Comparison of the Effects of Three Insulinotropic Drugs on Plasma Insulin Levels After a Standard Meal

Lawrence S. Cozma, MRCP, Stephen D. Luzio, PHD, Gareth J. Dunseath, BSC, Kirsten W. Langendorg, MSC, Thomas Pieber and David R. Owens, MD, FRCP

Disclosures

Diabetes Care. 2002;25(8) 

In This Article

Research Design and Methods

This study was a randomized, double-blind, crossover trial performed at two centers, one in the U.K. and the second in Austria. A total of 12 diet-treated type 2 diabetic patients and 12 nondiabetic control subjects matched for age, sex, and weight were enrolled in the study. The Austrian center recruited four diabetic subjects. All healthy control subjects and eight diabetic patients were recruited in the U.K. center. All subjects gave written informed consent to participate in the trial. The study received approval of the local ethics committee and was conducted in accordance with the Declaration of Helsinki. The diabetic population recruited in our study had early type 2 diabetes with a mean HbA1c of 6.1% (laboratory normal range ≤6.4%). Eight patients had good control with HbA1c ≤6.5%, two had borderline control with HbA1c between 6.5 and 7.5%, and two had poor control with HbA1c >7.5%.

The treatment period started within 30 days after the screening visit and consisted of four visits with washout periods of 7-12 days between them. A follow-up visit was conducted 7-12 days after the last treatment day. The maximum duration of participation for each subject was 77 days from the first visit to the last visit.

After a 10-h overnight fast, an intravenous cannula was inserted and saline infusion was started. Each subject received placebo, 2 mg repaglinide, 5 mg glipizide, and 5 mg glibenclamide in a random fashion. Administration of the drug was followed 15 min later by a standard 500-kcal meal tolerance test (55% carbohydrate, 30% fat, and 15% protein). Blood sampling for glucose, insulin, and C-peptide was performed at -30, -20, -15, and 0 min before the meal. Postmeal samples were collected every 10 min during the first hour, every 15 min during the second hour, and hourly thereafter for a total of 4 h.

All specimens were centralized and processed in a single laboratory in the U.K. The samples were taken into fluoride-oxalate for assay of blood glucose (YSI 2300; YSI, Aldershot, Hants, U.K.). Blood samples for assay of insulin and C-peptide were taken into lithium heparin and centrifuged, and the plasma was stored at -20°C before assay. Insulin was measured by a specific immunoassay (MLT Research, Cardiff, S. Glam, U.K.) and the cross-reactivity of proinsulin in the insulin assay was <2%. C-peptide was measured by immunoassay (Dako Diagnostics, Ely, Cambs, U.K.), which cross-reacted < 2% with insulin and ~100% with proinsulin.

Data were analyzed using SAS 6.11 software on a UNIX platform. Metabolic parameters with a normal distribution are presented as means with SD or 95% CI. Nonnormally distributed data parameters are shown as median with minimum and maximum also given. Area under the curve (AUC) was calculated using the trapezoidal rule. Fasting levels for glucose, insulin, and C-peptide were calculated by averaging premeal values (-30, -20, -15, and 0 min). Insulin secretion was analyzed as early phase, terminal phase, and total insulin secretion by calculating insulin AUCs for the first 30 min, the last 120 min, and the total 240 min, respectively. AUC and the maximal plasma concentration (Cmax) were logarithmically transformed to obtain normally distributed data. The transformed end points were compared across groups using ANOVA for a crossover design accounting for sequence of treatment, subject (within a treatment sequence), visit (period), and treatment. Wilcoxon’s signed-rank test was used to compare the individual groups. To account for multiple comparisons, the Bonferroni method was applied. Using an overall level of significance of 0.05, the nominal level of significance was 0.05/3 = 0.02 with three comparisons.

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