Differential effects of metformin glycinate and hydrochloride in glucose production, AMPK phosphorylation and insulin sensitivity in hepatocytes from non-diabetic and diabetic mice

Autor: Alejandra Mosquera, Leocadio Rodríguez-Mañas, Jordi Muntané, Ángela M. Valverde, Francisco Ferrandiz, Jorge González-Canudas, Flora de Pablo, Patricia Rada
Přispěvatelé: Laboratorios Silanes, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Comunidad de Madrid
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Male
endocrine system diseases
medicine.medical_treatment
Mice
Obese
AMP-Activated Protein Kinases
Toxicology
Glucose homeostasis
Mice
Insulin
Phosphorylation
0303 health sciences
Hígado
Biguanide
Chemistry
digestive
oral
and skin physiology
Diabetes
04 agricultural and veterinary sciences
General Medicine
040401 food science
Metformin
3. Good health
Sistema endocrino
Liver
Female
medicine.drug
medicine.medical_specialty
medicine.drug_class
Resistencia a la insulina
03 medical and health sciences
0404 agricultural biotechnology
Insulin resistance
Internal medicine
Diabetes mellitus
Toxicología
medicine
Animals
Humans
Protein kinase B
030304 developmental biology
Glycated Hemoglobin
AMPK
nutritional and metabolic diseases
medicine.disease
Mice
Inbred C57BL
Endocrinology
Glucose
Diabetes Mellitus
Type 2
Hepatocytes
Food Science
Acetyl-CoA Carboxylase
Zdroj: Food and Chemical Toxicology
Digital.CSIC. Repositorio Institucional del CSIC
instname
Popis: 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.
Financial support was received from Laboratorios Silanes S.A. de C.V. (Project reference 20159770) as a research agreement with the Instituto de Investigaciones Biomedicas Alberto Sols (CSIC). This work was also funded by grants SAF2015-65267-R (MINECO/FEDER), S2017/BMD-3684 MOIR2-CM (Comunidad de Madrid, Spain), CIBERdem (ISCIII, Spain), and H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant Agreement number 721236) (European Commission) to A.M.V. and IJCI-2014-19381 (MINECO/FEDER) to P.R and A.M.V.
Databáze: OpenAIRE
Externí odkaz: