nateglinide and mitiglinide

Glinides, including repaglinide, nateglinide and mitiglinide, are a type of fasting insulin secretagogue that could help to mimic early-phase insulin release, thus providing improved control of the postprandial glucose levels. Glinides stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in the pancreatic β-cell membrane. Although glinides have been widely used clinically and display excellent safety and efficacy, the response to glinides varies among individuals, which is partially due to genetic factors involved in drug absorption, distribution, metabolism and targeting. Several pharmacogenomic studies have demonstrated that variants of genes involved in the pharmacokinetics or pharmacodynamics of glinides are associated with the drug response. Polymorphisms of genes involved in drug metabolism, such as CYP2C9, CYP2C8 and SLCO1B1, may influence the efficacy of glinides and the incidence of adverse effects. In addition, Type 2 diabetes mellitus susceptibility genes, such as KCNQ1, PAX4 and BETA2, also influence the efficacy of glinides. In this article, we review and discuss current pharmacogenomics researches on glinides, and hopefully provide useful data and proof for clinical application.

Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Inactivation, Metabolic; Insulin; Insulin Secretion; Insulin-Secreting Cells; Isoindoles; KATP Channels; Nateglinide; Pharmacogenetics; Phenylalanine; Piperidines

Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses.. Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug.. Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values.. Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

Topics: Animals; ATP-Binding Cassette Transporters; Carbamates; Cardiovascular Diseases; Cricetinae; Cyclohexanes; Diabetes Mellitus, Type 2; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Isoindoles; Mice; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nateglinide; Phenylalanine; Piperidines; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Risk Factors; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide

Diabetic macroangiopathy has already developed before diagnosis of diabetes mellitus. Postprandial hyperglycemia has been known as a risk factor for diabetic macroangiopathy and may be more powerful than fasting hyperglycemia. To intervene in hyperglycemia, insulin secretagogues, glinides which selectively stimulate early meal-induced insulin secretion and improve postprandial hyperglycemia, and sulfonylureas which enhance total daily insulin secretion and improve fasting hyperglycemia, have been prescribed as major oral antidiabetic agents. Few evidences that amelioration of glycemic control with insulin secretagogues lower the risk of cardiovascular diseases have been reported. But current studies have shown that intervention in postprandial hyperglycemia with drugs including glinides decreased thickness of carotid IMT as a surrogate marker of atherosclerosis. Results from on-going large scale intervention study with glinides may clarify whether amelioration of hyperglycemia lower the risk of atherosclerotic events.

Topics: Arteriosclerosis; Cardiovascular Diseases; Cyclohexanes; Diabetic Angiopathies; Glucose Intolerance; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Postprandial Period; Risk Factors; Sulfonylurea Compounds

The mechanisms by which postprandial hyperglycemia is elicited were discussed through therapies of type 2 diabetes using "glinides". It has been believed that the earliest determinant of progression to type 2 diabetes is a loss of early insulin secretion, a defect which results in postprandial hyperglycemia and is often believed to reflect insulin resistance. To prove that, we improved insulin secretion pattern without increase of total amount of insulin secretion using glinide and assessed glucose response. Glinide which selectively enhances early meal-induced insulin secretion improved postprandial hyperglycemia, could provide a valuable treatment option in the prevention and treatment of type 2 diabetes.

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Eating; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine

Patients with type 2 diabetes mellitus are associated with insulin resistance and/or impaired insulin secretion. Previous observations indicate that Japanese patients with type 2 diabetes tend to have impaired insulin response after glycemic load more often than Caucasian counterparts. Recently it has been reported that hyperglycemia after glucose load is itself a risk factor for the development of cardiovascular complications in the absence of elevated fasting plasma glucose. Recent observations on the association of post-challenge or post-prandial hyperglycemia with cardiovascular events suggest that lowering post-prandial plasma glucose may protect patients from developing cardiovascular diseases. Results of STOP-NIDDM trial suggest that nateglinide, which attenuates post-prandial glycemic surge in type 2 diabetes, may also be helpful for the protection against cardiovascular events. Nateglinide exerts its effects shortly after its administration and the effects continue for only about 3 hours. The patients receiving this agent rarely gain weight and develop hypoglycemia. This agent exerts hypoglycemic effects additively with alpha-gulucosidase inhibitors or metformin.

Topics: Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Resistance; Insulin Secretion; Isoindoles; Metformin; Nateglinide; Phenylalanine; Postprandial Period; Stimulation, Chemical

Topics: Adenosine Triphosphate; Animals; ATP-Binding Cassette Transporters; Calcium Channels; Carbamates; Cyclohexanes; Exocytosis; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Islets of Langerhans; Isoindoles; Nateglinide; Organ Specificity; Phenylalanine; Piperidines; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors

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.

Topics: Animals; Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose; Guanidines; Humans; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Piperidines

The chemical structures, mechanisms of actions, bioavailabilities, insulinotrophic and hypoglycemic actions, and clinical trials of three novel oral hypoglycemic agents, NN-623, A-4166 and KAD-1229 are overviewed. They are non-SU insulin secretagogues and they induce quicker and shorter hypoglycemia than sulphonylureas do, presumably because they are rapidly absorbed into (Tmax: < 30 min) and excreted from blood (T 1/2: < 60 min). They bind to the SU-receptors and suppress K-ATP channels like sulphonylureas do. They stimulate mainly the initial phase of insulin release and evoke a decrease in postprandial rises in plasma glucose in several animals and humans. Clinical trials demonstrated they are efficacious and safe in the treatment of NIDDM subjects. They are useful as a first choice drug for the early stage of NIDDM.

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Indoles; Isoindoles; Nateglinide; Phenylalanine

This study was performed to examine the efficacy and safety of mitiglinide in type 2 diabetes patients (T2DM). Enrolled patients had received treatment with diet and exercise in the previous 3 months with glycosylated haemoglobin (HbA1c) 7-10%, and were randomized to receive mitiglinide (n = 111, 5-20 mg/meal) or nateglinide (n = 114,60-120 mg/meal) for 16 weeks. Primary and secondary efficacy endpoints were assessed by the changes in HbA1c, fasting blood glucose (FBG) and postprandial glucose (PBG) levels. The baseline HbA1c value was 8.2 and 8.3% in both groups. At the end of study, the reduction of HbA1c values from baseline by mitiglinide was slightly more than that by nateglinide (-1.11% vs. -0.76%), but not statically significant (p = 0.06). Final FBG and PBG were comparable for the two treatments. There were 2.8% subjects treated with nateglinide who had hypoglycaemic episodes, but none in the mitiglinide treatment group. The results indicate that mitiglinide and nateglinide had similar effects on FBG, PBG and HbA1c in T2DM patients after the 16-week treatments.

Topics: Blood Glucose; Body Mass Index; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Isoindoles; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Treatment Outcome; Waist-Hip Ratio

The effect of rapid-acting insulin secretagogues (glinides) on glycemic control when included with insulin therapy for type 2 diabetes remains uncertain. To examine this, we added glinide once a day to twice daily injections of premixed insulin.. Seventy-four type 2 diabetic patients, taking twice daily injections of premixed insulin and whose diabetic control was stable, were registered at 6 independent institutions. After a 3-month observation period, 60 patients were administered 10 mg mitiglinide or 90 mg nateglinide at lunchtime without changing their insulin regimen. After 12 weeks, administration of glinide was discontinued and observation was continued. HbA1c levels were measured at the start of glinide administration, after 12 weeks of glinide , and at 12 weeks after discontinuation.. HbA1c improved from 7.72+/-0.66% to 7.55+/-0.71% (p <0.01) at Week 12 of glinide administration. Twelve weeks after discontinuation, HbA1c returned to the baseline level (7.72+/-0.81%).. This study indicates that the addition of glinide once a day at lunchtime to twice daily injections of premixed insulin is effective for the treatment of type 2 diabetes.

