Can combination therapy with insulin and metformin improve metabolic function of the liver, in type I diabetic patients? An animal model study on CYP2D1 activity

Abstract

Introduction Changes in hepatic clearance and CYP2D1 activity after combination therapy with insulin and metformin in type-1 diabetes and insulin administration in type-2 diabetes was assessed in an animal model. Methods Ten male Wistar rats were divided into two groups. Seven days after induction of diabetes, in treatment groups, type-1 diabetic rats received insulin plus metformin, and type-2 diabetic rats received insulin daily for 14 days. On day 21, rats were subjected to liver perfusion using Krebs-Henseleit buffer containing dextromethorphan as a CYP2D1 probe. Perfusate samples were analyzed by HPLC-FL. ResultsThe average metabolic rate of dextromethorphan and hepatic clearance changed from 0.012 ± 0.004 and 6.3 ± 0.1 ml/min in the control group to 0.006 ± 0.001 and 5.2 ± 0.2 ml/min in the untreated type-1 diabetic group, and 0.008 ± 0.003 and 5 ± 0.6 ml/min in the untreated type-2 diabetic rats [1]. In the present study, metabolic rate and hepatic clearance changed to 0.0112 ± 0.0008 and 6.2 ± 0.1 ml/min in the type-1 diabetic group treated with insulin plus metformin, and 0.0149 ± 0.0012 and 6.03 ± 0.06 ml/min in the insulin-receiving type-2 diabetic rats. Conclusions Administration of insulin plus metformin in type-1 diabetes could modulate the function of CYP2D1 to the observed levels in the control group and made it clearer to predict the fate of drugs that are metabolized by this enzyme. Moreover, good glycemic control with insulin administration has a significant effect on the balance between hepatic clearance and CYP2D1 activity in type-2 diabetes.

Evaluation of important human CYP450 isoforms and P‐glycoprotein phenotype changes and genotype in type 2 diabetic patients, before and after intensifying treatment regimen using Geneva cocktail

“…Several studies have been performed in animals and humans to evaluate the effects of inflammation and acute and chronic inflammatory disease on the P450 cytochrome genes expression and enzyme activity. [29][30][31][32] All of these studies have shown that the activity of most CYP450s changes, especially the activity of 3A and 2C families. The lowest changes pertain to the 1A and 2D families, which are slightly affected by inflammation.…”

Frequency of Important CYP450 Enzyme Gene Polymorphisms in the Iranian Population in Comparison with Other Major Populations: A Comprehensive Review of the Human Data

“…Modulation of CYP enzymes activity results in altered pharmacokinetics of drugs metabolized by these enzymes [ 6 , 7 ]. Apart from intra-individual changes in the activity of these enzymes by a number of physiological, pathological, and environmental factors [ 8 , 9 , 10 , 11 , 12 ], the expression of CYP genes can present consequential inter-individual variations in the basal expression, giving rise to diversities in the rates of drug elimination and response [ 13 ].…”

Study the effect of 3,4-Methylenedioxy methamphetamine on cytochrome P450 2E1 activity

“…To evaluate the extent of activity alteration for enzymes that are not involved in MDMA metabolism, we focused on investigating the activity of Cytochrome P450 2E1 upon exposure to MDMA in a series of ex-vivo experiments using the isolated perfused rat liver (IPRL) method. Liver perfusion has been extensively used in pharmacological and toxicological studies in recent years (Neyshaburinezhad et al, 2021;Neyshaburinezhad et al, 2020a;Neyshaburinezhad et al, 2020b;Rezai et al, 2020).…”