title: Combined therapy with metformin and insulin attenuates systemic and hepatic alterations in a model of high-fat diet-/streptozotocin-induced diabetes.
abstract: In this study we have explored the pathogenesis of the hepatic alterations which occur in diabetes and the modulation of these complications by the combination of metformin adjunct treatment and insulin monotherapy. For this purpose, diabetic rats were treated with insulin (DM + Ins) or metformin plus insulin (DM + Met + Ins). Biochemical and cardiometabolic parameters were analysed by spectrophotometry. Intravital microscopy was used to study the hepatic microcirculation. In the liver tissue, real-time PCR was used to analyse oxidative stress enzymes, inflammatory markers and receptors for advanced glycation end products (AGE) (RAGE) gene expression. Lipid peroxidation was assessed by thiobarbituric acid reactive species (TBARs) analyses. AGE deposition and RAGE protein expression were studied by fluorescence spectrophotometry and Western blot respectively. Body weight, %HbA1c , urea, total proteins and oxidative stress parameters were found to be similarly improved by insulin or Met + Ins treatments. On the other hand, Met + Ins treatment showed a more pronounced effect on fasting blood glucose level than insulin monotherapy. Fructosamine, uric acid, creatinine, albumin and amylase levels and daily insulin dose requirements were found to be only improved by the combined Met + Ins treatment. Liver, renal and pancreatic dysfunction markers were found to be more positively affected by metformin adjunct therapy when compared to insulin treatment. Liver microcirculation damage was found to be completely protected by Met + Ins treatment, while insulin monotherapy showed no effect. Our results suggest that oxidative stress, microcirculatory damage and glycated proteins could be involved in the aetiology of liver disease due to diabetes. Additionally, metformin adjunct treatment improved systemic and liver injury in induced diabetes and showed a more pronounced effect than insulin monotherapy.
authors.affiliation: Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Raquel Rangel
authors.initials: RR
authors.lastname: Silvares
authors.affiliation: Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Evelyn Nunes Goulart da Silva
authors.initials: EN
authors.lastname: Pereira
authors.affiliation: Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Edgar Eduardo Ilaquita
authors.initials: EE
authors.lastname: Flores
authors.affiliation: Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Estato
authors.affiliation: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Patrícia Alves
authors.initials: PA
authors.lastname: Reis
authors.affiliation: Laboratório de Patologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Igor José da
authors.initials: IJ
authors.lastname: Silva
authors.affiliation: Laboratório de Patologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Marcelo Pelajo
authors.initials: MP
authors.lastname: Machado
authors.affiliation: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Hugo Caire de Castro Faria
authors.initials: HC
authors.lastname: Neto
authors.affiliation: Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tibiriça
authors.affiliation: Laboratório de Investigação Cardiovascular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Anissa
authors.initials: A
authors.lastname: Daliry
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D059305:Diet, High-Fat; D004357:Drug Synergism; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008833:Microcirculation / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D017208:Rats, Wistar; D013311:Streptozocin
chemical_list: D001786:Blood Glucose; D007328:Insulin; D013311:Streptozocin; D008687:Metformin
keywords: AGE; Microcirculation; RAGE; Type 1 diabetes; inflammation; liver; metformin; oxidative stress