As several studies have shown a link between T1D and liver disease we explored the hepatic alterations due to diabetes and the modulation of this complication by the metformin adjunct therapy.Design and method:
Fifty five Wistar rats were divided in three groups: control (CTL, n = 20), high-fat diet/streptozotocin induced diabetic (DM, n = 20) and diabetic treated with metformin plus insulin (DM + Met + Ins, n = 15). The biochemical parameters (%HbA1c, cholesterol, fructosamine, triglycerides, total proteins, bilirubin, urea, uric acid, and ALT, AST, ALP, GGT, and amylase activities) were analyzed by spectrophotometry. Intravital microscopy was used to study the hepatic microcirculation. In the liver tissue, real-time PCR was used to analyze oxidative stress enzymes, the inflammatory marker MCP-1 and RAGE gene expression. Lipid peroxidation was assessed by TBARs. AGE deposition and RAGE protein expression were studied in the liver by fluorescence spectrophotometry and western blot, respectively.Results:
The following parameters were maintained at levels similar to the control values after the adjunct treatment: body weight, insulin, fasting blood glucose, fructosamine, triglycerides, %HbA1c, and pancreas, renal and liver function serum markers. Regarding the microvascular effects, the dual therapy protected from the increase in rolling and adhesion of leukocytes. In the liver, metformin adjunct therapy protected the diabetic animals from increase in lipid peroxidation, rolling and adhesion of leukocytes, advanced glycation end products deposition and decrease in catalase gene expression and activity. The histopathological analysis of the liver showed no differences among the studied groups. AMPK activation was shown to be reduced in DM and DM + Met + Ins groups.Conclusions:
Our results suggest that oxidative stress, catalase gene expression and activity, microcirculatory damage and glycated proteins could be involved in the etiology of liver disease due to diabetes and could explain at least in part the mechanism of action of metformin adjunct therapy. The better understanding of the mechanisms of action of metformin and pathophysiology of liver disease would lead to further advances in the management of T1D patients.