Topics: Aged; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Isoindoles; Japan; Male; Middle Aged; Multicenter Studies as Topic; Nateglinide; Phenylalanine; Treatment Outcome

The glinides are the therapeutic agents for indications for type 2 diabetic patients with postprandial hyperglycemia. These are a class of drug which have a similar response as sulfonylureas but act for a shorter time and are prescribed to be taken by patients with type 2 diabetes within 5-10 min before eating. As the drugs act for a shorter period than sulfonylureas, the side effects of hypoglycemia and weight gain have a smaller likelihood. Combination with glinides and DPP4 inhibitors is a good choice for type 2 diabetic patients in early stage. Also combination therapy with glinides and alpha-glucosidase inhibitors shows a good profile of daily blood glucose level in these patients.

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Isoindoles; Nateglinide; Phenylalanine

Nateglinide and mitiglinide are immediate short-acting insulinotropic agents. Both are administered preprandially to control postprandial hyperglycemia. Glinide drugs are characterized by immediate onset as well as rapid disappearance of effect as compared with sulfonylurea drugs. We examined the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by pharmacokinetic/pharmacodynamic analysis using the receptor-binding-dissociation model in rats. Nateglinide or mitiglinide was administered orally or intravenously to rats and blood samples were collected at various time-points post administration. The plasma concentrations of the unbound drug forms and the blood glucose were measured. When the simultaneous fitting of oral administration and intravenous administration was performed using the receptor-binding-dissociation model, the measured values exhibited good correspondence with the fitting curve. Moreover, the time-courses of changes of the receptor-binding rate (sulfonylurea receptor) were examined using the parameters (k (on): second-order binding association constant to the receptor, Φ: receptor-binding occupancy ratio) obtained from the analysis. The results showed that the binding rate, which is important for glinide drugs in the early phase after administration, was obviously higher for nateglinide than that for mitiglinide from 10 min after oral administration and between 0 and 30 min after intravenous administration. These results suggest a more rapid onset of the therapeutic effect of nateglinide than that of mitiglinide after the drug is distributed into the blood.

Topics: Administration, Intravenous; Administration, Oral; Animals; ATP-Binding Cassette Transporters; Cyclohexanes; Hypoglycemic Agents; Isoindoles; Models, Biological; Nateglinide; Phenylalanine; Potassium Channels, Inwardly Rectifying; Rats; Rats, Sprague-Dawley; Receptors, Drug; Sulfonylurea Receptors; Time Factors

The common ATP-sensitive potassium (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes, respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure-activity relationships in KATP channels containing either the E23/S1369 nonrisk or K23/A1369 risk haplotypes.. The patch-clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23/S1369 or the K23/A1369 haplotype.. KATP channels containing the K23/A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide, chlorpropamide, and glimepiride (IC50 values for K23/A1369 vs. E23/S1369=1.15 vs. 0.71 μmol/l; 4.19 vs. 3.04 μmol/l; 4.38 vs. 2.41 nmol/l, respectively). In contrast, KATP channels containing the K23/A1369 haplotype were significantly more sensitive to inhibition by mitiglinide (IC50=9.73 vs. 28.19 nmol/l for K23/A1369 vs. E23/S1369) and gliclazide. Nateglinide, glipizide, and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype.. Our results demonstrate that the ring-fused pyrrole moiety in several A-site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the K23/A1369 risk haplotype. It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes.

Topics: ATP-Binding Cassette Transporters; Chlorpropamide; Cyclohexanes; Diabetes Mellitus, Type 2; Gene Expression Regulation; Gliclazide; Glyburide; Haplotypes; Homozygote; Humans; Isoindoles; Nateglinide; Patch-Clamp Techniques; Phenylalanine; Polymorphism, Single Nucleotide; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Structure-Activity Relationship; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide

Nateglinide and mitiglinide (glinides) are characterized as rapid-onset 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 microM tolbutamide and 1 nM glibenclamide was completely inhibited by 10 microM diazoxide and 3 microM verapamil, although the latter half-component of insulin secretion profile induced by 3 microM nateglinide or 30 nM mitiglinide remained with the existence of those agents. Glinides enhanced insulin secretion even in Ca2+-depleted medium, and its pattern of secretion was same as the pattern with existence of verapamil. The latter half was suppressed by 1 microM 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.

Topics: Animals; Calcium; Cell Line; Cyclohexanes; Dose-Response Relationship, Drug; Endoplasmic Reticulum; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Insulin-Secreting Cells; Isoindoles; Mice; Nateglinide; Phenylalanine; Ryanodine Receptor Calcium Release Channel; Sulfonylurea Compounds

The effect of single-dose mitiglinide on glucose and lipid metabolism was examined in OLETF rats with spontaneous type 2 diabetes in which the early insulin response following glucose challenge is known to diminish over time and become lost with aging.. (1) With catheters inserted into the portal veins, 12-wk-old prediabetic OLETF rats were given an OGTT of 1 g/kg after 17 h of fasting. Eight rats each were orally given mitiglinide 1 mg/kg, nateglinide 50 mg/kg, or glibenclamide 1 mg/kg, vs 0.5% carboxymethylcellulose (CMC) as control, and were given an OGTT immediately afterward. Following oral administration of mitiglinide, nateglinide, glibenclamide, or 0.5% CMC, the 24-wk-old overt-diabetic OLETF rats were immediately given an OGTT of 1g/kg. (2) After 17 h of fasting, 24-wk-old OLETF rats were subjected to a fat-loading test. Eight rats each were given mitiglinide 3 mg/kg, glibenclamide 1 mg/kg, or glimepiride 1 mg/kg, vs 0.5% CMC, and were given soy oil 2 g/kg immediately afterward. They were also given mitiglinide orally and examined for LPL mRNA expression in their adipose tissue.. (1) After OGTT, mitiglinide produced a significant increase in portal insulin levels 15 min after its administration, as well as a significant decrease in peripheral glucose levels 15-120 min after its administration in the OLETF rats. Likewise, nateglinide produced an increase in portal insulin levels and a decrease in peripheral glucose levels shortly after its administration in these rats. Glibenclamide increased portal insulin levels for an extended time after its administration, and significantly decreased peripheral glucose levels in the rats 120-300 min after its administration in the rats. In contrast, as in the 12-wk-old rats, a precipitous rise in insulin secretion was seen in the portal vein of 24-wk-old rats given mitiglinide, which peaked 15 min after mitiglinide administration, but the insulin levels continued to increase for 120 min or longer in the 24-wk-old rats given glibenclamide. In addition, as in the 12-wk-old rats, a significant decrease in glucose levels in peripheral blood was noted 30 and 60 min after mitiglinide administration and 300 min after glibenclamide administration in the 24-wk-old rats. (2) Mitiglinide increased LPL mRNA expression 120 min after its administration, and significantly decreased peripheral TG and chylomicron- TG levels after fat challenge in the 24-wk-old OLETF rats.. Mitiglinide exhibited fast-onset and short-acting insulin-secretagogic effects, inhibiting post-glucose challenge increases in glucose levels and post-fat challenge increases in TG levels.

Topics: Adipose Tissue; Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose Tolerance Test; Glyburide; Indoles; Insulin; Insulin Secretion; Isoindoles; Lipoprotein Lipase; Male; Nateglinide; Phenylalanine; Portal Vein; Postprandial Period; Prediabetic State; Rats; Rats, Inbred OLETF; RNA, Messenger; Sulfonylurea Compounds; Triglycerides

To design and synthesize new compounds of prandial glucose regulator with more simple structure.. The target compounds were synthesized from diethyl succinate and benzaldehyde or 4-fluorobenzaldehyde by four-step reactions. Thus 18 compounds were synthesized. Their structures were comfirmed by NMR, MS and IR.. Seventeen compounds had different hypoglycemic activity in mice, among them, 9 compounds had higher hypoglycemic activity and 6 compounds had character of prandial glucose regulator.. Part of the compounds have higher hypoglycemic activity deserve to be further investigated.

Topics: Animals; Benzylidene Compounds; Blood Glucose; Carbamates; Cyclohexanes; Hypoglycemic Agents; Indoles; Isoindoles; Mice; Molecular Structure; Nateglinide; Phenylalanine; Piperidines; Structure-Activity Relationship; Succinates

Topics: Administration, Oral; Cardiovascular Diseases; Cyclohexanes; Diabetes Complications; Diabetes Mellitus; Drug Therapy, Combination; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Indoles; Inositol; Insulin; Insulin Resistance; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Risk Factors; Stimulation, Chemical; Sulfonylurea Compounds; Thiazolidinediones

Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate insulin secretion by closing the ATP-sensitive K+ (K(ATP)) channels in pancreatic beta-cells. However, its selectivity for the various K(ATP) channels is not known. In this study, we examined the effects of mitiglinide on various cloned K(ATP) channels (Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B) reconstituted in COS-1 cells, and compared them to another meglitinide-related compound, nateglinide. Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high doses (more than 10 microM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 microM). Binding experiments on mitiglinide, nateglinide, and repaglinide to SUR1 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide, 8 microM; repaglinide, 1.6 microM), suggesting that they all share a glibenclamide binding site. The insulin responses to glucose, mitiglinide, tolbutamide, and glibenclamide in MIN6 cells after chronic mitiglinide, nateglinide, or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment. These results indicate that, similar to the sulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i.e., the pancreatic beta-cell K(ATP) channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug.

Topics: Animals; ATP-Binding Cassette Transporters; Cell Line; COS Cells; Cyclohexanes; Glyburide; Hypoglycemic Agents; Indoles; Insulin; Isoindoles; Nateglinide; Patch-Clamp Techniques; Phenylalanine; Potassium Channels; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide; Transfection

The insulinotropic action of the meglitinide analogues KAD-1229, A-4166 and repaglinide was examined in rat pancreatic islets deprived of exogenous nutrient or incubated in the presence of nutrient secretagogues such as D-glucose and the methyl esters of pyruvic acid, succinic acid and glutamic acid. The meglitinide analogues exerted little effect on insulin release in the absence of exogenous nutrient or in the presence of methyl pyruvate. They caused obvious stimulation of insulin output in the presence of D-glucose, dimethyl succinate or dimethyl glutamate. It is proposed, therefore, that suitable esters of dicarboxylic nutrients could be used to potentiate the secretory response to meglitinide analogues in non-insulin-dependent diabetes mellitus.

Topics: Animals; Carbamates; Cells, Cultured; Cyclohexanes; Glucose; Glutamates; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Islets of Langerhans; Isoindoles; Nateglinide; Phenylalanine; Piperidines; Pyruvates; Rats; Succinates

The non-sulphonylurea hypoglycaemic agents A-4166 and KAD-1229 were both found to cause 45Ca or 22Na translocation from an aqueous medium into an organic immiscible phase. This ionophoretic effect was more marked with A-4166 than KAD-1229, in mirror image of their insulinotropic potency. Such a dissociated behaviour argues against the view that the ionophoretic properties of these agents represent a major determinant of their insulinotropic action.

Topics: Calcium; Calcium Radioisotopes; Cyclohexanes; Hypoglycemic Agents; Indoles; Ionophores; Isoindoles; Kinetics; Membranes, Artificial; Nateglinide; Phenylalanine; Sodium Chloride

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

At normal extracellular K+ concentration (5 mM), the meglitinide analogues A-4166, KAD-1229, repaglinide and S3075, all tested at a 10 mu M concentration, markedly enhanced insulin release evoked by 6 mM D-glucose in isolated rat pancreatic islets. They failed, however, to augment the much higher rate of insulin release evoked by D-glucose in islets exposed to a high K+ concentration (30 mM). Under the latter conditions, the potent diazoxide analogue BPDZ-44 (50 mu M) did not exert any sizeable effect upon insulin release. Even at normal K+ concentration, BPDZ-44 (50 mu M), which suppressed glucose-stimulated insulin release, only caused a partial inhibition of the insulinotropic action of A-4166 and failed to affect significantly insulin secretion in the presence of KAD-1229, repaglinide or S3075. These findings argue against the view that meglitinide analogues could affect cytosolic Ca2+ activity independently of the closing of ATP-sensitive K+ channels. The present results also indicate that, with the possible exception of A-4166 which in the least potent secretagogue in this series, meglitinide analogues are able, like hypoglycemic sulphonylureas, to fully protect ATP-sensitive K+ channels against their activation by BPDZ-44.

Topics: Animals; Benzamides; Carbamates; Cyclohexanes; Female; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Islets of Langerhans; Isoindoles; Nateglinide; Phenylalanine; Piperidines; Potassium; Rats

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