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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study assessed the synergistic effects of nateglinide (a non-sulfonylurea D-phenylalanine derivative) and meals on insulin secretion in 24 patients with type 2 diabetes. Oral doses of 60 and 180 mg or 120 and 240 mg were administered to two cohorts of subjects 10 min before meals (or fasting) three times daily for 7 days, with washout intervals between treatment periods. Dose-dependent increases in plasma insulin occurred, with the peak effect within 2 h after treatment. Significantly greater insulin secretion was observed when nateglinide was taken before a meal compared to nateglinide given in the fasted state or in response to just the meal. Nateglinide lowered plasma glucose concentrations significantly vs. placebo at all doses, and doses of 120 and 240 mg were more effective than 60 mg (P < 0.05). Adverse event rates were similar for nateglinide and placebo, and no hypoglycemic episodes or serious adverse events were reported during the study. Nateglinide (120 mg) was the maximum effective dose in this study and was shown to be a safe and well tolerated therapy for control of mealtime glucose excursions in patients with type 2 diabetes. Results indicate that a synergistic interaction occurs between nateglinide and elevated mealtime plasma glucose concentrations to stimulate insulin secretion.
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PMID:Synergistic effects of nateglinide and meal administration on insulin secretion in patients with type 2 diabetes mellitus. 1072 43

Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the K(ATP) channel/sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models. Binding studies were carried out with membranes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1 (SUR1). The relative order for displacement of [(3)H]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L-nateglinide > tolbutamide. The results with HEK-293/recombinant human SUR1 cells were similar with the exception that glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [(3)H]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [(3)H]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with K(ATP) channels in rat pancreatic beta-cells was investigated with the patch-clamp method. The relative potency for inhibition of the K(ATP) channel was repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect on K(ATP) current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide. These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K(ATP) channel.
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PMID:Pancreatic beta-cell K(ATP) channel activity and membrane-binding studies with nateglinide: A comparison with sulfonylureas and repaglinide. 1077 14

A central finding of the UKPDS was that in type 2 diabetic patients, tight glycemic control with HbA1c targets as close to the normal range as possible must be achieved to further reduce diabetes related-complications, -mortality, and -cardiovascular disease, highlighting the need for new, optimized treatment strategies. With a focus on clinical efficacy, this paper discusses the results from the 20 major therapeutical trials published in the years 1997-1999, that evaluated the new insulinsensitizing thiazolidinediones Rosiglitazone and Pioglitazone and the new insulin-releasing potassium channel blockers Repaglinide and Nateglinide. While for Nateglinide, promising, but only preliminary data is available at current, Rosiglitazone, Pioglitazone, and Repaglinide have been shown appropriate for both mono- and combination therapy with current standard drug treatment of type 2 diabetes. Similar to the known, older antidiabetic drugs, the new agents discussed have comparable blood glucose lowering potentials with a dose-related capacity of 0.5 to 1.5% HbA1c reduction. These beneficial effects were both seen in drug-naive patients previously treated with diet only and in combination therapies where patients had previous antidiabetic standard drug treatment suggesting effectiveness of glitazones and glinides also in more advanced stages of the disease. Problems with adverse effects appeared minor although long-range implications of weight gain, edema, lowering of hemoglobin, increase of total cholesterol for the glitazones, and hypoglycemia for glinides warrant further consideration. What becomes clear from the variety of most recent mono- and combination treatment studies with as much as five different classes of antidiabetic drugs is that individually tailored therapies that recognize quality of life parameters and target the predominant features of metabolic pathology (such as early postprandial versus fasting hyperglycemia, degree of insulin resistance, progressive loss of 1-cell function) may become a feasible goal in the future.
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PMID:Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2 diabetes mellitus. 1092 9

Nateglinide is a novel D-phenylalanine derivative that inhibits ATP-sensitive K+ channels in pancreatic beta-cells in the presence of glucose and thereby stimulates the prandial release of insulin. Nateglinide reduces fasting and mealtime blood glucose levels in animals, healthy volunteers, and patients with type 2 (non-insulin-dependent) diabetes mellitus, and produces prompt prandial insulin responses with return to baseline insulin levels between meals. In randomised, double-blind 24-week studies in patients with type 2 diabetes, oral nateglinide 120 mg 3 times daily before meals improved glycaemic control significantly relative to placebo. Nateglinide 120 mg plus metformin 500 mg, both 3 times daily, conferred greater glycaemic improvement than either drug given alone, and nateglinide 60 or 120 mg 3 times daily plus metformin 1 g twice daily was superior to metformin plus placebo. Nateglinide 120 mg 3 times daily significantly reduced hyperglycaemia relative to placebo in a 16-week double-blind study in patients with type 2 diabetes mellitus. Combination therapy with troglitazone 600 mg daily produced significantly better glycaemic control than either drug given as monotherapy. Mild hypoglycaemia was the most frequently reported adverse event (1.3% of patients) after treatment with nateglinide 120 mg 3 times daily in a 16-week clinical study. No clinically significant abnormalities in laboratory results, ECGs, vital signs or physical examination findings have been noted in patients taking the drug.
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PMID:Nateglinide. 1103 Apr 70

