Hexarelin Protects Rodent Pancreatic Β-Cells Function from Cytotoxic Effects of Streptozotocin Involving Mitochondrial Signalling Pathways In Vivo and In Vitro

PLoS One. 2016 Feb 26;11(2):e0149730. doi: 10.1371/journal.pone.0149730. eCollection 2016.


Mitochondrial functions are crucial for pancreatic β-cell survival and glucose-induced insulin secretion. Hexarelin (Hex) is a synthetic small peptide ghrelin analogue, which has been shown to protect cardiomyocytes from the ischemia-reperfusion process. In this study, we used in vitro and in vivo models of streptozotocin (STZ)-induced β-cell damage to study the protective effect of Hex and the associated mechanisms. We found that STZ produced a cytotoxic effect in a dose- and time-dependent manner in MIN6 cells (a mouse β-cell line). Hex (1.0 μM) decreased the STZ-induced damage in β-cells. Rhodamine 123 assay and superoxide DHE production assay revealed that Hex ameliorated STZ-induced mitochondrial damage and excessive superoxide activity in β-cells. In addition, Hex significantly reduced STZ-induced expression of cleaved Caspases-3, Caspases-9 and the ratio of pro-apoptotic protein Bax to anti-apoptotic protein Bcl-2 in MIN6 cells. We further examined the in vivo effect of Hex in a rat model of type 1 diabetes induced by STZ injection. Hex ameliorated STZ-induced decrease in plasma insulin and protected the structure of islets from STZ-induced disruption. Hex also ameliorated STZ-induced expression of cleaved Caspase-9 and the Bax in β-cells. In conclusion, our data indicate that Hex is able to protects β-cell mass from STZ-caused cytotoxic effects involving mitochondrial pathways in vitro and in vivo. Hex may serve as a potential protective agent for the management of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Cytoprotection / drug effects
  • Cytotoxins / toxicity*
  • Dose-Response Relationship, Drug
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / drug effects*
  • Male
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Oligopeptides / pharmacology*
  • Oxidative Stress / drug effects
  • Proteolysis / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Signal Transduction / drug effects*
  • Streptozocin / toxicity*
  • Time Factors
  • bcl-2-Associated X Protein / metabolism


  • Blood Glucose
  • Cytotoxins
  • Insulin
  • Oligopeptides
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • hexarelin
  • Streptozocin
  • Caspase 3
  • Caspase 9

Grant support

Research work was supported by NHMRC, the University of Queensland, the National Nature Science Foundation of China (NSFC grant no. 81501175) and the Leading Disciplines Development Government Foundation of Shaanxi, China. YZ is a recipient of overseas postgraduate research scholarship from the China Scholarship Council (CSC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.