The Postnatal Offspring of Finasteride-Treated Male Rats Shows Hyperglycaemia, Elevated Hepatic Glycogen Storage and Altered GLUT2, IR, and AR Expression in the Liver

Paulina Kur,Maciej Tarnowski,Andrzej Kram,Barbara Wiszniewska,Sylwia Rzeszotek,Irena Baranowska-Bosiacka,Agnieszka Kolasa-Wołosiuk,Marta Grabowska,Małgorzata Piasecka

doi:10.3390/ijms22031242

Paulina Kur, Maciej Tarnowski + Show 7 more

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https://doi.org/10.3390/ijms22031242

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Abstract

Background: A growing body of data indicates that the physiology of the liver is sex-hormone dependent, with some types of liver failure occurring more frequently in males, and some in females. In males, in physiological conditions, testosterone acts via androgen receptors (AR) to increase insulin receptor (IR) expression and glycogen synthesis, and to decrease glucose uptake controlled by liver-specific glucose transporter 2 (GLUT-2). Our previous study indicated that this mechanism may be impaired by finasteride, a popular drug used in urology and dermatology, inhibiting 5α-reductase 2, which converts testosterone (T) into dihydrotestosterone (DHT). Our research has also shown that the offspring of rats exposed to finasteride have an altered T–DHT ratio and show changes in their testes and epididymides. Therefore, the goal of this study was to assess whether the administration of finasteride had an trans-generational effect on (i) GLUT-2 dependent accumulation of glycogen in the liver, (ii) IR and AR expression in the hepatocytes of male rat offspring, (iii) a relation between serum T and DHT levels and the expression of GLUT2, IR, and AR mRNAs, (iv) a serum glucose level and it correlation with GLUT-2 mRNA. Methods: The study was conducted on the liver (an androgen-dependent organ) from 7, 14, 21, 28, and 90-day old Wistar male rats (F1:Fin) born by females fertilized by finasteride-treated rats. The control group was the offspring (F1:Control) of untreated Wistar parents. In the histological sections of liver the Periodic Acid Schiff (PAS) staining (to visualize glycogen) and IHC (to detect GLUT-2, IR, and AR) were performed. The liver homogenates were used in qRT-PCR to assess GLUT2, IR, and AR mRNA expression. The percentage of PAS-positive glycogen areas were correlated with the immunoexpression of GLUT-2, serum levels of T and DHT were correlated with GLUT-2, IR, and AR transcript levels, and serum glucose concentration was correlated with the age of animals and with the GLUT-2 mRNA by Spearman’s rank correlation coefficients. Results: In each age group of F1:Fin rats, the accumulation of glycogen was elevated but did not correlate with changes in GLUT-2 expression. The levels of GLUT-2, IR, and AR transcripts and their immunoreactivity statistically significantly decreased in F1:Fin animals. In F1:Fin rats the serum levels of T and DHT negatively correlated with androgen receptor mRNA. The animals from F1:Fin group have statistically elevated level of glucose. Additionally, in adult F1:Fin rats, steatosis was observed in the liver (see Appendix A). Conclusions: It seems that treating male adult rats with finasteride causes changes in the carbohydrate metabolism in the liver of their offspring. This can lead to improper hepatic energy homeostasis or even hyperglycaemia, insulin resistance, as well as some symptoms of metabolic syndrome and liver steatosis.

Highlights

The liver is one of the organs responsible for glucose metabolism
Given this trans-generational effect of finasteride on the male reproductive system and the aforementioned information on the role of androgens and androgen receptors (AR) in glucose metabolism, the aim of this study was to assess whether the androgen (T, DHT) imbalance in the F1:Fin generation of rats from males receiving finasteride can affect the accumulation of glycogen in the liver, serum glucose concentration and the hepatic mRNAs and proteins, GLUT2, insulin receptor (IR), and AR expression
The F1:Fin rats had an increased level of serum T, decreased serum DHT levels, an elevated expression of glucose transporter 2 (GLUT-2), and much higher hepatic glycogen accumulation than the control F1 generation. These findings suggest that DHT, to testosterone in Shen et al [13], is crucial for glucose homeostasis by regulating hepatic glucose output, and that testosterone deprivation due to castration increases hepatic glucose output, induces hyperglycaemia, and develops symptoms seen in type 2 diabetes and metabolic syndrome

Summary

Introduction

The liver is one of the organs responsible for glucose metabolism. It is involved in the production of glucose and its storage as glycogen—a branched polymer of glucose produced mostly in the liver, in skeletal muscles and, to a smaller degree, in the brain.Glucose can be converted into glycogen and vice versa other via synthesis or degradation involving various steps in the glycogen metabolism pathways [1]. In physiological conditions, testosterone acts via androgen receptors (AR) to increase insulin receptor (IR) expression and glycogen synthesis, and to decrease glucose uptake controlled by liver-specific glucose transporter 2 (GLUT-2). The goal of this study was to assess whether the administration of finasteride had an trans-generational effect on (i) GLUT-2 dependent accumulation of glycogen in the liver, (ii) IR and AR expression in the hepatocytes of male rat offspring, (iii) a relation between serum T and DHT levels and the expression of GLUT2, IR, and AR mRNAs, (iv) a serum glucose level and it correlation with GLUT-2 mRNA. Results: In each age group of F1:Fin rats, the accumulation of glycogen was elevated but did not correlate with changes in GLUT-2 expression. In adult F1:Fin rats, steatosis was observed in the liver

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