Entero-pancreatic hormone secretion, gastric emptying and glucose absorption after frequently sampled meal tests

Context Entero-pancreatic hormone secretion has been reported during the pre-absorptive cephalic and gastric meal phases, but never with a blood sampling frequency providing a temporal resolution that allows close scrutiny and correlations with gastric emptying and glucose-absorption. Objective We hypothesized that entero-pancreatic hormone secretion after nutrient ingestion would be rapid and correlate with gastric emptying and glucose absorption. Design and setting Two visits in a clinical research facility. Participants Ten healthy young men. Interventions A 75g glucose drink (OG) and a liquid mixed meal (LMM) were ingested (t 0-2 min) on separate days. Acetaminophen and 3-O-methyl-D-glucopyranose (3-OMG) were added to the drinks to evaluate gastric emptying and glucose absorption, respectively. Arterialized venous blood was sampled (t -30,-20,-18,-16,-14,-12,-10,-8,-6,-4,-2, 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30 min). Main outcome measures Plasma glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), gastrin, cholecystokinin (CCK), glucagon, pancreatic polypeptide (PP), 3-OMG and glucose. Serum insulin, C-peptide and acetaminophen. Results Acetaminophen increased 8min after OG(p<0.001) and LMM(p<0.05). 3-OMG; 8min after LMM(p<0.0001), 10min after OG(p=0.04). PP; 4min after LMM(p<0.03). Gastrin; 6min after LMM(p<0.003) and OG(p<0.003). CCK; 6min after LMM(p=0.0001). GIP; 8min after OG(p<0.05) and LMM(p<0.03). Glucose; 8min after OG(p<0.001), 12min after LMM(p<0.02). GLP-1; 12min after OG(p<0.01), 10min after LMM (p<0.01).. Insulin; 12min after LMM(p=0.02) and OG(p=0.002). C-peptide; 12min after OG(p=0.002) and LMM(p=0.04). Conclusions Early postprandial hormone responses show characteristic differences with regards to timing and amplitude, but also great individual differences. This should be considered when interpreting mean responses and designing study protocols. ClinicalTrials.gov number NCT03543423.

Managing clinical trials during COVID-19: experience from a clinical research facility

There is a dearth of literature on best practices for managing clinical trials, and little is understood on the role of the clinical trial manager. The COVID-19 pandemic has brought this into focus, and the continuance of clinical trials worldwide has been catapulted into a state of uncertainty as countries enter lockdown to manage the spread of the virus. Participant retention is an ongoing issue in clinical trials, and the concern is that in the current pandemic environment, attrition will be an issue which could potentially jeopardise trial completion. The current situation has necessitated timely problem solving by the trial manager to ensure trials remain open, and most importantly, that participant safety, paramount in clinical trials, is monitored. The purpose of our study is to highlight key issues arising in the management of clinical trials during a pandemic from first-hand experience in a clinical research facility managing both academic and commercial clinical trials. We offer some practical guidance on solution implementation.

Effects of Obesity And Insulin on Tissue-Specific Recycling Between Cortisol And Cortisone in Men

Context 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) reduces inert cortisone into active cortisol but also catalyzes reverse dehydrogenase activity. Drivers of cortisol/cortisone equilibrium are unclear. With obesity, 11βHSD1 transcripts are more abundant in adipose, but consequences for oxidation versus reduction remain unknown. Objective Determine whether 11βHSD1 equilibrium in metabolic tissues is regulated by insulin and obesity. Design Two-phase randomized crossover single-blinded study. Setting Clinical Research Facility. Participants Ten lean and obese healthy men. Main Outcome Measure(s) 11β-Reductase and 11β-dehydrogenase activities were measured during infusion of 9,11,12,12-[ 2H]4-cortisol and 1,2-[ 2H]2-cortisone, respectively, on two occasions, once during saline infusion and once during a hyperinsulinemic-euglycemic clamp. Arterialized and venous samples were obtained across forearm skeletal muscle and abdominal subcutaneous adipose. Steroids were quantified by liquid chromatography tandem mass spectrometry and adipose tissue transcripts by qPCR. Results Neither whole-body nor tissue-specific rates of production of cortisol or cortisone differed between lean and obese men, however insulin attenuated the diurnal decrease. Whole body 11β-HSD1 reductase activity tended to be higher in obesity (~10%) and was further increased by insulin. Across adipose tissue, 11β-reductase activity was detected in obese individuals only and increased in the presence of insulin (18.99±9.62 vs placebo 11.68±3.63 pmol/100g; p<0.05). Across skeletal muscle, 11β-dehydrogenase activity was reduced by insulin in lean men only (2.55±0.90 vs 4.50±1.42 pmol/100g, p<0.05). Conclusions Regeneration of cortisol is up-regulated by insulin in adipose tissue but not skeletal muscle. In obesity, the equilibrium between 11β-reductase and 11β-dehydrogenase activities likely promotes cortisol accumulation in adipose, which may lead to adverse metabolic consequences.

