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Context: The enterohepatic circulation of bile acids depends on intestinal absorption by bile acid transporters and activation of bile acid receptors, which stimulates secretion of hormones regulating glucose and lipid metabolism and appetite. Distribution of bile acid transporters and receptors in the human gut and their potential involvement in type 2 diabetes (T2D) pathophysiology remain unknown., Objective: We explored the expression of genes involved in bile acid metabolism throughout the intestines of patients with T2D and matched healthy controls., Methods: Intestinal mucosa biopsies sampled along the intestinal tract in 12 individuals with T2D and 12 healthy controls were subjected to mRNA sequencing. We report expression profiles of apical sodium-dependent bile acid transporter (ASBT), organic solute transporter (OST) α/β, farnesoid X receptor (FXR), Takeda G receptor 5 (TGR5), fibroblast growth factor 19 (FGF19) and FGF receptor 4 (FGFR4)., Results: Expression of ASBT and OSTα/β was evident in the duodenum of both groups with increasing levels through the small intestine, and no (ASBT) or decreasing levels (OSTα/β) through the large intestine. The FXR expression pattern followed that of OSTα/β whereas FGFR4 were evenly expressed through the intestines. Negligible levels of TGR5 and FGF19 were evident. Patients with T2D exhibited lower levels of FGF19, FXR, ASBT and OSTα/β mRNAs compared with healthy controls, although the differences were not statistically significant after adjusting for multiple testing., Conclusions: We demonstrate distinct expression patterns of bile acid transporters and receptors through the intestinal tract with signs of reduced ASBT, OSTα/β, FXR and FGF19 mRNAs in T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: The hormone secretin (SCT) is released from intestinal S cells and acts via the SCT receptor (SCTR). Circulating SCT levels increase after Roux-en-Y gastric bypass surgery and have been associated with massive weight loss and high remission rates of type 2 diabetes (T2D) linked to these operations. Exogenous SCT was recently shown to reduce ad libitum food intake in healthy volunteers., Objective: To understand SCT biology and its potential role in T2D pathophysiology, we examined the intestinal mucosal expression profile of SCT and SCTR and evaluated the density of S cells along the intestinal tract of individuals with T2D and healthy controls., Methods: Using immunohistochemistry and messenger RNA (mRNA) sequencing, we analyzed intestinal mucosa biopsies sampled along the small intestine at 30-cm intervals and from 7 well-defined anatomical sites along the large intestine (during 2 sessions of double-balloon enteroscopy) in 12 individuals with T2D and 12 healthy controls., Results: Both groups exhibited a progressive and similar decrease in SCT and SCTR mRNA expression and S-cell density along the small intestine, with reductions of 14, 100, and 50 times, respectively, in the ileum compared to the duodenum (used as reference). Negligible amounts of SCTR and SCT mRNA, as well as low S-cell density, were found in the large intestine. No significant differences were observed between the groups., Conclusion: SCT and SCTR mRNA expression and S-cell density were abundant in the duodenum and decreased along the small intestine. Very low SCT and SCTR mRNA levels and S-cell numbers were observed in the large intestine, without aberrations in individuals with T2D compared to healthy controls., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: People with human immunodeficiency virus (PWH) have an increased risk of chronic lung diseases and chronic inflammation. We aimed to investigate if inflammatory markers and monocyte activation are associated with faster lung function decline in PWH., Methods: We included 655 PWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study. Eligible participants were aged ≥25 years and had 2 spirometries separated by >2 years. Inflammatory markers (interleukin [IL]-1β, IL-2, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ) were measured at baseline by Luminex, and soluble CD14 and soluble CD163 by enzyme-linked immunosorbent assay. Using linear mixed models, we investigated whether elevated cytokine levels were associated with faster lung function decline., Results: The majority of PWH were males (85.2%) with undetectable viral replication (95.3%). We found a faster decline in forced expiratory volume in 1 second (FEV1) in PWH with elevated IL-1β and IL-10, with an additional decline of 10.3 mL/year (95% confidence interval [CI], 2.1-18.6; P = .014) and 10.0 mL/year (95% CI, 1.8-18.2; P = .017), respectively. We found no interaction between smoking and IL-1β or IL-10 on FEV1 decline., Conclusions: Elevated IL-1β and IL-10 were independently associated with faster lung function decline in PWH, suggesting that dysregulated systemic inflammation may play a role in the pathogenesis of chronic lung diseases., Competing Interests: Potential conflicts of interest. R. F. T. has received a travel grant from Gilead. J. V. has received personal fees from ALK, AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, and Teva for advising/presenting. K. M. K. has received personal fees for data and safety monitoring board activities from Nuvaira and Organicell and for consulting from Allergan/AbbVie. S. D. N. has received a research grant from the Novo Nordisk Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Enteroendocrine N cells secrete neurotensin (NTS). NTS reduces food intake in rodents and may increase insulin release. In humans, postprandial NTS responses increase following Roux-en-Y gastric bypass, associating the hormone with the glucose- and body weight-lowering effects of these procedures., Objective: We looked at N cell density and mucosal messenger RNA (mRNA) expression profiles of NTS and NTS receptors in type 2 diabetes (T2D) patients and healthy controls., Methods: Using double-balloon enteroscopy, 12 patients with T2D and 12 sex-, age-, and body mass index-matched healthy controls had mucosa biopsies taken from the entire length of the small intestine (at 30-cm intervals) and from 7 anatomically well-defined locations in the large intestine. Biopsies were analyzed using immunohistochemistry and mRNA sequencing., Results: N cell density and NTS mRNA expression gradually increased from the duodenum to the ileum, while negligible NTS-positive cells and NTS mRNA expression were observed in the large intestine. NTS receptor 1 and 2 mRNA expression were not detected, but sortilin, a single-pass transmembrane neuropeptide receptor of which NTS also is a ligand, was uniformly expressed in the intestines. Patients with T2D exhibited lower levels of NTS-positive cells and mRNA expression than healthy controls, but this was not statistically significant after adjusting for multiple testing., Conclusion: This unique intestinal mapping of N cell density and NTS expression shows increasing levels from the small intestine's proximal to distal end (without differences between patients with T2D and healthy controls), while negligible N-cells and NTS mRNA expression were observed in the large intestine. Sortilin was expressed throughout the intestines in both groups; no NTS receptor 1 or 2 mRNA expression were detected., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Gastrointestinal-mediated glucose disposal (GIGD) during oral glucose tolerance test (OGTT) reflects the percentage of glucose disposal caused by mechanisms elicited by the oral route of glucose administration. GIGD is reduced in patients with type 2 diabetes (T2D) due to a reduced incretin effect and possibly also due to inappropriate suppression of glucagon after oral glucose. We investigated the effect of glucagon receptor antagonism on GIGD, the incretin effect and glucose excursions in patients with T2D and controls without diabetes., Design: A double-blind, randomised, placebo-controlled crossover study was conducted., Methods: Ten patients with T2D and 10 gender-, age- and BMI-matched controls underwent two 50 g OGTTs and 2 isoglycaemic i.v. glucose infusions, succeeding (~10 h) single-dose administration of 100 mg of the glucagon receptor antagonist LY2409021 or placebo, respectively., Results: Compared to placebo, LY2409021 reduced fasting plasma glucose in patients with T2D and controls. Plasma glucose excursions after oral glucose assessed by baseline-subtracted area under the curve were increased by LY2409021 compared to placebo in both groups, but no effect of LY2409021 on GIGD or the incretin effect was observed. LY2409021 increased fasting glucagon concentrations three-fold compared to placebo concentrations., Conclusions: Glucagon receptor antagonism with LY2409021 had no effect on the impaired GIGD or the impaired incretin effect in patients with T2D and did also not affect these parameters in the controls. Surprisingly, we observed reduced oral glucose tolerance with LY2409021 which may be specific for this glucagon receptor antagonist.

Objective: Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate the consequences of hyperglucagonemia in T2D., Design: A double-blinded, randomized, placebo-controlled crossover study was conducted., Methods: Ten patients with T2D and ten matched non-diabetic controls underwent two liquid mixed meal tests preceded by single-dose administration of LY2409021 (100 mg) or placebo. Double-tracer technique was used to quantify EGP. Antagonist selectivity toward related incretin receptors was determined in vitro., Results: Compared to placebo, LY2409021 lowered the fasting plasma glucose (FPG) from 9.1 to 7.1 mmol/L in patients and from 5.6 to 5.0 mmol/L in controls (both P < 0.001) by mechanisms involving reduction of EGP. Postprandial plasma glucose excursions (baseline-subtracted area under the curve) were unaffected by LY2409021 in patients and increased in controls compared to placebo. Glucagon concentrations more than doubled during glucagon receptor antagonism. The antagonist interfered with both glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptors, complicating the interpretation of the postprandial data., Conclusions: LY2409021 lowered FPG concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors.

Background: Central nervous system (CNS) tumors cause the highest death rates among childhood cancers, and survivors frequently have severe late effects. Magnetic resonance imaging (MRI) is the imaging modality of choice, but its specificity can be challenged by treatment-induced signal changes. In adults, O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) PET can assist in interpreting MRI findings. We assessed the clinical impact and diagnostic accuracy of adding [18F]FET PET to MRI in children with CNS tumors., Methods: A total of 169 [18F]FET PET scans were performed in 97 prospectively and consecutively included patients with known or suspected childhood CNS tumors. Scans were performed at primary diagnosis, before or after treatment, or at relapse., Results: Adding [18F]FET PET to MRI impacted clinical management in 8% [95% confidence interval (CI): 4%-13%] of all scans (n = 151) and in 33% [CI: 17%-53%] of scans deemed clinically indicated due to difficult decision making on MRI alone (n = 30). Using pathology or follow-up as reference standard, the addition of [18F]FET PET increased specificity (1.00 [0.82-1.00] vs 0.48 [0.30-0.70], P = .0001) and accuracy (0.91 [CI: 0.87-0.96] vs 0.81 [CI: 0.75-0.89], P = .04) in 83 treated lesions and accuracy in 58 untreated lesions (0.96 [CI: 0.91-1.00] vs 0.90 [CI: 0.82-0.92], P < .001). Further, in a subset of patients (n = 15) [18F]FET uptake correlated positively with genomic proliferation index., Conclusions: The addition of [18F]FET PET to MRI helped discriminate tumor from non-tumor lesions in the largest consecutive cohort of pediatric CNS tumor patients presented to date., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Increased potassium intake lowers blood pressure (BP) in hypertensive patients. The underlying mechanism is not fully understood but must be complex because increased potassium intake elevates circulating concentrations of the BP-raising hormone aldosterone., Methods: In a randomized placebo-controlled crossover study in 25 normotensive men, we investigated the effect of 4 weeks of potassium supplement (90 mmol/day) compared with 4 weeks of placebo on the renin-angiotensin-aldosterone system (RAAS), urine composition and 24-h ambulatory BP. Vascular function was also assessed through wire myograph experiments on subcutaneous resistance arteries from gluteal fat biopsies., Results: Higher potassium intake increased urinary potassium excretion (144.7 ± 28.7 versus 67.5 ± 25.5 mmol/24-h; P < 0.0001) and plasma concentrations of potassium (4.3 ± 0.2 versus 4.0 ± 0.2 mmol/L; P = 0.0002), renin {mean 16 [95% confidence interval (CI) 12-23] versus 11 [5-16] mIU/L; P = 0.0047}, angiotensin II [mean 10.0 (95% CI 6.2-13.0) versus 6.1 (4.0-10.0) pmol/L; P = 0.0025] and aldosterone [mean 440 (95% CI 336-521) versus 237 (173-386) pmol/L; P < 0.0001]. Despite RAAS activation, systolic BP (117.6 ± 5.8 versus 118.2 ± 5.2 mmHg; P = 0.48) and diastolic BP (70.8 ± 6.2 versus 70.8 ± 6.3 mmHg; P = 0.97) were unchanged. In