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PubMed2001

Lack of antidiabetic effect of a Eugenia jambolana leaf decoction on rat streptozotocin diabetes.

Streptozotocin-diabetic rats were treated for 17 days with a decoction of Eugenia jambolana (Myrtaceae) leaves (15%, w/v) as a substitute for water. Body weight, food and fluid intake, urine volume, glycemia, urinary glucose and urea were evaluated every 5 days. The animals were sacrificed by decapitation and blood samples collected for the determination of glycemia, serum cholesterol, HDL-cholesterol, triglycerides and angiotensin-converting enzyme. The weight of adipose and muscle tissues was also determined. There were no statistically significant differences between treated and untreated rats for any of the biochemical or physiological parameters. We conclude that, at least in this experimental model, Eugenia jambolana leaf decoction has no antidiabetic activity.

Analysis of Variance↗
PubMed2005

Preclinical evaluation of the antidiabetic effect of Eugenia jambolana seed powder in streptozotocin-diabetic rats.

The world is facing an explosive increase in the incidence of diabetes mellitus and cost-effective complementary therapies are needed. The effects of Eugenia jambolana, a household remedy for diabetes, were studied. Streptozotocin diabetic female albino Wistar rats weighing 150-200 g (N = 6) were fed E. jambolana seed powder (250, 500 or 1000 mg/kg) for 15 days. Diabetic rats fed 500 and 1000 mg/kg seed powder showed an increase in body weight on day 20 in relation to day 5 (6 +/- 4.7, 9 +/- 7.8 vs diabetic control -16 +/- 7.1 g, P < 0.001), a decrease in fasting blood glucose (75 +/- 11.9, 123 +/- 14.4 vs diabetic control -34 +/- 12.1 mg/dl, P < 0.001), a difference in post-treatment fasting and peak blood glucose (38 +/- 11.9, 36 +/- 14.2 vs diabetic control 78 +/- 11.9 mg/dl, P < 0.001), and a difference in liver glycogen (50 +/- 6.8, 52 +/- 7.5 vs normal control 90 +/- 6.6 microg/g of liver tissue, P < 0.001). Tri-terpenoids, tannins, gallic acid, and oxalic acid were the chemical constituents detected in E. jambolana seed. The best results were obtained with an oral dose of 500 mg/kg. Subacute toxicity studies with a single administration of 2.5 and 5.0 g/kg seed powder showed no mortality or abnormality. These data on the antidiabetic effect of E. jambolana seed are adequate for approval of phase 2 clinical trials to evaluate this seed powder as complementary therapy in type 2 and type 1 diabetes.

Animals↗
PubMed1999

Insulin-secreting activity of the traditional antidiabetic plant Viscum album (mistletoe).

Viscum album (mistletoe) has been documented as a traditional treatment of diabetes. In acute 20-min tests, 1-10 mg/ml aqueous extract of mistletoe evoked a stepwise 1.1- to 12.2-fold stimulation of insulin secretion from clonal pancreatic B-cells. This effect was abolished by 0.5 mM diazoxide and prior exposure to extract did not alter subsequent stimulation of insulin secretion induced by 10 mM L-alanine, thereby negating a detrimental effect on cell viability. The insulin-releasing effect of mistletoe extract was unaltered by 16.7 mM glucose, l-alanine (10 mM), 3-isobutyl-1-methylxanthine (IBMX) (1 mM), or a depolarising concentration of KCl (25 mM). The ability of extract to enhance insulin secretion did not depend upon the use of heat during extract preparation and was not mediated by lectins. These results demonstrate the presence of insulin-releasing natural product(s) in Viscum album which may contribute to the reported antidiabetic property of the plant.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Chronic toxicity in monkeys with the thiazolidinedione antidiabetic agent troglitazone.

The antidiabetic agent troglitazone was given to groups of 4 cynomolgus monkeys per sex at 300, 600, or 1200 mg/kg daily by gavage for 52 weeks. A group of 4 monkeys per sex received vehicle alone and served as controls. Emesis and soft stool or diarrhea occurred sporadically in all troglitazone-treated groups, but did not compromise animal health. There were no effects on body weight or food consumption, or ophthalmologic, electrocardiographic, or echocardiographic parameters. Erythrocyte count, hemoglobin, and hematocrit decreased 8% to 16% in males at all doses and serum cholesterol decreased 30% to 46% in both sexes at all doses. Urinary ketones were increased in several animals at 600 and 1200 mg/kg. Absolute and relative liver weights increased at all doses in both sexes by 40% to 71%. The only microscopic change attributable to troglitazone treatment was minimal to mild bile duct hyperplasia in males at all doses and in females at 600 and 1200 mg/kg. No differences in systemic exposure were apparent between sexes. Over the dose range tested, AUC(0-24) values were 27 to 102 micrograms.hr/ml of troglitazone, 401 to 2060 micrograms.hr/ml of its sulfate conjugate, and 34 to 312 micrograms.hr/ml of its quinone metabolite. Therefore, oral administration of troglitazone to monkeys at 300, 600, and 1200 mg/kg for 52 weeks resulted in significant systemic exposure, with only minimal gastrointestinal, hematologic, and hepatic effects.

