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Medical research on amaryl
Diabetes Obes Metab. 2008 Jun 16;
Jojima T, Suzuki K, Hirama N, Uchida K, Hattori Y
Aims: Several studies suggest increased mortality postcoronary angioplasty in patients on sulphonylureas. However, a theoretical reduction in cardiac risk has been suggested with the newer sulphonylurea agents, which differ from the first-generation agents. In the present study, we investigated whether a third generation of sulphonylurea, glimepiride, might stimulate nitric oxide (NO) production and thereby inhibit cytokine-induced nuclear factor (NF)-kappaB activation in endothelial cells compared with the classical sulphonylurea glibenclamide. Methods and Results: We demonstrated that glimepiride, but not glibenclamide, induces NO production in human umbilical vein endothelial cells (HUVEC). A significant increase in endothelial NO synthase (eNOS) activity, measured in terms of citrulline production, was observed with glimepiride treatment. Akt phosphorylation followed by phosphorylation of eNOS (Ser1177) was observed with glimepiride treatment in HUVEC. Moreover, two phosphoinoside 3-kinase inhibitors, wortmannin and LY294002, significantly inhibited glimepiride-induced NO production. We also demonstrated inhibition of tumour necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation in HUVEC treated with glimepiride, which was attenuated by pretreatment with N(omega)-nitro-l-arginine methyl ester. We also demonstrated a marked increase in p65 in nuclear extracts from untreated HUVEC following stimulation with TNFalpha, which was dose dependently inhibited by glimepiride, but not by glibenclimide in association with NF-kappaB levels. Conclusion: These data suggest that glimepiride might be a preferable sulphonylurea agent in the setting of type 2 diabetes and vascular disease because it may have protective effects on vascular endothelial cells.
Pharmacogenet Genomics. 2008 Jul; 18(7): 591-597
Becker ML, Aarnoudse AJ, Newton-Cheh C, Hofman A, Witteman JC, Uitterlinden AG, Visser LE, Stricker BH
OBJECTIVE: The single nucleotide polymorphism rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene is associated with QTc prolongation, through an effect on the intracellular Ca levels. As sulfonylurea stimulate insulin secretion by an increased influx of Ca, we hypothesized that this polymorphism is associated with the glucose-lowering effect and mortality risk in sulfonylurea users. METHODS: Associations between the NOS1AP polymorphism, prescribed doses, and mortality rates in sulfonylurea, metformin, and insulin users were assessed in the Rotterdam Study, a population-based cohort study of 7983 elderly people. RESULTS: We identified 619 participants who were prescribed oral antidiabetic drugs during follow-up. In glibenclamide users carrying the TG genotype, the prescribed doses were higher compared with the glibenclamide users carrying the TT genotype [0.38 defined daily dose units, 95% confidence interval (CI) 0.14-0.63]. Glibenclamide users with the TG or GG genotype had an increased mortality risk compared with glibenclamide users with the TT genotype [hazard ratio (HR) 2.80, 95% CI: 1.09-7.22]. Tolbutamide users with the TG or GG genotype (HR: 0.30, 95% CI: 0.14-0.63) and glimepiride users with the TG or GG genotype (HR: 0.18, 95% CI: 0.04-0.74) had a decreased mortality risk compared with tolbutamide and glimepiride users with the TT genotype. CONCLUSION: In participants with the TG or GG genotype at rs10494366 in the NOS1AP gene, glibenclamide is less effective in reducing glucose levels and mortality rates were higher compared with glibenclamide users with the TT genotype. In tolbutamide and glimepiride users, the TG and GG genotype were associated with a reduced mortality rate.