the wire myograph experiments, higher potassium intake did not affect endothelial function as assessed by acetylcholine [logarithmically transformed half maximal effective concentration (pEC50): 7.66 ± 0.95 versus 7.59 ± 0.85; P = 0.86] and substance P (pEC50: 8.42 ± 0.77 versus 8.41 ± 0.89; P = 0.97) or vascular smooth muscle cell reactivity as assessed by angiotensin II (pEC50: 9.01 ± 0.86 versus 9.02 ± 0.59; P = 0.93) and sodium nitroprusside (pEC50: 7.85 ± 1.07 versus 8.25 ± 1.32; P = 0.25) but attenuated the vasodilatory response of retigabine (pEC50: 7.47 ± 1.16 versus 8.14 ± 0.90; P = 0.0084), an activator of Kv7 channels., Conclusions: Four weeks of increased potassium intake activates the RAAS in normotensive men without changing BP and this is not explained by improved vasodilatory responses ex vivo., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Context: After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1)., Objective: To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut., Design and Setting: Substudy of a prospective cross-sectional study at a university hospital in Copenhagen, Denmark., Participants: Morbidly obese individuals undergoing RYGB (n = 8) with or without type 2 diabetes., Interventions: Three months before and after RYGB, participants underwent upper enteroscopy with retrieval of gastrointestinal mucosal biopsy specimens. Mixed-meal tests were performed 1 week and 3 months before and after RYGB., Main Outcome Measures: The 29-amino acid glucagon concentrations in plasma and in mucosal gastrointestinal biopsy specimens were assessed using mass spectrometry-validated immunoassays, and a new monoclonal antibody reacting with immunoreactive glucagon was used for immunohistochemistry., Results: Postprandial plasma concentrations of glucagon after RYGB were increased. Expression of the glucagon gene in the small intestine increased after surgery. Glucagon was identified in the small-intestine biopsy specimens obtained after, but not before, RYGB. Immunohistochemically, mucosal biopsy specimens from the small intestine harbored cells costained for GLP-1 and immunoreactive glucagon., Conclusion: Increased concentrations of glucagon were observed in small-intestine biopsy specimens and postprandially in plasma after RYGB. The small intestine harbored cells immunohistochemically costaining for GLP-1 and glucagon-like immunoreactivity after RYGB. Glucagon derived from small-intestine enteroendocrine l cells may contribute to postprandial plasma concentrations of glucagon after RYGB., (Copyright © 2019 Endocrine Society.)

Background and Aims: Epithelial expression of the insulin receptor in the colon has previously been reported to correlate with extent of colonic inflammation. However, the impact of insulin signalling in the intestinal mucosa is still unknown. Here, we investigated the effects of inactivating the epithelial insulin receptor in the intestinal tract, in an experimental model of inflammation-induced colorectal cancer., Methods: The mice were generated by utilizing the intestinal- and epithelial-specific villin promoter and the Cre-Lox technology. All mice included in the cohorts were generated by crossing [vil-Cre-INSR+/-] × [INSRfl/fl] to obtain [vil-Cre-INSR-/-], and their floxed littermates [INSRfl/fl] served as the control group. For the intervention study, phosphate-buffered saline with or without insulin was instilled rectally in anaesthetized wild-type mice with chemically induced colitis., Results: We found higher endoscopic colitis scores together with potentiated colonic tumorigenesis in the knockout mice. Furthermore, we showed that topically administered insulin in inflamed colons of wild-type mice reduced inflammation-induced weight loss and improved remission in a dose-dependent manner. Mice receiving rectal insulin enemas exhibited lower colitis endoscopic scores and reduced cyclooxygenase 2 mRNA expression, and developed significantly fewer and smaller tumours compared with the control group receiving phosphate-buffered saline only., Conclusions: Rectal insulin therapy could potentially be a novel treatment, targeting the epithelial layer to enhance mucosal healing in ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies.