piperidines and meglitinide

The cytochrome P4502C enzymes account for the metabolism of approximately 20% of therapeutic drugs including certain oral antidiabetic drugs (OADs).. This review focuses on the effect of CYP2C enzymes on metabolism of sulphonylureas (SUs), meglitinides, and thiazolidinediones (TZDs) discussing their impact on pharmacokinetics, drug interactions and toxicological profiles. Pharmacogenetic aspects reflecting individual gene variants and variable drug effects are also considered.. Genetic polymorphisms of CYP2C9 enzymes (*2/*2, *2/*3, *3/*3) influence the glycaemic response to SUs and impair their substrate metabolism. Restricted data from small-sized studies with heterogenous definitions of hypoglycaemia revealed no clear association between CYP2C9 genotypes and the risk of hypoglycaemia. Functional polymorphisms of CYP2C8- and CYP2C9 drug metabolizing genes affect markedly pharmacokinetics of meglitinides. Compared to wild-type carriers, patients treated with TZDs and carrying the common CYP2C8*3 and *4 variants showed a reduced glycaemic control. The strong CYP2C8 and OATP1B1 inhibitor gemfibrozil increases substantially the plasma concentrations of repaglinide and TZDs. Numerous metabolic drug interactions exist between SUs and commonly prescribed drugs, especially anti-infectives. The complex pharmacokinetic and pharmacogenetic properties and the unfavourable short and long term risk profile of glibenclamide and glimepiride raise the question whether their use can be justified any longer.

Topics: Administration, Oral; Benzamides; Blood Glucose; Carbamates; Cytochrome P-450 Enzyme System; Drug Interactions; Gemfibrozil; Humans; Hypoglycemic Agents; Inactivation, Metabolic; Pharmacogenetics; Piperidines; Polymorphism, Single Nucleotide; Sulfonylurea Compounds; Thiazolidinediones

In type 2 diabetes mellitus, impairment of insulin secretion is an important component of the disease. Meglitinide analogues are a class of oral hypoglycaemic agents that increase insulin secretion, in particular, during the early phase of insulin release.. The aim of this review was to assess the effects of meglitinide analogues in patients with type 2 diabetes mellitus.. We searched several databases including The Cochrane Library, MEDLINE and EMBASE. We also contacted manufacturers and searched ongoing trials databases, and the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) websites.. We included randomised controlled, parallel or cross-over trials comparing at least 10 weeks of treatment with meglitinide analogues to placebo, head-to-head, metformin or in combination with insulin.. Two authors independently extracted data and assessed trial quality.. Fifteen trials involving 3781 participants were included. No studies reported the effect of meglitinides on mortality or morbidity. In the eleven studies comparing meglitinides to placebo, both repaglinide and nateglinide resulted in a reductions in glycosylated haemoglobin (0.1% to 2.1% reduction in HbA1c for repaglinide; 0.2% to 0.6% for nateglinide). Only two trials compared repaglinide to nateglinide (342 participants), with greater reduction in glycosylated haemoglobin in those receiving repaglinide. Repaglinide (248 participants in three trials) had a similar degree of effect in reducing glycosylated haemoglobin as metformin. Nateglinide had a similar or slightly less marked effect on glycosylated haemoglobin than metformin (one study, 355 participants). Weight gain was generally greater in those treated with meglitinides compared with metformin (up to three kg in three months). Diarrhoea occurred less frequently and hypoglycaemia occurred more frequently but rarely severely enough as to require assistance.. Meglitinides may offer an alternative oral hypoglycaemic agent of similar potency to metformin, and may be indicated where side effects of metformin are intolerable or where metformin is contraindicated. However, there is no evidence available to indicate what effect meglitinides will have on important long-term outcomes, particularly mortality.

Topics: Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Nateglinide; Phenylalanine; Piperidines; Randomized Controlled Trials as Topic

The expression meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with meglitinide, such as repaglinide, nateglinide, and mitiglinide. Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of antihyperglycemic sulfonylureas such as glibenclamide (glyburide) and glimepiride. In rat pancreatic islets incubated in the presence of 7.0 mmol/L D-glucose, repaglinide and mitiglinide demonstrate comparable concentration-response relationships for stimulation of insulin release, with a threshold value < 10 nmol/L and a maximal secretory response at about 10 nmol/L. Several findings indicate that meglitinide analogs provoke the closing of adenosine triphosphate-sensitive potassium channels, with subsequent gating of voltage-sensitive calcium channels. The effects of meglitinide analogs upon the binding of [3H]glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other meglitinide analogs, the ionic and secretory response to repaglinide (10 micromol/L) is not rapidly reversible in perifused rat islets. In experiments conducted in vivo in control and diabetic rats, repaglinide provokes a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than glibenclamide or glimepiride. Onset of effect is also more rapid and duration of effect shorter with nateglinide versus glibenclamide. In clinical studies, single or repeated daily administration of repaglinide increased plasma insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after repaglinide intake. Plasma concentrations of repaglinide are about 5.0 microg/L 2-2.5 hours after oral intake of the drug. Despite the slow reversibility of repaglinide action in vitro, this drug offers advantages over glibenclamide in terms of the possible occurrence of hypoglycemia if a meal is missed. In volunteers receiving a single oral dose of nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of nateglinide were reached within 2 hours in most volunteers. Peak plasma concentrations of mitiglinide were reached 30 minutes after a sing

Topics: Animals; Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Piperidines

Diabetes is a major and growing health problem in the US. An incredible array of different oral medications is now on the market. Clinicians should understand all these new medications and in which clinical picture they will work best.

Topics: Benzamides; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Metformin; Piperidines; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones

The loss of early-phase insulin secretion is an important and early event in the natural history of type 2 diabetes. Because a normal pattern of insulin secretion is essential for the effective control of postprandial metabolism, a rational basis for the development of agents that target early-phase insulin release exists. Conventional oral hypoglycaemic agents do not target, or adequately control, postprandial glycaemia. The emergence of new classes of oral agent with a more specific mode of action provides, for the first time, an opportunity to restore early-phase insulin release. One such drug class is the meglitinide analogues (repaglinide, nateglinide, and mitiglinide). These drugs are ideally suited for combination use with metformin. They could also prove effective in combination with a thiazolidinedione, a drug class that targets insulin resistance. Exogenous insulin is frequently required in the late management of type 2 diabetes. However, one hope for newer combinations of diabetic drugs is that the functional life of the beta cell can be extended, thereby delaying the need for insulin injections.

Topics: Adult; Animals; Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Piperidines; Rats

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise blood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e.g. nephropathy with creatinine clearance < or = 50 ml/min). Meglitinide analogues act synergistically with metformin and thiazolidinediones (pioglitazone and rosiglitazone) and can be also combined with long-acting insulin (NPH insulin at bedtime). Therefore, these drugs enrich the palette of antidiabetic drugs and make the treatment more flexible and better tolerated, which both add to better metabolic control and support the empowerment and compliance of the patient. However, this will only be the

Topics: Benzamides; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glyburide; Humans; Hypoglycemic Agents; Molecular Structure; Nateglinide; Phenylalanine; Piperidines

A progressive weight gain is associated with various pharmacological options improving glycemic control in type 2 diabetes mellitus (T2DM). Ghrelin has been implicated in the regulation of feeding behavior and energy balance in humans. Based on evidence that functional ATP-sensitive channels are present in ghrelin-producing cells, we hypothesized that meglitinides may affect circulating ghrelin levels in subjects with type 2 diabetes.. In a single-blinded randomized three-period crossover study (n = 20), repaglinide or nateglinide was given in combination with metformin for two treatment periods over a 1-week period, respectively, separated by a 1-week treatment with placebo. Liquid meal challenge tests (LMCTs) with single preprandial doses of repaglinide (2 mg), nateglinide (120 mg), or placebo were performed at the end of each treatment period. Ten control subjects without diabetes underwent a single LMCT without any medication.. Fasting ghrelin concentrations were not different between all treatments and between patients with diabetes and control subjects. Subjects with T2DM treated with placebo showed no suppression of ghrelin in the LMCT. After administration of meglitinides a nadir of serum ghrelin was observed at 60 min (8.6% of baseline [P = 0.038] for repaglinide and 7.5% of baseline [P = 0.081] for nateglinide), which was similar to the secretion pattern seen in control subjects. No correlations between postprandial insulin or glucose levels and circulating ghrelin concentrations were observed.. Treatment with meglitinides reconstructed postprandial ghrelin secretion patterns to those of controls without diabetes. This observation may help to improve the control of feeding behavior in patients with T2DM.

