Search

Aim: To evaluate sex differences in gastric emptying and the glycaemic response to a glucose drink and a high carbohydrate meal in type 2 diabetes (T2D). Methods: In cohort 1, 70 newly diagnosed, treatment‐naïve Chinese patients with T2D (44 men) recruited from a diabetes outpatient clinic ingested a 75‐g glucose drink containing 150 mg 13C‐acetate. In cohort 2, 101 Australian patients with T2D (67 male) recruited from the community, managed by diet and/or metformin monotherapy, ingested a semi‐solid mashed potato meal, labelled with 100 μl 13C‐octanoic acid. Breath samples were collected over 3 and 4 h, respectively, for assessment of gastric emptying, and venous blood was sampled for evaluation of glycaemia (with and without adjustment for each participant's estimated total blood volume). Results: Gastric emptying was slower in female than male subjects in both cohorts (both p <.01). Multiple linear regression analyses revealed that gastric emptying was independently associated with sex (both p <.05). Without adjustment for blood volume, the glycaemic responses to oral glucose and the mixed meal were greater in female subjects (both p <.001). However, after adjustment for blood volume, the glycaemic responses were greater in men (both p <.05). Conclusions: Gastric emptying is slower in women than men with T2D, associated with a reduced blood volume‐adjusted glycaemic response to oral glucose and a mixed meal in women. These observations highlight the sex difference in postprandial glucose handling, which is relevant to the personalized management of postprandial glycaemia in T2D. [ABSTRACT FROM AUTHOR]

Aim: To evaluate gastric emptying (GE) and the glycaemic response to a 75‐g oral glucose load in newly diagnosed, treatment‐naïve Han Chinese with type 2 diabetes (T2D) before insulin pump therapy, after 4 weeks of insulin pump therapy, and 12–15 months after insulin pump therapy. Materials and Methods: Twenty participants with T2D (baseline glycated haemoglobin [± SD] 10.7% [± 1.2%] 93 [± 10] mmol/mol) ingested a 75‐g glucose drink containing 150 mg 13C‐acetate, to determine the gastric half‐emptying time, and underwent assessment of plasma glucose and serum insulin, C‐peptide and glucagon‐like peptide‐1 (GLP‐1) over 180 min before and after 4 weeks of insulin pump therapy (discontinued for 48 h before re‐assessment). Data were compared to those in 19 healthy participants matched for sex and age. After 12–15 months, GE was re‐measured in 14 of the T2D participants. Results: At baseline, participants with T2D exhibited substantially augmented fasting and post‐glucose glycaemia, diminished insulin secretion, and more rapid GE (p < 0.05 each), but comparable GLP‐1, compared to healthy participants. Following insulin pump therapy, insulin secretion increased, GLP‐1 secretion was attenuated, fasting and post‐glucose glycaemia were lower, and GE was slowed (p < 0.05 each). The slowing of GE in T2D participants was sustained over 12–15 months of follow‐up. Conclusions: In newly diagnosed Han Chinese with T2D, GE is often accelerated despite poor glycaemic control and is slowed by short‐term insulin pump therapy. The effect on GE is maintained for at least 12 months. [ABSTRACT FROM AUTHOR]

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]

To achieve accurate deformation prediction and assess the temporal stability of surrounding rock in underground mines, this study utilizes the G-P algorithm to determine the optimal embedding dimension and time delay for the reconstructed phase space of the deformation time series. Analyzing the dynamic evolution of the nearest phase point and employing grey prediction theory in the phase space reconstruction, we predict the time series of surrounding rock deformation. Results indicate that the optimal embedding dimension and time delay for the deformation time series are 3. The larger the average distance of the nearest phase point, the more pronounced the chaotic characteristics of perimeter rock deformation, signifying a complex intrinsic dynamical system. The grey theory proves effective in short-term, accurate deformation prediction for perimeter rock. Additionally, the identified stability of perimeter rock based on neighboring phase points and deformation prediction results offers a novel approach for evaluating surrounding rock stability in underground mining processes. [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]

Currently, numerous population pharmacokinetic (popPK) models for methotrexate (MTX) have been published for estimating PK parameters and variability. However, it is unclear whether the accuracy of these models is sufficient for clinical application. The aim of this study is to evaluate published models and assess their predictive performance according to the standards of scientific research. A total of 237 samples from 74 adult patients who underwent high‐dose MTX (HDMTX) treatment at Shanghai Changzheng Hospital were collected. The software package NONMEM was used to perform an external evaluation for each model, including prediction‐based diagnosis, simulation‐based diagnosis, and Bayesian forecasting. The simulation‐based diagnosis includes normalized prediction distribution error (NPDE) and visual predictive check (VPC). Following screening, 7 candidate models suitable for external validation were identified for comparison. However, none of these models exhibited excellent predictive performance. Bayesian simulation results indicated that the prediction precision and accuracy of all models significantly improved when incorporating prior concentration information. The published popPK models for MTX exhibit significant differences in their predictive performance, and none of the models were able to accurately predict MTX concentrations in our data set. Therefore, before adopting any model in clinical practice, extensive evaluation should be conducted. [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]

Aim: To determine the serum bile acid (BA) response to 75‐g oral glucose in individuals without diabetes, and whether this is attenuated in patients with 'early' type 2 diabetes (T2D) and related to the glycaemic response at 2 hours in either group. Methods: Forty newly diagnosed, treatment‐naïve Han Chinese T2D subjects and 40 age‐, gender‐, and body mass index‐matched controls without T2D ingested a 75‐g glucose drink after an overnight fast. Plasma glucose and serum concentrations of total and individual BAs, fibroblast growth factor‐19 (FGF‐19), total glucagon‐like peptide‐1 (GLP‐1), and insulin, were measured before and 2 hours after oral glucose. Results: Fasting total BA levels were higher in T2D than control subjects (P <.05). At 2 hours, the BA profile exhibited a shift from baseline in both groups, with increases in conjugated BAs and/or decreases in unconjugated BAs. There were increases in total BA and FGF‐19 levels in control (both P <.05), but not T2D, subjects. Plasma glucose concentrations at 2 hours related inversely to serum total BA levels in control subjects (r = −0.42, P =.006). Total GLP‐1 and the insulin/glucose ratio were increased at 2 hours in both groups, and the magnitude of the increase was greater in control subjects. Conclusions: The serum BA response to a 75‐g oral glucose load is attenuated in patients with 'early' T2D, as is the secretion of FGF‐19 and GLP‐1, while in individuals without T2D it correlates with 2‐hour plasma glucose levels. These observations support a role for BAs in the regulation of postprandial glucose metabolism. [ABSTRACT FROM AUTHOR]

Busulfan is a bifunctional alkylating agent that is widely used before hematopoietic stem cell transplantation (HSCT), in combination with other chemotherapeutic drugs. As of 2020, there is no population pharmacokinetic (popPK) model for busulfan in Chinese pediatric patients. A systemic external evaluation of 11 published popPK models was conducted in Chinese pediatric patients undergoing HSCT. Forty pediatric patients were enrolled in this study, with a total of 183 blood concentrations. The relative prediction error (PE%), median PE%, median absolute PE%, and percentage of PE% within ±20% and ±30% were calculated in prediction‐based diagnostics. Simulation‐based diagnostics were conducted through a prediction‐ and variability‐corrected visual predictive check and the normalized prediction distribution error. The relative individual prediction error was calculated using Bayesian forecasting with 1 to 3 concentration points. The 1‐compartment open linear popPK model, which was built by Su‐jin Rhee et al (model H), incorporating the patient's body surface area, age, dosing day, and aspartate aminotransferase as significant covariates had preferable predictability than other popPK models. In prediction‐based diagnostics, the median PE%, percentage of PE% within ±20%, and percentage of PE% within ±30% of model H were 8.48%, 45.35%, and 59.56%, respectively. The normalized prediction distribution error of model H showed that it followed the normal distribution. Based on Bayesian forecasting, model H showed good predictive performance. Thus, model H was the most appropriate model that can be used clinically for individualized dosage adjustments in Chinese pediatric HSCT patients. [ABSTRACT FROM AUTHOR]

Context: Both gastric emptying and the secretion of glucagon-like peptide-1 (GLP-1) are major determinants of postprandial glycemia in health and type 2 diabetes (T2D). GLP-1 secretion after a meal is dependent on the entry of nutrients into the small intestine, which, in turn, slows gastric emptying. Objective: To define the relationship between gastric emptying and the GLP-1 response to both oral and small intestinal nutrients in subjects with and without T2D. Methods: We evaluated: (i) the relationship between gastric emptying (breath test) and postprandial GLP-1 levels after a mashed potato meal in 73 individuals with T2D; (ii) interindividual variations in GLP-1 response to (a) intraduodenal glucose (4 kcal/min) during euglycemia and hyperglycemia in 11 healthy and 12 T2D, subjects, (b) intraduodenal fat (2 kcal/min) in 15 T2D subjects, and (c) intraduodenal protein (3 kcal/min) in 10 healthy subjects; and (iii) the relationship between gastric emptying (breath test) of 75 g oral glucose and the GLP-1 response to intraduodenal glucose (4 kcal/min) in 21 subjects (9 healthy, 12 T2D). Results: The GLP-1 response to the mashed potato meal was unrelated to the gastric half-emptying time (T50). The GLP-1 responses to intraduodenal glucose, fat, and protein varied substantially between individuals, but intra-individual variation to glucose was modest. The T50 of oral glucose was related directly to the GLP-1 response to intraduodenal glucose (r = 0.65, P = 0.002). Conclusion: In a given individual, gastric emptying is not a determinant of the postprandial GLP-1 response. However, the intrinsic gastric emptying rate is determined in part by the responsiveness of GLP-1 to intestinal nutrients. [ABSTRACT FROM AUTHOR]

Calcium ions (Ca2+) take part in intra‐ and inter‐cellular signaling to mediate cellular functions. Sensing this ubiquitous messenger is instrumental in disentangling the specific functions of cellular sub‐compartments and/or intercellular communications. In this review, the authors first describe intra‐ and inter‐cellular Ca2+ signaling in relation to insulin secretion from the pancreatic islets, and then outline the development of diverse sensors, for example, chemically synthesized indicators, genetically encoded proteins, and ion‐selective microelectrodes, for intra‐ and extra‐cellular sensing of Ca2+. Particular emphasis is placed on emerging approaches in this field, such as low‐affinity Ca2+ indicators and unique Ca2+‐responsive composite materials. The authors conclude by remarking on the challenges and opportunities for further developments in this field, which may facilitate a more comprehensive understanding of Ca2+ signaling within and outside the islets, and its relevance in health and disease. [ABSTRACT FROM AUTHOR]

Local activation of an anti-cancer drug when and where needed can improve selectivity and reduce undesirable side effects. Photoswitchable drugs can be selectively switched between active and inactive states by illumination with light; however, the clinical development of these drugs has been restricted by the difficulty in delivering light deep into tissue where needed. Optical fibres have great potential for light delivery in vivo, but their use in facilitating photoswitching in anti-cancer compounds has not yet been explored. In this paper, a photoswitchable chemotherapeutic is switched using an optical fibre, and the cytotoxicity of each state is measured against HCT-116 colorectal cancer cells. The performance of optical-fibre-enabled photoswitching is characterised through its dose response. The UV–Vis spectra confirm light delivered by an optical fibre effectively enables photoswitching. The activated drug is shown to be twice as effective as the inactive drug in causing cancer cell death, characterised using an MTT assay and fluorescent microscopy. This is the first study in which a photoswitchable anti-cancer compound is switched using an optical fibre and demonstrates the feasibility of using optical fibres to activate photoswitchable drugs for potential future clinical applications. [ABSTRACT FROM AUTHOR]

Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders. [ABSTRACT FROM AUTHOR]