Long-term treatment with EXf, a peptide analog of Exendin-4, improves β-cell function and survival in diabetic KKAy mice.
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.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Guo-jiang
GJ
Hou
Cai-na
CN
Li
Shuai-nan
SN
Liu
Yi
Y
Huan
Quan
Q
Liu
Su-juan
SJ
Sun
Lin-yi
LY
Li
Shao-cong
SC
Hou
Zhu-fang
ZF
Shen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014688:Venoms / Q000737:chemistry / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D019394:Ki-67 Antigen; D010446:Peptide Fragments; D010455:Peptides; D014280:Triglycerides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt