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At least 523 records · Page 29Linked to original sources
PubMed1984

In vivo and in vitro effects of a new hypoglycemic agent, 2-(3-methylcinnamylhydrazono)-propionate (BM 42.304) on glucose metabolism in guinea pigs.

A new compound, 2-(3- methylcinnamylhydrazono )-propionate (BM 42.304), showed a dose dependent hypoglycemic effect in starved guinea pigs after both oral and intraperitoneal administration. In contrast to biguanides (phenformin and metformin) the new compound produced only a moderate increase in blood lactate concentration and did not alter the content of adenine nucleotides in the freeze-clamped liver in vivo. Gluconeogenesis from a variety of precursors in the perfused guinea-pig liver was also inhibited by BM 42.304. These properties suggest that the compound deserves further investigation in connection with its potential usefulness for the treatment of diabetes.

Animals↗
PubMed1995

The new oral hypoglycemic agent, CS-045, inhibits the lipid peroxidation of human plasma low density lipoprotein in vitro.

Several lines of evidence have revealed that the oxidative modification of low-density lipoprotein (LDL) is probably associated with the genesis of the atherosclerotic region. CS-045 is a new (thiazolidine) class of oral hypoglycemic agent which has a hindered phenol in the side chain (an analogue of alpha-tocopherol). The present results indicate that CS-045 had a relatively high antioxidative potency in inhibiting the lipid peroxidation of human plasma LDL in vitro induced by 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) compared with that of alpha-tocopherol. These findings suggest that CS-045 may be useful in preventing the progression of atherosclerosis in diabetic patients.

Administration, Oral↗
PubMed1996

Importance of the hydrophobic energy: structural determination of a hypoglycemic drug of the meglitinide family by nuclear magnetic resonance and molecular modeling.

The molecular structure of (2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionic acid (KAD-1229), a hypoglycemic drug of the meglitinide family, was studied by nuclear magnetic resonance (NMR) and molecular modeling. The results of the NMR experiments indicated that KAD-1229 existed in solution in the form of two stable conformers of equal population, called KADI and KADII in this paper. Three different molecular modelings were then applied: the classical molecular dynamics using the commercial Biosym and Hyperchem softwares and the Prot+ program, which is not based on a dynamical study but on a systematic conformational analysis of the molecule, which includes a term that allows the estimation of the hydrophobic interaction. The modeling results showed the following points. First, in contrast with classical molecular dynamics, which uses restraints from two-dimensional nuclear Overhauser effect (NOE) data, the Prot+ KAD structure provides conformations that support experimental NMR data without any external intervention. In the structures in agreement with NMR data, an important hydrophobic interaction between the phenyl cycle and the perhydroisoindole ring of KAD is observed. This interaction, which seems to play a role in the biological activity of the drug, is lost when no restraints are considered in classical molecular dynamics. Second, the difference between KADI and KADII arises mainly from slight distance geometric differences at the level of the perhydroisoindole and the phenyl rings.

Benzamides↗
PubMed1994

Structural features and hypoglycemic activities of two polysaccharides from a hot-water extract of Agrocybe cylindracea.

A glucan (AG-HN1, [alpha]D +24 degrees) and a heteroglycan (AG-HN2, [alpha]D +26 degrees) were isolated from a hot-water extract of the fruiting bodies of Agrocybe cylindracea. The structures were investigated by a combination of chemical and spectroscopic methods. The results indicated that high molecular weight glucan AG-HN1 is primarily a beta-(1-->6)-branched (1-->3)-beta-D-glucan containing small amounts of (1-->4)-linked and (1-->6)-linked glucopyranosyl residues. Low molecular weight heteroglycan AG-HN2 gives galactose, glucose, fucose, and mannose on hydrolysis and appears to be chiefly composed of (1-->6)-linked gluco- and galacto-pyranosyl residues, many of them branched, and various nonreducing terminal residues. AG-HN1 showed a remarkable hypoglycemic activity in both normal and streptozotocin-induced diabetic mice by ip administration, and its activity was higher than that of AG-HN2.

Animals↗
PubMed1985

Direct measurements of increased free cytoplasmic Ca2+ in mouse pancreatic beta-cells following stimulation by hypoglycemic sulfonylureas.

The effects of the hypoglycemic sulfonylureas tolbutamide and glibenclamide on free cytoplasmic Ca2+, [Ca2+]i, were compared with that of a depolarizing concentration of K+ in dispersed and cultured pancreatic beta-cells from ob/ob mice. [Ca2+]i was measured with the fluorescent Ca2+-indicator quin2. The basal level corresponded to 150 nM and increased to 600 nM after exposure to 30.9 mM K+. The corresponding levels after stimulation with 1 microM glibenclamide and 100 microM tolbutamide were 390 and 270 nM respectively. K+ depolarization increased [Ca2+]i more rapidly than either of the sulfonylureas. It is suggested that the increased [Ca2+]i obtained after stimulation by sulfonylureas is due to depolarization of the beta-cells with subsequent entry of Ca2+ through voltage-dependent channels.

Aminoquinolines↗
PubMed1995

Concentration and separation of hypoglycemic drugs using solid-phase extraction-capillary electrophoresis.

Solid-phase extraction-capillary electrophoresis (SPE-CE) is a technique whereby very dilute analytes may be selectively extracted from a sample matrix and concentrated on-line for analysis. This study describes the first phase in the development of a method exploiting this technique for the direct analysis of hypoglycemic drugs in urine. Effective separation and detection of six sulfonylurea drug standards at concentrations below the detection limit of conventional capillary electrophoretic techniques is shown to be attainable. Since surfactant interfered with the on-line concentration process, non-MEKC (micellar electrokinetic chromatography) separation conditions were defined. Using 250 mM borate/5 mM phosphate at pH 8.4, all drugs in a mixture at 285 ng/ml were effectively extracted, concentrated from an injected volume of 2.5 microliters, non-selectively desorbed with an organic-based elution buffer and electrophoretically resolved. Sample loading was found to be linear in the 0.12-1.9 microliters range and drugs in a volume of up to 190 microliters could be concentrated and detected with a sensitivity of approximately 5 ng/ml. Not only was resolution of the desorbed material uncompromised by the presence of the SPE-tip, but separation of glipizide and glyburide was observed despite the fact that these drugs were unresolved under the same separation conditions by standard capillary zone electrophoresis (CZE). From these results, it is clear that SPE-CE not only increases the sensitivity for detection but that selectivity may be altered due to chromatographic processes occurring on the solid-phase resin.

Electrophoresis, Capillary↗
PubMed1984

Hypoglycemic therapy in patients diagnosed to have diabetes at 30 years of age or older.

Treatment patterns were investigated for a population of diabetic persons diagnosed at 30 years of age or older who received primary medical care in an eleven county area in southern Wisconsin. Of the 6074 patients who met the diagnostic criteria for diabetes, 51% received their primary care from internists, 35% from general practitioners, and 14% from family practitioners. Insulin usage was more frequent in patients with a longer duration of diabetes, younger age at diagnosis and poor recent glucose control. Prescription of oral medications increased with increasing current age and age at diagnosis. A greater proportion of the patients of internists than those of general practitioners were treated with insulin. Oral hypoglycemic agents were prescribed more frequently for patients of general practitioners than for patients of internists. These differences remained after controlling for duration, age at diagnosis, and status of recent glucose control. Therefore, practitioner type is associated with treatment prescribed for diabetic patients diagnosed after 30 years of age.

Administration, Oral↗
PubMed1980

The mechanism of the acute hypoglycemic action of phenformin (DBI).

The mechanisms by which biguanide (phenformin) acutely brings about a reduction in blood glucose in diabetic subjects has been studied with the aid of C-6 14C glucose. Six diabetic subjects were studied, each at three separate dose levels of phenformin. Two of these same subjects were studied with placebo. Consistent and increasingly pronounced effects of drug versus placebo were noted as the level of biguanide was increased. Biguanide consistently lowered hepatic glucose output while not significantly affecting the removal of glucose from the circulation. It was noted that glucogenesis from lactate was not significantly curtailed. However, a lack of stimulation in Cori Cycle activity in the presence of significant elevations of circulating lactate were taken as an indication of inhibition of glucogenesis from this substrate. On balance, it is concluded that the acute hypoglycemic action of this biguanide is mediated primarily through a restriction in the supply of glucose from the liver to the circulation. The data support the contention that these drugs inhibit hepatic glucogenesis even though Cori Cycle activity may be increased and also suggest that a portion of the decrease in hepatic glucose supply may be the result of impaired glycogenolysis.

Adult↗
PubMed1983

Extrapancreatic action of sulfonylureas: hypoglycemic effects are not dependent on altered insulin binding or inhibition of transglutaminase.

