Pharmacokinetics and pharmacodynamics of gliclazide in Caucasians and Australian Aborigines with type 2 diabetes. (1/79)

AIMS: Gliclazide pharmacokinetics and pharmacodynamics were assessed in 9 Caucasians and 10 Australian Aborigines with uncomplicated type 2 diabetes. METHODS: Subjects were on a stable dose of 80 mg gliclazide twice daily, took 160 mg on the morning of study and had a standard breakfast. No further gliclazide was given over the next 48 h. Regular blood samples were drawn for serum glucose, insulin and gliclazide assay. Gliclazide was measured using h.p.l.c. Noncompartmental analysis was used to describe primary data. A multicompartment model incorporating entero-hepatic recirculation was fitted to group mean serum gliclazide profiles. RESULTS: The Caucasians were older than the Aborigines (mean +/- s.d. age 53.4 +/- 12.2 vs 40.3 +/- 6.9 years, P < 0.05) but had similar diabetes duration, body mass index and glycated haemoglobin. Noncompartmental analysis revealed no between-group differences in gliclazide kinetics. Post-breakfast serum glucose and insulin responses were also similar apart from a longer time to maximum concentration (tmax) for glucose amongst the Aborigines (2.6 +/- 0.4 vs 2.2 +/- 0. 3 h in Caucasians; P = 0.024). Gliclazide tmax exhibited a skewed unimodal distribution and was not associated with gliclazide maximum concentration, or glucose or insulin responses. Most patients had a serum gliclazide profile suggestive of enterohepatic recirculation and/or biphasic absorption. Model-derived estimates of the extent of putative enterohepatic recirculation were 30% and 20% of dose in Caucasians and Aborigines, respectively. CONCLUSIONS: Gliclazide is equally effective in Caucasian and Aboriginal diabetic patients. The pharmacokinetics of oral gliclazide appear more complex than previously thought. Gliclazide pharmacodynamics are unrelated to rate and extent of absorption, consistent with a threshold concentration for hypoglycaemic effect.  (+info)

Effects of oral hypoglycemic agents and diet on protein metabolism in type 2 diabetes. (2/79)

OBJECTIVE: We tested whether oral hypoglycemic agents (OHA), gliclazide with or without metformin, during an isoenergetic (ISO) and then a low-energy diet (LED) improve the altered kinetics of whole-body protein metabolism in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 13 type 2 diabetic patients (aged 51+/-2 years, weight 110+/-5 kg, BMI 41+/-1 kg/m2, fasting glucose [FSG] 11.5+/-0.9 mmol/l) (means+/-SEM) and 10 obese control subjects (48+/-3 years, 98+/-6 kg, 37+/-2 kg/m2, FSG 5.5+/-0.3 mmol/l) consumed an ISO, 1.5 g x kg(-1) x day(-1) protein for a body weight corresponding to a BMI of 25 (BMI25), a formula diet (7 days for obese control subjects, 15 days for diabetic patients), and then a 28-day LED with 50% of the energy of ISO but the same protein intake (101+/-2 g/day). OHAs were given during ISO (days 8-15) and LED. On days 6-8 (and 12-14 for diabetic subjects) of ISO and 26-28 of LED, the 60-h oral 15N-glycine method was used to obtain nitrogen flux (Q), synthesis (S), and breakdown (B). Muscle protein catabolism was estimated from N(tau)-methylhistidine (3MH) excretion. RESULTS: During ISO with hyperglycemia, Q, and B adjusted for fat-free mass, sex, and age were higher and nitrogen balance and net endogenous protein synthesis (S-B) lower than in control subjects (P<0.05). OHA decreased FSG (9+/-1 mmol/l) and 3MH and increased plasma insulin-to-glucose ratio, nitrogen retention, and S-B to levels in control subjects. The change in S-B correlated with that in FSG (r = -0.845, P = 0.001) and in fasting plasma C-peptide (r = 0.852, P = 0.0005). With LED and OHA, weight decreased 6.3 kg, glycemia reached near-normal levels, and nitrogen equilibrium was maintained; Q decreased by 7%, S and B by 11% (P<0.05) to values found in control subjects. CONCLUSIONS: OHA during ISO corrected protein turnover in relation to glycemia and plasma C-peptide. The LED maintained protein homeostasis in obese control subjects and, in diabetes patients with OHA, normalized protein metabolism. These findings have implications for diet and OHA prescription.  (+info)

Comparison of capillary electrophoresis with HPLC for diagnosis of factitious hypoglycemia. (3/79)

BACKGROUND: The diagnosis of "factitious hypoglycemia" is essentially based on the disclosure of hypoglycemic agents in blood or urine. The aim of this study was to evaluate the performance of capillary electrophoresis (CE) as a quantitative method for determination of chlorpropamide, tolbutamide, glipizide, gliclazide, and glibenclamide in serum. METHODS: Serum samples (1 mL), with internal standard added, were purified by solid-phase extraction on OASIS(TM) HLB cartridges (Waters), dried under reduced pressure, and reconstituted with 30-60 microL of acetonitrile:H(2)O. Analysis was carried out by micellar electrokinetic capillary chromatography in 5 mmol/L borate, 5 mmol/L phosphate, 75 mmol/L sodium cholate, pH 8.5, containing 25 mL/L methanol. Separation was accomplished in a 20 cm x 50 microm (i.d.) silica capillary at 25 degrees C and a constant voltage of +10 kV. Pharmacokinetics of gliclazide (80-mg tablet) in a diabetic patient were assayed by both HPLC and CE. Two hypoglycemic patients positive by HPLC analysis for unreported gliclazide and tolbutamide overdose were also screened by CE. RESULTS: Separation of six drugs (including the internal standard) was accomplished in 5 min plus 5 min rinsing. The between-day CV of the ratio of the areas of the sulfonylurea drugs to internal standard was <1% (n = 10). Linearity (r(2) > or =0.998) and recovery (> or =80%) were good for all sulfonylurea drugs tested. Pharmacokinetic curves for gliclazide by CE and HPLC were superimposable. CE analysis confirmed the HPLC diagnosis of surreptitious abuse of gliclazide and tolbutamide. CONCLUSION: CE is a useful tool in the clinical chemistry and toxicology laboratory for drug monitoring and pharmacokinetic investigations.  (+info)

Gliclazide and bedtime insulin are more efficient than insulin alone for type 2 diabetic patients with sulfonylurea secondary failure. (4/79)

To determine the effects of combined therapy of gliclazide and bedtime insulin on glycemic control and C-peptide secretion, we studied 25 patients with type 2 diabetes and sulfonylurea secondary failure, aged 56.8 +/- 8.3 years, with a duration of diabetes of 10.6 +/- 6.6 years, fasting plasma glucose of 277.3 +/- 64.6 mg/dl and a body mass index of 27.4 +/- 4.8 kg/m2. Patients were submitted to three therapeutic regimens lasting 2 months each: 320 mg gliclazide (phase 1), 320 mg gliclazide and bedtime NPH insulin (phase 2), and insulin (phase 3). At the end of each period, glycemic and C-peptide curves in response to a mixed meal were determined. During combined therapy, there was a decrease in all glycemic curve values (P<0.01). Twelve patients (48%) reached fasting plasma glucose <140 mg/dl with a significant weight gain of 64.8 kg (43.1-98.8) vs 66.7 kg (42.8-101.4) (P<0.05), with no increase in C-peptide secretion or decrease in HbA1. C-Peptide glucose score (C-peptide/glucose x 100) increased from 0.9 (0.2-2.1) to 1.3 (0.2-4.7) during combined therapy (P<0.01). Despite a 50% increase in insulin doses in phase 3 (12 U (9-30) vs 18 U (11-60); P<0.01) only 3 patients who responded to combined therapy maintained fasting plasma glucose <140 mg/dl (P<0.02). A tendency to a higher absolute increase in C-peptide (0.99 (0.15-2.5) vs 0.6 (0-2.15); P = 0.08) and C-peptide incremental area (2.47 (0.22-6.2) vs 1.2 (0-3.35); P = 0.07) was observed among responders. We conclude that combined therapy resulted in a better glucose response to a mixed meal than insulin alone and should be tried in type 2 diabetic patients before starting insulin monotherapy, despite difficulties in predicting the response.  (+info)

24-hour glycemic profile in type 2 diabetic patients treated with gliclazide modified release once daily. (5/79)

OBJECTIVES: In type 2 diabetes, the primary and secondary prevention of long-term micro- and macrovascular complications requires a control of blood glucose levels 24 hours a day. The present study was undertaken to assess the effect of a new formulation of gliclazide administered once daily, gliclazide modified release, on plasma glucose levels over 24 hours. MATERIAL AND METHODS: In 21 type 2 diabetic patients previously treated by diet alone or oral antidiabetic agents, glycemic profile (8 am, 10 am, 12 am, 2 pm, 5 pm, 8 pm, 10 pm, 3 am and 8 am), overall glycemic control, acceptability, and compliance with treatment were assessed before and after a 10-week treatment with gliclazide modified release, (30-60 mg), given once daily at breakfast. RESULTS: The results indicate a significant decrease in plasma glucose levels at all points of the cycle. Mean plasma glucose levels over 24 hours and mean plasma glucose levels during the fasting and the postprandial periods were significantly improved after treatment. In previous drug-naive patients, decrease in HbA1C was observed (1.0 +/- 1.1%, P=0.022). The acceptability was good, with no hypoglycemic events, and a high compliance with treatment was also observed. CONCLUSION: We can therefore conclude that gliclazide modified release, given once daily at breakfast, is effective over 24 hours in reducing plasma glucose levels in type 2 diabetes. This once-daily administration should lead to an optimal patient compliance with treatment.  (+info)

Acute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetes. (6/79)

The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 +/- 2 years, BMI 27.5 +/- 1.1 kg/m(2), fasting plasma glucose 9.8 +/- 0.8 mmol/l, HbA(1c) 7.5 +/- 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40-80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means +/- SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 +/- 0.9 vs. 7.8 +/- 0.6 mmol/l; placebo, 10.0 +/- 0.8 vs. 11.0 +/- 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 +/- 12.0 vs. 61.0 +/- 17.0 pmol. l(-1). pulse(-1); placebo, 36.1 +/- 8.4 vs. 30.3 +/- 7.4 pmol. l(-1). pulse(-1), P = 0.047; 5 weeks-elevated: gliclazide vs. placebo, 49.7 +/- 13.3 vs. 37.1 +/- 9.5 pmol. l(-1). pulse(-1), P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 +/- 2.2 vs. 16.7 +/- 4.3 pmol. l(-1). pulse(-1); placebo, 5.9 +/- 0.9 vs. 7.2 +/- 0.9 pmol. l(-1). pulse(-1), P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 +/- 2.5 vs. 9.4 +/- 2.1 pmol. l(-1). pulse(-1), P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between individual values for the acute improvement of regularity, as measured by ApEn, and the decrease in fasting plasma glucose during short-term (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coarse ApEn, respectively). In conclusion, the sulfonylurea agent gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity. The data suggest a possible relationship between the improvement in short-term glycemic control and the acute improvement of regularity of the in vivo insulin release process.  (+info)

ATP-Sensitive potassium channels modulate glucose transport in cultured human skeletal muscle cells. (7/79)

