Nateglinide Stimulates Glucagon-Like Peptide-1 Release by Human Intestinal L Cells via a KATP Channel-Independent Mechanism

Abstract

The incretin effect is markedly reduced in patients with type 2 diabetes, mainly due to defective glucagon-like peptide-1 (GLP-1) secretion from the intestinal L cells in response to stimulation by various nutrients. 1,2) This leads to impairment of early-phase insulin secretion after food intake and consequently results in postprandial hyperglycemia and hyperlipidemia. [3][4][5][6] GLP-1 is an incretin hormone that is released by intestinal L cells following their stimulation by nutrients, 7,8) and it promotes glucose-stimulated insulin secretion by pancreatic bcells. GLP-1 has also been reported to have various other beneficial effects, such as promoting b-cell proliferation, 9) suppressing glucagon release, 10) suppressing food intake, 11,12) slowing gastric emptying, 13,14) and cardiovascular protection.15) Therefore, restoration of GLP-1 secretion by intestinal L cells could be an important new therapeutic option for the management of metabolic syndrome. Although the exact mechanism of GLP-1 secretion by intestinal L cells remains to be elucidated, the sulfonylurea receptor 1 (SUR1)/K ATP channel, 16,17) Na ϩ /glucose co-transporter 1 (SGLT1), 18) glucose transporter 2 (GLUT2), 19) sweet taste receptor, 20)TGR5 21) and G-protein coupled receptors (GPRs) [22][23][24][25] have all been reported to be involved in this process. In the present study, we investigated the effect of nateglinide on GLP-1 secretion by human intestinal L cells.Nateglinide is a short-acting insulin secretagogue with a rapid effect, which restores early-phase insulin secretion in patients with type 2 diabetes by rapidly binding to SUR1 [26][27][28][29][30] and thus suppresses postprandial hyperglycemia. It has been unclear whether or not GLP-1 is involved in these effects of nateglinide. Recently, Duffy et al. reported that nateglinide increases the plasma GLP-1 level by inhibiting dipeptidyl peptidase IV (DPP IV), 31) but the influence of nateglinide on GLP-1 secretion is still unknown. Therefore, we investigated the effect of nateglinide on GLP-1 secretion in vivo by monitoring GLP-1 levels in the portal venous blood after oral administration of nateglinide to normal Wistar rats. We also conducted an in vitro study to assess the direct effect of nateglinide on GLP-1 secretion by human intestinal L cells (NCI-H716). MATERIALS AND METHODSAnimals Male Goto-Kakizaki (GK) rats and male Wistar rats (6 weeks old) were purchased from Japan SLC Inc. (Hamamatsu, Japan). The animals were housed in individual polycarbonate cages with woodchip bedding, and were provided with food and water ad libitum. The animal room was maintained on a 12-h light/dark cycle (7 a.m.-7 p.m.: dark; 7 p.m.-7 a.m.: light), with a temperature range of 22Ϯ1°C and a relative humidity of 55Ϯ5%, throughout the experimental period. These animal experiments were performed in accordance with the Guiding Principles for the care and use of laboratory animals approved by the Japanese Pharmacological Society. In addition, this study was approved by the Animal Care and Use Committ...

Comparison of sitagliptin with nateglinide on postprandial glucose and related hormones in drug‐naïve Japanese patients with type 2 diabetes mellitus: A pilot study

“…In the present study, nateglinide significantly increased the AUC of glucagon during the meal test compared with sitagliptin. In contrast, regarding the effect on GLP‐1 in vitro , nateglinide increases the plasma GLP‐1 level by inhibition of DPP‐4 activity and direct stimulation of GLP‐1 release from L‐cells. However, in the present study, this difference could be related to the study condition.…”

“…However, in the present study, this difference could be related to the study condition. In fact, the use of nateglinide at a dose higher than the clinical dose was reported to have a direct effect on L‐cells to enhance GLP‐1 release. Taking these previous studies into consideration, the inhibitory effect of DPP‐4 activity and the stimulatory effect of GLP‐1 after the administration of a clinical dose of nateglinide might be very modest.…”

Biophysical and Pharmacological Properties of Glucagon-Like Peptide-1 in Rats Under Isoflurane Anesthesia

“…As previously reported, 21 GLP-1 release from NCI-H716 cells was stimulated by glucose in a dose-dependent manner (Fig. 4, control, n ϭ 10 each).…”

Efficacy of mitiglinide and sitagliptin, alone or in combination, on postprandial excursion and glycemic variability assessed by continuous glucose monitoring: apost hocanalysis with single-day treatment

“…The rationale for combination therapy was based on previous preclinical studies that evaluated the effect of meglitinide on DPP-4 activity. In these studies, it was demonstrated that meglitinide (nateglinide) prevents DPP-4-mediated GLP-1 degradation in both a time-and concentration-dependent manner [26,27]. However, a glucose-lowering effect of combination therapy in this study was not better than mitiglinide monotherapy, although it was better than sitagliptin monotherapy.…”