Topics: Adult; Aged; Benzamides; Blood Glucose; Body Mass Index; C-Peptide; Carbamates; Cross-Over Studies; Diabetes Mellitus, Type 2; Eating; Feeding Behavior; Ghrelin; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Metformin; Middle Aged; Piperidines; Reference Values; Single-Blind Method

Permanent neonatal diabetes mellitus (PNDM) presents with dehydration and hyperglycemia, which usually occurs during the first 12 months of life. Activating mutations of beta-cell adenosine triphosphate-sensitive potassium [KATP] channel subunits that cause opening of the channel are associated with PNDM. Some patients with PNDM respond to administration of a sulfonylurea derivative, which has long action on blood glucose even during hypoglycemia and has an apoptotic effect on beta cells. However, there have been no reports regarding treatment with meglitinide (repaglinide), which has rapid and short duration of action during the rise in blood glucose after meals that is more similar to beta cell function. It has no effects during hypoglycemia, so it does not cause neurological damage, and has no apoptotic effect on beta cells. We report herein the effects of repaglinide administration in the management and clinical outcome of two patients with PNDM during 9 and 10 years of follow-up.. Two Iranian infants were brought to our institution with poor general condition, dehydration, lethargy, and poor feeding. They had diabetic ketoacidosis at 52 days and 3.5 months of age, respectively. Their genetic analysis revealed mutations in the KCNJ11 gene encoding KIR6.2, so they both had PNDM. After treatment of diabetic ketoacidosis with insulin, they responded to sulfonylurea (glibenclamide) treatment, but were switched to repaglinide because of blood sugar fluctuations in terms of hyper- and hypoglycemia. Repaglinide was administered with the dosage of 0.04 mg/kg/day divided before every meal.. The patients were 10 and 9 years old at the last visit, with normal growth parameters. The values of self-monitored blood glucose were well-controlled, and the hemoglobin A1C (HbA1C) levels ranged from 3.6 to 6.4% during the follow-up period. There was no complication of diabetes, neurological disorder, or adverse effects related to repaglinide.. In every neonate or infant < 6 months of age with diabetes mellitus, PNDM should be considered. A trial of oral repaglinide can be performed and substituted for glibenclamide for prevention of hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration.

Topics: Benzamides; Carbamates; Diabetes Mellitus; Humans; Hypoglycemic Agents; Iran; Mutation; Piperidines

To assess the association of metformin monotherapy with the risk of all-cause deaths and cardiovascular deaths and events in type 2 diabetes patients in real clinical practice.. This retrospective, observational study comprised patients with type 2 diabetes initially treated with metformin or nonmetformin monotherapy over 2011-2016. Data were extracted from the National Healthcare Big Data database in Fuzhou, China. Propensity score matching (PSM) was performed, matching each patient on metformin to one on nonmetformin in terms of a set of covariates. The primary endpoint was all-cause death, and secondary endpoints were cardiovascular death, heart failure, and heart failure hospitalization. Covariate-adjusted associations of metformin use with all the endpoints were assessed by Cox proportional hazards models.. Among 24,099 patients, 5491 were initially treated with metformin and 18,608 with nonmetformin. PSM yielded 5482 patients in each cohort. During a median follow-up of 2.02 years, we observed 110 and 211 deaths in the metformin and nonmetformin groups, respectively. Metformin was significantly associated with reduced risk of all-cause death (adjusted hazard ratio (aHR) 0.52, 95% confidence interval (CI) 0.39-0.69), cardiovascular death (aHR 0.63, 95% CI 0.43-0.91), and heart failure (aHR 0.61, 95% CI 0.52-0.73), whereas the reduced risk in heart failure hospitalization was not statistically significant (aHR 0.70, 95% CI 0.47-1.02).. In this analysis of electronic health record data from a large database in China, metformin as first-line monotherapy greatly reduced the risk of all-cause death, cardiovascular death, and heart failure in diabetes patients as compared with nonmetformin medications.

Topics: Aged; Benzamides; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycoside Hydrolase Inhibitors; Heart Failure; Hospitalization; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Mortality; Nateglinide; Piperidines; Proportional Hazards Models; Retrospective Studies; Sulfonylurea Compounds; Thiazolidinediones

Intrasperm calcium concentration ([Ca2+]is) is known to play a vital role in regulating motility and viability of ejaculated spermatozoa. K ATP channel blockers are reported to block K ATP channels, leading to depolarization of the cell membrane. This activates the voltage-gated calcium channels, resulting in enhanced Ca2+ influx, which eventually elevates the intracellular [Ca2+] level. Hence, it can be hypothesized that drugs acting on K ATP channels could possess the ability to elevate [Ca2+]is. Sulfonylureas such as glibenclamide or gliclazide, as well as meglitinide analogues such as repaglinide, produced a dose- and time-dependent decrease in viability, each requiring 7.5 mM, 10 mM and 6.5 mM, respectively, to produce death of all sperm cells immediately upon addition to ejaculated human semen samples. The reduction in sperm viability was accompanied by an elevation of [Ca2+]is and was affected by removal of extracellular Ca2+. Significantly (P < 0.05) less time was required to elevate [Ca2+](is) and produce complete loss of sperm viability when any of these drugs were added to sperm cells simultaneously with selected agents affecting Ca2+ homeostasis. Thus, the spermicidal activity of these drugs attributed to elevation of [Ca2+]is and their synergism can be potentially exploited for developing contact spermicidal formulations.

