Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with an increased risk of macro- and microvascular degenerative complications. Gliclazide is a second generation sulfonylurea that is widely used in the treatment of type II diabetes mellitus. Its hypoglycemic activity is well documented. In addition to its metabolic effects, gliclazide has beneficial effects on the hemobiological abnormalities of NIDDM. These effects are mediated by the azabicyclo-octyl ring grafted on to its aulfonylurea core. Numerous studies have demonstrated that gliclazide reduces platelet hyperadhesion and platelet hyperaggregability. These actions have been extensively confirmed in diabetic patients over periods of up to 3 years. With regard to platelet functions, several groups have demonstrated a significant reduction in serum and intraplatelet beta thromboglobulin and thromboxane B2. In animal models, in-vitro and in-vivo gliclazide stimulates endothelial prostacyclin synthesis. The beneficial effects of the compound on thromboxane/prostacyclin balance have been recently confirmed in type II diabetic patients after a 3-month treatment period. Concerning fibrinolysis, gliclazide restores low plasminogen activity to normal in NIDDM patients previously treated with first-generation sulfonyl-ureas. Gliclazide increases fibrinolytic potential by increasing endothelial cell tissue plasminogen activator and pre-kallikrein activity. More recent studies suggest that gliclazide may have effects on fibrin network structure, rendering the fibrin more amenable to fibrinolysis. Finally, it has been shown that gliclazide has a potent free-radical-scavenging activity in vitro. This property has been recently confirmed in vivo in type II diabetic patients and may suggest that platelet reactivity and oxidative stress are related in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemobiological properties of gliclazide. 783

We have previously shown that the mRNA expression of muscle glycogen synthase is decreased in non-insulin-dependent diabetic (NIDDM) patients; the objective of the present protocol was to examine whether the gene expression of muscle glycogen synthase in NIDDM is affected by chronic sulphonylurea treatment. Ten obese patients with NIDDM were studied before and after 8 weeks of treatment with a weight-maintaining diet in combination with the sulphonylurea gliclazide. Gliclazide treatment was associated with significant reductions in HbA1C (p=0.001) and fasting plasma glucose (p=0.005) as well as enhanced beta-cell responses to an oral glucose load. During euglycaemic, hyperinsulinaemic clamp (2 mU x kg-1 x min-1) in combination with indirect calorimetry, a 35% (p=0.005) increase in whole-body insulin-stimulated glucose disposal rate, predominantly due to an increased non-oxidative glucose metabolism (p=0.02) was demonstrated in teh gliclazide-treated patients when compared to pre-treatment values. In biopsies obtained from vastus lateralis muscle during insulin infusion, the half-maximal activation of glycogen synthase was achieved at a significantly lower concentration of the allosteric activator glucose 6-phosphate (p=0.01). However, despite significant increases in both insulin-stimulated non-oxidative glucose metabolism and muscle glycogen synthase activation in gliclazide-treated patients no changes were found in levels of glycogen synthase mRNA or immunoreactive protein in muscle. In conclusion, improved blood glucose control in gliclazide-treated obese NIDDM patients has no impact on the gene expression of muscle glycogen synthase.
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PMID:Unchanged gene expression of glycogen synthase in muscle from patients with NIDDM following sulphonylurea-induced improvement of glycaemic control. 869 Jan 77

Low-density lipoprotein (LDL) oxidation has been suggested to play a key role in the pathogenesis of atherosclerosis, a major complication of diabetes mellitus. Gliclazide, a second-generation sulfonylurea, is widely used in the treatment of type II diabetes mellitus. Recently, a free-radical-scavenging activity of gliclazide has been reported. In the present study, we examined the effects of gliclazide on cell-mediated LDL oxidation and monocyte adhesion to endothelial cells induced by oxidatively modified LDL. Incubation of human monocytes and bovine aortic endothelial cells (BAE cells) with increasing concentrations of gliclazide (0 to 10 micrograms/mL) and native LDL (100 micrograms/mL) resulted in a dose-dependent diminution of cell-mediated LDL oxidation as assayed by measurement of thiobarbituric acid (TBA)-reactive substances (TBARS). In addition, exposure of BAE cells to gliclazide (0 to 10 micrograms/mL) and native LDL (100 micrograms/mL) induced a dose-dependent diminution of the oxidized LDL-induced monocyte adhesion to BAE cells as measured by the myeloperoxidase (MPO) assay. The effects of glyburide, another second-generation sulfonylurea, were also tested on cell-mediated oxidation of LDL and LDL-induced monocyte adhesion to the endothelium. No significant effect of this drug was observed on these two processes. These results therefore demonstrate that gliclazide is effective in vitro in reducing both cell-mediated LDL oxidation and monocyte adhesion to the endothelium. These findings suggest a potential beneficial effect of gliclazide in the prevention of atherosclerosis in diabetic patients.
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PMID:Gliclazide decreases cell-mediated low-density lipoprotein (LDL) oxidation and reduces monocyte adhesion to endothelial cells induced by oxidatively modified LDL. 932 98

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

Enhanced monocyte-endothelial cell interactions have been documented in diabetes. Because adherence of monocytes to the endothelium is one of the earliest events in the development of atherosclerosis, its alteration may represent one of the mechanisms leading to accelerated atherosclerosis in diabetic patients. Previous studies have suggested that lipoprotein oxidation and protein glycation may contribute to the increased monocyte binding to the diabetic vasculature. Based on the recent finding that gliclazide has free-radical scavenging activity, we examined the ex vivo and in vitro effects of this drug on human monocyte binding to endothelial cells. Our results demonstrate that short-term administration of gliclazide to patients with type 2 diabetes lowers the enhanced adhesion of diabetic monocytes observed before gliclazide treatment (163+/-24% over control values, p<0.005) to levels similar to those observed in controls. They also show that gliclazide (10 microg/ml) reduces in vitro by approximately 35% both oxidized low-density lipoprotein (LDL)- and glycated albumin-induced monocyte adhesion to endothelial cells. Based on these results, we next investigated the molecular mechanisms responsible for the inhibitory effect of gliclazide on glycated albumin-induced monocyte adhesion to endothelium. In glycated albumin-treated endothelial cells, we observed induction of cell-associated expression of E-selectin (ELAM-1; 170+/-10% over control values, p<0.005), intercellular cell adhesion molecule-1 (ICAM-1; 131+/-8% over control values, p<0.005) and vascular cell adhesion molecule-1 (VCAM-1; 134+/-8% over control values, p<0.005), augmentation in the levels of the transcripts of these molecules, and an increase in the DNA binding of NF-kappaB in the promoters of these antigens. Gliclazide markedly inhibited the induction of all these parameters. Because the oxidative stress-sensitive transcription factor NF-kappaB is implicated in endothelial cell activation, the observed inhibitory effect of gliclazide on NF-kappaB activation and glycated albumin-induced expression of DNA binding activity for the NF-kappaB site in the ELAM-1, ICAM-1 and VCAM-1 promoters seems to be due to its antioxidant properties. These results suggest that gliclazide, by its ability to reduce endothelial activation, may exert potential beneficial effects in the prevention of atherosclerosis associated with type 2 diabetes.
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PMID:Effect of gliclazide on monocyte-endothelium interactions in diabetes. 1100 31

Hypoglycemic agents with a rapid onset and short duration of action should be useful for controlling postprandial hyperglycemia. Our aim was to establish a diabetes mellitus model in dogs, and then during an oral glucose tolerance test to compare the hypoglycemic effect and insulinotropic action of KAD-1229, a new hypoglycemic agent, with that of gliclazide, a conventional sulfonylurea. In this model, KAD-1229 reduced the increase in plasma glucose level without producing hypoglycemia. Gliclazide had a weaker effect on reduction of the glucose increase and caused hypoglycemia via a significantly raised insulin secretion in the late phase. A rapid insulinotropic action of KAD-1229 was clearly observed in the portal venous blood. The results suggest that in type 2 diabetes caused by, at least, insulin deficiency, KAD-1229 may improve impaired insulin secretion in the early phase and attenuate hyperglycemia without causing a sustained hypoglycemia.
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PMID:Effect of KAD-1229, a nonsulfonylurea hypoglycemic agent, on plasma glucose and insulin in streptozotocin-induced diabetic dogs. 1117 74

Gliclazide modified release (MR) is a new formulation of the drug gliclazide and is given once daily. The hydrophilic matrix of hypromellose-based polymer in the new formulation effects a progressive release of the drug which parallels the 24-hour glycaemic profile in untreated patients with type 2 diabetes mellitus. The formulation shows high bioavailability and its absorption profile is unaffected by coadministration with food. Mean plasma glucose levels are significantly reduced over a 24-hour period in patients with type 2 diabetes mellitus treated with gliclazide MR once daily, in both fasting and postprandial states. No cardiovascular ATP-sensitive potassium channel interaction has been observed at therapeutic concentrations of gliclazide MR. Gliclazide MR has also demonstrated antioxidant properties that are independent of glycaemic control. In a randomised, double-blind, multicentre study, gliclazide MR 30 to 120 mg once daily showed similar efficacy to gliclazide immediate release (IR) 80 to 320 mg/day (in divided doses for doses >80 mg) in patients with type 2 diabetes mellitus over a 10-month period, reducing glycosylated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) to a similar extent. The drug appeared most efficacious in patients who had previously been treated by diet alone, where significant reductions in HbA(1c) from baseline of 0.9% and 0.95% were seen at 10 and 24 months. Similarly, a sustained effect of gliclazide MR was observed in a subgroup of elderly patients defined a priori; HbA(1c) was decreased to a similar degree to that observed in the general study population. Gliclazide MR showed similar tolerability to gliclazide IR after 10 months' treatment in the randomised trial. The most commonly observed adverse events were arthralgia, arthritis, back pain and bronchitis (each <5%). Bodyweight remained stable. In this study no episodes of nocturnal hypoglycaemia or hypoglycaemia requiring third party assistance were observed during treatment with gliclazide MR. Episodes of symptomatic hypoglycaemia were infrequent, occurring in approximately 5% of patients.
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PMID:Gliclazide modified release. 1207 88

