Search

Aims/hypothesis: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. Methods: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = −60, −30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0–60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = −60 min and t = 120 min. Results: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = −60 or −30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = −60 or −30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. Conclusions/interpretation: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. Trial registration: www.anzctr.org.au ACTRN12621000878875 Funding: The study was not funded by a specific research grant. [ABSTRACT FROM AUTHOR]

Background: Gastric emptying (GE), with wide inter-individual but lesser intra-individual variations, is a major determinant of postprandial glycaemia in health and type 2 diabetes (T2D). However, it is uncertain whether GE of a carbohydrate-containing liquid meal is predictive of the glycaemic response to physiological meals, and whether antecedent hyperglycaemia influences GE in T2D. We evaluated the relationships of (i) the glycaemic response to both a glucose drink and mixed meals with GE of a 75 g glucose drink, and (ii) GE of a glucose drink with antecedent glycaemic control, in T2D. Methods: Fifty-five treatment-naive Chinese adults with newly diagnosed T2D consumed standardised meals at breakfast, lunch and dinner with continuous interstitial glucose monitoring. On the subsequent day, a 75 g glucose drink containing 150 mg 13C-acetate was ingested to assess GE (breath test) and plasma glucose response. Serum fructosamine and HbA1c were also measured. Results: Plasma glucose incremental area under the curve (iAUC) within 2 hours after oral glucose was related inversely to the gastric half-emptying time (T50) (r = −0.34, P = 0.012). The iAUCs for interstitial glucose within 2 hours after breakfast (r = −0.34, P = 0.012) and dinner (r = −0.28, P = 0.040) were also related inversely to the T50 of oral glucose. The latter, however, was unrelated to antecedent fasting plasma glucose, 24-hour mean interstitial glucose, serum fructosamine, or HbA1c. Conclusions: In newly diagnosed, treatment-naive, Chinese with T2D, GE of a 75 g glucose drink predicts the glycaemic response to both a glucose drink and mixed meals, but is not influenced by spontaneous short-, medium- or longer-term elevation in glycaemia. [ABSTRACT FROM AUTHOR]

Objectives: Patients with hematological malignancies are prone to invasive fungal disease due to long-term chemotherapy or radiotherapy. Voriconazole is a second-generation triazole broad-spectrum antibiotic used to prevent or treat invasive fungal infections. Many population pharmacokinetic (pop PK) models have been published for voriconazole, and various diagnostic methods are available to validate the performance of these pop PK models. However, most of the published models have not been strictly evaluated externally. The purpose of this study is to evaluate these models externally and assess their predictive capabilities. Methods: The external dataset consists of adults receiving voriconazole treatment at Fujian Medical University Union Hospital. We re-established the published models based on their final estimated values in the literature and used our external dataset for initial screening. Each model was evaluated based on the following outcomes: prediction-based diagnostics, prediction- and variability-corrected visual predictive check (pvcVPC), normalized prediction distribution errors (NPDE), and Bayesian simulation results with one to two prior observations. Results: A total of 237 samples from 166 patients were collected as an external dataset. After screening, six candidate models suitable for the external dataset were finally obtained for comparison. Among the models, none demonstrated excellent predictive performance. Bayesian simulation shows that all models' prediction precision and accuracy were significantly improved when one or two prior concentrations were given. Conclusions: The published pop PK models of voriconazole have significant differences in prediction performance, and none of the models could perfectly predict the concentrations of voriconazole for our data. Therefore, extensive evaluation should precede the adoption of any model in clinical practice. [ABSTRACT FROM AUTHOR]