Effects of a long-acting secretin peptide analog alone and in combination with a GLP-1R agonist in a diet-induced obesity mouse model.

OBJECTIVE: Obesity is a major global health problem which can be targeted with new mechanistic diverse pharmacological interventions. Here we evaluate a new long-acting secretin receptor agonist as a potential treatment for obesity. METHODS: BI-3434 was designed as a secretin analog with stabilized peptide backbone and attached fatty acid-based half-life extension group. The peptide was evaluated in vitro for its ability to stimulate cAMP accumulation in a cell line stably expressing recombinant secretin receptor. On the functional level, stimulation of lipolysis in primary adipocytes after treatment with BI-3434 was determined. The ability of BI-3434 to activate secretin receptor in vivo was assessed in a cAMP reporter CRE-Luc mouse model. Furthermore, a diet-induced obesity mouse model was used to test the effects of BI-3434 on body weight and food intake following repeated daily subcutaneous administration alone and in combination with a GLP-1R agonist. RESULTS: BI-3434 potently activated human secretin receptor. However, lipolysis was only weakly induced in primary murine adipocytes. BI-3434 had an extended half-life compared to endogenous secretin and activated target tissues like pancreas, adipose tissue, and stomach in vivo. BI-3434 did not lower food intake in lean or diet-induced obese mice, but it increased energy expenditure after daily administration. This led to a loss of fat mass, which did not translate in a significant effect on body weight. However, treatment in combination with a GLP-1R agonist led to a synergistic effect on body weight loss. CONCLUSIONS: BI-3434 is a highly potent and selective agonist of secretin receptor with an extended pharmacokinetic (PK) profile. Increased energy expenditure after daily treatment with BI-3434 suggests that secretin receptor is involved in metabolic regulation and energy homeostasis. Targeting secretin receptor alone may not be an efficient anti-obesity treatment, but could be combined with anorectic principles like GLP-1R agonists.

Pleiotropic Effects of Secretin: A Potential Drug Candidate in the Treatment of Obesity?

Secretin is the first hormone that has been discovered, inaugurating the era and the field of endocrinology. Despite the initial focus, the interest in its actions faded away over the decades. However, there is mounting evidence regarding the pleiotropic beneficial effects of secretin on whole-body homeostasis. In this review, we discuss the evidence from preclinical and clinical studies based on which secretin may have a role in the treatment of obesity.

Secretin as a Satiation Whisperer With the Potential to Turn into an Obesity-curbing Knight.

The obesity pandemic requires effective preventative and therapeutic intervention strategies. Successful and sustained obesity treatment is currently limited to bariatric surgery. Modulating the release of gut hormones is considered promising to mimic bariatric surgery with its beneficial effects on food intake, body weight, and blood glucose levels. The gut peptide secretin was the first molecule to be termed a hormone; nevertheless, only recently has it been established as a legitimate anorexigenic peptide. In contrast to gut hormones that crosstalk with the brain either directly or by afferent neuronal projections, secretin mediates meal-associated brown fat thermogenesis to induce meal termination, thereby qualifying this physiological mechanism as an attractive, peripheral target for the treatment of obesity. In this perspective, it is of pivotal interest to deepen our as yet superficial knowledge on the physiological roles of secretin as well as meal-associated thermogenesis in energy balance and body weight regulation. Of note, the emerging differences between meal-associated thermogenesis and cold-induced thermogenesis must be taken into account. In fact, there is no correlation between these 2 entities. In addition, the investigation of potential effects of secretin in hedonic-driven food intake, bariatric surgery and chronic treatment using suitable application strategies to overcome pharmacokinetic limitations will provide further insight into its potential to influence energy balance. The aim of this article is to review the facts on secretin's metabolic effects, address prevailing gaps in our knowledge, and provide an overview on the opportunities and challenges of the therapeutic potential of secretin in body weight control.

Safety of Secretin Administration in Children.

OBJECTIVE: The aim of this study was to compare the hemodynamic parameters from the anesthesia records of children who underwent upper gastrointestinal endoscopy (esophagogastroduodenoscopy [EGD]) with and without secretin pancreatic function tests (sPFTs). METHODS: The hemodynamic parameters were retrieved from an electronic anesthesia database. The secretin group consisted of 186 children, and the age- and sex-matched control group included 136 patients who did not have sPFTs. RESULTS: There was no difference in the demographic parameters (age and sex) between the 2 groups. The secretin group had a lower height and body mass index. The sPFT resulted in an average 3-minute extension of the endoscopic procedure. The heart rate increased during the EGD in both groups and was higher (averaged 7 beats per minute) in the secretin group than the EGD-only group. There were mild elevations on the systolic and diastolic blood pressures. None of these changes were clinically significant. There were no complications reported during the anesthesia and procedures in the 2 groups. CONCLUSIONS: Secretin PFT is a safe procedure. It only slightly prolongs the total procedure and anesthesia time. There were no clinically significant changes in the vital parameters in the secretin group, and there were no adverse effects recorded.

Complementary and alternative medicine for autism spectrum disorders: rationale, safety and efficacy.

Complementary and alternative medicine is widely used for children with autism spectrum disorder, despite uncertainty regarding efficacy. This review describes complementary and alternative practices commonly used among this population, the rationale for the use of each practice, as well as the side-effect profile and evidence for efficacy. The existing evidence base indicates that melatonin can be recommended as a treatment for sleeping disturbances associated with autism spectrum disorder, while secretin can be rejected as an efficacious treatment for broader autistic symptoms. There is insufficient evidence to draw conclusions on the efficacy of modified diets, hyperbaric oxygen therapy, immune therapy, and vitamin and fatty acid supplementation. There is a clear need for methodologically rigorous studies to provide evidence-based guidance to families and clinicians regarding complementary and alternative practices for individuals with autism spectrum disorders.

Eating behaviors, diet quality, and gastrointestinal symptoms in children with autism spectrum disorders: a brief review.

Children with autism spectrum disorders (ASD) and their caregivers face unique challenges in the children's daily eating routines and food intake patterns. The aim of this brief review is to describe eating behaviors of children with ASD, including increased food neophobia and food selectivity, and review findings on children's diet quality, and gastrointestinal (GI) symptoms. Advancing knowledge about the interrelationships between these nutrition-related domains in children with ASD is expected to have important implications for clinical nursing practice and caregiver care.

Intranasal application of secretin, similarly to intracerebroventricular administration, influences the motor behavior of mice probably through specific receptors.

Secretin and its receptors show wide distribution in the central nervous system. It was demonstrated previously that intravenous (i.v.) and intracerebroventricular (i.c.v.) application of secretin influenced the behavior of rat, mouse, and human. In our previous experiment, we used a special animal model, Japanese waltzing mice (JWM). These animals run around without stopping (the ambulation distance is very limited) and they do not bother with their environment. The i.c.v. secretin attenuated this hyperactive repetitive movement. In the present work, the effect of i.c.v. and intranasal (i.n.) application of secretin was compared. We have also looked for the presence of secretin receptors in the brain structures related to motor functions. Two micrograms of i.c.v. secretin improved the horizontal movement of JWM, enhancing the ambulation distance. It was nearly threefold higher in treated than in control animals. The i.n. application of secretin to the left nostril once or twice a day or once for 3 days more effectively enhanced the ambulation distance than i.c.v. administration. When secretin was given twice a day for 3 days it had no effect. Secretin did not improve the explorative behavior (the rearing), of JWM. With the use of in situ hybridization, we have found very dense secretin receptor labeling in the cerebellum. In the primary motor cortex and in the striatum, only a few labeled cells were seen. It was supposed that secretin exerted its effect through specific receptors, mainly present in the cerebellum.

Intravenous synthetic secretin reduces the incidence of pancreatitis induced by endoscopic retrograde cholangiopancreatography.

