GLP-1 C-terminal structures affect its blood glucose lowering-function.
Glucagon-like peptide-1 (GLP-1), which is an endogenous insulinotropic peptide that can stimulate islet cells to secret insulin, is a promising new drug candidate for the treatment of type 2 diabetes. However, due to the very short half-life of this peptide, the clinical value of GLP-1 is restricted. A GLP-1 peptide analog that had been altered by deletion of five amino acids from the C-terminus (sGLP-1) was selected and investigated in vivo for the therapeutic effect on GK rats with type II DM (T2DM). The results revealed that sGLP-1 exhibited decreased blood glucose-lowering ability compared to GLP-1 in the first week, as measured after once-daily administration. However, after drug administration for 2 weeks, the blood glucose-lowering effect of sGLP-1 became superior to that of GLP-1. sGLP-1 reduced apoptosis of the old islets, enhanced insulin production, and promoted new islets replication. sGLP-1 is a shorter but more efficient GLP-1 analog for type 2 diabetes management. Because sGLP-1 prolonged the proliferation and recovery of islet cells, the ability to maintain blood glucose (BG) within a normal range was still present 2 weeks after drug withdrawal. These results confirmed the importance of the C-terminus of GLP-1 molecule, and further demonstrated that GLP-1 (7-37) can be truncated till the 32nd amino acid to have a better long-term BG lowing function. This result may imply for the presence of glucagon family clearance receptors in vivo and demonstrates that the C-terminus participates in GLP-1 clearance.
Li
Yuan
Y
Dalian DN Bio-Engineering Co., Ltd., Dalian, Liaoning, PRC.
Shi
Changhong
C
Lv
Qiujun
Q
Zhang
Huming
H
Li
Biehu
B
Bian
Guangxing
G
Huang
Qingsheng
Q
Zhang
Weihua
W
Xue
Xiaoping
X
Ren
Xin
X
Gao
Hua
H
Sun
Chunyi
C
Wang
Juan
J
Zhang
Mingjie
M
D000821:Animal Feed; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D005223:Fats / Q000494:pharmacology; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D013311:Streptozocin / Q000494:pharmacology
D001786:Blood Glucose; D005223:Fats; D010446:Peptide Fragments; D013311:Streptozocin; D052216:Glucagon-Like Peptide 1