Renal dysfunction in a mouse model of GDM is prevented by metformin through MAPKs

Abstract

Gestational diabetes mellitus (GDM) incidence is increasing worldwide. In the present study, the effects of metformin on high fat diet (HFD)-induced renal dysfunction were investigated in GDM mice. In addition, the molecular mechanisms underlying metformin function were examined. GDM was induced by feeding pregnant mice a HFD, and mice were treated with two different doses of metformin (300 and 600 mg/kg/day) or PBS between embryonic day 11.5 (E11.5) and E17.5. The pregnant mice at E18.5 were utilized to analyze the effects of metformin on renal dysfunction. Renal function and the protein expression levels of inflammatory cytokines and factors of the mitogen-activated protein kinase (MAPK) signaling pathway in the kidneys of pregnant mice were assessed by ELISA and western blotting. Data obtained during late pregnancy suggested that metformin significantly decreased body weight and the levels of blood glucose in GDM mice, as assessed by the glucose tolerance test and the homeostatic model assessment for insulin resistance. The levels of microalbumin and serum β2-microglobulin in GDM mice during late pregnancy were decreased following treatment with metformin. Furthermore, serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and phosphorylation of MAPK1/3, MAPK14 and MAPK8 in the kidneys were decreased in GDM mice following metformin treatment at E18.5, compared with the untreated GDM group. The present study suggested that inflammation may be associated with renal dysfunction in GDM mice, and that the MAPK signaling pathway may be involved in the protective effect of metformin on renal dysfunction in GDM mice.

Metformin: A Novel Weapon Against Inflammation

“…Pre-treatment with metformin significantly decreases urine microalbumin levels and serum β2-microglobulin in GDM mice during late pregnancy. Furthermore, GDM mice following metformin treatment have reduced serum levels of IL-6, TNF-α, and low phosphorylation of MAPK1/3, MAPK14, and MAPK8 in the kidneys (Liu et al, 2019). In addition, metformin treatment can protect diabetic nephropathy by improving glycoxidation, together with inhibition of fibrosis and inflammation in the kidneys of diabetic GK rats fed with an atherogenic diet.…”

Long Non-Coding RNA TUG1 Attenuates Insulin Resistance in Mice with Gestational Diabetes Mellitus via Regulation of the MicroRNA-328-3p/SREBP-2/ERK Axis

“…If the vaginal plug appeared the next morning, the mice were deemed to be pregnant for 0.5 days. The mice in the GDM group continued to be fed with HFD until embryonic day 18 [ 22 , 23 ]. For the GDM mice, on the 7.5-day of pregnancy, the blood glucose level in mouse tail vein blood was measured with the assistance of an Accu-Chek Performa glucose meter (Roche Diagnostics GmbH, Mannheim, Germany).…”

“…The injection volume of NPs was 200 µL/mouse (containing 2 µL of oligonucleotides [AMO], 50 µmol/L). Each mouse was given at 100 µL/mouse by tail vein (GenePharma) [ 22 , 23 ].…”

Administration of metformin in type 2 diabetes mellitus patients with chronic kidney disease; facts and myths

“…A double-blind, placebo-controlled, parallel design study for rosiglitazone versus placebo groups with T2DM patients showed that serum creatinine concentration was similar in placebo, rosiglitazone, and metformin groups (18). However, a cross sectional observational study demonstrated that metformin use could enable reduction of creatinine levels and provided unique cardiac and renal protection (19).…”