The liver is a main target tissue of the biguanide metformin which activates AMP-activated protein kinase (AMPK). We have previously reported that administration of metformin glycinate showed a greater decrease in glycated hemoglobin A1c than placebo in patients with type 2 diabetes mellitus (T2DM). Herein, we have compared the effects of metformin hydrochloride, the oral antidiabetic drug of first choice, with those of metformin glycinate in hepatocytes from non-diabetic, diabetic mice and humans. Both formulations were equally potent in the reduction of basal and glucagon-induced glucose production and mRNA levels of gluconeogenic enzymes (Pck1 and G6pc) in hepatocytes from C57/Bl6 mice and humans. In contrast, phosphorylation of AMPK and its substrate acetyl CoA carboxylase (ACC) was more rapid in hepatocytes treated with metformin glycinate. Likewise, in hepatocytes from obese/diabetic db/db mice we found stronger reduction of glucagon-induced glucose output and more sustained AMPK phosphorylation by the treatment with metformin glycinate. Importantly, insulin sensitization regarding phosphorylation of AKT (Ser473) was enhanced in hepatocytes from db/db mice or humans pretreated with metformin glycinate. Altogether, our data point out preclinical mechanistic evidences in hepatocytes suggesting that metformin glycinate might represent a superior alternative therapy against insulin resistance during obesity and/or T2DM. Response to Reviewers: Point-by-point response to the Reviewer´s comments. Reviewer #1: This manuscript compares the effects of metformin hydrochloride and metformin glycinate in reducing basal and induced glucose production as well as the regulation of gluconeogenesis. The authors use hepatocytes from mice, db/db mice as well as from humans for their study. The experimental data reported by the authors suggests that metformin glycinate can effect some facets of glucose regulation at a INSTITUTO DE INVESTIGACIONES BIOMÉDICAS "ALBERTO SOLS", IIBM http://www.iib.uam.es C/Arturo Duperier, nº 4 28029 MADRID ESPAÑA PHO: (34) 91 585 4400 FAX: (34) 91 585 4401 Dear Editor: Find enclosed the electronic submission of the revised manuscript referenced as FCT-D-18-01715 entitled "Differential effects of metformin glycinate and hydrochloride in glucose production, AMPK phosphorylation and insulin sensitivity in hepatocytes from non-diabetic and diabetic mice" to be considered for publication in Food and Chemical Toxicology. In this revised manuscript we have addressed all the minor issues raised by the Reviewers (highlighted in red font). We also provide a detailed point-by-point response letter to the Reviewer´s comments.
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