Low-Dose Metformin Treatment Offers Modest Nephroprotection in a Mouse Model of Diabetic Kidney Disease

Abstract

<b>Abstract ID 16082</b> <b>Poster Board 160</b> <b>Background:</b> Diabetes mellitus affects more than 30 million people in the US, and about one-third of these patients develop diabetic kidney disease (DKD). Metformin is a widely prescribed antidiabetic medication for patients with type 2 diabetes; however, its direct effects on renal function are poorly understood. This study investigates the effects of non-glucose lowering, low-dose metformin treatment against the progression of DKD using a genetic mouse model of type 2 diabetes. <b>Methods:</b> To accelerate the progression of kidney disease, non-diabetic (control) and diabetic mice were subjected to left nephrectomy at ten weeks of age. Following two weeks of recovery, mice were divided into four treatment groups: and received vehicle or metformin (100 mg/kg/day) for four weeks in four treatment groups: 1) vehicle-treated control, 2) metformin-treated control, 3) diabetic, vehicle-treated, and 4) diabetic, metformin-treated. Mice received vehicle or metformin (100 mg/kg/day) for four weeks. Urine, plasma, and kidney tissue samples were collected at the end of the study to measure markers of renal dysfunction—elevations in urine albumin-creatinine ratio (UACR), plasma creatinine, and kidney injury molecule 1 (KIM-1)—markers of renal injury—transforming growth factor-beta (TGF-β), alpha-smooth muscle actin (α-SMA), and NLR family pyrin domain containing 3 (NLRP3)—and markers of nephroprotection—pyruvate kinase M2 (PKM2), mitochondrially encoded cytochrome c oxidase II (MTCO2), and microtubule-associated protein 1 light chain 3 type II (LC3II). <b>Results:</b> Low-dose metformin treatment in diabetic mice decreased UACR (117.5 ± 61.6 vs. 205.3 ± 112.5 ug albumin/mg creatinine) and KIM-1 immunostaining (1.5 ± 0.9 vs. 2.7 ± 0.6) compared to vehicle-treated diabetic mice. In contrast, low-dose metformin treatment in diabetic mice did not alter plasma creatinine levels and only marginally reduced renal injury markers (TGF-β, α-SMA, and NLRP3) or increased nephroprotection markers (such as PKM2, MTCO2, and LC3II) compared to vehicle-treated diabetic mice. <b>Conclusion:</b> Findings from this study indicate modest improvement of renal markers in response to low-dose metformin treatment, mitigating the need to pursue this treatment option for DKD in future studies. Future studies must use a longer-term and higher dose to investigate metformin’s nephroprotective potential against DKD. <b>Support or Funding Information:</b> This study was supported by Drake University’s intramural funds - Harris Research Endowment, Kresge Research Endowment, and Provost fund.