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Yoshihisa Kurachi - One of the best experts on this subject based on the ideXlab platform.
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Nateglinide a d phenylalanine derivative lacking either a sulfonylurea or benzamido moiety specifically inhibits pancreatic β cell type katp channels
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita, Yoshihisa KurachiAbstract:A novel antidiabetic agent, Nateglinide, is ad-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of Nateglinide on recombinant ATP-sensitive K + (K ATP ) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, Nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities ( K i = 75 nM and 114 μM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity ( K i = 105 and 111 μM, respectively). Nateglinide inhibited the K ATP current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity ( K i = 290 μM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by Nateglinide. MgADP or MgUDP (100 μM) augmented the inhibitory effect of Nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of Nateglinide (∼10 μM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
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Nateglinide a d phenylalanine derivative lacking either a sulfonylurea or benzamido moiety specifically inhibits pancreatic β cell type katp channels
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita, Yoshihisa KurachiAbstract:A novel antidiabetic agent, Nateglinide, is a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of Nateglinide on recombinant ATP-sensitive K(+) (K(ATP)) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, Nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities (K(i) = 75 nM and 114 microM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K(i) = 105 and 111 microM, respectively). Nateglinide inhibited the K(ATP) current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K(i) = 290 microM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by Nateglinide. MgADP or MgUDP (100 microM) augmented the inhibitory effect of Nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of Nateglinide (approximately 10 microM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
Steven M Haffner - One of the best experts on this subject based on the ideXlab platform.
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incidence of atrial fibrillation in a population with impaired glucose tolerance the contribution of glucose metabolism and other risk factors a post hoc analysis of the Nateglinide and valsartan in impaired glucose tolerance outcomes research trial
American Heart Journal, 2013Co-Authors: Roberto Latini, Steven M Haffner, R R Holman, Angelyn M Bethel, Lidia Staszewsky, Jielena Sun, Marcello Disertori, Futien Chang, Thomas D GilesAbstract:Background The role of dysglycemia as an additional risk factor for atrial fibrillation (AF) is controversial. Therefore, it was of interest to assess risk factors for incident AF in a large, representative population of patients with cardiovascular risk factors and impaired glucose tolerance but not overt diabetes in NAVIGATOR. Methods Predictors of incident AF were analyzed in 8,943 patients without AF at baseline by Cox proportional hazards regression. Study treatments (valsartan vs no valsartan and Nateglinide vs no Nateglinide) and the time-dependent covariate for progression to type 2 diabetes mellitus were added separately to the model. Results The median age of the 8,943 patients included in the present analysis of the NAVIGATOR trial was 63 years. Half of those patients were men, 6,922 (77.4%) had a history of hypertension, and 255 (2.9%) had heart failure. The median glycated hemoglobin was 6%. During the study, 613 of the 8,943 patients without AF at baseline presented with at least 1 episode of AF (6.9% 5-year incidence). Besides established predictors of incident AF, a 1 mmol/L increment of baseline fasting glucose, but not progression to diabetes, was found to be associated with a 33% increased risk of incident AF. Neither valsartan nor Nateglinide affected AF incidence. Conclusions In a trial population with impaired glucose tolerance, fasting plasma glucose and well-known risk factors (age, hypertension, and elevated body weight), but not progression to diabetes, predict risk of AF.
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predictors of incident heart failure hospitalizations among patients with impaired glucose tolerance insight from the Nateglinide and valsartan in impaired glucose tolerance outcomes research study
Circulation-heart Failure, 2013Co-Authors: Y Wong, John J V Mcmurray, Jielena Sun, Laine Thomas, Henry Krum, Adrian F Hernandez, Guy E H M Rutten, Lawrence A Leiter, Eberhard Standl, Steven M HaffnerAbstract:Background—Impaired glucose tolerance and metabolic syndrome are associated with increased risk of heart failure (HF). However, predictors associated with the increased risk of incident HF have not been well characterized. We aimed to identify independent predictors of incident HF hospitalization among patients with impaired glucose tolerance. Methods and Results—In Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR), 9306 research participants with impaired glucose tolerance and ≥1 cardiovascular risk factors were randomized to valsartan versus placebo and Nateglinide versus placebo in a 2×2 factorial manner, with a median follow-up of 6.5 years. Using a multivariable Cox proportional hazards model, we analyzed the relationships among baseline clinical factors and the outcome of incident HF hospitalization in patients without history of HF. Significant predictors were identified by forward selection. Increasing age, history of coronary heart disease, and atrial fibrillat...