OBJECTIVES: This study aimed to evaluate whether synthetic secretin is effective in reducing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. METHODS: This is a single academic medical center, prospective, randomized, double-blind, placebo-controlled trial using secretin (dose of 16 µg) administered intravenously immediately before ERCP. Patients were evaluated for the primary outcome of post-ERCP pancreatitis as diagnosed by a single investigator. RESULTS: A total of 1100 patients were screened, of whom 869 were randomly assigned to receive secretin (n = 426) or placebo (n = 443) before ERCP and were evaluated after the procedure for efficacy of secretin. The incidence of pancreatitis in the secretin group compared with the placebo group was 36 (8.7%) of 413 patients versus 65 (15.1%) of 431 patients, respectively, P = 0.004. In the subgroup analysis, secretin was highly protective against post-ERCP pancreatitis for patients undergoing biliary sphincterotomy (6/129 vs 32/142, P < 0.001), patients undergoing cannulation of the common bile duct (26/339 vs 56/342, P < 0.001), and patients not undergoing pancreatic sphincterotomy (26/388 vs 57/403, P = 0.001). Analysis of the interaction between these groups reveals that the primary effect of secretin prophylaxis was prevention of post-ERCP pancreatitis in patients undergoing biliary sphincterotomy. CONCLUSIONS: Synthetic secretin reduces the risk of post-ERCP pancreatitis, particularly in patients in undergoing biliary sphincterotomy.

Combined administration of secretin and oxytocin inhibits chronic colitis and associated activation of forebrain neurons.

BACKGROUND: The pathogenesis of inflammatory bowel disease is unknown; however, the disorder is aggravated by psychological stress and is itself psychologically stressful. Chronic intestinal inflammation, moreover, has been reported to activate forebrain neurons. We tested the hypotheses that the chronically inflamed bowel signals to the brain through the vagi and that administration of a combination of secretin (S) and oxytocin (OT) inhibits this signaling. METHODS: Three daily enemas containing 2,4,6-trinitrobenzene sulfonic acid (TNBS), which were given to rats produced chronic colitis and ongoing activation of Fos in brain neurons. KEY RESULTS: Fos was induced in neurons in the paraventricular nucleus of the hypothalamus, basolateral amygdala, central amygdala, and piriform cortex. Subdiaphragmatic vagotomy failed to inhibit this activation of Fos, suggesting that colitis activates forebrain neurons independently of the vagi. When administered intravenously, but not when given intracerebroventricularly, in doses that were individually ineffective, combined S/OT prevented colitis-associated activation of central neurons. Strikingly, S/OT decreased inflammatory infiltrates into the colon and colonic expression of tumor necrosis factor-alpha and interferon-gamma. CONCLUSIONS & INFERENCES: These observations suggest that chronic colonic inflammation is ameliorated by the systemic administration of S/OT, which probably explains the parallel ability of systemic S/OT to inhibit the colitis-associated activation of forebrain neurons. It is possible that S and OT, which are endogenous to the colon, might normally combine to restrict the severity of colonic inflammatory responses and that advantage might be taken of this system to develop novel means of treating inflammation-associated intestinal disorders.

Autism.

INTRODUCTION: Evidence for the efficacy of treatments for autism has improved in recent years. In this systematic review the evidence for both drug and non-drug treatments is appraised and clinical guidance is provided for their use. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of early intensive multidisciplinary intervention programmes in children with autism? What are the effects of dietary interventions in children with autism? What are the effects of drug treatments in children with autism? What are the effects of non-drug treatments in children with autism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2009 (Clinical evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 30 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: applied behavioural analysis; auditory integration training; Autism Preschool Programme; casein-free diet; chelation; Child's Talk programme; cognitive behavioural therapy; digestive enzymes; EarlyBird programme; facilitated communication; Floortime therapy; gluten-free diet; immunoglobulins; melatonin; memantine; methylphenidate; More Than Words programme; music therapy; olanzapine; omega-3 fish oil; picture exchange communication system; Portage scheme; probiotics; relationship development interventions; risperidone; secretin; selective serotonin reuptake inhibitors (SSRIs); sensory integration training; social stories; social skills training; Son-Rise programme; TEACCH; vitamin A; vitamin B6 (pyridoxine) plus magnesium; and vitamin C.

Secretin effects on cerebellar-dependent motor learning in schizophrenia.