Several lines of evidence suggest that ATP-sensitive potassium (KATP) channels are involved in glucose uptake by insulin target tissues. The aim of the present study was to prove directly the effect of KATP channel activity on glucose transport into cultured human skeletal muscle cells. We used potassium channel openers PCO-400 and nicorandil alone or in combination with channel blockers glibenclamide and gliclazide to examine their effects on insulin- or high glucose concentration-induced glucose uptake using 2-deoxy-D-3H-glucose or 3-O-methyl-D-3H-glucose as tracer, respectively. PCO-400 inhibited the basal (non-stimulated) uptake of 2-DG or 3-OMG at the glucose concentration of 5 mM. PCO-400 and nicorandil dose-dependently inhibited insulin-stimulated glucose uptake, and their inhibitory effects were reversed by glibenclamide or gliclazide. In addition, PCO-400 inhibited high glucose concentration-facilitated glucose transport in the absence of insulin, and this effect was also antagonized by both sulfonylurea drugs. Regarding the mechanism by which KATP channels modulate glucose transport, we focused on protein kinase C (PKC), because PKC has been supposed to participate in both insulin- and high glucose concentration-stimulated glucose transport. PMA (phorbol 12-myristate 13-acetate) dose-dependently reversed the PCO-400-induced suppression of insulin-stimulated glucose uptake. On the other hand, PCO-400 at the concentration that inhibited glucose uptake caused no alteration of membrane-associated PKC activity in the presence of insulin or PMA. From these results we conclude that KATP channels modulate the basal and insulin-or high glucose level-stimulated glucose transport in skeletal muscle through a mechanism independent of PKC.  (+info)

Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes. (8/79)

To test the hypothesis that changes in the expression of the glucocorticoid receptor (GCR) and the beta(2)-adrenoceptor (beta(2)-AR) contribute significantly to the abnormal glucose metabolism in skeletal muscle from patients with Type II diabetes, we have examined (1) the levels of total GCR (alpha+beta isoforms), the alpha/alpha 2 isoform of GCR and beta(2)-AR mRNAs in skeletal muscle from insulin-resistant patients with Type II diabetes (n=10) and healthy controls (n=15), and (2) the effects of 8 weeks of intensive treatment on the whole-body glucose disposal rate and on total GCR, alpha/alpha 2 GCR and beta(2)-AR mRNA levels in diabetic patients. The total glucose disposal rate was measured by the euglycaemic hyperinsulinaemic (2 m-units x min(-1) x kg(-1)) clamp technique, and mRNA levels were assessed by reverse transcriptase-PCR and HPLC for separation of standard and unknown and quantification. Mean levels of total GCR and alpha/alpha 2 GCR mRNAs were increased in patients with Type II diabetes when compared with control subjects [total GCR, 2.06+/-0.30 and 1.47+/-0.10 amol/microg of total RNA respectively (P=0.09); alpha/alpha 2 GCR mRNA, 1.69+/-0.31 and 0.92+/-0.09 amol/microg of total RNA respectively (P=0.02)], whereas mRNA levels of the beta isoform of GCR (total GCR minus alpha/alpha 2 GCR) were decreased (P=0.006). beta(2)-AR mRNA levels were comparable in diabetic patients and control subjects (0.53+/-0.05 and 0.45+/-0.02 amol/microg of total RNA respectively; P=0.2). Intensive treatment for 8 weeks was associated with improved glycaemic control (P=0.019), and during the clamp a 75% (P=0.001) increase in the whole-body insulin-stimulated glucose disposal rate was demonstrated. Total GCR (P=0.005), alpha/alpha 2 GCR (P=0.005) and beta(2)-AR (P=0.03) mRNA levels all decreased significantly after intensive insulin treatment. A close correlation was found between increments in glucose uptake during intensive treatment and decrements in skeletal muscle total GCR mRNA (r=0.95, P<0.001; multiple regression analysis), and between glucose uptake and alpha/alpha 2 GCR m RNA levels (r=0.88, P<0.001; simple correlation). In conclusion, the abnormal regulation of GCR mRNA is likely to play a significant role in the insulin resistance observed in obese patients with Type II diabetes.  (+info)

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