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

Christine Driver,Julia Achieng Hayangah,Peter Mark Oroma Owira,Ntsoaki Annah Nyane

doi:10.15171/jnp.2018.37

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.

Highlights

Oxidative stress and impaired antioxidant capacity in diabetes are associated with diabetic nephropathy
Metformin is not metabolized in the body and is excreted unchanged by the kidneys [28] yet chronic renal disease is very common in diabetes patients
This study seeks to investigate the merits of using metformin as an adjunctive therapy to insulin in the treatment of type 1 diabetes (T1D) in order to prevent or delay the occurrence of renal dysfunction and aspects of diabetic nephropathy

Summary

Introduction

Oxidative stress and impaired antioxidant capacity in diabetes are associated with diabetic nephropathy. 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. These were reversed by treatment with metformin and insulin. Two petitions have been logged with the American Food and Drug Administration (FDA) to consider use of metformin in diabetic patients with moderate kidney disease [32] These appeals have been supported by experimental evidence which suggest that metformin could exert renoprotection by reducing ROS due to its antioxidant effects [33,34,35]. This suggests that patients with T1D could benefit from metformin therapy to mitigate end-stage renal disease

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Conclusion