Astragaloside IV Ameliorates Streptozotocin Induced Pancreatic β-Cell Apoptosis and Dysfunction Through SIRT1/P53 and Akt/GSK3β/Nrf2 Signaling Pathways

Abstract

Background

Absolute or relative lack of insulin secretion caused by pancreatic β-cell dysfunction can lead to diabetes. Astragaloside IV (AS-IV), the main components of the traditional Chinese medicine Astragalus, has anti-oxidant, anti-inflammatory and anti-apoptotic properties, and exerts anti-diabetic pharmacological effects.

Purpose

To explore whether AS-IV can protect the apoptosis and dysfunction of pancreatic β-cells induced by streptozotocin (STZ) and its underlying molecular mechanism.

Methods

STZ-induced pancreatic β-cell line INS-1 was treated with different concentrations of AS-IV, then cell viability, apoptosis, oxidative stress and insulin secretion was assessed by CCK-8, TUNEL staining, Western blot, commercial kits and qRT-PCR, respectively. The expression of proteins involved in Sirtuin 1 (SIRT1)/p53 and Akt/glycogen synthase kinase-3 β (GSK3β)/nuclear factor E2-related factor 2 (Nrf2) signaling was measured by Western blot assay. Besides, Akt inhibitor MK-2206 and SIRT1 inhibitor EX-527 were used to co-treat STZ-induced INS-1 cells in the presence of AS-IV, and the above experiments were repeated.

Results

AS-IV increased the cell viability of INS-1 cells induced by STZ. AS-IV also reduced the increase in apoptosis rate and reversed STZ-induced down-regulation of Bcl-2 and up-regulation of Bax and Cleaved caspase 3. In addition, AS-IV significantly reduced STZ-induced malondialdehyde upregulation and reduced superoxide dismutase and glutathione peroxidase levels. Furthermore, the use of AS-IV was found to increase the insulin secretion capacity of INS-1 cells with impaired function, along with the increase of the mRNA levels of insulin 1 and insulin 2. Mechanism studies further showed that MK-2206 and EX-527 reversed the protective effect of AS-IV against STZ-induced injury on INS-1 cells.

Conclusion

AS-IV exerted cytoprotective effect on STZ-induced INS-1 cells through regulating SIRT1/p53 and Akt/GSK3β/Nrf2 signaling pathways. These findings are expected to provide new supplements to the molecular mechanism of AS-IV in the treatment of diabetes.

Keywords:

• astragaloside IV
• pancreatic β-cell
• apoptosis
• dysfunction
• SIRT1/p53
• Akt/GSK3β/Nrf2

Data Sharing Statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

This study was supported by the Project of the Fujian Provincial Department of Education (JAT201217).