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PubMed2005

Antidiabetic effect of Nitobegiku, the herb Tithonia diversifolia, in KK-Ay diabetic mice.

Nitobegiku (the herb of Tithonia diversifolia (HEMSL) A. GRAY) has been used as a medicinal plant for diabetes. The antidiabetic effect of an 80% ethanol extract of Nitobegiku (Td) was investigated in KK-Ay-mice, an animal model of type 2 diabetes. Td (500 mg/kg body weight) reduced the blood glucose of KK-Ay mice 7 h after a single oral dose. No change in blood glucose in Td-treated normal mice (ddY) was seen. Td (500 mg/kg) reduced blood glucose in KK-Ay mice 3 weeks after a single oral dose and also significantly lowered plasma insulin in KK-Ay mice under similar conditions. Td-treated KK-Ay mouse blood glucose was significantly decreased in an insulin tolerance test. These results support the hypothesis that Td improves glucose metabolism by reducing insulin resistance. Therefore, Nitobegiku may be useful for the treatment of type 2 diabetes.

Animals↗
PubMed2006

Antidiabetic effects of corosolic acid in KK-Ay diabetic mice.

The antidiabetic effects of corosolic acid (CA) were investigated in KK-Ay mice, an animal model of type 2 diabetes. CA (2 mg/kg body weight) reduced the blood glucose levels of KK-Ay mice 4 h after a single oral dose. CA (2 mg/kg) reduced the blood glucose levels in KK-Ay mice 2 weeks after a single oral dose and also significantly lowered plasma insulin levels were in KK-Ay mice under similar conditions. CA-treated KK-Ay mouse blood glucose significantly decreased in an insulin tolerance test. These results support the hypothesis that CA improves glucose metabolism by reducing insulin resistance. Therefore CA may be useful for the treatment of type 2 diabetes.

Animals↗
PubMed1991

Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds.

Various analogues of a new antidiabetic agent, pioglitazone (AD-4833, U-72107), were synthesized in order to study in more detail the structure-activity relationships of this class of drug. 5-(4-Pyridylalkylthiobenzyl)-2,4-thiazolidinediones (I), thia-analogues of pioglitazone, were prepared via Meerwein arylation of the alkylthioanilines (IV). 5-(4-Pyridylalkoxybenzylidene)-2,4-thiazolidinediones (IIa) and related heterocyclic analogues (IIb) were synthesized by Knoevenagel condensation of the aldehydes (VIII) with the corresponding azolidinones. Compounds I and II were evaluated for hypoglycemic and hypolipidemic activity in genetically obese and diabetic yellow KK (KKAy) mice. Several 5-[4-[2-(2-pyridyl)ethoxy]-benzylidene]-2,4- thiazolidinediones (IIa) were equipotent to pioglitazone. However, the thia-analogues (I) and the benzylideneheterocycles (IIb) had decreased activity. Catalytic hydrogenation of the 5-benzylidene analogue (14) was found to be a convenient new synthetic method for pioglitazone. The configuration of 14 is also discussed.

Animals↗
PubMed1998

Kotalanol, a potent alpha-glucosidase inhibitor with thiosugar sulfonium sulfate structure, from antidiabetic ayurvedic medicine Salacia reticulata.

A potent natural alpha-glucosidase inhibitor called kotalanol has been isolated from an antidiabetic traditional Ayurvedic medicine, the roots and stems of Salacia reticulata Wight, through bioassay-guided separation. The structure of kotalanol was elucidated on the basis of chemical and physicochemical evidence to be the inner salt comprised of 1-deoxyheptosyl-3-sulfate anion and 1-deoxy-4-thio-D-arabinofuranosyl sulfonium cation. Kotalanol was found to show more potent inhibitory activity against sucrase than salacinol and acarbose.

Animals↗
PubMed2003

Physicochemical and crystal structure analyses of the antidiabetic agent troglitazone.

