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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes is associated with increased oxidant stress. This may contribute to the development of diabetic macrovascular complications through increased oxidation of low-density lipoprotein (LDL), which is thought to be a crucial step in the development of atherosclerosis. The sulfonylurea gliclazide has been shown to have free radical-scavenging activity in vitro, but its effects on LDL oxidation, and these effects of other sulfonylureas, are unknown. To investigate this we studied the effects of in vitro supplementation with gliclazide 1 mumol/L on copper-induced oxidation of LDL isolated from 20 control subjects and 22 type II diabetic patients. The effects of 1 mumol/L vitamin C, a known water-soluble antioxidant, were studied simultaneously. The resistance to oxidation, expressed as the lag time between the addition of copper and commencement of oxidation, was significantly increased by both gliclazide and vitamin C, and the effect was similar for LDL from diabetic and control subjects. The baseline oxidation lag time was 63.4 +/- 2.1 minutes, and increased to 108 +/- 4.4 minutes with gliclazide and 88.7 +/- 5.6 minutes with vitamin C (P = .0001, baseline v either treatment). The increase in lag time with gliclazide of 70% +/- 3% was greater than the 30% +/- 5% increase with vitamin C (P < .0005). In a separate experiment, LDL isolated from eight control and 10 diabetic subjects was supplemented with 1 mumol/L gliclazide, glibenclamide, glipizide, and tolbutamide. For each LDL sample, all drugs were studied simultaneously and the oxidation lag time was compared against that of untreated LDL. Gliclazide increased the lag time from 53.7 +/- 2.4 minutes to 108.4 +/- 4.5 minutes (P = .0001). None of the other sulfonylureas had any effect on lag time. These findings demonstrate that gliclazide is an effective inhibitor of in vitro LDL oxidation, and in this respect, it is more potent on a molar basis than vitamin C. This antioxidant property of gliclazide was not shared by the other sulfonylureas studied.
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PMID:The effects of gliclazide and other sulfonylureas on low-density lipoprotein oxidation in vitro. 943 54

The hamster cheek pouch is an experimental model in which quantitative studies of macromolecular permeability can be made by direct observation of extravasated fluorescein isothiocyanate (FITC)-dextran (leaks). The advantage of this model is that simultaneous light and fluorescent-light microscopy observations can be performed with instantaneous correlations between the site of FITC-dextran extravasation and the vessel morphology. The aims of our study were to compare, using the cheek pouch preparation, the effects of two sulfonylureas, gliclazide and glibenclamide, on the macromolecular permeability increase induced by histamine using control (normoglycemic) hamsters. In these studies, FITC-labeled dextran 150,000 daltons was administered intravenously and quantified by UV-light microscopy, and the drugs used were applied topically at therapeutic concentrations. Gliclazide and glibenclamide dose-dependently decreased the macromolecular permeability increase induced by histamine. This effect of gliclazide could be blocked by nifedipine (Ca2+ channel blocker) and not by diazoxide (K+ channel opener), whereas for glibenclamide it could be blocked by diazoxide and not by nifedipine. To better characterize the antioxidant capacity of gliclazide and glibenclamide, their effect on the macromolecular permeability increase induced by ischemia/reperfusion was also compared with the effect of vitamin C in diabetic hamsters (glycemia > 240 mg/dL). Total ischemia of the preparation was obtained with a cuff placed around the neck of the everted pouch. Diabetes was induced by three intraperitoneal injections of streptozotocin 50 mg/kg/d in 3 days. In diabetic hamsters during ischemia/reperfusion, gliclazide was more effective in inhibiting the macromolecular permeability increase than glibenclamide (136.0 +/- 5.8 leaks/cm2 for placebo; 68.0 +/- 2.9 for 1.2 x 10(-6) mol/L gliclazide; 55.3 +/- 3.5 for 1.2 x 10(-5) mol/L gliclazide; 89.2 +/- 5.7 for 8 x 10(-8) mol/L glibenclamide; 107.0 +/- 3.8 for 8 x 10(-7) mol/L glibenclamide; 56.7 +/- 3.4 for 10(-6) mol/L vitamin C; and 20.5 +/- 0.6 for 10(-5) mol/L vitamin C). Our results suggest that (1) the inhibition of the permeability increase induced by histamine elicited by gliclazide may be mediated by Ca2+ channels, while that of glibenclamide may be mediated by K+ channels, and (2) gliclazide appears to have an antioxidant capacity in ischemia/reperfusion injury similar to that of 10(-6) mol/L vitamin C. Improvement in the microcirculation was independent of the hypoglycemic properties of the drug.
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PMID:Microvascular permeability with sulfonylureas in normal and diabetic hamsters. 943 55

