期刊
FOOD AND CHEMICAL TOXICOLOGY
卷 123, 期 -, 页码 470-480出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.fct.2018.11.019
关键词
Diabetes; Metformin; Insulin resistance; Glucose homeostasis; Liver
资金
- Laboratorios Silanes S.A. de C.V. [20159770]
- MINECO/FEDER [SAF2015-65267-R, IJCI-2014-19381]
- Comunidad de Madrid, Spain [S2017/BMD-3684 MOIR2-CM]
- CIBERdem (ISCIII, Spain)
- H2020 Marie Sklodowska-Curie ITN-TREATMENT [721236]
- Institute de Investigaciones Biomedicas Alberto Sols (CSIC)
The liver is a main target tissue of the biguanide metformin which activates AMP-activated protein kinase (AMPK). We previously reported that administration of metformin glycinate showed a greater decrease of glycated hemoglobin A1c than a placebo in patients with type 2 diabetes mellitus (T2DM). In this study, we compared the effects of metformin hydrochloride, the oral antidiabetic drug of first choice, with those of metformin glycinate in hepatocytes from non-diabetic and diabetic mice and humans. Both formulations were equally potent regard to 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. On the contrary, phosphorylation of AMPK and its substrate acetyl CoA carboxylase (ACC) was faster in hepatocytes treated with metformin glycinate. Likewise, we found stronger reduction in hepatocytes from obese/diabetic db/db mice of glucagon-induced glucose output and more sustained AMPK phosphorylation after 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. In conclusion, our data indicate that metformin glycinate may be an alternative therapy against insulin resistance during obesity and/or T2DM.
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