Long-term treatment with EXf, a peptide analog of Exendin-4, improves β-cell function and survival in diabetic KKAy mice.

Abstract

EXf is a C-terminally truncated fragment of Exendin-4 with two amino acid substitutions. Previous studies showed that EXf controls plasma glucose level acting as a glucagon-like peptide 1 (GLP-1) receptor agonist. The purpose of this study was to evaluate the effects of EXf on β-cell function and survival in diabetic KKAy mice. EXf treatment significantly improved the glucose intolerance and reduced non-fasting and fasting plasma glucose levels, as well as plasma triglyceride levels in diabetic KKAy mice. In hyperglycemic clamp test, EXf-treated mice displayed an increased glucose infusion rate and first-phase insulin secretion. Treatment with EXf also led to a significant restoration of islet morphology, an increase in Ki67 expression in β-cells, and a reduction in the number of TUNEL positive β-cells. In the pancreas, comparative transcription analysis showed up-regulation of Akt1. The up-regulation of phosphorylated Akt1 was confirmed by Western blot, and changes in the protein levels of members of the Akt1 pathway, such as PI3K, Bim, Bcl-2, Bax, Caspase-3, and Caspase-9, PDX-1, were observed as well. Therefore, EXf treatment could improve β-cell function and survival in diabetic KKAy mice, likely as a result of islet morphology restoration, stimulation of β-cell proliferation, and inhibition of β-cell apoptosis.

• Authors: Guo-jiang Hou, Cai-na Li, Shuai-nan Liu, Yi Huan, Quan Liu, Su-juan Sun, Lin-yi Li, Shao-cong Hou, Zhu-fang Shen
• Journal: Peptides (Peptides) Vol. 40 Pg. 123-32 (Feb 2013) ISSN: 1873-5169 [Electronic] United States
• PMID: 23353893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Blood Glucose
• Insulin
• Ki-67 Antigen
• Peptide Fragments
• Peptides
• Triglycerides
• Venoms
• Glucagon-Like Peptide 1
• Exenatide
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis (drug effects)
• Blood Glucose (drug effects)
• Exenatide
• Glucagon-Like Peptide 1 (antagonists & inhibitors)
• Glucose Intolerance (drug therapy, metabolism)
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (drug effects, metabolism)
• Ki-67 Antigen (metabolism)
• Mice
• Mice, Inbred NOD
• Peptide Fragments (pharmacology)
• Peptides (chemistry, pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Triglycerides (blood)
• Venoms (chemistry, pharmacology)