The sulphonylurea receptor (SUR) subunits of K(ATP) channels are the targets for several classes of therapeutic drugs. Sulphonylureas close K(ATP) channels in pancreatic beta-cells and are used to stimulate insulin release in type 2 diabetes, whereas the K(ATP) channel opener nicorandil acts as an antianginal agent by opening K(ATP) channels in cardiac and vascular smooth muscle. The predominant type of SUR varies between tissues: SUR1 in beta-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle. Sulphonylureas and related drugs exhibit differences in tissue specificity, as the drugs interact to varying degrees with different types of SUR. Gliclazide and tolbutamide are beta-cell selective and reversible. Glimepiride, glibenclamide, and repaglinide, however, inhibit cardiac and smooth muscle K(ATP) channels in addition to those in beta-cells and are only slowly reversible. Similar properties have been observed by recording K(ATP) channel activity in intact cells and in Xenopus oocytes expressing cloned K(ATP) channel subunits. While K(ATP) channels in cardiac and smooth muscle are largely closed under physiological conditions (but open during ischaemia), they are activated by antianginal agents such as nicorandil. Under these conditions, they may be inhibited by sulphonylureas that block SUR2-type K(ATP) channels (e.g., glibenclamide). Care should, therefore, be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K(ATP) channels are to be avoided.
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PMID:Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions. 1262 63

Increased interaction of monocytes with vascular cells is linked to the development and progression of atherosclerosis in patients with diabetes. One major determinant of increased monocyte binding to vascular cells could be oxidative stress. Given the free-radical scavenging properties of gliclazide, we evaluated the ex vivo and in vitro effects of this drug on human monocyte binding to endothelial cells and smooth muscle cells (SMCs). Short-term administration of gliclazide to patients with type 2 diabetes decreases plasma lipid peroxides and lowers the enhanced adhesion of diabetic monocytes to cultured endothelial cells observed before gliclazide treatment. Gliclazide (10 microg/ml) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to cultured endothelial cells. The suppressive effect of gliclazide on AGE-induced monocyte adhesion to endothelium involves a reduction of cell adhesion molecule mRNA and protein expression and an inhibition of NF-kappaB activation. Gliclazide also inhibits oxLDL-induced monocyte adhesion to cultured human aortic smooth muscle cells (HASMCs). Furthermore, treatment of HASMCs with gliclazide results in a marked decrease in oxLDL-induced monocyte chemoattractant protein-1 expression, both at the gene and protein levels. These results suggest that gliclazide, at concentrations in the therapeutic range (5-10 microg/ml), by its ability to decrease monocyte-vascular cell interactions could reduce monocyte accumulation in the atherosclerotic plaque and thereby contribute to attenuate the sustained inflammatory process that occurs in the vessel wall. These findings suggest that treatment of diabetic patients with gliclazide may prevent or retard the development of vascular disturbances associated with diabetes.
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PMID:Monocyte adhesion in diabetic angiopathy: effects of free-radical scavenging. 1262 65

Diabetes mellitus is characterized by oxidative stress, which in turn determines endothelial dysfunction. It has been recently demonstrated that gliclazide, a second-generation sulfonylurea with antioxidant properties, is able to protect endothelial function in animal models of diabetes. In streptozotocin-induced diabetic rats, gliclazide prevented endothelial dysfunction when given orally and improved the impaired relaxations to exogenous nitric oxide (NO) when applied on aortic segments. Moreover, gliclazide was able to inhibit glycosylated oxyhemoglobin-induced endothelial dysfunction both in animal and human microvessels. All these effects were not shared by glibenclamide, but were mimicked by vitamin C or superoxide dismutase (SOD), thus suggesting that gliclazide's action on endothelium-dependent vasodilation is mediated by its antioxidant properties. Thus far, there are no clinical studies that describe the influence of gliclazide on both oxidative status and NO-mediated vasodilation. We therefore evaluated the effects of gliclazide on plasma lipid peroxides, plasma total radical trapping antioxidant parameter (TRAP), and NO-mediated vasodilation assessed by blood pressure modifications following intravenous L-arginine in 30 subjects with Type 2 diabetes mellitus. The patients received glibenclamide (n=15) or gliclazide (n=15) in a 12-week, randomized, observer-blinded, parallel study, and were studied pre- and post-treatment. At 12 weeks, gliclazide-treated patients had lower plasma lipid peroxides (13.3+/-3.8 vs. 19.2+/-4.3 micromol/l; P=.0001, respectively) and higher plasma TRAP (1155.6+/-143.0 vs. 957.7+/-104.3 micromol/l; P=.0001, respectively) than the glibenclamide-treated patients. Gliclazide, but not glibenclamide, significantly reduced the systolic and diastolic blood pressure (P=.0199 and P=.00199, respectively, two-way repeated-measures analysis of variance) in response to intravenous L-arginine. In conclusion, our results demonstrate that glicazide treatment improves both antioxidant status and NO-mediated vasodilation in diabetic patients.
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PMID:Diabetic endothelial dysfunction: effect of free radical scavenging in Type 2 diabetic patients. 1262 66


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