Administration, Oral↗
PubMed2006

Imaging docking and fusion of insulin granules induced by antidiabetes agents: sulfonylurea and glinide drugs preferentially mediate the fusion of newcomer, but not previously docked, insulin granules.

Sulfonylurea and glinide drugs, commonly used for antidiabetes therapies, are known to stimulate insulin release from pancreatic beta-cells by closing ATP-sensitive K+ channels. However, the specific actions of these drugs on insulin granule motion are largely unknown. Here, we used total internal reflection fluorescence (TIRF) microscopy to analyze the docking and fusion of single insulin granules in live beta-cells exposed to either the sulfonylurea drug glibenclamide or the glinide drug mitiglinide. TIRF images showed that both agents caused rapid fusion of newcomer insulin granules with the cell membrane in both control and diabetic Goto-Kakizaki (GK) rat pancreatic beta-cells. However, in the context of beta-cells from sulfonylurea receptor 1 (SUR1) knockout mice, TIRF images showed that only mitiglinide, but not glibenclamide, caused fusion of newcomer insulin granules. Compositely, our data indicate that 1) the mechanism by which both sulfonylurea and glinide drugs promote insulin release entails the preferential fusion of newcomer, rather than previously docked, insulin granules, and that 2) mitiglinide can induce insulin release by a mechanism independent of mitiglinide binding to SUR1.

ATP-Binding Cassette Transporters↗
PubMed2006

Halofenate is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic activity.

Halofenate has been shown previously to lower triglycerides in dyslipidemic subjects. In addition, significant decreases in fasting plasma glucose were observed but only in type 2 diabetic patients. We hypothesized that halofenate might be an insulin sensitizer, and we present data to suggest that halofenate is a selective peroxisome proliferator-activated receptor (PPAR)-gamma modulator (SPPARgammaM). We demonstrate that the circulating form of halofenate, halofenic acid (HA), binds to and selectively modulates PPAR-gamma. Reporter assays show that HA is a partial PPAR-gamma agonist, which can antagonize the activity of the full agonist rosiglitazone. The data suggest that the partial agonism of HA may be explained in part by effective displacement of corepressors (N-CoR and SMRT) coupled with inefficient recruitment of coactivators (p300, CBP, and TRAP 220). In human preadipocytes, HA displays weak adipogenic activity and antagonizes rosiglitazone-mediated adipogenic differentiation. Moreover, in 3T3-L1 adipocytes, HA selectively modulates the expression of multiple PPAR-gamma-responsive genes. Studies in the diabetic ob/ob mouse demonstrate halofenate's acute antidiabetic properties. Longer-term studies in the obese Zucker (fa/fa) rat demonstrate halofenate's comparable insulin sensitization to rosiglitazone in the absence of body weight increases. Our data establish halofenate as a novel SPPARgammaM with promising therapeutic utility with the potential for less weight gain.

3T3-L1 Cells↗
PubMed1975

Antidiabetic action of somatostatin--assessed by the artificial pancreas.

By means of a glucose-controlled insulin- and glucose-infusion system (GCIGIS) we examined the effect of somatostatin on insulin and glucose requirements following meals or oral glucose loads in juvenile diabetics. In six of seven patients the insulin requirement with somatostatin was remarkably reduced to between 38 per cent and 79 per cent of that of otherwise identical control experiments. No reduction could be found in the seventh case, fed only 575 kcal. In all cases we observed an increase in dextrose demanded from the GCIGIS ranging between 28 per cent and 192 per cent of the control amounts. In addition, a lowering and smoothing of postprandial blood glucose curves caused by somatostatin application was a general finding. It seems to us most likely that the well-known suppression of the secretion of growth hormone and glucagon, both insulin antagonists, is responsible for the antidiabetic action of somatostatin.

Adolescent↗
PubMed1990

Insulinlike activity of new antidiabetic agent CP 68722 in 3T3-L1 adipocytes.

We examined the in vitro effects of CP 68722, a novel antidiabetic agent, in 3T3-L1 adipocytes. CP 68722 stimulated 2-deoxyglucose uptake in the absence of insulin. At least 30 min of incubation were required for stimulation of uptake. This effect increased over 5 h and was sustained up to 72 h. The stimulation of 2-deoxyglucose uptake by CP 68722 could be inhibited approximately 60% by inhibition of protein synthesis with cycloheximide. Half-maximal and maximal responses to CP 68722 at 72 h of incubation were observed at 10 and 100 microM of drug, respectively, with a threefold stimulation of uptake at 100 microM approximating the maximal response of these cells to acute insulin stimulation. CP 68722 was able to overcome insulin resistance induced by dexamethasone in 3T3-L1 cells. The effect of drug, like that of insulin, was primarily to increase the Vmax of 2-deoxyglucose uptake. The stimulation of uptake by CP 68722 or insulin could be prevented by incubating the cells at 10 degrees C, a temperature that impedes translocation of glucose transporters to the plasma membrane. Therefore, it appears that CP 68722, like insulin, stimulates glucose uptake by a mechanism that involves translocation of intracellular glucose transporters to the plasma membrane and de novo protein synthesis. We compared the effect of CP 68722 with the sulfonylureas, the primary drugs used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). CP 68722 was a more potent and effective stimulator of 2-deoxyglucose uptake in 3T3-L1 cells than either first- or second-generation sulfonylureas.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1991

Antidiabetic action of vanadyl in rats independent of in vivo insulin-receptor kinase activity.

The effects of oral vanadyl sulfate administration for 9-12 days on carbohydrate and lipid metabolism in the basal state and on glucose dynamics during submaximal hyperinsulinemic clamps were investigated in nondiabetic and streptozocin-induced diabetic rats. Decreases in growth rate and water and food consumption were the only significant alterations noted in control animals receiving vanadyl. Administration of vanadyl to diabetic rats resulted in weight loss; a significant decrease in plasma glucose, triglyceride, and cholesterol levels; and decreases in food and water intake, without a concomitant change in plasma insulin concentrations. Vanadyl treatment did not modify either peripheral glucose utilization or hepatic glucose production in control rats during submaximal insulin clamps. In contrast, vanadyl therapy increased insulin-induced glucose utilization significantly and had a small but nonsignificant effect on insulin-mediated suppression of glucose production in diabetic rats. The tyrosine kinase activity of liver- and muscle-derived insulin receptors from diabetic rats that underwent clamp study, which reflected the in vivo phosphorylation state of insulin receptor, was not altered by vanadyl treatment. In conclusion, these results show that augmentation of peripheral glucose utilization is the major determinant of the antidiabetic action of vanadyl and support the notion that the action of vanadyl is independent of insulin-receptor kinase activity.

Animals↗
PubMed1998

Differential effect of the antidiabetic thiazolidinediones troglitazone and pioglitazone on human platelet aggregation mechanism.

Troglitazone and pioglitazone, antidiabetic thiazolidinediones, are known to improve insulin resistance. However, the effect of these drugs on platelet aggregation remains unclear. The chemical structure of troglitazone contains vitamin E. Accordingly, we studied the effect of troglitazone, pioglitazone, and vitamin E on thrombin-induced platelet aggregation, metabolism of phosphoinositide, protein phosphorylation, protein kinase C (PKC)-alpha and -beta, and phosphatidylinositol (PI) 3-kinase activation in vitro in human platelets. Maximum platelet aggregation by ADP, collagen, and thrombin decreased in the presence of 0.1-1 micromol/l troglitazone and 500 nmol/l vitamin E for 60 min compared with controls. However, pioglitazone did not inhibit ADP-, collagen-, or thrombin-induced platelet aggregation. Pretreatment with troglitazone and vitamin E, but not with pioglitazone, resulted in decreases in thrombin-induced phosphatidic acid production, hydrolysis of phosphatidylinositol 4,5-bisphosphate by phospholipase C, and 47-kDa protein phosphorylation. Thrombin-induced PKC-alpha and -beta activation in membrane fraction was suppressed by pretreatment with troglitazone and vitamin E, but not with pioglitazone. Separately, troglitazone and pioglitazone stimulated PI 3-kinase activity, but thrombin-induced PI 3-kinase activation was suppressed by pretreatment with troglitazone and pioglitazone for 60 min. These results suggest that troglitazone and vitamin E, but not pioglitazone, have a potent inhibitory effect on platelet aggregation via suppression of the thrombin-induced activation of phosphoinositide signaling in human platelets. Finally, the chemical structure of vitamin E may contribute to the inhibitory effect of troglitazone on platelet aggregation in human platelets.

Adenosine Diphosphate↗
PubMed1999

Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator-activated receptor-gamma.

Troglitazone is an antidiabetic agent of the thiazolidinedione family. It is generally believed that thiazolidinediones exert their insulin-sensitizing activity through activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the steroid nuclear receptor superfamily. In the present study, we examined the effect of troglitazone on cholesterol biosynthesis in cultured Chinese hamster ovary (CHO) cells. Troglitazone inhibited biosynthesis of cholesterol, but not that of total sterols, in a dose-dependent manner, with a half-maximal concentration (IC50) value of 8 micromol/l. At 20 micromol/l, troglitazone inhibited cholesterol biosynthesis by more than 80%, resulting in the accumulation of lanosterol and several other sterol products. This inhibitory effect observed in CHO cells was also reproduced in HepG2, L6, and 3T3-L1 cells, suggesting that there is a common pathway for this troglitazone action. One hour after removal of troglitazone from the culture medium, disappearance of the accumulated sterols was accompanied by restored cholesterol synthesis, indicating that those accumulated sterols are precursors of cholesterol. PPAR-gamma reporter assays showed that PPAR-gamma activation by troglitazone was completely blocked by actinomycin D and cycloheximide. In contrast, the inhibition of cholesterol synthesis by troglitazone remained unchanged in the presence of the above compounds, suggesting that this inhibition is mechanistically distinct from the transcriptional regulation by PPAR-gamma. Like troglitazone, two other thiazolidinediones, ciglitazone and englitazone, exhibited similar inhibitory effect on cholesterol synthesis; however, other known PPAR-gamma ligands such as BRL49653, pioglitazone, and 15-deoxy-delta(12,14)-prostaglandin J2 showed only weak or no inhibition. The dissociation of PPAR-gamma binding ability from the potency for inhibition of cholesterol synthesis further supports the conclusion that inhibition of cholesterol biosynthesis by troglitazone is unlikely to be mediated by PPAR-gamma.

3T3 Cells↗
PubMed2002

Antidiabetic effects of Panax ginseng berry extract and the identification of an effective component.

We evaluated antihyperglycemic and anti-obese effects of Panax ginseng berry extract and its major constituent, ginsenoside Re, in obese diabetic C57BL/6J ob/ ob mice and their lean littermates. Animals received daily intraperitoneal injections of Panax ginseng berry extract for 12 days. On day 12, 150 mg/kg extract-treated ob/ob mice became normoglycemic (137 +/- 6.7 mg/dl) and had significantly improved glucose tolerance. The overall glucose excursion during the 2-h intraperitoneal glucose tolerance test decreased by 46% (P < 0.01) compared with vehicle-treated ob/ob mice. The improvement in blood glucose levels in the extract-treated ob/ ob mice was associated with a significant reduction in serum insulin levels in fed and fasting mice. A hyperinsulinemic-euglycemic clamp study revealed a more than twofold increase in the rate of insulin-stimulated glucose disposal in treated ob/ ob mice (112 +/- 19.1 vs. 52 +/- 11.8 micromol x kg(-1) x min(-1) for the vehicle group, P < 0.01). In addition, the extract-treated ob/ob mice lost a significant amount of weight (from 51.7 +/- 1.9 g on day 0 to 45.7 +/- 1.2 on day 12, P < 0.01 vs. vehicle-treated ob/ob mice), associated with a significant reduction in food intake (P < 0.05) and a very significant increase in energy expenditure (P < 0.01) and body temperature (P < 0.01). Treatment with the extract also significantly reduced plasma cholesterol levels in ob/ob mice. Additional studies demonstrated that ginsenoside Re plays a significant role in antihyperglycemic action. This antidiabetic effect of ginsenoside Re was not associated with body weight changes, suggesting that other constituents in the extract have distinct pharmacological mechanisms on energy metabolism.

Animals↗
PubMed2003

Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors.

Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-gamma/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-gamma-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-gamma and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.

3T3 Cells↗
PubMed2005

Antidiabetic drugs and heart failure risk in patients with type 2 diabetes in the U.K. primary care setting.

OBJECTIVE: To assess the effects of antidiabetic drugs on the risk of heart failure in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study with a newly diagnosed diabetes cohort of 25,690 patients registered in the U.K. General Practice Research Database, 1988-1999. We categorized person-time drug exposures to monotherapies in insulin, sulfonylureas (SUs), metformins, and other oral hypoglycemic agents (i.e., acarbose, guar gum) and combination therapy including insulin, combination therapy without insulin, and triple combination therapy with or without insulin. A drug-free time interval served as a reference category. Cox interval-wise (piece-wise) regression analyses were used. The main outcome was incident heart failure. RESULTS: Among 43,390 drug exposure intervals for 25,690 patients who had a mean follow-up period of 2.5 years, 1,409 patients developed heart failure. Heart failure occurred most frequently in SU monotherapy exposure. After adjusting for duration of diabetes, the timing and order of treatments received, and known risk factors for heart failure, we found no differential effects among type-specific therapies. Patients with any drug use within the first year after diabetes diagnosis had a 4.75-fold higher risk (hazard ratio) for heart failure than those with drug-free status but had no increased risk during subsequent years. CONCLUSIONS: In conclusion, the use of any pharmacological therapy for type 2 diabetes appears to be associated with an increased risk of heart failure. This risk does not persist beyond the first year after diagnosis of diabetes and does not appear to differ among the types of drug therapy examined. This observation suggests that the severity of diabetes or the preclinical duration of diabetes and the need for drug therapy, and not the therapy itself, is an explanation for heart failure in patients with type 2 diabetes.

Adult↗
PubMed1984

Rat-plasma metabolites of ciglitazone, a new antidiabetic agent.

The rat-plasma metabolites of ciglitazone, a new antidiabetic agent, were characterized by g.l.c.-mass spectrometry as follows: the 2'-, cis-3'-, trans-3'-, cis-4'- and trans-4'-hydroxycyclohexyl derivatives, and 3'- and 4'-oxocyclohexyl derivatives. The 2'-hydroxycyclohexyl derivative contains cis- and/or trans-isomers (unresolved). Three other metabolites, which were postulated to be dihydroxy derivatives of ciglitazone, were also detected in the plasma. All monohydroxy and monoketo metabolites showed hypoglycaemic and hypotriglyceridemic activities in genetically obese-diabetic mice. These results suggest that the pharmacological activities of ciglitazone are due, at least partly, to the metabolites.

Animals↗
PubMed1996

The fate of a thiazolidinedione antidiabetic agent in rat and dog.

1. The fate of [14C]BRL 49653C, a novel thiazolidinedione antidiabetic agent, has been studied following oral administration to the rat and dog. 2. Clearance was almost exclusively by metabolism, with only small amounts of unchanged BRL 49653 being excreted by either species. 3. Phase I metabolism resulted in ring hydroxylation, N-demethylation and oxidative removal of the pyridinylamino function to yield a phenoxyacetic acid derivative. 4. Sulphation of phase I metabolites occurred in both species, but glucuronidation was only observed in the rat. 5. The parent compound was the major circulating component in both species at early times, but at later times sulphate conjugates of phase 1 metabolites were predominant.

Animals↗
PubMed2005

Antidiabetic effects of ajoene in genetically diabetic KK-A(y) mice.

Antidiabetic effects of ajoene, derived from garlic, were investigated in genetically diabetic KK-A(y) mice. Four-week-old male KK-A(y) mice were kept on a laboratory diet containing 0.02 or 0.05% of ajoene for 8 wk. The elevation of water intake was suppressed depending on ajoene intake. The levels of plasma glucose in the 0.05% ajoene-containing diet group was significantly suppressed to 73.8% compared with the control group at the 8th wk. Similarly, the plasma triglyceride level was significantly suppressed. It is suggested that hyperglycemia and hypertriglyceridemia are suppressed by ajoene treatment.

Animals↗
PubMed2005

Antidiabetic thiazolidinediones induce ductal differentiation but not apoptosis in pancreatic cancer cells.

AIM: Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of same epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), the mechanism by which TZD exert their anticancer effect is presently unclear. In this study, we analyzed the mechanism by which TZD inhibit growth of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. METHODS: The effects of TZD in pancreatic cancer cells were assessed in anchorage-independent growth assay. Expression of PPARgamma was measured by reverse-transcription polymerase chain reaction and confirmed by Western blot analysis. PPARgamma activity was evaluated by transient reporter gene assay. Flow cytometry and DNA fragmentation assay were used to determine the effect of TZD on cell cycle progression and apoptosis respectively. The effect of TZD on ductal differentiation markers was performed by Western blot. RESULTS: Exposure to TZD inhibited colony formation in a PPARgamma-dependent manner. Growth inhibition was linked to G1 phase cell cycle arrest through induction of the ductal differentiation program without any increase of the apoptotic rate. CONCLUSION: TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth by a PPAR-dependent induction of pancreatic ductal differentiation.

Adenocarcinoma↗