Transl Res. 2008 Jun; 151(6): 309-14
Lin KD, Chang YH, Wang CL, Yang YH, Hsiao PJ, Li TH, Shin SJ
Retinol-binding protein 4 (RBP4) has been found to induce insulin resistance and to be increased in type 2 diabetes. Thiazolidinediones (TZDs) can improve insulin sensitivity through the activation of peroxisome proliferators-activated receptor-gamma (PPAR-gamma) and have been suggested as an adjunct to metformin (MF) and sulfonylurea (SU) in type 2 diabetes in a consensus statement from the ADA and EASD. Therefore, we investigated whether TZD could affect serum RBP4 level in type 2 diabetes already treated with MF and/or SU. Eighty-one type 2 diabetic patients were divided into 2 groups: (1) TZD group (n = 55): Pioglitazone 30 mg/day was given as an add-on medication; (2) SU group (n = 26): Gliclazide MR 30-120 mg or glimepiride 2-8 mg/day was prescribed. The average period of study was 97.1 days. Serum RBP4 and adiponectin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. The addition of pioglitazone (TZD group) markedly decreased homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.021) compared with the SU group (P = 0.688). The change of RBP4 in the TZD group (-3.87 +/- 11.27 microg/mL) significantly differed from that in the SU group (2.52 +/- 8.24 microg/mL, P < 0.012). The increase of adiponectin in the TZD group (11.49 +/- 7.85 microg/mL) was apparently higher than that in the SU group (1.54 +/- 5.62 microg/mL, P < 0.001). Despite the change of glycosylated hemoglobin (HbA1c) did not differ (-0.77 +/- 1.3 vs -0.50 +/- 1.7, P = 0.446), the addition of pioglitazone could significantly lower serum RBP4 and HOMA-IR values, whereas an increased dosage of sulfonylurea agents did not alter HOMA-IR, RBP4, or adiponectin in type 2 diabetic patients who had been treated with metformin and/or sulfonylurea.
Diabetes Res Clin Pract. 2008 Jul; 81(1): 13-8
Kanda Y, Matsuda M, Tawaramoto K, Kawasaki F, Hashiramoto M, Matsuki M, Kaku K
Adiponectin is a fat-derived cytokine with anti-diabetic and anti-atherogenic properties. In this study, effects of sulfonylureas (SUs) on adiponectin production and the action mechanism were evaluated using 3T3-L1 adipocytes. The cells were incubated with glimepiride, glibenclamide, gliclazide, pioglitazone, metformin and the medium only as the control. In the control, the adiponectin level evaluated as the production rate per 24 h was not changed, while pioglitazone significantly increased the adiponectin level. SUs also increased the adiponectin level, but metformin failed to show any increase in adiponectin production. SUs induced adiponectin gene expression as well as pioglitazone. Pioglitazone significantly increased adipogenesis, but glimepiride did not. The aP2 gene expression was increased by pioglitazone, but not by glimepiride. Forskolin, a protein kinase A stimulator, reduced the adiponectin production stimulated by glimepiride but not by pioglitazone. These observations strongly suggest that SUs stimulate the adiponectin production through a different mechanism from pioglitazone, namely an interaction with protein kinase A activity. The significance of the extrapancreatic action of SUs observed in this study should be further evaluated in the clinical field.
Br J Pharmacol. 2008 Jun; 154(4): 901-13
Müller G, Wied S, Jung C, Over S
BACKGROUND: The insulin-independent inhibition of lipolysis by palmitate, the anti-diabetic sulphonylurea glimepiride and H2O2 in rat adipocytes involves stimulation of the glycosylphosphatidylinositol (GPI)-specific phospholipase-C (GPI-PLC) and subsequent translocation of the GPI-anchored membrane ectoproteins (GPI-proteins), Gce1 and cluster of differentiation antigen (CD73), from specialized plasma membrane microdomains (DIGs) to cytosolic lipid droplets (LDs). This results in cAMP degradation at the LD surface and failure to activate hormone-sensitive lipase. Reactive oxygen species (ROS) may trigger this sequence of events in response to palmitate and glimepiride. EXPERIMENTAL APPROACH: The effects of various inhibitors of ROS production on the release of H2O2, GPI anchor cleavage and translocation of the photoaffinity-labelled or metabolically labelled Gce1 and CD73 from DIGs to LD and inhibition of lipolysis by different fatty acids and sulphonylureas were studied with primary rat adipocytes. KEY RESULTS: Glimepiride and palmitate induced the production of H2O2 via the plasma membrane NADPH oxidase and mitochondrial complexes I and III, respectively. Inhibition of ROS production was accompanied by the loss of (i) GPI-PLC activation, (ii) Gce1 and CD73 translocation and (iii) lipolysis inhibition in response to palmitate and glimepiride. Non-metabolizable fatty acids and the sulphonylurea drug tolbutamide were inactive. NADPH oxidase and GPI-PLC activities colocalized at DIGs were stimulated by glimepiride but not tolbutamide. CONCLUSIONS AND IMPLICATIONS: The data suggest that ROS mediate GPI-PLC activation at DIGs and subsequent GPI-protein translocation from DIGs to LD in adipocytes which leads to inhibition of lipolysis by palmitate and glimepiride. This insulin-independent anti-lipolytic mechanism may be engaged by future anti-diabetic drugs.