Topics: Adult; Benzamides; Calcium; Carbamates; Cross-Over Studies; Dose-Response Relationship, Drug; Gliclazide; Glyburide; Homeostasis; Humans; Hypoglycemic Agents; KATP Channels; Male; Piperidines; Sperm Motility; Spermatocidal Agents; Spermatozoa; Sulfonylurea Compounds; Time Factors

1. Hypoglycaemia-inducing sulphonylureas, such as glibenclamide, inhibit cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels. In search of modulators of CFTR, we investigated the effects of the non-sulphonylurea hypoglycaemic agents meglitinide, repaglinide, and mitiglinide (KAD-1229) on CFTR Cl- channels in excised inside-out membrane patches from C127 cells expressing wild-type human CFTR. 2. When added to the intracellular solution, meglitinide and mitiglinide inhibited CFTR Cl- currents with half-maximal concentrations of 164+/-19 microM and 148+/-36 microM, respectively. However, repaglinide only weakly inhibited CFTR Cl- currents. 3. To understand better how non-sulphonylurea hypoglycaemic agents inhibit CFTR, we studied single channels. Channel blockade by both meglitinide and mitiglinide was characterized by flickery closures and a significant decrease in open probability (Po). In contrast, repaglinide was without effect on either channel gating or Po, but caused a small decrease in single-channel current amplitude. 4. Analysis of the dwell time distributions of single channels indicated that both meglitinide and mitiglinide greatly decreased the open time of CFTR. Mitiglinide-induced channel closures were about 3-fold longer than those of meglitinide. 5. Inhibition of CFTR by meglitinide and mitiglinide was voltage-dependent: at positive voltages channel blockade was relieved. 6. The data demonstrate that non-sulphonylurea hypoglycaemic agents inhibit CFTR. This indicates that these agents have a wider specificity of action than previously recognized. Like glibenclamide, non-sulphonylurea hypoglycaemic agents may inhibit CFTR by occluding the channel pore and preventing Cl- permeation.

Topics: Adenosine Triphosphate; Animals; Benzamides; Carbamates; Cell Line; Chloride Channels; Cyclic AMP-Dependent Protein Kinases; Cystic Fibrosis Transmembrane Conductance Regulator; Electric Conductivity; Epithelial Cells; Glyburide; Humans; Hypoglycemic Agents; Indoles; Ion Channel Gating; Isoindoles; Kinetics; Mice; Patch-Clamp Techniques; Piperidines; Sulfonylurea Compounds; Transfection

This study investigates the insulin secretory responsiveness of pancreatic islets to repaglinide in an experimental model of B-cell glucose incompetence. Rats were infused for 2 d with a 1.67 M solution of D-glucose administered at a rate close to 2.8 mL/h. This resulted in a modest rise in glycemia, a severe increase in plasma insulin concentration, an increased sensitivity of B-cells to adrenergic stress, an abnormally high insulin output from isolated islets perifused in the presence of 16.7 mM D-glucose, and a paradoxical transient increase in insulin release from the islets in response to a fall in hexose concentration. The early increment in insulin output evoked by repaglinide, in the presence of 16.7 mM D-glucose, was not lower in the islets from glucose-infused rats than in those from control rats. Moreover, when the meglitinide analog was administered concomitantly with the removal of D-glucose from the perifusion medium, the early response to repaglinide was further increased. Even after 24 min of glucose deprivation, the output of insulin by the islets from glucose-infused rats was higher in the presence of repaglinide than in its absence. These findings indicate that, in this model of B-cell dysfunction, the secretory responsiveness to repaglinide, as distinct from that to glucose, is fully preserved. Therefore, when taken into consideration together with prior observations, these findings argue in support of the use of this insulinotropic agent in the treatment of noninsulin-dependent diabetes.

