Dataset Information

Effect of short-term prednisone on beta-cell function in subjects with type 2 diabetes mellitus and healthy subjects.

ABSTRACT: OBJECTIVE:For those with type 2 diabetes mellitus (T2DM), impact of short-term high-dose glucocorticoid exposure on beta-cell function is unknown. This study aims to compare the impact on beta-cell function and insulin resistance of prednisone 40 mg between adults with newly diagnosed T2DM and healthy adults. METHODS:Five adults with T2DM and five healthy adults, all between 18-50 years, were enrolled. T2DM diagnosis was less than one year prior, HbA1c<75 mmol/mol (9.0%), with metformin treatment only. Pre- and post-therapy testing included 75-g oral glucose tolerance, plasma glucose, C-peptide, and insulin. Intervention therapy was prednisone 40mg daily for 3 days. RESULTS:Upon therapy completion, HOMA-IR did not increase or differ between groups. Percentile difference for HOMA-%B and insulinogenic index in those with T2DM was significantly lower statistically (50.4% and 69.2% respectively) compared to healthy subjects (19% and 32.2%). CONCLUSIONS:Contrary to the assumption that insulin resistance is the main driver of glucocorticoid-induced hyperglycemia, results indicate that decreased beta-cell insulin secretion is the more likely cause in those with T2DM. This is evidenced by significant drops in C-peptide AUC and HOMA-%B and increased glucose AUC in T2DM group only. These results may be caused by increased beta-cell fragility along with reduced recovery ability after glucocorticoid exposure. ClinicalTrials.gov NCT03661684.

SUBMITTER: Shah M

PROVIDER: S-EPMC7199958 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of short-term prednisone on beta-cell function in subjects with type 2 diabetes mellitus and healthy subjects.

Shah Monica M Adel May M MM Tahsin Bettina B Guerra Yannis Y Fogelfeld Leon L

PloS one 20200505 5

<h4>Objective</h4>For those with type 2 diabetes mellitus (T2DM), impact of short-term high-dose glucocorticoid exposure on beta-cell function is unknown. This study aims to compare the impact on beta-cell function and insulin resistance of prednisone 40 mg between adults with newly diagnosed T2DM and healthy adults.<h4>Methods</h4>Five adults with T2DM and five healthy adults, all between 18-50 years, were enrolled. T2DM diagnosis was less than one year prior, HbA1c<75 mmol/mol (9.0%), with met ...[more]

PMID: 32369480

Similar Datasets

Project description:BackgroundGlucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7-14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose-response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism.MethodsIn this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5-60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8.ResultsDaily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects.ConclusionsThis characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile.Trial registration numberNCT02767089 (retrospectively registered: 21 April 2016).

Project description:In the recent years, short-term heart rate variability (HRV) describing complex variations of beat-to-beat interval series that are mainly controlled by the autonomic nervous system (ANS) has been increasingly analyzed to assess the ANS activity in different diseases and under various conditions. In contrast to long-term HRV analysis, short-term investigations (<30 min) provide a test result almost immediately. Thus, short-term HRV analysis is suitable for ambulatory care, patient monitoring and all those applications where the result is urgently needed. In a previous study, we could show significant variations of 5-min HRV indices according to age in almost all domains (linear and nonlinear) in 1906 healthy subjects from the KORA S4 cohort. Based on the same group of subjects, general gender-related influences on HRV indices are to be determined in this study. Short-term 5-min HRV indices from linear time and frequency domain and from nonlinear methods (compression entropy, detrended fluctuation analysis, traditional and segmented Poincaré plot analysis, irreversibility analysis, symbolic dynamics, correlation and mutual information analysis) were determined from 782 females and 1124 males. First, we examined the gender differences in two age clusters (25-49 years and 50-74 years). Secondly, we investigated the gender-specific development of HRV indices in five age decade categories, namely for ages 25-34, 35-44, 45-54, 55-64 and 65-74 years. In this study, significant modifications of the indices according to gender could be obtained, especially in the frequency domain and correlation analyses. Furthermore, there were significant modifications according to age in nearly all of the domains. The gender differences disappeared within the last two age decades and the age dependencies disappeared in the last decade. To summarize gender and age influences need to be considered when performing HRV studies even if these influences only partly differ.

Project description:BackgroundEffects of systemic corticosteroids on blood gene expression are largely unknown. This study determined gene expression signature associated with short-term oral prednisone therapy in patients with chronic obstructive pulmonary disease (COPD) and its relationship to 1-year mortality following an acute exacerbation of COPD (AECOPD).MethodsGene expression in whole blood was profiled using the Affymetrix Human Gene 1.1 ST microarray chips from two cohorts: 1) a prednisone cohort with 37 stable COPD patients randomly assigned to prednisone 30 mg/d + standard therapy for 4 days or standard therapy alone and 2) the Rapid Transition Program (RTP) cohort with 218 COPD patients who experienced AECOPD and were treated with systemic corticosteroids. All gene expression data were adjusted for the total number of white blood cells and their differential cell counts.ResultsIn the prednisone cohort, 51 genes were differentially expressed between prednisone and standard therapy group at a false discovery rate of < 0.05. The top 3 genes with the largest fold-changes were KLRF1, GZMH and ADGRG1; and 21 genes were significantly enriched in immune system pathways including the natural killer cell mediated cytotoxicity. In the RTP cohort, 27 patients (12.4%) died within 1 year after hospitalisation of AECOPD; 32 of 51 genes differentially expressed in the prednisone cohort significantly changed from AECOPD to the convalescent state and were enriched in similar cellular immune pathways to that in the prednisone cohort. Of these, 10 genes including CX3CR1, KLRD1, S1PR5 and PRF1 were significantly associated with 1-year mortality.ConclusionsShort-term daily prednisone therapy produces a distinct blood gene signature that may be used to determine and monitor treatment responses to prednisone in COPD patients during AECOPD.Trial registrationThe prednisone cohort was registered at clinicalTrials.gov ( NCT02534402 ) and the RTP cohort was registered at ClinicalTrials.gov ( NCT02050022 ).

Project description:Background and objectivesDorzagliatin is a first-in-class small molecule glucokinase activator (GKA) that improves pancreatic insulin secretion behavior and regulates hepatic glucose conversion in a glucose concentration-dependent manner. The primary objective of this study was to develop a population pharmacokinetic model of dorzagliatin to evaluate the influence of covariates, such as demographic characteristics and liver and kidney function, on the pharmacokinetics of dorzagliatin and provide a basis for medication guidance.MethodThe pharmacokinetic data of dorzagliatin in this study came from six clinical trials. Based on the combined data, a population pharmacokinetic model of dorzagliatin was established using NONMEM software (ICON, MD, USA, version 7.4.3). The algorithm used was first-order conditional estimation with interaction (FOCEI). The dorzagliatin population pharmacokinetic modeling analysis included 1062 subjects and 7686 observable concentrations. Covariates, including age (AGE), sex (GEND), body weight (TBW), body mass index (BMI), body surface area (BSA), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (CR), creatinine clearance (CRCL), and total bilirubin (TBIL), were screened using the forward-backward method. Model evaluation was performed using goodness-of-fit plots, prediction corrected visual prediction check (pcVPC), and bootstrap.ResultsConcentration data of dorzagliatin in the dose range were best characterized by a two-compartment model with sequential zero-order then first-order absorption and first-order elimination. The final model estimated dorzagliatin data for typical male subjects (69 kg body weight, 18 U/L AST and 55 years old); the apparent total clearance (CL/F) was 10.4 L/h, apparent volume of central compartment distribution (Vc/F) was 80.6 L, inter-compartmental clearance (Q/F) was 3.02 L/h, apparent volume of peripheral compartment distribution (Vp/F) was 26.5 L, absorption rate constant (Ka) was 3.29 h-1, and duration of zero-order absorption (D1) was 0.418 h. The inter-individual variation of CL/F, Vc/F, Vp/F, and D1 was 22.5%, 14.9%, 48.8%, and 82.8%, respectively.ConclusionThe two-compartment linear pharmacokinetic model with zero- and first-order sequential absorption adequately described the pharmacokinetic characteristics of dorzagliatin. Body weight, aspartate aminotransferase, and age had a statistically significant effect on the CL/F of dorzagliatin. Body weight and sex had a statistically significant effect on Vc/F. However, considering the clinically insignificant changes in the magnitude of steady-state exposure caused by these covariates, as well as the minimal changes in the steady-state exposure for individuals with mild and moderate impaired hepatic function and all stages of renal impairment, dose adjustments based on the tested covariates or for specific populations are deemed unnecessary.

Dataset Information

Effect of short-term prednisone on beta-cell function in subjects with type 2 diabetes mellitus and healthy subjects.

Publications

Effect of short-term prednisone on beta-cell function in subjects with type 2 diabetes mellitus and healthy subjects.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets