Secretin release after Roux-en-Y gastric bypass reveals a population of glucose-sensitive S cells in distal small intestine.

OBJECTIVES: Gastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the postoperative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release. METHODS: A specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after, and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA sequencing, mass-spectrometry and in situ hybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin, and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation. RESULTS: Plasma postprandial secretin was more than doubled in humans after RYGB (P < 0.001). The distal small intestine harbored secretin expressing cells in both rats and humans. Glucose increased the secretion of secretin in a sodium-glucose cotransporter dependent manner when administered to the distal part but not into the proximal part of the rat small intestine. Secretin stimulated somatostatin secretion (fold change: 1.59, P < 0.05) from the perfused rat pancreas but affected neither insulin (P = 0.2) nor glucagon (P = 0.97) secretion. When administered to rats in vivo, insulin secretion was attenuated and glucagon secretion increased (P = 0.04), while blood glucose peak time was delayed (from 15 to 45 min) and gastric emptying time prolonged (P = 0.004). CONCLUSIONS: Glucose-sensing secretin cells located in the distal part of the small intestine may contribute to increased plasma concentrations observed after RYGB. The metabolic role of the distal S cells warrants further studies.

Bile acids drive colonic secretion of glucagon-like-peptide 1 and peptide-YY in rodents.

A large number of glucagon-like-peptide-1 (GLP-1)- and peptide-YY (PYY)-producing L cells are located in the colon, but little is known about their contribution to whole body metabolism. Since bile acids (BAs) increase GLP-1 and PYY release, and since BAs spill over from the ileum to the colon, we decided to investigate the ability of BAs to stimulate colonic GLP-1 and PYY secretion. Using isolated perfused rat/mouse colon as well as stimulation of the rat colon in vivo, we demonstrate that BAs significantly enhance secretion of GLP-1 and PYY from the colon with average increases of 3.5- and 2.9-fold, respectively. Furthermore, we find that responses depend on BA absorption followed by basolateral activation of the BA-receptor Takeda-G protein-coupled-receptor 5. Surprisingly, the apical sodium-dependent BA transporter, which serves to absorb conjugated BAs, was not required for colonic conjugated BA absorption or conjugated BA-induced peptide secretion. In conclusion, we demonstrate that BAs represent a major physiological stimulus for colonic L-cell secretion. NEW & NOTEWORTHY By the use of isolated perfused rodent colon preparations we show that bile acids are potent and direct promoters of colonic glucagon-like-peptide 1 and peptide-YY secretion. The study provides convincing evidence that basolateral Takeda-G protein-coupled-receptor 5 activation is mediating the effects of bile acids in the colon and thus add to the existing literature described for L cells in the ileum.

Abscisic acid stimulates the release of insulin and of GLP-1 in the rat perfused pancreas and intestine.

AIMS: Previous results indicate that nanomolar concentrations of abscisic acid (ABA) stimulate insulin release from ß-pancreatic cells in vitro and that oral ABA at 50 mg/kg increases plasma GLP-1 in the fasted rat. The aim of this study was to test the effect of ABA on the perfused rat pancreas and intestine, to verify the insulin- and incretin-releasing actions of ABA in controlled physiological models. MATERIALS AND METHODS: Rat pancreas and small intestine were perfused with solutions containing ABA at high-micromolar concentrations, or control secretagogues. Insulin and GLP-1 concentrations in the venous effluent were analysed by radioimmunoassay, and ABA levels were determined by ELISA. RESULTS: High micromolar concentrations of ABA induced GLP-1 secretion from the proximal half of the small intestine and insulin secretion from pancreas. GLP-1 stimulated ABA secretion from pancreas in a biphasic manner. Notably, a positive correlation was found between the ABA area under the curve (AUC) and the insulin AUC upon GLP-1 administration. CONCLUSION: Our results indicate the existence of a cross talk between GLP-1 and ABA, whereby ABA stimulates GLP-1 secretion, and vice versa. Release of ABA could be considered as a new promising molecule in the strategy of type 2 diabetes treatment and as a new endogenous hormone in the regulation of glycaemia.

The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon.

The colonic epithelium harbors a large number of endocrine cells, but little is known about the endocrine functions of the colon. However, the high density of glucagon like peptide-1 (GLP-1)- and peptide-YY (PYY)-secreting L cells is of great interest because of the potential antidiabetic and antiobesity effects of GLP-1 and PYY. Short-chain fatty acids (SCFAs) produced by local bacterial fermentation are suggested to activate the colonic free fatty acid receptors FFAR2 (GPR43) and FFAR3 (GPR41), stimulating the colonic L cells. We used the isolated perfused rat colon as a model of colonic endocrine secretion and studied the effects of the predominant SCFAs formed: acetate, propionate, and butyrate. We show that luminal and especially vascular infusion of acetate and butyrate significantly increases colonic GLP-1 secretion, and to a minor extent also PYY secretion, but only after enhancement of intracellular cAMP. Propionate neither affected GLP-1 nor PYY secretion whether administered luminally or vascularly. A FFAR2- and FFAR3-specific agonist [( S)-2-(4-chlorophenyl)-3,3-dimethyl- N-(5-phenylthiazol-2-yl)butamide (CFMB)/ AR420626 ] had no effect on colonic GLP-1 output, and a FFAR3 antagonist ( AR399519 ) did not decrease the SCFA-induced GLP-1 response. However, the voltage-gated Ca2+-channel blocker nifedipine, the KATP-channel opener diazoxide, and the ATP synthesis inhibitor 2,4-dinitrophenol completely abolished the responses. FFAR2 receptor studies confirmed low-potent partial agonism of acetate, propionate, and butyrate, compared with CFMB, which is a full agonist with ~750-fold higher potency than the SCFAs. In conclusion, SCFAs may increase colonic GLP-1/PYY secretion, but FFAR2/FFAR3 do not seem to be involved. Rather, SCFAs are metabolized and appear to function as a colonocyte energy source. NEW & NOTEWORTHY By the use of in situ isolated perfused rat colon we show that short-chain fatty acids (SCFAs) primarily are used as a colonocyte energy source in the rat, subsequently triggering glucagon like peptide-1 (GLP-1) secretion independent of the free fatty acid receptors FFAR2 and FFAR3. Opposite many previous studies on SCFAs and FFAR2/FFAR3 and GLP-1 secretion, this experimental model allows investigation of the physiological interactions between luminal nutrients and secretion from cells whose function depend critically on their blood supply as well as nerve and paracrine interactions.

18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT scans as diagnostic tools in focal congenital hyperinsulinism: a blinded evaluation.

PURPOSE: Focal congenital hyperinsulinism (CHI) is curable by surgery, which is why identification of the focal lesion is crucial. We aimed to determine the use of 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) PET/CT vs. 68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic-acid-1-Nal3-octreotide (68Ga-DOTANOC) PET/CT as diagnostic tools in focal CHI. METHODS: PET/CT scans of children with CHI admitted to Odense University Hospital between August 2005 and June 2016 were retrospectively evaluated visually and by their maximal standardized uptake values (SUVmax) by two independent examiners, blinded for clinical, surgical and pathological data. Pancreatic histology was used as the gold standard. For patients without surgery, the genetic profile served as the gold standard. RESULTS: Fifty-five CHI patients were examined by PET/CT (18F-DOPA n = 53, 68Ga-DOTANOC n = 18). Surgery was performed in 34 patients, no surgery in 21 patients. Fifty-one patients had a classifiable outcome, either by histology (n = 33, 22 focal lesions, 11 non-focal) or by genetics (n = 18, all non-focal). The predictive performance of 18F-DOPA PET/CT to identify focal CHI was identical by visual- and cut-off-based evaluation: sensitivity (95% CI) of 1 (0.85-1); specificity of 0.96 (0.82-0.99). The optimal 18F-DOPA PET SUVmax ratio cut-off was 1.44 and the optimal 68Ga-DOTANOC PET SUVmax cut-off was 6.77 g/ml. The area under the receiver operating curve was 0.98 (0.93-1) for 18F-DOPA PET vs. 0.71 (0.43-0.95) for 68Ga-DOTANOC PET (p < 0.03). In patients subjected to surgery, localization of the focal lesion was correct in 91%, and 100%, by 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT, respectively. CONCLUSION: 18F-DOPA PET/CT was excellent in predicting focal CHI and superior compared to 68Ga-DOTANOC PET/CT. Further use of 68GA-DOTANOC PET/CT in predicting focal CHI is discouraged.

Preconception care: advancing from 'important to do and can be done' to 'is being done and is making a difference'.

There is a growing evidence base for preconception care--the provision of biomedical, behavioral and social interventions to women and couples before conception occurs. Firstly, there is evidence that health problems, problem behaviours and individual and environmental risks contribute to poor maternal and child health outcomes. Secondly, there are biomedical, behavioural and social interventions that when delivered beforeconception occurs, effectively address many of these health problems, problem behaviours and risk factors.And thirdly, there is emerging experience of how to deliver these interventions in low and middle income countries (LMIC).The preconception care interventions delivered and whom they are delivered to, will need to be tailored to local realities. The package of preconception care interventions delivered in a particular setting will depend on the local epidemiology, the interventions already being delivered, and the resources in place to deliver additionalinterventions. Although a range of population groups could benefit from preconception care, prioritization based on need and feasibility will be needed.There are both potential benefits and risks associated with preconception care. Preconception care could result in large health and social benefits in LMIC. It could also be misused to limit the autonomy of women and reinforce the notion that the focus of all efforts to improve the health of girls and women should be at improving maternal and child health outcomes rather than at improving the health of girls and women as individuals in their own right.There are challenges in delivering preconception care. While the potential benefits of preconception care programmes could be substantial, extending the traditional Maternal and Child Health package will be both a logistic and financial challenge.We need to help countries set and achieve pragmatic and meaningful short term goals. While our longterm goal for preconception care should be for a full package of health and social interventions to be delivered to all women and couples of reproductive age everywhere, our short-term goals must be pragmatic. This is because countries that need preconception care most are the ones least likely to be able to afford them and deliver them.If we want these countries to take on the additional challenge of providing preconception care while they struggle to increase the coverage of prenatal care, skilled care at birth etc., we must help them identify and deliver a small number of effective interventions based on epidemiology and feasibility.

The Severity of DSS-Induced Colitis Is Independent of the SCFA-FFAR2/3-GLP-1 Pathway Despite SCFAs Inducing GLP-1 Secretion via FFAR2/3.

Short-chain fatty acids (SCFAs) are the major microbial metabolites produced from the fermentation of dietary fiber in the gut. They are recognised as secretagogues of the glucagon-like peptides, GLP-1 and GLP-2, likely mediated by the activation of free fatty acid receptors 2 and 3 (FFAR2 and 3) expressed on enteroendocrine L-cells. Fiber-deficient diets are associated with decreased intestinal function and decreased colonic GLP-1 and GLP-2 content. Here, we speculated that the lowered colonic GLP-1 observed following a fiber-free diet was a consequence of decreased SCFA production and a subsequent decrease in FFAR2/3 activation. Furthermore, we explored the consequences of a fiber-free diet followed by intestinal injury, and we mechanistically explored the SCFA-FFAR2/3-GLP-1 pathway to explain the increased severity. Colonic luminal content from mice fed either a fiber-free or chow diet were analysed for SCFA content by LC-MS. FFAR2/3 receptor contributions to SCFA-mediated colonic GLP-1 secretion were assessed in isolated perfused preparations of the colon from FFAR2/3 double knockout (KO) and wild-type (WT) mice. Colitis was induced by the delivery of 3% dextran sulfate sodium (DSS) for 4 days in the drinking water of mice exposed to a fiber-free diet for 21 days. Colitis was induced by the delivery of 3% DSS for 7 days in FFAR2/3 KO mice. The removal of dietary fiber significantly decreased SCFA concentrations in the luminal contents of fiber-free fed mice compared to chow-fed mice. In the perfused colon, luminal SCFAs significantly increased colonic GLP-1 secretion in WT mice but not in FFAR2/3 KO mice. In the DSS-induced colitis model, the removal of dietary fiber increased the severity and prevented the recovery from intestinal injury. Additionally, colitis severity was similar in FFAR2/3 KO and WT mice after DSS application. In conclusion, the results confirm that the removal of dietary fiber is sufficient to decrease the colonic concentrations of SCFAs. Additionally, we show that a fiber-free diet predisposes the colon to increased intestinal injury, but this effect is independent of FFAR2 and FFAR3 signalling; therefore, it is unlikely that a fiber-free diet induces a decrease in luminal SCFAs and sensitivity to intestinal disease involves the SCFA-FFAR2/3-GLP-1 pathway.

Effects of Exogenous GIP and GLP-2 on Bone Turnover in Individuals With Type 2 Diabetes.

CONTEXT: Individuals with type 2 diabetes (T2D) have an increased risk of bone fractures despite normal or increased bone mineral density. The underlying causes are not well understood but may include disturbances in the gut-bone axis, in which both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are regulators of bone turnover. Thus, in healthy fasting participants, both exogenous GIP and GLP-2 acutely reduce bone resorption. OBJECTIVE: The objective of this study was to investigate the acute effects of subcutaneously administered GIP and GLP-2 on bone turnover in individuals with T2D. METHODS: We included 10 men with T2D. Participants met fasting in the morning on 3 separate test days and were injected subcutaneously with GIP, GLP-2, or placebo in a randomized crossover design. Blood samples were drawn at baseline and regularly after injections. Bone turnover was estimated by circulating levels of collagen type 1 C-terminal telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), sclerostin, and PTH. RESULTS: GIP and GLP-2 significantly reduced CTX to (mean ± SEM) 66 ± 7.8% and 74 ± 5.9% of baseline, respectively, compared with after placebo (P = .001). In addition, P1NP and sclerostin increased acutely after GIP whereas a decrease in P1NP was seen after GLP-2. PTH levels decreased to 67 ± 2.5% of baseline after GLP-2 and to only 86 ± 3.4% after GIP. CONCLUSION: Subcutaneous GIP and GLP-2 affect CTX and P1NP in individuals with T2D to the same extent as previously demonstrated in healthy individuals.

GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

CONTEXT: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. OBJECTIVE: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. MAIN OUTCOME MEASURE: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. RESULTS: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. CONCLUSIONS: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Setting research priorities for adolescent sexual and reproductive health in low- and middle-income countries.

OBJECTIVE: To conduct an expert-led process for identifying research priorities in adolescent sexual and reproductive health in low- and middle-income countries. METHODS: The authors modified the priority-setting method of the Child Health and Nutrition Research Initiative (CHNRI) to obtain input from nearly 300 researchers, health programme managers and donors with wide-ranging backgrounds and experiences and from all geographic regions. In a three-Phase process, they asked these experts to: (i) rank outcome areas in order of importance; (ii) formulate research questions within each area, and (iii) rank the formulated questions. FINDINGS: seven areas of adolescent sexual and reproductive health were identified as important: (i) maternal health; (ii) contraception; (iii) gender-based violence; (iv) treatment and care of patients with human immunodeficiency virus (HIV) infection; (v) abortion; (vi) integration of family planning and HIV-related services and (vii) sexually transmitted infections. Experts generated from 30 to 40 research questions in each area, and to prioritize these questions, they applied five criteria focused on: clarity, answerability, impact, implementation and relevance for equity. Rankings were based on overall mean scores derived by averaging the scores for individual criteria. Experts agreed strongly on the relative importance of the questions in each area. CONCLUSION: Research questions on the prevalence of conditions affecting adolescents are giving way to research questions on the scale-up of existing interventions and the development of new ones. CHNRI methods can be used by donors and health programme managers to prioritize research on adolescent sexual and reproductive health.

Résumé OBJECTIF: Établir un processus, sous la direction d'experts, visant à identifier les priorités de la recherche en matière de santé sexuelle et reproductive chez l'adolescent dans les pays à revenu faible et moyen. MÉTHODES: Les auteurs ont modifié la méthode d'établissement des priorités de l'Initiative pour la recherche en santé et nutrition infantiles (CHNRI) afin d'obtenir la contribution de près de 300 chercheurs, gestionnaires de programmes de santé et donateurs, de formation et d'expérience très diverses, et provenant de toutes les régions géographiques. Dans le cadre d'un processus en trois phases, ils ont demandé à ces experts de: (i) classer les domaines de résultats par ordre d'importance, (ii) formuler des questions de recherche au sein de chaque domaine, et (iii) classer les questions formulées. RÉSULTATS: Sept domaines de la santé sexuelle et reproductive des adolescents ont été identifiés comme importants: (i) la santé maternelle; (ii) la contraception; (iii) la violence sexiste; (iv) le traitement et les soins des patients infectés par le virus de l'immunodéficience humaine (VIH); (v) l'avortement; (vi) l'intégration de la planification familiale et des services liés au VIH et (vii) les infections sexuellement transmissibles. Les experts ont généré de 30 à 40 questions de recherche dans chaque domaine. Pour déterminer le caractère prioritaire de ces questions, ils ont appliqué cinq critères: clarté, capacité de réponse, impact, mise en œuvre et pertinence en termes d'équité. Les classements se basaient sur les scores moyens généraux, dérivés de la moyenne des scores pour les critères individuels. Les experts étaient entièrement d'accord sur l'importance relative des questions dans chaque domaine. CONCLUSION: Les questions de recherche sur la prévalence des maladies qui affectent les adolescents cèdent la place à des questions de recherche sur l'intensification des interventions existantes et le développement de nouvelles interventions. Les méthodes de la CHNRI peuvent être utilisées par les donateurs et les gestionnaires de programmes de santé pour fixer les priorités de la recherche sur la santé sexuelle et reproductive chez les adolescents.

Resumen OBJETIVO: Llevar a cabo un proceso dirigido por expertos a fin de identificar las prioridades en la investigación sobre la salud sexual y reproductiva de los adolescentes en países con ingresos bajos y medios. MÉTODOS: Los autores modificaron el método de establecimiento de prioridades de la Iniciativa de Salud del Niño e Investigación Nutricional para conseguir la contribución de casi 300 investigadores, gestores de programas sanitarios y donantes con diversas trayectorias y experiencias y procedentes de todas las regiones geográficas. En un proceso que constó de tres fases, se solicitó a dichos expertos que: (i) clasificaran las áreas de resultados según su importancia; (ii) formularan temas de investigación en cada área y (iii) clasificaran los temas formulados. RESULTADOS: Se identificaron como importantes siete áreas de la salud sexual y reproductiva de los adolescentes: (i) la salud materna; (ii) la anticoncepción; (iii) la violencia de género; (iv) el tratamiento y cuidado de los pacientes con el virus de la inmunodeficiencia humana (VIH); (v) el aborto; (vi) la unificación de la planificación familiar y los servicios relacionados con el VIH y (vii) las infecciones de transmisión sexual. Los expertos crearon entre 30 y 40 temas de investigación en cada área y, con objeto de priorizar dichos temas, aplicaron cinco criterios: claridad, responsabilidad, impacto, aplicación y pertinencia para la equidad. Las clasificaciones se basaron en las puntuaciones medias globales obtenidas al calcular el promedio de las puntuaciones de los criterios individuales. Los expertos coincidieron en la importancia relativa de los temas en cada área. CONCLUSIÓN: Los temas de investigación sobre el predominio de las situaciones que afectan a los adolescentes dan paso a temas que tratan tanto la ampliación de las intervenciones existentes como el desarrollo de nuevas intervenciones. Tanto donantes como gestores de programas sanitarios pueden emplear los métodos de la Iniciativa de Salud del Niño e Investigación Nutricional para establecer las prioridades en la investigación sobre la salud sexual y reproductiva de los adolescentes.

How does mHealth influence consulting practice between health professionals and individuals with low back pain? - A qualitative study from the perspective of health professionals.

PURPOSE: This study explored how health professionals experience in what way a digital self-monitoring solution influences their consulting practice targeting individuals with low back pain. MATERIAL AND METHODS: This was a qualitative study adopting a constructivist grounded theory approach. Nineteen health professionals participated in the pilot test of the digital self-monitoring solution BackTrace. Data were collected cross-sectionally and consisted of: (a) audio recordings from focus groups with health professionals, (b) field notes from participant observation of online meetings with health professionals, (c) field notes from participant observations of consultations between health professionals and individuals with low back pain and (d) audio recordings from workshops with health professionals. RESULTS: Two main themes and one sub-theme were identified, describing how BackTrace enabled more focused consulting practices, supported patient-self management and improved the relationship between individuals with low back pain and health professionals. Barriers were identified describing how the implementation of digital health solutions required a change in workflow, resources and culture - as well as management support. CONCLUSIONS: Findings indicated a need for a change at the system level, including a changed view of digitisation in healthcare systems containing a more supporting approach.

Low back pain is a leading cause of disability which not only impacts physically but restricts quality of life.This study shows how health professionals experience in what way digital self-monitoring solutions influence their consulting practices targeting individuals with low back pain.A digital self-monitoring solution may contribute to a more focused consulting practice and improve the quality of the relationship between individuals with low back pain and health professionals but require changes at a system level.A change in workflow and culture is recommended if digital health is to be a success.

The practice of information appraisal: An ethnographic study of a health information intervention.

As healthcare systems grow increasingly complex, greater demands are placed on patients' abilities to find, understand, appraise, and use health information - often termed their 'health literacy'. Most health literacy research does not focus on information appraisal. When it does, there is a tendency to equate it with patients' assessment of credibility. This reproduces a healthcare-centric understanding of information appraisal where patient agency is omitted. This study explores how participants in a health information intervention practiced information appraisal. The intervention aimed to increase information uptake for people with low back pain by delivering health information to them through animations. This study draws on ethnographic participant observation of the encounters between the intervention and its participants, including 49 rapid interviews and semi-structured telephone interviews with 23 participants carried out in the spring of 2021. Inspired by a social practice approach, the study thoroughly grounds the health literacy subcategory of 'appraisal' in practice. It illustrates that participants appraised the information provided in the intervention according to several factors. These include relating the information to their personal health needs, interpreting the intended audience of the health animations, and prioritising their attention situationally between the animations and other immediate concerns. We suggest that information appraisal is a fundamental component of health literacy and should be considered key in research, policy and practice. To accommodate current healthcare ideals of patient centeredness, empowerment and informed choice, the complex and dynamic ways in which people appraise health information need be considered legitimate practices of health literacy.

Visualising, navigating and making time: The use of a digital solution in treatment and rehabilitation from low back pain.

Illness trajectories are particularly characterised by the temporal dimension of human existence. In the area of low back pain, patients often have challenging temporal experiences such as unproductive waiting time and fragmented, repetitive consultations over many years. This study seeks to investigate relationships between digital technologies, temporal agency, and illness, through describing how users experienced a new digital solution, BackTrace, targeting patients with low back pain. The study builds on six months of ethnographic fieldwork, including semi-structured interviews, participant observation and a workshop. The study shows how the introduction of the digital solution could facilitate new possibilities of temporal actions for individuals living with and receiving care for low back pain. For many research participants, the use of BackTrace facilitated a useful visualisation of their past and present low back pain state; BackTrace could assist participants in navigating different external temporal demands; and it allocated time devoted to managing their back pain in everyday life and in consultations with health professionals. The study discusses how temporality can be a useful analytical entrance point to operationalise and explore the often-desired goal of empowerment in patient pathways.

Preventing child marriages: first international day of the girl child "my life, my right, end child marriage".

On 17 November 2011, the United Nations General Assembly adopted a resolution (A/RES/66/170) designating 11 October as the first International Day of the Girl Child choosing ending child marriages as the theme of the day. Child marriage is a fundamental human rights violation and impacts all aspects of a girl's life. These marriages deny a girl of her childhood, disrupts her education, limits her opportunities, increases her risk of violence and abuse, and jeopardizes her health. The article presents data about the prevalence and effects, contributing factors and recommends action for prevention.

Colonic Lactulose Fermentation Has No Impact on Glucagon-like Peptide-1 and Peptide-YY Secretion in Healthy Young Men.

CONTEXT: The colon houses most of humans' gut microbiota, which ferments indigestible carbohydrates. The products of fermentation have been proposed to influence the secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) from the many endocrine cells in the colonic epithelium. However, little is known about the colonic contribution to fasting or postprandial plasma levels of L-cell products. OBJECTIVE: To determine the impact of colonic lactulose fermentation on gut peptide secretion and to evaluate whether colonic endocrine secretion contributes to gut hormone concentrations measurable in the fasting state. METHODS: Ten healthy young men were studied on 3 occasions after an overnight fast. On 2 study days, lactulose (20 g) was given orally and compared to water intake on a third study day. For 1 of the lactulose visits, participants underwent a full colonic evacuation. Over a 6-h study protocol, lactulose fermentation was assessed by measuring exhaled hydrogen, and gut peptide secretion, paracetamol, and short-chain fatty acid levels were measured in plasma. RESULTS: Colonic evacuation markedly reduced hydrogen exhalation after lactulose intake (P = 0.013). Our analysis suggests that the colon does not account for the measurable amounts of GLP-1 and PYY present in the circulation during fasting and that fermentation and peptide secretion are not acutely related. CONCLUSION: Whether colonic luminal contents affect colonic L-cell secretion sufficiently to influence circulating concentrations requires further investigation. Colonic evacuation markedly reduced lactulose fermentation, but hormone releases were unchanged in the present study.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with short bowel syndrome and colon in continuity: an open-label pilot study.

OBJECTIVE: Patients with short bowel syndrome (SBS) and colon in continuity have better adaptation potential compared with patients with jejunostomy. Adaptation may involve enhanced postprandial secretion of the enteroendocrine hormones glucagon-like peptide (GLP)-1 and GLP-2 which are normally degraded by dipeptidyl peptidase (DPP)-4. Nevertheless, some patients with SBS with colon in continuity suffer from high-volume faecal excretions and have been shown to benefit from treatment with GLP-2. Therefore, we aimed to evaluate efficacy of sitagliptin, a DPP-4 inhibitor, on reducing faecal excretions in this patient group. DESIGN: In an open-label, case series, proof-of-concept pilot study, 100 mg oral sitagliptin was given two times per day for 8 weeks to patients with SBS with ≥50% colon in continuity with or without the need for parenteral support (PS). To assess intestinal function, metabolic balance studies were done at baseline and following 8 weeks of treatment. RESULTS: Of the 10 patients planned for enrolment, 8 patients were included; 7 patients completed the study. Although postprandial endogenous GLP-2 concentrations increased by 49 hours×pmol/L (39, 105; p=0.018) (median (min, max)), sitagliptin did not significantly reduce median faecal wet weight (-174 g/day (-1510, 675; p=0.176)) or increase intestinal wet weight absorption. However, heterogeneity in the treatment effect was observed: intestinal wet weight absorption increased in all four patients with intestinal failure. One patient achieved a reduction in PS by 500 mL per administration day. CONCLUSION: Following this negative, small pilot study, larger, placebo-controlled, studies are needed to establish the therapeutic potential of DPP-4 inhibition in patients with SBS.

GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats.

Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification in the incretin hormone glucagon-like peptide (GLP-1) that alters the signaling capabilities of the GLP-1 receptor (GLP-1R) by making it G protein biased over internalization but was originally designed to confer DPP-4 resistance and thereby prolong the half-life of GLP-1. Despite similar binding affinity, cAMP production, and calcium mobilization, substitution of a single amino acid (Ala8 to Val8) in the N-terminus of GLP-1(7-36)NH2 (GLP-1 Val8) severely impaired its ability to internalize GLP-1R compared to endogenous GLP-1. In-depth binding kinetics analyses revealed shorter residence time for GLP-1 Val8 as well as a slower observed association rate. Molecular dynamics (MD) displayed weaker and less interactions of GLP-1 Val8 with GLP-1R, as well as distinct conformational changes in the receptor compared to GLP-1. In vitro validation of the MD, by receptor alanine substitutions, confirmed stronger impairments of GLP-1 Val8-mediated signaling compared to GLP-1. In a perfused rat pancreas, acute stimulation with GLP-1 Val8 resulted in a lower insulin and somatostatin secretion compared to GLP-1. Our study illustrates that profound differences in molecular pharmacological properties, which are essential for the therapeutic targeting of the GLP-1 system, can be induced by subtle changes in the N-terminus of GLP-1. This information could facilitate the development of optimized GLP-1R agonists.

