β-aminoisobutyric acid ameliorated type 1 diabetes-induced germ cell toxicity in rat: Studies on the role of oxidative stress and IGF-1/AMPK/SIRT-1 signaling pathway

Mutat Res Genet Toxicol Environ Mutagen. 2024 Oct:899:503820. doi: 10.1016/j.mrgentox.2024.503820. Epub 2024 Aug 13.

Abstract

Diabetes mellitus is known as the "epidemic of the century" due to its global prevalence. Several pre-clinical and clinical studies have shown that male germ cell toxicity is one of the major consequences of diabetes mellitus. Although β-aminoisobutyric acid (BAIBA) has been shown to be advantageous in the diabetic nephropathy and cardiomyopathy, its specific role in the diabetes-induced testicular toxicity remains unknown. In this study, an attempt was made to elucidate the molecular mechanisms of BAIBA-mediated germ cell protection in diabetic rats. Adult male Sprague-dawley rats were subjected to either no treatment (control) or BAIBA (100 mg/kg; BAIBA control) or Streptozotocin (50 mg/kg; diabetic control) or low (25 mg/kg), medium (50 mg/kg) and high (100 mg/kg) doses of BAIBA in diabetic conditions. Significant alterations in sperm related parameters, oxidative stress and apoptotic biomarkers, pancreatic and testicular histology, DNA damage and changes in expression of proteins in testes were found in the diabetic rats. 100 mg/kg of BAIBA significantly reduced the elevated blood glucose levels (P ≤ 0.05), increased body weight (P ≤ 0.01 in the 4th week), lowered malondialdehyde (P ≤ 0.05) and nitrite levels (P ≤ 0.01), elevated testosterone (P ≤ 0.05) and FSH levels (P ≤ 0.05), increased sperm count and motility (P ≤ 0.01), decreased testicular DNA damage (P ≤ 0.001), improved histological features of pancreas and testes, decreased TUNEL positive cells (P ≤ 0.01), decreased RAGE (P ≤ 0.01) and Bax (P ≤ 0.05) expressions and increased SIRT1 (P ≤ 0.05) and Atg 12 (P ≤ 0.05) expressions in the testes. 50 mg/kg of BAIBA partially restored the above-mentioned parameters whereas 25 mg/kg of BAIBA was found to be insignificant in counteracting the toxicity. It is interesting to note that BAIBA protects male germ cell damage in diabetic rats by regulating the IGF-1/AMPK/SIRT-1 signaling pathway.

Keywords: Apoptosis; BAIBA; Diabetes mellitus; IGF-1/AMPK/SIRT-1; Testes.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Aminoisobutyric Acids* / pharmacology
  • Animals
  • Apoptosis / drug effects
  • DNA Damage / drug effects
  • Diabetes Mellitus, Experimental* / drug therapy
  • Diabetes Mellitus, Experimental* / metabolism
  • Diabetes Mellitus, Type 1* / drug therapy
  • Diabetes Mellitus, Type 1* / metabolism
  • Insulin-Like Growth Factor I* / metabolism
  • Male
  • Oxidative Stress* / drug effects
  • Rats
  • Rats, Sprague-Dawley*
  • Signal Transduction* / drug effects
  • Sirtuin 1* / genetics
  • Sirtuin 1* / metabolism
  • Spermatozoa / drug effects
  • Spermatozoa / metabolism
  • Testis* / drug effects
  • Testis* / metabolism
  • Testis* / pathology

Substances

  • Sirtuin 1
  • Aminoisobutyric Acids
  • Insulin-Like Growth Factor I
  • 3-aminoisobutyric acid
  • Sirt1 protein, rat
  • AMP-Activated Protein Kinases