Repeatability of monolithic HPLC columns while using a flow program.
J Sep Sci. 2008 Jun; 31(10): 1745-9
Kaminski L, El Deeb S, Wätzig H
Fast HPLC methods are becoming more and more important. Using monolithic HPLC columns for fast separations, a flow program can be applied for further decrease in the total run time. An interesting issue was whether the flow program affects repeatability. The investigated method was a generic assay for the oral antidiabetic drugs glibenclamide and glimepiride in the presence of two of their degradation products. A flow program ranging from 5.0 to 9.9 mL/min had been set up to decrease the run time to approximately 1.7 min. Within-day RSD% (n = 40) for both retention times and peak areas were less than 1%. At flow rates higher than 7 mL/min, repeatability was impaired to some extent. It became mainly noticeable through the day-to-day precision (n = 60) which showed RSD% up to 2%. However, further investigations indicated that this was rather related to pump inefficiency at high flow rates than to the flow program as such. Presuming the use of appropriate equipment, qualified for high flow rates, the application of a flow program for shortening the run time is absolutely reasonable and does not affect repeatability.
Circulation. 2008 Apr 22; 117(16): 2123-30
Davidson M, Meyer PM, Haffner S, Feinstein S, D'Agostino R, Kondos GT, Perez A, Chen Z, Mazzone T
BACKGROUND: Measurement of carotid intima-media thickness (CIMT) has been validated as a measure of atherosclerosis and as a predictor of future cardiovascular events. Compared with glimepiride, pioglitazone has been shown to slow the progression of atherosclerosis measured by CIMT in patients with type 2 diabetes mellitus. METHODS AND RESULTS: We evaluated individual cardiovascular risk factors as predictors of the change in CIMT produced by pioglitazone treatment by determining whether their addition to a baseline model resulted in loss of significance for the treatment effect on CIMT. Pioglitazone treatment led to improvement in levels of multiple cardiovascular risk markers, including high-sensitivity C-reactive protein, apolipoprotein B, apolipoprotein A1, high-density lipoprotein (HDL) cholesterol, triglyceride, insulin, and free fatty acid. At 24 weeks, there were significant differences in HDL cholesterol, triglyceride, total cholesterol, low-density lipoprotein cholesterol, insulin, body mass index, hip circumference, and high-sensitivity C-reactive protein between the pioglitazone and glimepiride treatment groups. After adjustment for 24-week on-treatment values of cardiovascular risk factors, only inclusion of the changes in HDL cholesterol and insulin significantly impacted the magnitude and significance of the treatment effect on CIMT. Furthermore, irrespective of treatment assignment, increased HDL cholesterol at 24 weeks was a significant predictor of reduced CIMT progression at 72 weeks. CONCLUSIONS: The beneficial effect of pioglitazone on HDL cholesterol at 24 weeks predicted its beneficial effect for reducing CIMT progression at 72 weeks. Changes in HDL cholesterol at 24 weeks, irrespective of treatment, predicted less progression of CIMT at 72 weeks. These results suggest that suppression of atherosclerosis with pioglitazone therapy is linked to its ability to raise HDL cholesterol.