Five thousand five hundred seventy-two newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM) patients (3,225 men and 2,347 women; mean age, 58.5 years) were recruited through the General Practitioners (GPs) network in France. All had persistent hyperglycemia after a preliminary 3-month period with dietary and life-style modification. Gliclazide (80 to 320 mg/d) was then prescribed as diabetic pharmacotherapy for 2 years. Additional therapy for hypertension and dyslipidemia was started if necessary. The aim of the study was mainly to determine the feasibility of a GP-directed protocol for the monitoring and treatment of newly diagnosed NIDDM patients, and to assess the effectiveness of diabetic therapy in this cohort. Diabetes was diagnosed in 78% of the cohort during routine screening. Among the women, 6.5% had a history of gestational diabetes. Eighteen percent of the patients had a parental history of diabetes, and the dominant maternal role in the genesis of NIDDM was confirmed. High blood pressure (Joint National Committee V criteria) was found at inclusion in 38.8% of the whole cohort. Hyperlipidemia was known in 44.6%. A history of stroke was present in 1.6% of the patients, and coronary heart disease (CHD) in 6.3%. These data support the relationship between the atherogenic state and development of NIDDM. Microalbuminuria defined as urinary albumin excretion (UAE) of at least 20 mg/L was found in 29.6% of the patients, and retinopathy in 9.8%. Among the included patients, 23% did not complete the study and were excluded from the efficacy analysis. Of these, 14% (808 patients) had only baseline evaluation data and 9% (499 patients) withdrew later. Comparison of mean baseline and final results in study completers uncovered a significant improvement in fasting blood glucose ([FBG] 182 +/- 48 v 137 +/- 40 mg/dL), post prandial blood glucose ([PPBG] 209 +/- 68 v 162 +/- 52 mg/dL), and hemoglobin A1c ([HbA1c] 8.7% +/- 2.5% v 7.3% +/- 2.0%). A slight improvement in total cholesterol (228 +/- 44 v 222 +/- 41 mg/dL), body mass index ([BMI] 28.5 +/- 4.7 v 27.9 +/- 4.5 kg/m2), and waist to hip ratio (0.99 +/- 0.1 v 0.98 +/- 0.1) was observed. There was a decrease in the percentage of patients with high blood pressure (38.5% v 30.7%). A mild increase in the prevalence of retinopathy (10.2% v 11.8%) was noted during the study, while the incidence of microalbuminuria remained unchanged (30.2% v 29.5%). In conclusion, the data indicate that the GPs involved in this study were able to successfully monitor and manage NIDDM patients in accordance with a standardized protocol. Gliclazide appeared to be an effective and well-tolerated treatment. The high prevalence of chronic diabetic complications at diagnosis emphasizes the delay encountered in reaching the diagnosis of NIDDM and the problems associated with this delay. In addition to the classic risk factors for NIDDM exhibited in this patient cohort, we have identified CHD and a maternal genetic component as further potential predicting factors.
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PMID:Management of newly diagnosed non-insulin-dependent diabetes mellitus in the primary care setting: effects of 2 years of gliclazide treatment--the Diadem Study. 943 56

ATP-dependent potassium channel blockers used as hypoglycaemic agents may have effects on vascular disease in diabetes mellitus beyond their effect on blood glucose control. This study was designed to determine the effects of treatment with gliclazide on the isolated abdominal aorta of diabetic rabbits in which endothelium-dependent relaxation is impaired by a mechanism involving oxygen-derived free radicals. After induction of diabetes with alloxan, there was no effect of gliclazide (10 mg x kg(-1) day(-1) orally) on blood glucose or insulin levels over a 6 week period. Hence, this permitted an examination of the vascular effects of gliclazide in diabetic rabbits exclusive of metabolic effects. Acetylcholine- and nitric oxide-induced relaxation in aortae from rabbits treated with or without gliclazide were measured in the absence or presence of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (L-NAME). Diabetes was associated with significant impairment of acetylcholine-induced endothelium-dependent relaxation of the abdominal aorta which was not significant in diabetic rabbits treated with gliclazide in vivo. Aortae from diabetic rabbits studied in the presence of L-NAME showed an exaggerated contraction to acetylcholine which was prevented in rabbits treated with gliclazide. Gliclazide treatment did not affect the response to acetylcholine of normal rabbit aorta, and gliclazide when added in vitro had no effect on the response of diabetic rabbit aorta, suggesting that the effect of gliclazide was specific to the abnormality arising with diabetes and was not due to an acute effect of the drug. These data indicate that gliclazide, aside from either a direct antioxidant action or an effect on insulin or glucose levels, may ameliorate diabetic endothelial cell dysfunction.
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PMID:Vascular action of the hypoglycaemic agent gliclazide in diabetic rabbits. 949 23

Gliclazide, a sulfonlyurea class molecule, is used to control glycaemic levels in non-insulin-dependent diabetes mellitus. Acute and chronic toxicity studies, conducted in various animal species, have demonstrated a very low toxicity. We report a patient who developed acute renal failure due to acute tubular necrosis following a massive ingestion of gliclazide in an suicide attempt. The patient ingested 28 grams of gliclazide; the normal dose of gliclazide is 80 mg one or twice a day. At admission the patient was hypoglycaemia and in a few days became oliguric with an increase in the serum creatinine concentration, but with a normal blood urea nitrogen level. He underwent dialysis and ten days after ingestion of gliclazide, his renal function improved rapidly.
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PMID:Acute renal failure after massive ingestion of gliclazide in a suicide attempt. 960 41

The Goto-Kakisaki rat is a genetic non-overweight model of non-insulin-dependent diabetes mellitus. Adult Goto-Kakisaki rats exhibit a mild basal hyperglycaemia (11 mmol/l) with impaired glucose tolerance, elevated basal plasma insulin level, a failure of insulin release in response to glucose together with a 50% depletion of the total pancreatic beta-cell mass and insulin stores. We have examined the effects of long-term (4 weeks) gliclazide treatment on the severity of diabetes in adult male Goto-Kakisaki rats (10-12 weeks of age). Gliclazide was administered orally (10 mg/kg per day). Gliclazide-treated Goto-Kakisaki rats were evaluated against Wistar and untreated Goto-Kakisaki rats. In the gliclazide-treated Goto-Kakisaki rats, basal plasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of treatment, and their basal insulin levels decreased to values similar to those in non-diabetic Wistar rats. Despite their total pancreatic beta-cell remaining unaffected, their pancreatic insulin stores were twice increased, with a similar improvement of the insulin content per individual beta-cell. Furthermore, the glucose-stimulated insulin release as evaluated in vivo during an intravenous glucose tolerance-test was significantly improved (twice increased) in the gliclazide-treated Goto-Kakisaki rats. This was correlated with a modest but significant enhancement of the early phase of insulin release in vitro (isolated perfused pancreas), in response to glucose. However, the overall insulin response in vitro remained clearly defective with no reappearance of the late phase of insulin release. The in vitro response to arginine (which was basically amplified in the Goto-Kakisaki model) or to gliclazide were kept unchanged after the gliclazide treatment. In conclusion, chronic gliclazide does not exert any beta-cytotrophic effect, but improves beta-cell function in the adult Goto-Kakisaki rat as far as it lowers basal insulin release, increases beta-cell insulin stores, and increases the glucose-induced insulin release.
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PMID:Effect of gliclazide treatment on insulin secretion and beta-cell mass in non-insulin dependent diabetic Goto-Kakisaki rats. 986 14

It has recently been indicated that tumor necrosis factor-alpha (TNF-alpha) production is increased under chronic hyperglycemia and TNF-alpha has harmful effects on insulin sensitivity and possibly on chronic diabetic complications. Therefore it will be favorable for diabetes treatment if anti-diabetic agents also have anti-TNF-alpha activities. In this study, we have investigated effects of hypoglycemic sulfonylureas (gliclazide and glibenclamide) and a thiazolidinedione (troglitazone) on lipopolysaccharide-induced TNF-alpha production, which was evaluated by immunoassay and bioassay, in vivo using mice and partly in vitro using human peripheral blood mononuclear cells. Gliclazide significantly inhibited TNF-alpha production in vivo and also in vitro at a concentration of 10(-3) mol/l. However, glibenclamide had neither effect on TNF-alpha production nor action. On the other hand, troglitazone inhibited action rather than production of TNF-alpha in vivo. In vitro troglitazone (10(-4) mol/l) significantly reduced cytolytic activity of TNF-alpha against LM cells. These results indicate that gliclazide and troglitazone have inhibitory effect on TNF-alpha.
Diabetes Res Clin Pract 1999 Mar
PMID:Inhibition of tumor necrosis factor-alpha with anti-diabetic agents. 1036 23

The role of reactive oxygen species in diabetes and its complications are well known. Two therapeutic agents commonly used in the treatment of diabetes are the sulfonylureas gliclazide and glibenclamide. These drugs effectively reduce blood sugar in non-insulin-dependent diabetes mellitus, by augmenting insulin release. Gliclazide is known to be a general free radical scavenger as shown by its inhibition of o-dianisidine photo-oxidation. In this study, the effects of gliclazide and glibenclamide on free radicals were examined in vitro, using electron spin resonance spectroscopy. Superoxide radical (O2*-) generated from the hypoxanthine-xanthine oxidase system or hydroxyl radical (OH*) generated via the Fenton reaction were analyzed as spin adducts of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). Gliclazide scavenged O2*- and OH* in a dose-dependent manner whereas glibenclamide was without effect. These findings suggest that gliclazide is not only effective in reducing blood sugar, but may also be beneficial as a result of inhibition of lipid and protein denaturation, which is believed to lead to the development of diabetic complications.
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PMID:Gliclazide scavenges hydroxyl and superoxide radicals: an electron spin resonance study. 1069 14

Subjects with type 2 diabetes have markedly increased rates of coronary heart disease (CHD) that are only partly explained by the increased levels of conventional cardiovascular risk factors such as total cholesterol, hypertension, and smoking. Although an increasing number of studies have suggested a role for glycemia in cardiovascular disease, considerable controversy remains. This issue may be resolved when the results of the UK Prospective Diabetes Study (UKPDS) are presented. One possible promising relatively new risk factor that may explain high levels of CHD in diabetic subjects is increased oxidative stress. Type 2 diabetic subjects have an increased preponderance of small dense low-density lipoprotein (LDL), which predisposes to the oxidation of LDL. Almost all studies show that diabetic subjects have increased oxidative stress. In addition, they may have lower levels of alpha-tocopherol. In most studies, increased oxidative stress has been associated with cardiovascular disease, although prospective data are lacking. If levels of oxidative stress are increased, what are the best levels to reduce it to? Improved glycemic control has been associated with decreased oxidative stress. Antioxidant replacement such as alpha-tocopherol may also be beneficial. Interestingly, some special properties of hypoglycemic agents have been described. Gliclazide has been reported to favorably affect both free radicals and platelet reactivity. Gliclazide may have a more favorable effect on tissue plasminogen activator (tPA) than tolbutamide. In conclusion, increased levels of oxidative stress may underlie some of the increased risk of cardiovascular disease in diabetic subjects. Interventions to decrease levels of oxidative stress by methods such as improved glycemic control, antioxidant therapy (ie, alpha-tocopherol), and gliclazide are indicated.
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PMID:Clinical relevance of the oxidative stress concept. 1069 18

In a double-blind, multicenter, multinational study, the long-term efficacy and safety of Diamicron(R)MR, a new gliclazide formulation taken once daily at lower dose (30-120 mg/day) was compared with Diamicron(R) (80-320 mg/day) taken twice daily in type 2 diabetic outpatients. After a 2-week run-in period, 800 patients with poor blood glucose control were randomized to Diamicron(R)MR (n=401) or Diamicron(R) (n=399). After a 4-month titration period, the efficacy and safety of Diamicron(R)MR was compared with Diamicron(R) over a 6-month fixed-dose treatment period. The ability to switch from Diamicron(R) to Diamicron(R)MR was then assessed during an additional 2-month follow-up period. Equivalence between treatment with Diamicron(R)MR and Diamicron(R) was compared by a non-inferiority test; the limit of equivalence was set at 0.5% for HbA(1c) and 1 mmol/l for fasting plasma glucose (FPG). The treatment groups were comparable at baseline. After 10 months of treatment, Diamicron(R)MR was as efficient as Diamicron(R) in controlling blood glucose, with a mean end point difference in HbA(1c) of -0.08 (0. 08)%, significantly lower than the equivalence limit (p<0.001). Similar results were obtained for FPG.The safety of Diamicron(R)MR and Diamicron(R) was equally high. The incidence of hypoglycemia was particularly low (0.2 hypoglycemia/100 patient months) in the elderly population, which represented almost 40% of the included patients. This study demonstrates that 30 to 120 mg of Diamicron(R)MR taken once daily is at least as efficient as 80 to 320 mg of Diamicron(R) taken in divided doses with respect to HbA(1c) and FPG levels, with a similar safety profile.
J Diabetes Complications
PMID:Diamicron MR once daily is effective and well tolerated in type 2 diabetes: a double-blind, randomized, multinational study. 1100 26


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