Combined therapy with metformin and insulin attenuates systemic and hepatic alterations in a model of high‐fat diet‐/streptozotocin‐induced diabetes

• Published in: International journal of experimental pathology Vol. 97; no. 3; pp. 266 - 277
• Main Authors: Silvares, Raquel Rangel, Pereira, Evelyn Nunes Goulart da Silva, Flores, Edgar Eduardo Ilaquita, Estato, Vanessa, Reis, Patrícia Alves, Silva, Igor José da, Machado, Marcelo Pelajo, Neto, Hugo Caire de Castro Faria, Tibiriça, Eduardo, Daliry, Anissa
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.06.2016
• Subjects: AGE; Animals; Blood Glucose - metabolism; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diet, High-Fat; Drug Synergism; inflammation; Insulin - administration & dosage; Insulin - therapeutic use; Lipid Peroxidation - drug effects; Liver; Liver - pathology; Male; metformin; Metformin - administration & dosage; Metformin - therapeutic use; Microcirculation; Microcirculation - drug effects; Original; oxidative stress; Oxidative Stress - drug effects; RAGE; Rats, Wistar; Streptozocin; Type 1 diabetes; Microcirculation; Type 1 diabetes; inflammation; liver; metformin; RAGE; oxidative stress; AGE
• ISSN: 0959-9673; 1365-2613
• DOI: 10.1111/iep.12184

Summary 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.