The antidiabetic agent troglitazone has two asymmetric carbons located at the chroman ring and the thiazolidine ring and is produced as a mixture of equal amounts of four optical isomers, 2R-5S, 2S-5R, 2R-5R, and 2S-5S. The crystalline powdered drug substance consists of two diastereomer pairs, 2R-5R/2S-5S and 2R-5S/2S-5R. There are many types of crystals obtained from various crystallization conditions. The X-ray structure analysis and the physicochemical analyses of troglitazone were performed. The solvated crystals of the 2R-5R/2S-5S pair were crystallized from several solutions: methanol, ethanol, acetonitrile, and dichloromethane. The ratio of solvent and troglitazone was 1 : 2 (L1/2-form). The monohydrate crystals were obtained from aqueous acetone solution (L1-form). On the other hand, only an anhydrate crystal of the 2R-5S/2S-5R pair was crystallized from various solutions (H0-form). The dihydrous mixed crystal (MA2-form) was obtained from a mixture of the two diastereomer pairs of 2R-5R/2S-5S and 2R-5S/2S-5R in equal amounts by the slow evaporation of aqueous acetone solution. The crystal structure of the MA2-form is similar to the H0-form. When the MA2 crystal was kept under low humidity, it was converted into the dehydrated form (MA0-form) with retention of the single crystal form. The structure of the MA0-form is isomorphous to the H0-form. The MA2-form was converted into the MA0-form and vice versa with retention of the single crystal under low and high humidity, respectively. The crystallization and storage conditions of the drug substances were successfully analyzed.

Chemical Phenomena↗
PubMed2006

Improvement of solubility and oral bioavailability of 2-(N-cyanoimino)-5-[(E)-4-styrylbenzylidene]-4-oxothiazolidine (FPFS-410) with antidiabetic and lipid-lowering activities in dogs by 2-hydroxypropyl-beta-cyclodextrin.

2-(N-Cyanoimino)-5-[(E)-4-styrylbenzylidene]-4-oxothiazolidine (FPFS-410) is a newly synthesized thiazolidine derivative having not only antidiabetic but also lipid-lowering activities. However, this compound has an extremely low aqueous solubility (2.8 (+/-0.33) x 10(-8) M (0.0094+/-0.0011 microg/ml) in 1.0 M phosphate buffer (pH 7.0) at 25 degrees C). In this study, we investigated the effect of various hydrophilic cyclodextrins (CyDs) on the solubility of FPFS-410 to select a CyD suitable for formulations of the compound. Among various CyDs, 2-hydroxypropyl-beta-CyD (HP-beta-CyD) had the highest solubilizing ability to FPFS-410, e.g., the solubility of the compound was increased 200000-fold by the addition of 40 mM HP-beta-CyD, which was attributable to the formation of the 1 : 2 (guest : host) inclusion complexes. The interaction of HP-beta-CyD with FPFS-410 was studied using 1H-nuclear magnetic resonance (NMR) spectroscopies including ROESY spectroscopy and a molecular modeling calculation. These results suggested that HP-beta-CyD forms a 1:2 (guest : host) inclusion complex with FPFS-410 by including both the stilbene and thiazolidine moieties. FPFS-410/HP-beta-CyD solid complexes with various stoichiometries were prepared by the spray drying and cogrinding methods, and confirmed by powder X-ray diffractometry that these complexes are in an amorphous state. The dissolution of FPFS-410 in water was significantly accelerated by the complexation with HP-beta-CyD. In vivo studies revealed that HP-beta-CyD markedly increases the bioavailability of FPFS-410 after oral administration in dogs. The present results suggest that HP-beta-CyD is useful for improvement of the extremely low bioavailability of FPFS-410.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2001

[Antidiabetic effect of folium mori in GK rats].

The antidiabetic effect of hot water extracts from Folium Mori was investigated in GK rat, one of the animal models of non-insulin dependent diabetic mellitus types. Folium Mori extracts (150 mg/kg) significantly reduced the blood glucose of GK rat from 203.8 +/- 29.8 to 138.5 +/- 21.2 mg/dl at 14 days after oral administration. However, in normal rats, blood glucose and insulin levels were not changed by treatment with Folium Mori. The Folium Mori also decreased blood glucose and improved glucose tolerance at 14 days after repeated administration in GK rats. The Folium Mori treatment significantly increased glucose metabolism in the glucose clamp test for GK rats. These results suggest that Folium Mori has quite unique properties such as raising insulin sensitivity and improving insulin resistance.

Animals↗
PubMed2001

Beneficial effect of troglitazone, an insulin-sensitizing antidiabetic agent, on coronary circulation in patients with non-insulin-dependent diabetes mellitus.

Evidence is increasing for small vessel remodeling and disturbance of endothelium-dependent vasodilation in diabetic patients. Insulin increases vascular wall thickening and produces endothelial dysfunction. Troglitazone, a new insulin-sensitizer antidiabetic agent, is considered to reduce plasma insulin level and the present study assessed its effect on the coronary circulation of the patients with non-insulin-dependent diabetes mellitus (NIDDM). Analysis of the myocardial washout rate with adenosine triphosphate-stress thallium-201 scintigraphy was used to estimate coronary circulation, and for estimation of insulin sensitivity, the homeostasis model insulin resistance index (HOMA-R) was calculated. Patients were treated with monotherapy of either troglitazone (200 mg bid, n=12) or glibenclamide (2.5 mg daily, n=12) for 3 months. Age-, sex- and risk factors-matched subjects without NIDDM were employed as a control. Fasting plasma glucose and hemoglobin A1c were similarly decreased by troglitazone or glibenclamide. Plasma insulin level (pmol/L) decreased from 66.6+/-10.8 to 39.0+/-7.2 with troglitazone, but was unchanged by glibenclamide (58.8+/-7.2 to 66.0+/-10.8). The diabetic groups had a significantly lower washout rate than controls, which was improved by troglitazone, but not by glibenclamide. In addition, the increase in washout rate correlated significantly with the decrease in HOMA-R in the troglitazone group. In conclusion, troglitazone can restore coronary circulation by improving insulin resistance in patients with NIDDM.

Adenosine Triphosphate↗
PubMed2000

Repaglinide: a novel oral antidiabetic agent.

Repaglinide is a novel oral antidiabetic agent, marking the development of a new class of drugs for type 2 diabetes. This article examines repaglinide and its position in the treatment of type 2 diabetes.

Administration, Oral↗
PubMed2003

Incretins and their analogues as new antidiabetic drugs.

Glucagon-like peptide 1 (GLP-1) is a gut (incretin) hormone with multiple actions that could potentially contribute to an antidiabetic effect. This includes: (a) glucose-dependent insulinotropic actions; (b) glucagonostatic actions; (c) a reduction in appetite/promotion of satiety leading to reduced food intake and weight reduction; (d) the deceleration of gastric emptying; and (e) the stimulation of islet growth, differentiation and regeneration. Thus, multiple aspects of the type 2 diabetic phenotype can potentially be improved or even corrected by GLP-1. The native gut hormone, however, after intravenous injection or absorption from subcutaneous depots, is proteolytically degraded and eliminated from the circulation too quickly to be useful for the treatment of diabetes. GLP-1 derivatives (receptor agonists) with prolonged pharmacokinetics that promise a potential for clinical use in the near future are being developed.

Animals↗
PubMed1997

Antidiabetic effects of an oral administration of Lactobacillus casei in a non-insulin-dependent diabetes mellitus (NIDDM) model using KK-Ay mice.

The antidiabetic effects of Lactobacillus casei (LC) on a non-insulin-dependent diabetes mellitus (NIDDM) model, KK-Ay mice, were investigated. The oral administration of LC to male 4-week-old KK-Ay mice, or raising the mice on a 0.05% LC-containing diet significantly decreased the plasma glucose at 8 to 10 weeks of age compared with the control group. The body weights of the LC-treated groups were lower than those of the control group, although the food intake was nearly the same in all groups. Phenotypic analysis of spleen cell surface markers revealed that the increase in CD4+ T cells at 12 weeks was significantly inhibited by the oral treatment with LC. Cytokine production, especially that of interferon-gamma and interleukin 2, was also inhibited in the oral LC-treated group. The plasma insulin levels of the LC-treated groups were also lower than those of the control group, and the insulin binding potential of red blood cells in the LC-treated mice was augmented more than that in the control group. Taken together, these findings led us to conclude that the oral administration of LC in the NIDDM model mice, KK-Ay, was involved in the decrease in the plasma glucose level and modified the host immune responses.

Animals↗
PubMed2005

Effects of antidiabetic treatment with metformin and insulin on serum and adipose tissue adiponectin levels in db/db mice.

Decreased circulating levels of adiponectin, a novel adipose-derived adipocytokine, in obesity possibly contribute to the development of insulin resistance which is a major factor in the pathogenesis of type 2 diabetes. The present study was conducted to examine whether circulating and adipose tissue adiponectin levels are modulated by chronic treatment with metformin and intensive treatment with insulin in murine models of obesity and type 2 diabetes, db/db mice with a C57BL/KsJ genetic background. Nine-week-old male db/db mice were treated with metformin, insulin, and vehicle for 4 weeks. Expectedly, metformin treatment led to inhibition of weight gain and improvement of hyperinsulinemia. Insulin treatment lowered fasting blood glucose levels to normal values, although it sustained hyperinsulinemic state. However, after 4 weeks of treatment, serum adiponectin levels were not significantly elevated in either metformin-treated or insulin-treated db/db mouse group (14.2 +/- 0.7 and 16.7 +/- 1.0 microg/ml, respectively) compared to vehicle-treated group (14.9 +/- 0.6 microg/ml). Similarly, adipose tissue adiponectin levels determined by Western blot analysis were not increased in either metformin-treated or insulin-treated group relative to vehicle-treated group. Recent studies have shown that adiponectin possibly has the same physiological effects on lipid and glucose metabolism that metformin has. Therefore, an elevation in blood concentration of metformin following the treatment might lead to suppression in adiponectin synthesis in adipose tissue, independent of inhibition in weight gain and improvement in hyperinsulinemia by metformin treatment. The present results indicate that adiponectin is not involved in the mechanism by which metformin treatment enhances insulin sensitivity. Moreover, our results suggest that adiponectin synthesis in adipose tissue may be suppressed under hyperinsulinemic state sustained by insulin treatment, even though hyperglycemia is markedly reduced. We conclude that antidiabetic treatment with metformin and insulin does not affect circulating and adipose tissue adiponectin levels.

Adiponectin↗
PubMed2005

Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37).

Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37). In contrast to GIP, which was rapidly degraded by in vitro incubation with dipeptidylpeptidase IV (DPP IV) (52% intact after 2 h), the analogues remained fully intact for up to 24 h. Both fatty acid-derivatised analogues stimulated cAMP production in GIP receptor Chinese hamster lung (CHL) fibroblasts (EC50 12.1-13.0 nM) and significantly improved in vitro insulin secretion from BRIN-BD11 cells (1.1- to 2.4-fold; p < 0.05 to p < 0.001) compared to control (5.6 mM glucose). Administration of N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37) together with glucose in obese diabetic (ob/ob) mice significantly reduced the glycaemic excursion (1.4- and 1.5-fold, respectively; p < 0.05 to p < 0.01) and improved the insulinotropic response (1.5- and 2.3-fold, respectively; p < 0.01 to p < 0.001) compared to native peptide. Dose-response studies with N-AcGIP(LysPAL37) revealed that even the lowest concentration (6.25 nmol/kg) induced a highly significant decrease (1.4-fold; p < 0.001) in the overall glycaemic excursion, coupled with a significant increase (2.0-fold; p < 0.01) in circulating insulin. Furthermore, basal glucose values remained significantly reduced (p < 0.05) and insulin values increased 24 h following a single injection of N-AcGIP(LysPAL37). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of N-AcGIP. These data demonstrate that novel fatty acid-derivatised analogues of N-terminally modified AcGIP function as long-acting GIP-receptor agonists, with significant antidiabetic potential.

Animals↗
PubMed2006

Vildagliptin: an inhibitor of dipeptidyl peptidase-4 with antidiabetic properties.

Vildagliptin is a competitive and reversible inhibitor of dipeptidyl peptidase-4. Dipeptidyl peptidase-4 inhibitors act mainly by preventing the rapid degradation of glucagon-like peptide-1. In clinical trials, vildagliptin improves glycaemic control both as monotherapy and in combination with metformin for periods of < or = 52 weeks in subjects with Type 2 diabetes. This is evident by reduced fasting and prandial glucose levels, and reduced glycosylated haemoglobin levels. Vildagliptin acts by increasing active glucagon-like peptide-1, improving beta-cell function and inhibiting glucagon secretion. Furthermore, vildagliptin has proven to be safe and tolerable, with a low occurrence of hypoglycaemia. Further studies are now required to evaluate its long-term durability, effects, safety and tolerability in comparison with other antidiabetic agents and in different patient subgroups.

Adamantane↗
PubMed2006

The potential of antidiabetic thiazolidinediones for anticancer therapy.

The thiazolidinediones (TZDs) are a class of synthetic compounds for treatment of insulin-resistant Type 2 diabetes mellitus. TZDs are known activators of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), and exert their antidiabetic action largely through this nuclear receptor family. Moreover, increasing experimental evidences of PPAR-gamma-independent effects are accumulating. Apart from the established metabolic actions, TZD treatment exerts additional biological effect such as control of cell growth, differentiation, motility and programmed cell death. In this context, considerable interest has focused on TZDs as potential chemopreventive agents in oncology; however, despite encouraging observation on the potential anticancer effect of these drugs in several in vitro experimental models, controversial results have been obtained with animal models and in pilot clinical trials. This review summarises the molecular mechanisms of the antineoplastic actions of TZDs and the relevance of these findings in human pathology and therapy.

Animals↗
PubMed1998

In vivo antidiabetic drug discovery.

All of the glucose-lowering agents available today for the treatment of diabetes resulted from the in vivo antidiabetic drug discovery approach. This is not surprising given the limited understanding of the biochemical basis of diabetes. With new developments in the elucidation of the biochemistry and physiology of diabetes, along with the ever-increasing number of drug discovery technologies, screening tests have shifted from in vivo to in vitro and from a cellular to a molecular level. However, there are concerns with this shift because diabetes, especially type 2 diabetes, has multiple and independent molecular defects and most of the molecular targets currently used await clinical validation. One approach (employed by Shaman) has used focused in vivo screening and has been successful in avoiding or minimising the drawbacks of in vivo testing, while maintaining the benefits. It is hoped that the combined use of in vivo and in vitro approaches will generate new breakthroughs in diabetes.

Journal Article↗
PubMed2006

Comparative safety of newer oral antidiabetic drugs.

Oral antidiabetic agents were introduced into clinical practice during the 1950s. Biguanides and sulfonylureas are still used extensively today and their safety and tolerability profiles are well defined. Developments and refinements within these classes have included the introduction of second- and third-generation sulfonylureas, the introduction of modified-release preparations, and the emergence of fixed-dose preparations with metformin and with novel drugs. The latter include the thiazolidinediones, agents with a putative genomic mechanism of action that have been under intense scrutiny since the emergence of severe hepatotoxicity with troglitazone. Recent concerns about thiazolidinediones have centred on the issue of oedema and the risk of precipitating heart failure in vulnerable patients. Only prolonged exposure will determine the long-term safety of thiazolidinediones. Rapid-acting non-sulfonylurea secretagogues appear to be effective and perhaps safer than sulfonylureas in some groups of patients with certain comorbidities (e.g., those with renal impairment). alpha-Glucosidase inhibitors have an excellent safety record and acarbose has been shown to retard the progression from impaired glucose tolerance to Type 2 diabetes. However, their use is limited by tolerability issues.

Administration, Oral↗
PubMed2006

Pioglitazone: an antidiabetic drug with cardiovascular therapeutic effects.

The antidiabetic compound pioglitazone, an activator of the intracellular peroxisome proliferator-activated receptor-gamma, and decreases metabolic and vascular insulin resistance. The drug is well tolerated, and its metabolic effects include improvements in blood glucose and lipid control. Vascular effects consist of improvements in endothelial function and hypertension, and a reduction in surrogate markers of artherosclerosis. In a large, placebo-controlled, outcome study in secondary prevention, PROactive study, the use of pioglitazone in addition to an existing optimized macrovascular risk management resulted in a significant reduction of macrovascular endpoints within a short observation period that was comparable to the effect of statins and angiotensin converting enzyme inhibitors in other trials. These results underline the value of pioglitazone for managing the increased cardiovascular risk of patients with a metabolic syndrome or Type 2 diabetes mellitus.

Body Weight↗