Long-term co-administration of sodium nitrite and sodium hydrosulfide inhibits hepatic gluconeogenesis in male type 2 diabetic rats: Role of PI3K-Akt-eNOS pathway

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Objective: A deficiency in hydrogen sulfide (H2S) and nitric oxide (NO) contributes to the development of type 2 diabetes (T2D). An inhibitory effect on liver gluconeogenesis has been reported in rats with T2D with co-administration of sodium nitrite and sodium hydrosulfide (NaSH); the underlying mechanisms have however not yet been elucidated. The aim of this study is to determine the long-term effects of co-administering sodium nitrite and NaSH on expression of genes involved in liver gluconeogenesis in rats with T2D. Methods: T2D was induced using a high fat diet combined with low-dose of streptozotocin (30 mg/kg). Rats were divided into 5 groups (n = 7/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite (50 mg/L) and NaSH (0.28 mg/kg) were administered for 9 weeks. Intraperitoneal pyruvate tolerance test (PTT) was performed at the end of the ninth week and mRNA expressions of PI3K, Akt, eNOS, PEPCK, G6Pase, and FBPase were measured in the liver. Results: Co-administration of nitrite and NaSH decreased elevated serum glucose concentrations during PTT. Compared to T2D + nitrite, co-administration of nitrite and NaSH resulted in significant increases in mRNA expression of PI3K, Akt, and eNOS and significant decreases in mRNA expression of G6Pase and FBPase but had no effect on PEPCK expression. Conclusion: Long-term NaSH administration at low-dose, potentiated the inhibitory effects of nitrite on mRNA expression of key liver gluconeogenic enzymes in rats with T2D. This inhibitory effect of nitrite and NaSH co-administration on gluconeogenesis were associated with increased gene expression of PI3K, Akt, and eNOS in the liver.


  • Sajad Jeddi
  • Sevda Gheibi
  • Mattias Carlström
  • Khosrow Kashfi
  • Asghar Ghasemi
External organisations
  • Shahid Beheshti University of Medical Sciences
  • Karolinska Institutet
  • City University of New York
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes


  • Gene expression, Gluconeogenesis, Liver, Nitrite, Rat, Type 2 diabetes
Original languageEnglish
Article number118770
JournalLife Sciences
Early online date2020 Nov 16
Publication statusPublished - 2021 Jan 15
Publication categoryResearch