Nateglinide and Mitiglinide, but Not Sulfonylureas, Induce Insulin Secretion through a Mechanism Mediated by Calcium Release from Endoplasmic Reticulum

Abstract

Nateglinide and mitiglinide (glinides) are characterized as rapidonset 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 M tolbutamide and 1 nM glibenclamide was completely inhibited by 10 M diazoxide and 3 M verapamil, although the latter half-component of insulin secretion profile induced by 3 M nateglinide or 30 nM mitiglinide remained with the existence of those agents. Glinides enhanced insulin secretion even in Ca 2ϩ -depleted medium, and its pattern of secretion was same as the pattern with existence of verapamil. The latter half was suppressed by 1 M 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 K ATP channels. We also demonstrated that the latter pathway involves the intracellular calcium release from endoplasmic reticulum via ryanodine receptor activation.A decrease in the initial insulin secretion observed in an early stage of type 2 diabetes induces postprandial hyperglycemia. A large-scale clinical trial has demonstrated that postprandial hyperglycemia is closely related to complications of diabetes mellitus, particularly cardiovascular disorders affecting survival, and that the correction of postprandial hyperglycemia is important for the prevention of vascular events (DECODE Study

Glucose-Dependent Insulin Secretion in Pancreatic β-Cell Islets from Male Rats Requires Ca2+ Release via ROS-Stimulated Ryanodine Receptors

“…Previous reports have shown that pancreatic islets and β-cell lines express functional RyR channels [ 9 ] that give rise to nuclear Ca 2+ signals [ 42 ]. To explore the presence of RyR channels in β-cells, previous studies have employed pharmacological tools [ 11 ], endogenous RyR ligands [ 16 , 19 , 43 ], detection of RyR mRNA levels [ 16 , 17 , 38 ] and protein [ 14 , 15 , 21 , 44 ], or quantitative determinations of ryanodine binding using fluorescently-labeled ryanodine [ 38 ]. Here, we confirmed that β-cells dissociated from pancreatic rat islets and MIN6 pancreatic β-cells express the RyR2 isoform.…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Nateglinide binds the A‐site on SUR1 subunit while repaglinide binds the B‐site on both SUR1 and SUR2 subunits . In addition, glinides trigger intracellular Ca2+ release from the endoplasmic reticulum via ryanodine receptor activation, contributing to the enhancement of insulin secretion independently of KATP channel activity . However, long‐term exposure to glinides (as well as to SUs) accelerates KATP channel dysfunction and pancreatic β‐cell apoptosis and failure (“secondary failure”) over time …”

β‐Cell signalling and insulin secretagogues: A path for improved diabetes therapy

“…Thus, sulfonylureas and cAMP co‐operatively activate Epac2A . In addition to closure of the β‐cell K ATP channels, nateglinide and mitiglinide have been shown to mobilize Ca 2+ from endoplasmic reticulum (ER) “Sulfonylureas except for gliclazide stimulate insulin secretion through activation of Epac2A in addition to closure of K ATP channels.”…”