multiple cellular targets, either direct or indirect ones, via which it regulates numerous cellular pathways. Diabetic kidney disease (DKD), the serious complication of T2D, develops in up to 50% of the individuals with T2D. Various mechanisms contribute to the development of DKD, including hyperglycaemia, dyslipidemia, oxidative stress, chronic low-grade inflammation, altered autophagic activity and insulin resistance, among others. Metformin has been shown to affect these pathways, and thus, it could slow down or prevent the progression of DKD. Despite several animal studies demonstrating the renoprotective effects of metformin, there is no concrete evidence in clinical settings. This review summarizes the renoprotective effects of metformin in experimental settings. Special emphasis is on the effects of...