It has been proposed by others that sulfonylureas exert their extrapancreatic hypoglycemic effects by increasing insulin binding through inhibition of receptor-mediated hormone internalization. In this study, we examined the possibility that the drugs act by inhibiting transglutaminase, an enzyme thought important in the internalization process. For ten days, male rats were fed pulverized chow containing either no drug, glipizide (5 mg/kg initial body wt/d), or tolazamide (75 mg/kg initial body wt/d). Prior to sacrifice, the six-hour fasting level of serum glucose was significantly reduced from 96 mg/100 ml in the control rats to 81 and 42 mg/100 ml in the glipizide- and tolazamide-treated rats, respectively. In contrast, the serum level of insulin was similar for all groups. The activity of transglutaminase in the postnuclear fraction of liver homogenate also was the same for all experimental groups. The specific binding of labeled insulin to purified liver plasma membranes was examined over a broad range of insulin concentrations; once again, there was no difference between experimental groups. Thus, the hypoglycemia caused by sulfonylurea administration could not be attributed to increases in insulin binding, inhibition of transglutaminase activity, or enhanced insulin levels. These data support our previous suggestion, based on in vitro studies, that sulfonylureas act predominately on processes beyond the binding portion of the insulin receptor.

Acyltransferases↗
PubMed1988

Ciglitazone, a hypoglycemic agent: early effects on the pancreatic islets of ob/ob mice.

Chronic administration of ciglitazone (5-4[1-methyl-cyclohexylmethoxy)-benzyl]-thiazolidine-2,4 dione) decreased both plasma glucose and insulin concentrations in ob/ob mice. When given as an admixture to the feed, blood glucose levels were reduced as early as 12 hours after initiation of treatment. Concomitant with the decrease in circulating insulin, there was an increased hormone content in the beta-cells as judged by RIA and aldehyde-fuchsin staining. Acute oral dosing with ciglitazone produced a 41% reduction in circulating insulin at a time when glucose concentrations were as yet unaffected. Ciglitazone also inhibited glucose-stimulated insulin secretion in vitro. The results suggest that the hypoglycemic agent, ciglitazone, may reduce plasma glucose and insulin concentrations at least partially as the result of independent mechanisms.

Animals↗
PubMed1995

Regulation of glucose transport in cultured muscle cells by novel hypoglycemic agents.

The antidiabetic agent troglitazone (CS-045) and a metabolite designated M3 have potent blood glucose-lowering actions. The mechanism of the hypoglycemic effects of troglitazone and M3 was investigated in cultured L6 muscle cells. Short-term (2-hour) exposure of fully differentiated myotubes to troglitazone had no effect on glucose transport activity; M3 exposure caused a modest (50% to 60%) increase in basal and insulin-stimulated transport. Long-term (72-hour) treatment of myotubes with troglitazone resulted in a doubling of glucose transport in the absence of insulin, whereas M3 treatment resulted in a fivefold increase in basal glucose transport. Transport activity in M3-treated myotubes was greater than that seen after short-term insulin treatment. Insulin did not stimulate transport further in long-term M3-treated cells. A similar effect of prolonged exposure to M3 was observed in nondifferentiated myocytes. The agent had no influence on cell growth or the extent of differentiation. Augmentation of basal glucose transport by M3 was slow in onset, requiring 18 to 24 hours before significant effects were observed and 72 hours for full stimulation. M3 action on glucose transport was also dose-dependent, with half-maximal stimulation at 5 micrograms/mL of the agent and full effects at 10 to 20 micrograms/mL. Total membranes were prepared from control and M3-treated L6 myocytes and myotubes, and glucose transporter (GLUT1 and GLUT4) protein levels were measured by Western blotting. GLUT1 content was increased 2.9- +/- 1.3- and 2.8- +/- .2-fold by M3 treatment in myocytes and myotubes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Synthesis of some new amidine derivatives as potent hypoglycemic agents.

A series of S-arylformamidino-N-(alkyl/arylisothiourea) Cyclicamino dihydrochlorides were synthesised and screened for their hypoglycemic activity in normal as well as alloxanized diabetic rats. Some of the compounds (Id, Ie, Ih-1) showed more than 30% lowering of blood sugar level of Albino rats.

Amidines↗
PubMed1986

Protonophoretic activity of hypoglycemic sulfonylureas in black lipid membranes.

The ability of glibenclamide and of gliclazide to act as protonophores has been studied in black lipid membranes made of glycerol monoleate as a function of pH and drug concentration. Protons may effectively be transported across lipid membranes with a maximum at a pH close to the pKa of the sulfamide (pKa of glibenclamide = 5.4). It is suggested therefore that hypoglycemic sulfonylureas may act in part as Ca2+ inward and H+ outward ionophores through plasma membranes of pancreatic B cells.

Biological Transport↗
PubMed1989

A new hypoglycemic agent, midaglizole, blunts diabetic platelet aggregation: a possible role of alpha 2 blockade.

A newly developed alpha 2 blocker, midaglizole (DG-5128, 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesquihydrate) has been shown to have a hypoglycemic action in healthy controls as well as in diabetics. Since human platelets are rich in alpha 2 receptors, the effects of midaglizole on platelet aggregation were investigated. In normal controls, ADP- or epinephrine-induced platelet aggregation was significantly inhibited 2 h after oral administration of 300 mg midaglizole. Midaglizole also suppressed diabetic platelet aggregation stimulated by 10 or 100 microM epinephrine and delayed the initiation of collagen-induced aggregation at 30 micrograms/ml. In vitro addition of midaglizole at 9 or 90 microM significantly inhibited epinephrine-induced platelet aggregation. Furthermore, long-term administration of midaglizole suppressed diabetic platelet aggregation induced by 0.5-1 microM ADP or 1 microM epinephrine. These results suggest that alpha 2 blockade not only blunts diabetic epinephrine-induced platelet aggregation but also affects ADP- or collagen-stimulated platelet aggregation, indicating that this alpha 2 blocker may offer a new approach to the treatment of diabetic microangiopathy.

Adrenergic alpha-Antagonists↗
PubMed1990

Divergent cardiac effects of the first and second generation hypoglycemic sulfonylurea compounds.

The effects of first and second generation hypoglycemic sulfonylureas on the incidence of ventricular ectopic beats and on the duration of transitional ventricular fibrillation in the ischemic rat heart were investigated. First generation sulfonylurea compounds (tolbutamide, carbutamide and gliclazide) in 105 preparations increased, while second generation sulfonylurea compounds (glibenclamide and glipizide) in 50 preparations decreased in a dose-dependent manner both the number of ventricular ectopic beats and the duration of transitional ventricular fibrillation during the first 30 min after ligation of the left anterior descending coronary artery. Therefore, second generation sulfonylureas should be preferred in the treatment of type 2 diabetics with ischemic heart diseases, if satisfactory metabolic control cannot be achieved by a treatment regimen and diet alone.

Animals↗
PubMed1991

Remission of insulin requirement in late secondary failure to oral hypoglycemic agents (IRD): results at 24 months and analysis of predictive factors.

Over the last four years, we have done a prospective study of insulin requiring diabetes (IRD). We offered 59 patients insulin therapy during 10 to 14 days by means of continuous subcutaneous insulin injection with the help of a pump in order to maintain the patient under oral hypoglycemic agents (OHA). We divided our population into two characteristic groups and isolated parameters that were predictive of post-insulin therapy evolution by means of C peptide assays. In one group, in 50% of cases, endogenous insulin production appeared impaired and could not be restored by insulin therapy. The patients in this group suffered a renewed drug failure within 3 months. In the other group, 50% of cases, endogenous insulin production was preserved and the CP/blood glucose level ratio improved. On insulin treatment interruption, we observed a significantly improved fasting blood glucose level and we observed decreased insulin needs. The patients, who were probably insulin resistant, suffered only late failures or went into remission, often for longer than one year. The data bring us to the logical conclusion of IRD heterogeneity. Only some of these patients can benefit from temporary insulin therapy and the remission attempt should be limited to them.

Biomarkers↗
PubMed1992

Effects of the combination of insulin and gliclazide compared with insulin alone in type 2 diabetic patients with secondary failure to oral hypoglycemic agents.

Twenty non-insulin-dependent diabetic patients on insulin therapy for more than 2 months due to secondary failure to oral hypoglycemic agents (OHA) were additionally treated with gliclazide, 80 mg b.i.d., for 1 month and 160 mg b.i.d. for a further 2 months, while reducing insulin dose gradually according to glycemic control. At the end of the first month, fasting blood glucose had decreased from 12.8 +/- 0.7 to 9 +/- 0.8 mM (mean +/- standard error; P < 0.005) and thereafter remained stable. Insulin requirements decreased from 34.2 +/- 2.5 to 18.3 +/- 3.2 U/day (P < 0.001). Three patients were able to cease insulin treatment altogether. A direct correlation was found between final insulin dose and previous duration of infusion monotherapy (r = 0.52; P < 0.05). C-peptide/glucose score (fasting C-peptide/fasting BG x 100) increased from 0.11 +/- 0.03 to 0.21 +/- 0.05 (P < 0.05). We conclude that combined therapy reduces insulin requirement by increasing endogenous secretion, which may mainly affect hepatic glucose production as indicated by greater improvement in fasting vs. post-prandial blood glucose. This therapy could avoid hyperinsulinemia, which has been reported to be involved in macrovascular complications, and the additional haemovascular properties of gliclazide could make it more effective in such a combination.

Blood Glucose↗