Effects of liraglutide and semaglutide on stroke subtypes in patients with type 2 diabetes: a post hoc analysis of the LEADER, SUSTAIN 6 and PIONEER 6 trials

Introduction Diabetes is an independent risk factor for stroke, with approximately a two-fold excess risk in people with versus those without diabetes. Accumulating evidence suggests glucagon-like peptide-1 (GLP-1) analogues (including liraglutide and semaglutide) may reduce the risk of stroke in patients with type 2 diabetes (T2D). Purpose We examined the effect of liraglutide and semaglutide on stroke and its subtypes based on pooled data from LEADER, SUSTAIN 6 and PIONEER 6. Methods LEADER (NCT01179048), SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) were global randomised cardiovascular (CV) outcomes trials of liraglutide, subcutaneous semaglutide and oral semaglutide, respectively, in patients with T2D at high CV risk. In this post hoc analysis, we evaluated the effect of these GLP-1 analogue treatments (pooled) on time to first occurrence of all strokes and subtypes of stroke. Ischaemic stroke was subcategorised according to the TOAST classification, based on aetiology by an external blinded reviewer. A Cox proportional hazards model stratified by trial with pooled treatment as a factor was used to examine treatment effects. Results Across the three trials, 216/7907 (2.7%) patients in the GLP-1 analogue group and 262/7913 (3.3%) in the placebo group had a stroke. The risk of first occurrence of all strokes was significantly reduced in the GLP-1 analogue versus placebo group (HR 0.82, 95% CI 0.68–0.98; p=0.030). Treatment effects were consistent across stroke subtypes: ischaemic (HR 0.84, 95% CI 0.69–1.02; p=0.08), haemorrhagic (HR 0.72, 95% CI 0.42–1.22; p=0.22) and undetermined (HR 0.71, 95% CI 0.32–1.60; p=0.41; Figure 1). Across TOAST subcategories, there was a trend that GLP-1 analogue treatment had the greatest benefit versus placebo in small vessel occlusion strokes compared with large artery disease or cardioembolic strokes; however, no statistically significant effects were found in any subcategory. Conclusion In this post hoc analysis of the LEADER, SUSTAIN 6 and PIONEER 6 trials, GLP-1 analogue treatment reduced the risk of stroke in patients with T2D and high CV risk, with an indication using TOAST criteria of the strongest effect on stroke caused by small vessel occlusion. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Novo Nordisk A/S. WDS is supported by the NIHR Exeter Clinical Research Facility. MAJ is supported by the NIHR SW Peninsula Applied Research Collaboration. This abstract does not necessarily reflect the views of the NIHR, the Exeter Clinical Research Facility, the NHS or the UK Department of Health.

Kisspeptin and neurokinin B interactions in modulating gonadotropin secretion in women with polycystic ovary syndrome

STUDY QUESTION What is the role of the hypothalamic neuropeptide neurokinin B (NKB) and its interaction with kisspeptin on GnRH/LH secretion in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Administration of neurokinin 3 receptor antagonist (NK3Ra) for 7 days reduced LH and FSH secretion and LH pulse frequency in women with PCOS, whilst the stimulatory LH response to kisspeptin-10 was maintained. WHAT IS KNOWN ALREADY PCOS is characterized by abnormal GnRH/LH secretion. NKB and kisspeptin are master regulators of GnRH/LH secretion, but their role in PCOS is unclear. STUDY DESIGN, SIZE, DURATION The NK3Ra MLE4901, 40 mg orally twice a day, was administered to women with PCOS for 7 days (n = 8) (vs no treatment, n = 7). On the last day of NK3Ra administration or the equivalent day in those not treated, women were randomized to 7-h kisspeptin-10 (4 µg/kg/h i.v.) or vehicle infusion. This was repeated with the alternate infusion in a subsequent cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS Subjects were women with PCOS, studied in a Clinical Research Facility. Reproductive hormones were measured before and after NK3Ra administration. On the last day of NK3Ra administration (or the equivalent cycle day in untreated women), all women attended for an 8-h frequent blood sampling to allow analysis of the pulsatile LH secretion. MAIN RESULTS AND THE ROLE OF CHANCE NK3Ra reduced LH secretion (4.0 ± 0.4 vs 6.5 ± 0.8 IU/l, P < 0.05) and pulse frequency (0.5 ± 0.1 vs 0.8 ± 0.1 pulses/h, P < 0.05); FSH secretion was also reduced (2.0 ± 0.3 vs 2.5 ± 0.4 IU/l, P < 0.05). Without NK3Ra pre-treatment, kisspeptin-10 increased LH secretion (5.2 ± 0.5 to 7.8 ± 1.0 IU/L, P < 0.05), with a positive relationship to oestradiol concentrations (r2 = 0.59, P < 0.05). After NK3Ra administration, the LH response to kisspeptin-10 was preserved (vehicle 3.5 ± 0.3 vs 9.0 ± 2.2 IU/l with kisspeptin-10, P < 0.05), but the positive correlation with oestradiol concentrations was abolished (r2 = 0.07, ns. after NK3Ra). FSH secretion was increased by kisspeptin-10 after NK3Ra treatment, but not without NK3Ra treatment. LIMITATIONS, REASONS FOR CAUTION The study did not explore the dose relationship of the effect of NK3R antagonism. The impact of obesity or other aspects of the variability of the PCOS phenotype was not studied due to the small number of subjects. WIDER IMPLICATIONS OF THE FINDINGS These data demonstrate the interactive regulation of GnRH/LH secretion by NKB and kisspeptin in PCOS, and that the NKB system mediates aspects of oestrogenic feedback. STUDY FUNDING/COMPETING INTEREST(S) Wellcome Trust through Scottish Translational Medicine and Therapeutics Initiative (102419/Z/13/A) and MRC grants (G0701682 to R.P.M. and R.A.A.) and MR/N022556/1 to the MRC Centre for Reproductive Health. This work was performed within the Edinburgh Clinical Research Facility. J.T.G. has undertaken consultancy work for AstraZeneca and Takeda Pharmaceuticals and is an employee of Boehringer Ingelheim. R.P.M. has consulted for Ogeda and was CEO of Peptocrine. R.A.A. has undertaken consultancy work for Merck, Ferring, NeRRe Therapeutics and Sojournix Inc. J.D.V. and K.S. have nothing to disclose. TRIAL REGISTRATION NUMBER N/A.

MON-589 Studying Mechanisms of Satiety in the Human Ileum and Colon

Background The gut-brain axis plays important roles in the regulation of appetite and glucose homeostasis. The presence of nutrients and their digestive products in specific regions of the gastrointestinal tract modulates neuronal and hormonal signalling, including the release of the appetite-suppressing gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). While there has been significant research into the upper gut mechanisms behind satiation, i.e. the termination of meal, the role of the ileum and colon in satiety, i.e. the process which delays a subsequent meal, has been relatively little investigated, particularly in humans. Methods Ten healthy volunteers attended our Clinical Research Facility for two visits of four days each. At each visit they had either a nasoileal or a nasocolonic tube inserted under fluoroscopy. They were then provided a diet rich in protein and fibre to promote satiety. Gut contents and blood samples were taken before and during test meals at the start and end of the visit, and visual analogue scales were used to measure subjective feelings of appetite. Metabonomic analysis of gut fluid was carried out using a combination of in-house NMR and LC-MS-based methods. 16S rRNA gene sequencing was used to investigate effects on the colonic microbiome. Circulating levels of glucose, the gut hormones GLP-1 and PYY, and the pancreatic hormones insulin and glucagon were measured. Results and discussion The test meals resulted in sustained suppression of appetite and release of GLP-1 and PYY. Ileal and colonic microbial profiles were distinct from those identified in stool samples, and changed with adaptation to the high protein and fibre diet. Integrating hormonal, metabonomic and bacterial datasets from these human studies gives insight into how nutrient and metabolite sensing in the gastrointestinal tract regulates appetite and glucose homeostasis, and may suggest novel therapeutic targets for metabolic disease.