PMID- 33219494
OWN - NLM
STAT- MEDLINE
DCOM- 20210708
LR  - 20210708
IS  - 1559-0100 (Electronic)
IS  - 1355-008X (Linking)
VI  - 71
IP  - 2
DP  - 2021 Feb
TI  - Antidiabetic compounds 8a, 8b, 8k, and 9h enhance insulin secretion: activity and 
      mechanism.
PG  - 365-377
LID - 10.1007/s12020-020-02537-5 [doi]
AB  - PURPOSE: This study primarily investigated the effects of hypoglycemic compounds 
      (Imeglimin derivatives) on insulin secretion in type 2 diabetes mellitus (T2DM), 
      and further explored the possible mechanism underlying these effects. METHODS: 
      Firstly, Metformin was used as the initiating compound to synthesize three sets 
      of derivatives which contained Imeglimin structure core. At the cellular level, 
      we screened compounds with better effect on the activity of insulin receptor 
      tyrosine protein kinase (IFcTPK) after the islet beta cells were treated with the 
      compounds of different concentrations. The insulin secretion was assessed using 
      radioimmunoassay and the cytotoxicity to islet beta cells was evaluated by means of 
      MTT assay following treatment with the compounds. The Ca(2+)-related mechanism by 
      which these compounds promote insulin secretion was elucidated with whole cell 
      recordings from current-clamp mode. RESULTS: Totally, 48 synthesized compounds 
      were generated, wherein 10 compounds could increase the activity of IFcTPK in 
      HIT-T15 cells better among these compounds. The modified Imeglimin, especially in 
      the structure of hydrophilic hydroxyl or piperidine rings, could improve the 
      activity of the compound to promote insulin secretion. Furthermore, the compounds 
      8a, 8b, 8k, and 9h revealed high insulin secretion-promoting activity. These 
      compounds enhanced insulin secretion in islet beta cells by repressing the 
      ATP-sensitive K(+) and voltage-gated K+ pathway. CONCLUSIONS: Our findings 
      indicate that the hypoglycemic compounds 8a, 8b, 8k, and 9h confer better 
      promotive effect on insulin secretion, which provides a reference for the 
      development of drugs with better hypoglycemic activity.
FAU - Li, Hui
AU  - Li H
AD  - Department of Endocrinology, The Second Affiliated Hospital of Qiqihar Medical 
      University, Qiqihar, 161000, PR China.
FAU - Zhang, Jian
AU  - Zhang J
AD  - Department of Endocrinology, The Second Affiliated Hospital of Qiqihar Medical 
      University, Qiqihar, 161000, PR China.
FAU - Fu, Yongli
AU  - Fu Y
AD  - Department of Endocrinology, The Second Affiliated Hospital of Qiqihar Medical 
      University, Qiqihar, 161000, PR China.
FAU - Zhang, Yixin
AU  - Zhang Y
AD  - Department of Endocrinology, The Second Affiliated Hospital of Qiqihar Medical 
      University, Qiqihar, 161000, PR China.
FAU - Zhang, Chunhui
AU  - Zhang C
AD  - Department of Endocrinology, The Second Affiliated Hospital of Qiqihar Medical 
      University, Qiqihar, 161000, PR China.
FAU - Sun, Xiaozhu
AU  - Sun X
AD  - Department of Endocrinology, The Second Affiliated Hospital of Qiqihar Medical 
      University, Qiqihar, 161000, PR China.
FAU - Wu, Fang
AU  - Wu F
AD  - Department of Hepatology, The Seventh Hospital of Qiqihar, Qiqihar, 161000, PR 
      China.
FAU - He, Jing
AU  - He J
AD  - Department of Endocrinology, The Second Affiliated Hospital of Qiqihar Medical 
      University, Qiqihar, 161000, PR China. hejin096@163.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201120
PL  - United States
TA  - Endocrine
JT  - Endocrine
JID - 9434444
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - IY9XDZ35W2 (Glucose)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/metabolism
MH  - *Diabetes Mellitus, Type 2/drug therapy/metabolism
MH  - Glucose/metabolism
MH  - Humans
MH  - Hypoglycemic Agents/pharmacology
MH  - Insulin/metabolism
MH  - Insulin Secretion
MH  - *Islets of Langerhans/metabolism
OTO - NOTNLM
OT  - ATP-sensitive K(+) channel
OT  - Hypoglycemic compounds
OT  - Imeglimin derivatives
OT  - Insulin secretion
OT  - Type 2 diabetes mellitus
OT  - Voltage-gated K+ channel
EDAT- 2020/11/22 06:00
MHDA- 2021/07/09 06:00
CRDT- 2020/11/21 05:37
PHST- 2020/06/01 00:00 [received]
PHST- 2020/10/01 00:00 [accepted]
PHST- 2020/11/22 06:00 [pubmed]
PHST- 2021/07/09 06:00 [medline]
PHST- 2020/11/21 05:37 [entrez]
AID - 10.1007/s12020-020-02537-5 [pii]
AID - 10.1007/s12020-020-02537-5 [doi]
PST - ppublish
SO  - Endocrine. 2021 Feb;71(2):365-377. doi: 10.1007/s12020-020-02537-5. Epub 2020 Nov 
      20.