Metformin with insulin relieves oxidative stress and confers renoprotection in type 1 diabetes in vivo

Abstract

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 B-E 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.

By reducing oxidative stress, naringenin mitigates hyperglycaemia-induced upregulation of hepatic nuclear factor erythroid 2-related factor 2 protein

“…Our results therefore suggest that hyperglycaemia provoked increased expression of Nrf2 protein in diabetic rats but naringenin relieved the oxidative burden and obliterated the induction of Nrf2 protein expression which could have triggered the transcription of antioxidant enzyme systems. We have previously shown that hyperglycaemia is associated with increased oxidative stress in diabetic animals, [40] and our results obtained both in vitro and in vivo presented here therefore do corroborate the fact that hyperglycaemia-induced oxidative stress can be mitigated by naringenin which ultimately spares hepatocytes of the need to activate antioxidant defence systems. Our results should not be interpreted to suggest that naringenin does not activate Nrf2 protein expression leading to increased synthesis of endogenous antioxidant enzymes as has been previously reported.…”

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

“…Metformin is involved in controlling oxidative stress by controlling complex I of the mitochondrial electron transfer chain (Kinaan et al 2015 ; Wiernsperger 2015 ) and can be effective in reducing kidney damage induced by gentamicin (Darabi and Hasanvand 2018 ; Hasanvand 2018 ). Many studies have shown that the anti-inflammatory and antioxidative stress effects of metformin in various diseases, such as rheumatoid arthritis, neuropathic pain, renal disorders and Ankylosing spondylitis (Son et al 2014 , Afshari et al 2018 , Driver et al 2018 , Qin et al 2018a , b , Rajaei, Haybar et al 2018 ). This effect of metformin is achieved via activating multiple signalling pathways, including AMPK and Pi3K/AKT.…”