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Objective: Changes in eye protrusion in patients treated with pioglitazone., Design: Open-label prospective., Patients: Thirty-six patients with type 2 diabetes and HbA1c >or= 6.5% were included in a study where pioglitazone was added to current therapy with metformin and sulphonylurea., Measurements: The degree of eye protrusion before and 26 weeks after treatment with pioglitazone was measured using Krahn's exophthalmometer., Results: Thirteen patients (group A) exhibited an increase of >or= 2 mm and 23 patients (group B) exhibited an increase of < 2 mm (P (between groups) = 0.036). Patients of group A vs. group B had the same BMI, HbA1c and mean doses of pioglitazone, but had lower levels (mean +/- SD) of adiponectin in microg/ml at the start (4.9 +/- 2.1) vs. (7.1 +/- 2.5), P = 0.017 and at the end of study (10.2 +/- 4) vs. (14.9 +/- 5), P = 0.007. Patients with thyroid disturbance were more frequent in group A (five vs. one), P = 0.02. In a logistic regression analysis, thyroid disturbance, low adiponectin levels and pioglitazone dose predicted a significant change in eye protrusion., Conclusions: A subgroup of patients with type 2 diabetes treated with pioglitazone responded with increased eye protrusion. This subgroup showed decreased plasma concentration of adiponectin and more frequent thyroid disturbance, and was treated with higher doses of pioglitazone. The relationship between insulin resistance, thyroid disturbance and thiazolidinedione-induced eye protrusion should be further studied.

Objective: To study the effects and serum levels of glibenclamide (Gb) and its active metabolites in patients on chronic Gb medication on different daily doses., Material and Methods: Fifty patients with type 2 diabetes on regular Gb therapy (1.75-14.0 mg daily). Blood samples were taken immediately before and 90 min after regular Gb intake. A standardized breakfast was served 30 min after drug intake. Serum insulin and proinsulin levels were determined by ELISA methods without cross-reactivities. Serum drug levels were determined by HPLC. Fischer's R to Z-test (correlation coefficients) and paired Student t-tests were used when comparing values within the entire group and unpaired non-parametric Mann-Whitney tests were used when comparing high and low dose levels. A p-value < 0.05 was considered significant., Results: There were significant correlations between daily Gb dose, on the one hand, and, on the other, HbAlc (r = 0.55), Delta-insulin (r = - 0.59) and Delta-proinsulin (r = - 0.52) levels. Significant correlations between Gb therapy duration and insulin (r = - 0.40) and proinsulin (r = - 0.34) secretion and between Gb dose and ratio proinsulin/insulin (RPI) at both time points (r = 0.32 and 0.30) were also found. The RPI was lower after Gb intake. In patients on > or = 10.5 mg steady state serum metabolite levels (Ml and Ml + M2) were higher (29(0-120) and 33 (0-120) ng/ml) than those of Gb itself (18(0-64) ng/ml). A great inter-subject variability in Gb levels at both time points was seen., Conclusions: Our results indicate that, in patients on chronic medication, Gb is capable of stimulating both insulin and proinsulin secretion; the effect on insulin release is relatively greater. The effect was more pronounced in patients on a low Gb dose, either because of less impaired beta-cells in those receiving low doses, or due to reduced sulphonylurea sensitivity in those on high dosage (down-regulation). In patients on a daily dose of 10.5 mg or more, serum metabolite levels of clinical relevance were demonstrated; the metabolites may contribute to hypoglycaemic events.

The effects and kinetics of oral glibenclamide (Gb) and glipizide (Gz) were studied in Caucasian and Chinese patients (ten in each group) with type-2 diabetes. In randomised order, 2.5 mg Gb, 2.5 mg Gz or placebo was given orally before the administration of 75 g oral glucose. Concentrations of insulin and proinsulin were determined using radioimmunoassay (RIA) without cross-reactivities, and sulphonylurea concentrations were determined using high-performance liquid chromatography (HPLC). There were no significant interethnic differences in Gb or Gz effects whether on glucose, insulin or proinsulin/insulin ratio at any time point. Following Gz, however, Chinese patients had greater increments of serum proinsulin at 10-30 min compared with Caucasians. Apart from the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of Gz being higher among the Chinese, no significant interethnic differences in pharmacokinetics were found. It appears that the same dosage principles could be used for Caucasian and Chinese patients with type-2 diabetes when Gb or Gz are prescribed.

Objective: We analysed the kinetics and effects of glibenclamide (Gb) on glucose, insulin and proinsulin secretion in two ethnic groups (10 in each) of type-2 diabetic patients, one of Caucasian, the other of Chinese origin., Background: Diabetes mellitus type 2 is a global disease affecting all ethnic groups. There are ethnic differences in both the prevalence and metabolic characteristics of the disease. Important interethnic pharmacodynamic and pharmacokinetic differences have been reported for several drugs. With few exceptions, detailed studies on sulphonylurea are lacking., Material and Methods: The patients were studied on two occasions when either no Gb (control) or 1.25 mg Gb was administered i.v., immediately before the administration of a 75-g oral glucose tolerance test. Concentrations of insulin and proinsulin were determined by means of radioimmunoassay without cross-reactivities. Gb concentration was determined using high-performance liquid chromatography. Pharmacodynamic results were calculated using net areas under the curves, with basal values set as zero. A P value less than 0.05 was considered significant., Results: When glucose was administered orally without Gb, Chinese patients had higher plasma glucose increases at 10 min (7.6 mmol/l x min vs 2.6 mmol/l x min) and higher increases of plasma insulin levels than Caucasians at both 10 min (198 pmol/l x min vs 54 pmol/l x min) and 30 min (2286 pmol/l x min vs 1198 pmol/l x min). When Gb was administered, the plasma glucose increases were reduced, and the increases of serum insulin and proinsulin levels were greater in both ethnic groups. Compared with the basal values (-1 min), proinsulin/insulin ratios (RPI) were lowest at 10-30 min, followed by an increase. Chinese patients had higher increases of serum insulin levels at 10 min (1109 pmol/l x min vs 550 pmol/l x min) and a lower RPI at 30 min (6. 0% vs 7.6%) and 240 min (15.0% vs 21.0%) relative to Caucasians. Serum Gb data were best fitted to a biexponential i.v. model. There were no interethnic differences in any of the pharmacokinetic parameters., Conclusion: In summary, following oral glucose administration without Gb, Chinese type-2 diabetic patients had higher plasma insulin levels but also higher plasma glucose levels during the first 10 min, which might reflect reduced insulin sensitivity or more rapid glucose absorption. Gb augmented glucose-induced release of both insulin and proinsulin in both ethnic groups; the effect on insulin secretion was more pronounced. In conclusion, minor pharmacodynamic but no pharmacokinetic differences were found between the two groups. It seems appropriate to employ the same dosage principles when using Gb in Caucasians and Chinese.

Objective: To determine the terminal elimination half-life of glyburide in non-insulin-dependent diabetes mellitus (NIDDM) subjects after cessation of long-term treatment., Research Design and Methods: Ten NIDDM patients (5 of each sex, 36-72 years old, without hepatic or renal disease) taking a median glyburide dose of 14 mg/day, who were to start insulin therapy because of sulfonylurea failure, were studied. Serum glyburide concentrations, measured by a newly developed selective and sensitive liquid chromatographic method, were followed from 10 to 48 h after the last glyburide dose., Results: Serum glyburide levels declined in three different phases, with a terminal gamma-phase between 18 and 48 h having a mean +/- SD half-life of 15.0 +/- 6.7 h. Two patients had half-lives over 20 h. The half-life values did not correlate with fasting blood glucose, age, body weight, body mass index, or creatinine levels. The latter agrees with the assumption that glyburide is completely eliminated by metabolic transformation. Although longer than previously observed, the current half-life values are in accordance with clinical experience that glyburide is a long-acting sulfonylurea., Conclusions: The elimination of glyburide in NIDDM subjects is slower than previously reported. The long half-life adds support to the use of a once-daily dosage of glyburide. It also justifies increased caution when using this sulfonylurea.