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.

Carnosine decreased oxidation and glycation products in serum and liver of high‐fat diet and low‐dose streptozotocin‐induced diabetic rats

“…; Silvares et al . ) were reported by several investigators. Also in the current study, HFD+STZ treatment of rats resulted in hyperglycaemia, dyslipidaemia and hepatic steatosis and inflammation as assessed through biochemical and histopathologic findings.…”

“…; Silvares et al . ). In this study, although no significant changes were detected in body weight due to HFD+STZ treatment, HFD+STZ rats showed a tendency to decrease body weight.…”

“…Some investigators also reported that AGE levels increased in serum (Govindaraj & Sorimuthu Pillai ) and liver (Silvares et al . ) of HFD+STZ rats.…”

Effect of variable antidiabetic treatments strategy on oxidative stress markers in obese patients with T2DM

“…Silvares et al have shown an elevated oxidative stress with inflammation, microvascular damage and AGEs deposition in HFD-/STZ-induced diabetes in rats [11]. Hyperglycemia induces ROS production, that initiate a chain reaction leading to an increased inflammatory response and chemical modification of lipoproteins [12].…”

The influence of obesity by a diet high in saturated fats and carbohydrates balance in the manifestation of systemic complications and comorbidities

“…However, in this study, this type of carbohydrate was not used, since this would not allow knowing if the manifestation of the complications and comorbidities would be exclusively due to the increase of the amount of fat or its association with a carbohydrate with harmful capacity. It is believed that other factors may also have influenced this result as time of exposure to diet, fat percentage, and type (saturated or unsaturated) and source (animal or vegetable) of fatty acids and animal model [6,17,18,30,33,[35][36][37].…”