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, interactions, and dosage of nateglinide are reviewed. Nateglinide is an oral hypoglycemic agent approved for use alone or in combination with metformin as an adjunct to diet and exercise for the treatment of type 2 diabetes mellitus. Nateglinide, an amino acid derivative of D-phenylalanine, stimulates the secretion of insulin by binding to the ATP potassium channels in pancreatic beta cells. The result is an increase in beta-cell calcium influx, which leads to rapid, short-lived insulin release. The drug is rapidly and completely absorbed in the small intestine. The estimated bioavailability is 72%. Nateglinide is highly bound to plasma proteins, is metabolized extensively by the liver, and has an elimination half-life of 1.4 hours. Several clinical trials of nateglinide, alone and in combination with other oral hypoglycemic agents, have found the drug to be safe, effective, and well tolerated. The most common adverse effects are nausea, diarrhea, dizziness, and lightheadedness. There is a potential for interactions between nateglinide and medications affected by the cytochrome P-450 isoenzyme system. Dosage regimens ranging from 60 to 240 mg have been evaluated. The maximum effective dosage is 120 mg taken 10 minutes before meals three times a day. Nateglinide is an alternative to second-generation sulfonylureas for the treatment of type 2 diabetes mellitus. Additional comparative trials are needed to fully elucidate nateglinide's role.
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PMID:Nateglinide. 1144 77

The loss of early insulin secretion appears to be a critical event in the deterioration in glucose tolerance during the development of type 2 diabetes. There is therefore a strong rationale for developing new antidiabetic agents aimed at restoring or replacing early prandial insulin secretion and thereby curbing mealtime glucose excursions in patients with type 2 diabetes. Four such new agents are either now available (repaglinide and nateglinide) or in clinical development (KAD-1229 and BTS 67 582). Preclinical studies suggest that each of these new insulinotropic agents share a common receptor/effector mechanism with the sulfonylureas (SUs) but that each may have distinct characteristics that differentiate them from the SUs and from each other. Nateglinide and KAD-1229 clearly stimulate biphasic insulin secretion in vitro and in vivo and their effects are rapidly reversible, whereas the effects of repaglinide and BTS 67 582 are prolonged well beyond their removal from perfusion media in vitro or their clearance in vivo. Available data from human studies indicate that the pharmacokinetics of repaglinide and nateglinide are similar, i.e., they are both rapidly absorbed and eliminated, but consistent with findings from animal studies, the insulinotropic and glucose-lowering effects of repaglinide are slower in onset and more prolonged than those of nateglinide. Repaglinide and nateglinide have been shown to be safe and well-tolerated in patients with type 2 diabetes and to produce clinically-meaningful reductions of HbA1c, both alone and in combination with agents with complementary modes of action (e.g., metformin and thiazolidinediones). Because these new agents can potentially bring patients to near normoglycemia without an undue risk of hypoglycemia, they are important additions to the therapeutic armamentarium.
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PMID:Rapid acting insulinotropic agents: restoration of early insulin secretion as a physiologic approach to improve glucose control. 1147 74

Nateglinide is a new, fast-onset, short-acting hypoglycemic agent, which increases early phase insulin secretion and the total amount of insulin secreted. However, it is not clear which of these effects contribute more to the decrease in postprandial plasma glucose (PG). To further clarify the pharmacologic actions of nateglinide, we investigated the changes in PG and insulin levels during meal tolerance tests with and without nateglinide. Subjects were 10 newly diagnosed and untreated inpatients with type 2 diabetes. After diet and exercise therapy for 1 week, nateglinide at 270 mg divided 3 times a day, was started. Meal tolerance tests were performed before (baseline) and after a single nateglinide administration (day 1), after 7 days of repeated administration (day 7), and after cessation of nateglinide on day 8. Mean fasting PG was 146 +/- 6 mg/dl (mean +/- SEM) at baseline and 130 +/- 6 mg/dL on day 7 (P =.0004). The 2-hour postprandial PG level was 226 +/- 10 mg/dL at baseline, 145 +/- 11 mg/dL on day 1 (P =.0008), and 190 +/- 15 mg/dL on day 8 (P =.08, baseline; P =.01, day 7). The mean fasting insulin level was 5.4 +/- 1.0 microU/mL at baseline and did not change significantly during the study. The 30-minute postprandial insulin level was 14.4 +/- 1.9 microU/mL at baseline, 39.5 +/- 4.5 microU/mL on day 1 (P =.0004), and 23.6 +/- 3.6 microU/mL on day 8 (P =.045, baseline; P =.010, day 7). The total insulin amount, in terms of area under the curve (AUC. IRI), was 3.99 +/- 0.7 x 10(3) microU/mL. min at baseline, 5.47 +/- 0.8 microU/mL. min on day 1 (P =.029), and 6.01 +/- 1.9 microU/mL. min on day 8 (P =.047 v baseline). The early phase of insulin secretion, based on the ratio of delta IRI to delta PG from fasting to 30 minutes after a meal was 0.15 +/- 0.13 at baseline, 1.44 +/- 0.26 on day 1 (P =.0009) and 0.26 +/- 0.06 on day 8 (P =.05 v day 1). After cessation of nateglinide, the postprandial PG level increased immediately. Although early phase insulin secretion returned nearly to the baseline level, total insulin secretion remained at a high level. These results suggested that early phase insulin secretion contributes more than total insulin secretion to the improvement of postprandial hyperglycemia in type 2 diabetes.
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PMID:Improvement of glucose tolerance by nateglinide occurs through enhancement of early phase insulin secretion. 1178 67

Nateglinide is a novel insulinotropic agent for the treatment of type 2 diabetes. It is a D-phenylalanine derivative, chemically distinct from repaglinide and sulphonylureas (glyburide or glimepiride). Although each agent is known to stimulate insulin release via the signaling cascade initiated by closure of ATP-dependent K+ (K(ATP)) channels in pancreatic beta-cells, the pharmacological effect of nateglinide is reportedly fast-acting, short-lasting, sensitive to ambient glucose and more resistant to metabolic inhibition. The aim of the present study was to elucidate the molecular mechanism(s) underlying the distinct properties of the insulinotropic action of nateglinide. By using the patch-clamp methods, we comparatively characterized the potency and kinetics of the effect of these agents on K(ATP) channels in rat beta-cells at normal vs. elevated glucose and under physiological condition vs. experimentally induced metabolic inhibition. Our results demonstrated that the mode of the action of nateglinide on K(ATP) current was unique in (a) glucose dependency; (b) increased potency and efficacy under ATP depletion and uncoupling of mitochondrial oxidative phosphorylation than physiological condition; (c) substantially more rapid onset and offset kinetics. The data provide mechanistic rationale for the unique in vivo and ex vivo activity profile of nateglinide and may contribute to reduced hypoglycemic potential associated with excessive insulin secretion.
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PMID:Interaction of nateglinide with K(ATP) channel in beta-cells underlies its unique insulinotropic action. 1202 Jun 94

Repaglinide and nateglinide represent a new class of insulin secretagogues, structurally unrelated to sulphonylureas, that were developed for the treatment of type 2 diabetes. The inhibitory effect of these drugs was investigated on recombinant wild-type and mutant Kir6.2/SUR1 channels expressed in HEK293 cells. Nateglinide and repaglinide dose-dependently inhibited whole-cell Kir6.2/SUR1 currents with half-maximal inhibitory concentration (IC(50)) values of 800 and 21 nmol/l, respectively. Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K(+) channel. In contrast, repaglinide inhibition was unaffected by the S1237Y mutation (IC(50) = 23 nmol/l). Radioligand binding studies revealed a single high-affinity binding site for [(3)H]repaglinide on membranes prepared from HEK293 cells expressing wild-type (equilibrium dissociation constant [K(D)] = 0.40 nmol/l) or mutant (K(D) = 0.31 nmol/l) Kir6.2/SUR1 channels. Nateglinide and tolbutamide displaced [(3)H]repaglinide binding to wild-type channels with IC(50) values of 0.7 and 26 micro mol/l, respectively, but produced <10% displacement of [(3)H]repaglinide bound to mutant channels. This is consistent with the idea that binding of nateglinide and tolbutamide, but not repaglinide, is abolished by the SUR1[S1237Y] mutation and that the binding site for repaglinide is not identical to that of nateglinde/tolbutamide. These results are discussed in terms of a conformational analysis of the drug molecules.
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PMID:Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. 1219 72

Nateglinide is a fast-acting insulin secretion agent that specifically targets postprandial hyperglycemia in patients with type 2 diabetes. The recent reduction in the diagnostic criteria for diabetes and improved understanding of the importance of early insulin secretion served as the rationale for this multicenter, double-blind, randomized, parallel-group, 24-wk study performed in 675 patients with type 2 diabetes but only moderately elevated fasting plasma glucose (FPG) (FPG = 7.0-8.3 mmol/liter) to assess the efficacy and safety of three fixed doses of nateglinide (30, 60, or 120 mg, with meals). A substudy of the effects on early insulin release and prandial glucose excursions following a standardized breakfast was performed in 127 subjects. Nateglinide was well tolerated and elicited a dose-dependent reduction of placebo-adjusted hemoglobin A(1c) (Delta = -0.26 to -0.39%) and FPG (Delta = -0.51 to -0.73 mmol/liter) accompanied by a dose-related increase in suspected hypoglycemic episodes. However, confirmed hypoglycemia occurred in only 5.3% of patients treated with the highest dose, compared with 1.2% in placebo-treated patients (P < 0.05). Nateglinide increased early insulin release and reduced prandial glucose excursions (P < 0.05 vs. placebo). In sum, nateglinide is a safe and effective therapeutic option for treatment of patients with mild to moderate fasting hyperglycemia.
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PMID:Efficacy and safety of nateglinide in type 2 diabetic patients with modest fasting hyperglycemia. 1221 67


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