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effect of Nateglinide on the incidence of diabetes and cardiovascular events
The New England Journal of Medicine, 2010Co-Authors: R R Holman, Steven M Haffner, John J V Mcmurray, Angelyn M Bethel, Bjorn Holzhauer, Tsushung A Hua, Yuri N Belenkov, Mitradev BoolellAbstract:After adjustment for multiple testing, Nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P = 0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P = 0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P = 0.16). Nateglinide did, however, increase the risk of hypoglycemia. Conclusions Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to Nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)
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Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: Rationale and design of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial
American Heart Journal, 2008Co-Authors: Mitradev Boolell, Josephine Mcmurray, Steven M Haffner, Anil Duggal, M. Angelyn Bethel, Rury R. HolmanAbstract:Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 × 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged ≥50 years with known CVD or aged ≥55 years with ≥1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: Nateglinide with valsartan, Nateglinide with valsartan-placebo, Nateglinide-placebo with valsartan, or Nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a "core" composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an "extended" composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT. © 2008.
Motohiko Chachin - One of the best experts on this subject based on the ideXlab platform.
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Nateglinide a d phenylalanine derivative lacking either a sulfonylurea or benzamido moiety specifically inhibits pancreatic β cell type katp channels
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita, Yoshihisa KurachiAbstract:A novel antidiabetic agent, Nateglinide, is ad-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of Nateglinide on recombinant ATP-sensitive K + (K ATP ) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, Nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities ( K i = 75 nM and 114 μM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity ( K i = 105 and 111 μM, respectively). Nateglinide inhibited the K ATP current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity ( K i = 290 μM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by Nateglinide. MgADP or MgUDP (100 μM) augmented the inhibitory effect of Nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of Nateglinide (∼10 μM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
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Nateglinide a d phenylalanine derivative lacking either a sulfonylurea or benzamido moiety specifically inhibits pancreatic β cell type katp channels
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita, Yoshihisa KurachiAbstract:A novel antidiabetic agent, Nateglinide, is a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of Nateglinide on recombinant ATP-sensitive K(+) (K(ATP)) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, Nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities (K(i) = 75 nM and 114 microM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K(i) = 105 and 111 microM, respectively). Nateglinide inhibited the K(ATP) current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K(i) = 290 microM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by Nateglinide. MgADP or MgUDP (100 microM) augmented the inhibitory effect of Nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of Nateglinide (approximately 10 microM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
Tetsuro Matsuoka - One of the best experts on this subject based on the ideXlab platform.
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Nateglinide a d phenylalanine derivative lacking either a sulfonylurea or benzamido moiety specifically inhibits pancreatic β cell type katp channels
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita, Yoshihisa KurachiAbstract:A novel antidiabetic agent, Nateglinide, is ad-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of Nateglinide on recombinant ATP-sensitive K + (K ATP ) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, Nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities ( K i = 75 nM and 114 μM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity ( K i = 105 and 111 μM, respectively). Nateglinide inhibited the K ATP current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity ( K i = 290 μM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by Nateglinide. MgADP or MgUDP (100 μM) augmented the inhibitory effect of Nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of Nateglinide (∼10 μM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
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Nateglinide a d phenylalanine derivative lacking either a sulfonylurea or benzamido moiety specifically inhibits pancreatic β cell type katp channels
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita, Yoshihisa KurachiAbstract:A novel antidiabetic agent, Nateglinide, is a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of Nateglinide on recombinant ATP-sensitive K(+) (K(ATP)) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, Nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities (K(i) = 75 nM and 114 microM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K(i) = 105 and 111 microM, respectively). Nateglinide inhibited the K(ATP) current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K(i) = 290 microM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by Nateglinide. MgADP or MgUDP (100 microM) augmented the inhibitory effect of Nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of Nateglinide (approximately 10 microM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
Kenji Matsushita - One of the best experts on this subject based on the ideXlab platform.
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Nateglinide a d phenylalanine derivative lacking either a sulfonylurea or benzamido moiety specifically inhibits pancreatic β cell type katp channels
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita, Yoshihisa KurachiAbstract:A novel antidiabetic agent, Nateglinide, is ad-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of Nateglinide on recombinant ATP-sensitive K + (K ATP ) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, Nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities ( K i = 75 nM and 114 μM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity ( K i = 105 and 111 μM, respectively). Nateglinide inhibited the K ATP current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity ( K i = 290 μM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by Nateglinide. MgADP or MgUDP (100 μM) augmented the inhibitory effect of Nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of Nateglinide (∼10 μM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
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Nateglinide a d phenylalanine derivative lacking either a sulfonylurea or benzamido moiety specifically inhibits pancreatic β cell type katp channels
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Motohiko Chachin, Mitsuhiko Yamada, Akikazu Fujita, Tetsuro Matsuoka, Kenji Matsushita, Yoshihisa KurachiAbstract:A novel antidiabetic agent, Nateglinide, is a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of Nateglinide on recombinant ATP-sensitive K(+) (K(ATP)) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, Nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities (K(i) = 75 nM and 114 microM) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K(i) = 105 and 111 microM, respectively). Nateglinide inhibited the K(ATP) current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K(i) = 290 microM) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by Nateglinide. MgADP or MgUDP (100 microM) augmented the inhibitory effect of Nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of Nateglinide (approximately 10 microM) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety.