J Diabetes Complications. 2008 Apr 11;
Schaalan M, El-Abhar HS, Barakat M, El-Denshary ES
Wersternized diet, containing high fat diet intake combined with high consumption of softdrinks, is accused with the emerge of modern epidemic obesity and diabesity. Therefore, we aimed to study the effect of this diet combination on the homeostasis of glucose, lipids, and some adipohormones in rats and to simulate the metabolic perturbations induced by the unhealthy Westernized diet intake, leading to the development of type 2 diabetes. To achieve this, we divided male Wistar rats (80-120 g) into two main groups: the first was fed commercial normal fat diet and the second received an in-house-prepared high-fat diet (HFD), combined with fructose in drinking water for a period of 6 weeks, followed by a subdiabetogenic dose of streptozotocin (STZ) (35 mg/kg) to produce frank hyperglycemia. The effect of this diet alone or after 2 weeks of treatment with rosiglitazone or glimepiride on glucose homeostasis, lipid profile, and levels of resistin and leptin was studied. The HFD/fructose/STZ diet elevated fasting plasma glucose, fructosamine, insulin, and homeostasis model assessment (HOMA) index, as well as serum triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol, with a decrease in high-density lipoprotein cholesterol. Hepatic TG and TC levels, as well as serum activities of aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase (LDH), were increased, suggesting a diet-induced hepatic steatosis, beside the increased levels of serum resistin and leptin. Rosiglitazone corrected the altered parameters measured, except for liver TGs; similarly, glimepiride reinstated the inverted parameters but raised insulin level and, consequently, the HOMA index. These results show that this diet could be used to induce an effect that mimics human type 2 diabetes with its metabolic disturbances and is suitable for screening the antidiabetic agents used for management of this disease.
Does PERISCOPE provide a new perspective on diabetic treatment?
JAMA. 2008 Apr 2; 299(13): 1603-4
Steg PG, Marre M
JAMA. 2008 Apr 2; 299(13): 1561-73
Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De Larochellière R, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM, Tuzcu EM,
CONTEXT: No antidiabetic regimen has demonstrated the ability to reduce progression of coronary atherosclerosis. Commonly used oral glucose-lowering agents include sulfonylureas, which are insulin secretagogues, and thiazolidinediones, which are insulin sensitizers. OBJECTIVE: To compare the effects of an insulin sensitizer, pioglitazone, with an insulin secretagogue, glimepiride, on the progression of coronary atherosclerosis in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter trial at 97 academic and community hospitals in North and South America (enrollment August 2003-March 2006) in 543 patients with coronary disease and type 2 diabetes. INTERVENTIONS: A total of 543 patients underwent coronary intravascular ultrasonography and were randomized to receive glimepiride, 1 to 4 mg, or pioglitazone, 15 to 45 mg, for 18 months with titration to maximum dosage, if tolerated. Atherosclerosis progression was measured by repeat intravascular ultrasonography examination in 360 patients at study completion. MAIN OUTCOME MEASURE: Change in percent atheroma volume (PAV) from baseline to study completion. RESULTS: Least squares mean PAV increased 0.73% (95% CI, 0.33% to 1.12%) with glimepiride and decreased 0.16% (95% CI, -0.57% to 0.25%) with pioglitazone(P = .002). An alternative analysis imputing values for noncompleters based on baseline characteristics showed an increase in PAV of 0.64% (95% CI, 0.23% to 1.05%) for glimepiride and a decrease of 0.06% (-0.47% to 0.35%) for pioglitazone (between-group P = .02). Mean (SD) baseline HbA(1c) levels were 7.4% (1.0%) in both groups and declined during treatment an average 0.55% (95% CI, -0.68% to -0.42%) with pioglitazone and 0.36% (95% CI, -0.48% to -0.24%) with glimepiride (between-group P = .03). In the pioglitazone group, compared with glimepiride, high-density lipoprotein levels increased 5.7 mg/dL (95% CI, 4.4 to 7.0 mg/dL; 16.0%) vs 0.9 mg/dL (95% CI, -0.3 to 2.1 mg/dL; 4.1%), and median triglyceride levels decreased 16.3 mg/dL (95% CI, -27.7 to -11.0 mg/dL; 15.3%) vs an increase of 3.3 mg/dL (95% CI, -10.7 to 11.7 mg/dL; 0.6%) (P < .001 for both comparisons). Median fasting insulin levels decreased with pioglitazone and increased with glimepiride (P < .001). Hypoglycemia was more common in the glimepiride group and edema, fractures, and decreased hemoglobin levels occurred more frequently in the pioglitazone group. CONCLUSION: In patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone resulted in a significantly lower rate of progression of coronary atherosclerosis compared with glimepiride. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00225277.