Abstract
BackgroundSeveral epidemiological studies in diabetic patients have demonstrated a protective effect of metformin to the development of several types of cancer. The underlying mechanisms of such phenomenon is related to the effect of metformin on cell proliferation among which, mTOR, AMPK and other targets have been identified. However, little is known about the role that metformin treatment have on other cell types such as keratinocytes and whether exposure to metformin of these cells might have serious repercussions in wound healing delay and in the development of complications in diabetic patients with foot ulcers or in their exacerbation.Material and MethodsHaCaT Cells were exposed to various concentrations of metformin and cell viability was evaluated by a Resazurin assay; Proliferation was also evaluated with a colony formation assay and with CFSE dilution assay by flow cytometry. Cell cycle was also evaluated by flow cytometry by PI staining. An animal model of wound healing was used to evaluate the effect of metformin in wound closure. Also, an analysis of patients receiving metformin treatment was performed to determine the effect of metformin treatment on the outcome and wound area. Statistical analysis was performed on SPSS v. 18 and GraphPad software v.5.ResultsMetformin treatment significantly reduces cell proliferation; colony formation and alterations of the cell cycle are observed also in the metformin treated cells, particularly in the S phase. There is a significant increase in the area of the wound of the metformin treated animals at different time points (P<0.05). There is also a significant increase in the size and wound area of the patients with diabetic foot ulcers at the time of hospitalization. A protective effect of metformin was observed for amputation, probably associated with the anti inflammatory effects reported of metformin.ConclusionsMetformin treatment reduces cell proliferation and reduces wound healing in an animal model and affects clinical outcomes in diabetic foot ulcer patients. Chronic use of this drug should be further investigated to provide evidence of their security in association with DFU.
Highlights
Diabetes is a metabolic disease characterized by hyperglycemia and alterations in metabolism of lipids, carbohydrates and insulin resistance and is one of the leading causes of death worldwide for non-communicable diseases [1]
Cells were routinely evaluated for viability and cell number for passaging (>95% viability, 2 x 106 cells/ 25cm2), viability was evaluated with a resazurin assay at different concentrations of metformin to asses toxicity
We provide evidence that metformin can reduce cell proliferation in keratinocytes by different methodologies and the data suggest that the mechanism is not mediated by direct toxicity to the cells
Summary
Diabetes is a metabolic disease characterized by hyperglycemia and alterations in metabolism of lipids, carbohydrates and insulin resistance and is one of the leading causes of death worldwide for non-communicable diseases [1]. In 2013 an estimated of about 382 million people lived with DM worldwide and among them about 90% is type II diabetes mellitus (DM2). It is known that DM2 is associated with higher risk of developing cardiovascular complications, vascular insufficiency, renal damage, retinopathy and diabetic foot ulcers (DFU). All of these complications have been reported to be associated with reduced quality of life of diabetic patients [3] and increased costs for healthcare systems [4,5,6,7]. Several epidemiological studies in diabetic patients have demonstrated a protective effect of metformin to the development of several types of cancer. Little is known about the role that metformin treatment have on other cell types such as keratinocytes and whether exposure to metformin of these cells might have serious repercussions in wound healing delay and in the development of complications in diabetic patients with foot ulcers or in their exacerbation
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