Topics: Animals; Benzamides; Blood Glucose; Carbamates; Female; Glucose Solution, Hypertonic; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Piperidines; Rats; Rats, Wistar; Stereoisomerism

Several meglitinide analogs are currently under investigation as potential insulinotropic tools for the treatment of noninsulin-dependent diabetes. The present study aimed to further insight into the effect of these agents on the secretion of insulin, glucagon, and somatostatin by the isolated perfused pancreas. Both repaglinide (0.01 microM) and A-4166 (1.0 microM) stimulated insulin and somatostatin release, but failed to affect glucagon output, from pancreases exposed to 5.6 mM D-glucose. The secretory response of the B- and D-cells to the hypoglycemic agents was much less marked than that caused by a rise in hexose concentration from 5.6-16.7 mM. Although repaglinide was tested at a concentration a hundred times lower than that of A-4166, the drug-induced increase in both insulin and somatostatin secretion persisted for a longer time after exposure to repaglinide, than to A-4166. The relevance of these findings to the use of meglitinide analogs as antidiabetic agents is double. First, they document that these drugs, although enhancing both insulin and somatostatin release, do not provoke an undesirable stimulation of glucagon secretion. Second, they indicate that even at a very low concentration, repaglinide provokes a protracted insulinotropic action, thus suggesting that the reversibility of the secretory response to this or other meglitinide analogs represents an intrinsic molecular attribute, unrelated to either their biological potency or the relative extent of B-cell stimulation.

Topics: Animals; Benzamides; Blood Glucose; Carbamates; Cyclohexanes; Female; Glucagon; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Nateglinide; Perfusion; Phenylalanine; Piperidines; Rats; Rats, Wistar; Somatostatin

Non-sulfonylurea hypoglycemic agents of the meglitinide family such as S3075, repaglinide, KAD-1229, and A-4166, were found to display a comparable U-shaped conformation by molecular modelling, with hydrophobic cycles placed at the extremity of each branch and a peptidic bond placed at the bottom of the U. A comparable conformation was observed with the hypoglycemic sulfonylureas glibenclamide and glimepiride. A different conformation with a greater distance between the hydrophobic cycles at the extremity of each branch was found, however, with the biologically inactive enantiomers of A-4166 and repaglinide and the poorly efficient insulinotropic agent meglitinide. The identification of a common conformation of these hypoglycemic agents may help in the design of highly active compounds and provide an imprint of their postulated target receptor on the pancreatic B-cell plasma membrane.

Topics: Benzamides; Carbamates; Cyclohexanes; Drug Design; Glyburide; Hypoglycemic Agents; Indoles; Isoindoles; Molecular Conformation; Nateglinide; Phenylalanine; Piperidines; Stereoisomerism; Structure-Activity Relationship; Sulfonylurea Compounds

The sodium and calcium ionophoretic activity of meglitinide and three of its hypoglycemic analogs, namely S3075, KAD-1229 and repaglinide was examined in an artificial membrane model. All agents were able to cause the translocation of 45Ca and 22Na from an aqueous solution into an immiscible organic phase. The results were compatible with the formation of a calcium-ionophore complex with a 1-2 stoichiometry. The ionophoretic activity ranged in the following hierarchy: KAD-1229 > S3075 > repaglinide = meglitinide and, hence, did not closely parallel the insulinotropic potential of these non-sulfonylurea hypoglycemic agents. It is proposed, therefore, that the ionophoretic capacity of meglitinide analogs may not represent an essential determinant of their insulin-releasing action.

Topics: Benzamides; Biological Transport; Calcium; Carbamates; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Ionophores; Isoindoles; Membranes, Artificial; Models, Biological; Piperidines; Sodium; Structure-Activity Relationship

The insulinotropic action of meglitinide was compared to that of its analogs S 3075, A-4166, KAD-1229 and repaglinide. None of these hypoglycemic agents significantly enhanced insulin output from rat pancreatic islets incubated for 90 min in the absence of exogenous nutrient. However, all these agents, when tested at a 10 microM concentration, augmented insulin release evoked by either 7 mM D-glucose or 10 microM succinic acid monomethyl ester (SAM). In this respect, meglitinide was a less efficient secretagogue than the other non-sulfonylurea hypoglycemic agents. Moreover, in the presence of 7 mM D-glucose, the lowest concentration of the drug required to cause a significant increase in insulin output decreased from about 1.0 microM for meglitinide to 0.1 microM with A-4166, KAD-1229 or repaglinide and even close to 10 nM in the case of S 3075. The concentration-response relationship thus yielded the following hierarchy, S 3075 > KAD-1229 = repaglinide > A-4166 > meglitinide, there being a difference of more than two orders of magnitude between the weakest and most potent agent.

Topics: Animals; Benzamides; Carbamates; Cyclohexanes; Female; Glucose; Hypoglycemic Agents; In Vitro Techniques; Indoles; Insulin; Insulin Secretion; Islets of Langerhans; Isoindoles; Molecular Structure; Nateglinide; Phenylalanine; Piperidines; Rats; Structure-Activity Relationship; Succinates