PMID- 16158072
OWN - NLM
STAT- MEDLINE
DCOM- 20060203
LR  - 20181217
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 146
IP  - 6
DP  - 2005 Nov
TI  - Characterization of the action of S 21403 (mitiglinide) on insulin secretion and 
      biosynthesis in normal and diabetic beta-cells.
PG  - 872-81
AB  - S 21403 (mitiglinide) is a new drug for type 2 diabetes mellitus (T2DM). Its 
      action on insulin release and biosynthesis was investigated in several 
      experimental systems utilizing pancreas from normal and T2DM animals. At high 
      concentrations (10 microM), S 21403, like classical sulphonylurea, induced 
      insulin release in the absence of glucose. In contrast, at therapeutic (0.1-1.0 
      microM) concentrations, S 21403 amplified insulin secretion glucose 
      dose-dependently and with similar magnitude in normal and diabetic GK rat islets. 
      In perfused GK rat pancreas, S 21403 induced normal kinetics of insulin secretion 
      including first-phase response. The effect of S 21403 was strongly modulated by 
      physiological factors. Thus, 0.1 microM adrenaline inhibited S 21403-induced 
      insulin release. There was marked synergism between S 21403 and arginine in GK 
      rat islets, combination of the two normalizing insulin secretion. In primary 
      islet cultures from normal rats or prediabetic Psammomys obesus, prolonged 
      exposure to S 21403 did not induce further depletion of insulin stores under 
      normal or 'glucotoxic' conditions. Proinsulin biosynthesis was not affected by 
      2-h exposure of rat or prediabetic P. obesus islets to 1 microM S 21403. Yet, 
      24-h exposure of rat islets to S 21403 resulted in 30% increase in proinsulin 
      biosynthesis at 8.3 mM glucose. Amplification by S 21403 of glucose-induced 
      insulin secretion in diabetic GK beta-cells with restoration of first-phase 
      response, a strong synergistic interaction with arginine and marked inhibition by 
      adrenaline, make it a prime candidate for successful oral antidiabetic agent.
FAU - Kaiser, Nurit
AU  - Kaiser N
AD  - Endocrinology and Metabolism Service, Internal Medicine Department, 
      Hadassah-Hebrew University Medical Centre, Jerusalem 91120, Israel.
FAU - Nesher, Rafael
AU  - Nesher R
FAU - Oprescu, Andrei
AU  - Oprescu A
FAU - Efendic, Suad
AU  - Efendic S
FAU - Cerasi, Erol
AU  - Cerasi E
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Indoles)
RN  - 0 (Insulin)
RN  - 0 (Isoindoles)
RN  - 94ZLA3W45F (Arginine)
RN  - D86I0XLB13 (mitiglinide)
RN  - IY9XDZ35W2 (Glucose)
RN  - YKH834O4BH (Epinephrine)
SB  - IM
MH  - Animals
MH  - Arginine/pharmacology
MH  - Cells, Cultured
MH  - Diabetes Mellitus, Experimental/drug therapy/metabolism/physiopathology
MH  - Diabetes Mellitus, Type 2/drug therapy/metabolism/physiopathology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Epinephrine/pharmacology
MH  - Gerbillinae
MH  - Glucose/metabolism/pharmacology
MH  - Hypoglycemic Agents/pharmacology
MH  - Indoles/antagonists & inhibitors/*pharmacology
MH  - Insulin/*biosynthesis/*metabolism
MH  - Insulin Secretion
MH  - Insulin-Secreting Cells/*drug effects/metabolism/pathology
MH  - Isoindoles
MH  - Perfusion
MH  - Rats
MH  - Rats, Wistar
PMC - PMC1751216
EDAT- 2005/09/15 09:00
MHDA- 2006/02/04 09:00
PMCR- 2006/11/01
CRDT- 2005/09/15 09:00
PHST- 2005/09/15 09:00 [pubmed]
PHST- 2006/02/04 09:00 [medline]
PHST- 2005/09/15 09:00 [entrez]
PHST- 2006/11/01 00:00 [pmc-release]
AID - 0706374 [pii]
AID - 10.1038/sj.bjp.0706374 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2005 Nov;146(6):872-81. doi: 10.1038/sj.bjp.0706374.