CCK-1 and CCK-2 receptor agonism do not stimulate GLP-1 and neurotensin secretion in the isolated perfused rat small intestine or GLP-1 and PYY secretion in the rat colon.

Gastrin and cholecystokinin (CCK) are hormones released from endocrine cells in the antral stomach (gastrin), the duodenum, and the jejunum (CCK). Recent reports, based on secretion experiments in an enteroendocrine cell line (NCI-H716) and gastrin receptor expression in proglucagon-expressing cells from the rat colon, suggested that gastrin could be a regulator of glucagon-like peptide-1 (GLP-1) secretion. To investigate these findings, we studied the acute effects of CCK-8 (a CCK1/CCK2 (gastrin) receptor agonist) and gastrin-17 (a CCK2(gastrin) receptor agonist) in robust ex vivo models: the isolated perfused rat small intestine and the isolated perfused rat colon. Small intestines from Wistar rats (n = 6), were perfused intraarterially over 80 min. During the perfusion, CCK (1 nmol/L) and gastrin (1 nmol/L) were infused over 10-min periods separated by washout/baseline periods. Colons from Wistar rats (n = 6) were perfused intraarterially over 100 min. During the perfusion, CCK (1 nmol/L), vasoactive intestinal peptide (VIP) (10 nmol/L), and glucose-dependent insulinotropic polypeptide (GIP) (1 nmol/L) were infused over 10-min periods separated by washout/baseline periods. In the perfused rat small intestines neither CCK nor gastrin stimulated the release of GLP-1 or neurotensin. In the perfused rat colon, neither CCK or VIP stimulated GLP-1 or peptide YY (PYY) release, but GIP stimulated both GLP-1 and PYY release. In both sets of experiments, bombesin, a gastrin-releasing peptide analog, served as a positive control. Our findings do not support the suggestion that gastrin or CCK participate in the acute regulation of intestinal GLP-1 secretion, but that GIP may play a role in the regulation of hormone secretion from the colon.

Neuromedin U Does Not Act as a Decretin in Rats.

Studies on isolated pancreatic islets suggest that neuromedin U (NMU), a brain and gastrointestinal peptide, acts as a decretin hormone, inhibiting glucose-stimulated insulin secretion. We investigated whether this effect could be reproduced in vivo and in isolated perfused rat pancreas. Unlike the incretin hormone, glucagon-like peptide 1 (GLP-1), intravenous NMU administration had no effects on blood glucose and plasma insulin and glucagon in vivo. Moreover, NMU neither changed insulin, glucagon, or somatostatin secretion from isolated perfused rat pancreas, nor affected GLP-1-stimulated insulin and somatostatin secretion. For NMU to act as a decretin hormone, its secretion should increase following glucose ingestion; however, glucose did not affect NMU secretion from isolated perfused rat small intestine, which contained extractable NMU. Furthermore, the two NMU receptors were not detected in endocrine rat or human pancreas. We conclude that NMU does not act as a decretin hormone in rats.

Insulin Secretion Depends on Intra-islet Glucagon Signaling.

The intra-islet theory states that glucagon secretion is suppressed when insulin secretion is stimulated, but glucagon's role in intra-islet paracrine regulation is controversial. This study investigated intra-islet functions of glucagon in mice. We examined glucagon-induced insulin secretion using isolated perfused pancreata from wild-type, GLP-1 receptor (GLP-1R) knockout, diphtheria toxin-induced proglucagon knockdown, ß cell-specific glucagon receptor (Gcgr) knockout, and global Gcgr knockout (Gcgr-/-) mice. We found that glucagon stimulates insulin secretion through both Gcgr and GLP-1R. Moreover, loss of either Gcgr or GLP-1R does not change insulin responses, whereas combined blockage of both receptors significantly reduces insulin secretion. Active GLP-1 is identified in pancreatic perfusate from Gcgr-/- but not wild-type mice, suggesting that ß cell GLP-1R activation results predominantly from glucagon action. Our results suggest that combined activity of glucagon and GLP-1 receptors is essential for ß cell secretory responses, emphasizing a role for paracrine intra-islet glucagon actions to maintain appropriate insulin secretion.