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- Prystupa, Katsiaryna, et al.
(författare)
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Comprehensive validation of fasting-based and oral glucose tolerance test-based indices of insulin secretion against gold standard measures
- 2022
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Ingår i: BMJ Open Diabetes Research & Care. - : BMJ Publishing Group Ltd. - 2052-4897. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: With pre-diabetes and diabetes increasingly recognized as heterogeneous conditions, assessment of beta-cell function is gaining clinical importance to identify disease subphenotypes. Our study aims to comprehensively validate all types of surrogate indices based on oral glucose tolerance test (OGTT) and fasting measurements in comparison with gold standard methods.RESEARCH DESIGN AND METHODS: The hyperglycemic clamp extended with glucagon-like peptide 1 (GLP-1) infusion and intravenous glucose tolerance test (IVGTT), as well as OGTT, was performed in two well-phenotyped cohorts. The gold standard-derived indices were compared with surrogate insulin secretion markers, derived from fasting state and OGTT, using both Pearson's and Spearman's correlation coefficients. The insulin-based and C-peptide-based indices were analyzed separately in different groups of glucose tolerance and the entire cohorts.RESULTS: The highest correlation coefficients were found for area under curve (AUC) (I0-30)/AUC (G0-30), I30/G30, first-phase Stumvoll and Kadowaki model. These indices have high correlation coefficients with measures obtained from both insulin and C-peptide levels from IVGTT and hyperglycemic clamp. AUC (I0-120)/AUC (G0-120), BIGTT-AIR0-60-120, I30/G30, first-phase Stumvoll and AUC (I0-30)/AUC (G0-30) demonstrated the strongest association with incretin-stimulated insulin response.CONCLUSIONS: We have identified glucose-stimulated and GLP-1-stimulated insulin secretion indices, derived from OGTT and fasting state, that have the strongest correlation with gold standard measures and could be potentially used in future researches and clinical practice.
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| 2. |
- De Castelbajac, Thalia, et al.
(författare)
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Innovative tools and methods for toxicity testing within PARC work package 5 on hazard assessment
- 2023
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Ingår i: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 5
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Forskningsöversikt (refereegranskat)abstract
- New approach methodologies (NAMs) have the potential to become a major component of regulatory risk assessment, however, their actual implementation is challenging. The European Partnership for the Assessment of Risks from Chemicals (PARC) was designed to address many of the challenges that exist for the development and implementation of NAMs in modern chemical risk assessment. PARC's proximity to national and European regulatory agencies is envisioned to ensure that all the research and innovation projects that are initiated within PARC agree with actual regulatory needs. One of the main aims of PARC is to develop innovative methodologies that will directly aid chemical hazard identification, risk assessment, and regulation/policy. This will facilitate the development of NAMs for use in risk assessment, as well as the transition from an endpoint-based animal testing strategy to a more mechanistic-based NAMs testing strategy, as foreseen by the Tox21 and the EU Chemical's Strategy for Sustainability. This work falls under work package 5 (WP5) of the PARC initiative. There are three different tasks within WP5, and this paper is a general overview of the five main projects in the Task 5.2 'Innovative Tools and methods for Toxicity Testing,' with a focus on Human Health. This task will bridge essential regulatory data gaps pertaining to the assessment of toxicological prioritized endpoints such as non-genotoxic carcinogenicity, immunotoxicity, endocrine disruption (mainly thyroid), metabolic disruption, and (developmental and adult) neurotoxicity, thereby leveraging OECD's and PARC's AOP frameworks. This is intended to provide regulatory risk assessors and industry stakeholders with relevant, affordable and reliable assessment tools that will ultimately contribute to the application of next-generation risk assessment (NGRA) in Europe and worldwide.
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| 3. |
- Lupu, Diana, et al.
(författare)
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The ENDpoiNTs Project : Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:11
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Tidskriftsartikel (refereegranskat)abstract
- Ubiquitous exposure to endocrine-disrupting chemicals (EDCs) has caused serious concerns about the ability of these chemicals to affect neurodevelopment, among others. Since endocrine disruption (ED)-induced developmental neurotoxicity (DNT) is hardly covered by the chemical testing tools that are currently in regulatory use, the Horizon 2020 research and innovation action ENDpoiNTs has been launched to fill the scientific and methodological gaps related to the assessment of this type of chemical toxicity. The ENDpoiNTs project will generate new knowledge about ED-induced DNT and aims to develop and improve in vitro, in vivo, and in silico models pertaining to ED-linked DNT outcomes for chemical testing. This will be achieved by establishing correlative and causal links between known and novel neurodevelopmental endpoints and endocrine pathways through integration of molecular, cellular, and organismal data from in vitro and in vivo models. Based on this knowledge, the project aims to provide adverse outcome pathways (AOPs) for ED-induced DNT and to develop and integrate new testing tools with high relevance for human health into European and international regulatory frameworks.
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| 4. |
- 't Hart, Leen M., et al.
(författare)
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The CTRB1/2 Locus Affects Diabetes Susceptibility and Treatment via the Incretin Pathway
- 2013
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:9, s. 3275-3281
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Tidskriftsartikel (refereegranskat)abstract
- The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances -cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P 8.8 x 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 +/- 0.16% (5.6 +/- 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.
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