PT  - JOURNAL ARTICLE
AU  - Makoto Shigeto
AU  - Masashi Katsura
AU  - Masafumi Matsuda
AU  - Seitaro Ohkuma
AU  - Kohei Kaku
TI  - Nateglinide and Mitiglinide, but Not Sulfonylureas, Induce Insulin Secretion through a Mechanism Mediated by Calcium Release from Endoplasmic Reticulum
AID  - 10.1124/jpet.107.120592
DP  - 2007 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1--7
VI  - 322
IP  - 1
4099  - http://jpet.aspetjournals.org/content/322/1/1.short
4100  - http://jpet.aspetjournals.org/content/322/1/1.full
SO  - J Pharmacol Exp Ther2007 Jul 01; 322
AB  - Nateglinide and mitiglinide (glinides) are characterized as rapid-onset and short-acting insulinotropic agents. Although both compounds do not have a sulfonylurea structure, it has been postulated that insulin secretion is preceded by their binding to Kir6.2/SUR1 complex, and a mechanism of insulin secretion of glinides has been accounted for by this pathway. However, we hypothesized the involvement of additional mechanisms of insulin secretion enhanced by glinides, and we analyzed the pattern of time course of insulin secretion from MIN6 cells with the existence of agents that have specific pharmacologic actions. Dose-dependent effects of tolbutamide, glibenclamide, nateglinide, and mitiglinide were observed. Insulin secretion induced by 3 μM tolbutamide and 1 nM glibenclamide was completely inhibited by 10 μM diazoxide and 3 μM verapamil, although the latter half-component of insulin secretion profile induced by 3 μM nateglinide or 30 nM mitiglinide remained with the existence of those agents. Glinides enhanced insulin secretion even in Ca2+-depleted medium, and its pattern of secretion was same as the pattern with existence of verapamil. The latter half was suppressed by 1 μM dantrolene, and concomitant addition of verapamil and dantrolene completely suppressed the entire pattern of insulin secretion enhanced by nateglinide. Thus, we conclude that glinide action is demonstrated through two pathways, dependently and independently, from the pathway through KATP channels. We also demonstrated that the latter pathway involves the intracellular calcium release from endoplasmic reticulum via ryanodine receptor activation. The American Society for Pharmacology and Experimental Therapeutics