OBJECTIVE: Pervasive cognitive deficits in schizophrenia are a major cause of disability among individuals with the disorder. One such deficit is the loss of effective associative learning, which is readily assessed via eye-blink conditioning procedures. The authors examined the efficacy of secretin, a hormonal agonist for the prototype group B G-protein-coupled receptors, in ameliorating eye-blink conditioning deficits in schizophrenia patients. METHOD: Immediately following a pretreatment delay eye-blink conditioning recording session, 25 individuals with schizophrenia received either secretin (RG1068; 20 microg/kg [N=15]) or a saline placebo (20 microg/kg [N=10]) subcutaneously in a double-blind fashion. Comparison groups were formed by yoking pairs of subjects on the basis of performance during the pretreatment baseline eye-blink conditioning recording session, and thus 20 subjects underwent further analysis. Secretin was selected because eye-blink conditioning depends on the release of Purkinje cell inhibition on deep nuclei of the cerebellum and recent findings indicate that secretin is endogenously released in the cerebellum, where it acts as a retrograde messenger and neuromodulator on basket and Purkinje cells. RESULTS: Eye-blink conditioning was significantly improved at 2 and 24 hours after secretin administration but not after treatment with placebo. These results are consistent with evidence of intracellular signaling abnormalities in the pathophysiology of schizophrenia and indicate a possible role for secretin in modulating cerebellar-mediated classically conditioned learning. CONCLUSION: If cerebellar abnormalities in individuals with schizophrenia are associated with fundamental mechanisms and symptoms of the disorder, as suggested by the cognitive dysmetria model, then cerebellar-targeted treatments may provide a novel approach to treatment for schizophrenia.

Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders.

BACKGROUND: Gastrointestinal (GI) symptoms and abnormalities in stool consistency are frequently reported by parents of children with autism spectrum disorders (ASD). The purpose of this study was to 1) describe dietary intake of a cohort of children with ASD compared with normative data and 2) determine whether GI symptoms and stool consistency are related to dietary intake. METHODS: Data from diet diaries of children (3-8 years) with ASD (n = 62) were analyzed by a registered pediatric dietician to compare to RDA standards for total calories, protein, carbohydrate, and fat. Dietary intake was correlated with descriptors of stool consistency using cumulative logistic regression methods. RESULTS: Intake of calories, carbohydrates, and fat were in the average range; protein intake was increased (211% of RDA). Reported frequency of GI abnormalities, including abnormal stool consistency (e.g., bulky or loose), was increased (54%). No statistically significant relationships between stool consistency and dietary intake were observed. CONCLUSIONS: In this sample, there was a high rate of reported gastrointestinal symptoms, despite lack of medical causes. Intake was adequate for calories and carbohydrates and increased for protein. The children did not exhibit excessive carbohydrate intake. There was no association of nutrient intake to changes in stool consistency.

A case of secretin-responsive insulinoma with low serum C-peptide levels.

Insulinoma is the most common cause of fasting hypoglycemia resulting from autonomous insulin hypersecretion. A 59-year-old woman who had previously had an insulinoma and had undergone a partial pancreatectomy was admitted to our hospital because of recurrence of hypoglycemia after 27 years. She had two unusual endocrinological features: 1) the serum insulin response to intravenous secretin injection was not impaired, and 2) the serum C-peptide levels and ratios of serum C-peptide to insulin were relatively low. Two pancreatic tumors were readily detectable by computed tomography (CT) and magnetic resonance imaging (MRI). The selective arterial calcium injection (SACI) test showed a hyperinsulinemic response by calcium administration to the gastroduodenal artery. A partial pancreatectomy was done and her hypoglycemia disappeared. Histology revealed that the tumors were composed of monotonous, small round cells that were positive for both insulin and cathepsin B. As previous in vitro studies have shown that C-peptide can be metabolized within human insulinoma cells by proteolytic cleavage by cathepsin B, our patient's low serum C-peptide levels might have been caused by degradation of C-peptide by cathepsin B. According to the data from the literature, the molar ratio of serum C-peptide to insulin is generally decreased in patients with insulinoma than normal subjects. This case highlights the need for careful interpretation of C-peptide levels and the intravenous secretin injection test in the diagnosis of insulinoma.

Secretin: a pleiotrophic hormone.

Secretin holds a unique place in the history of endocrinology and gastrointestinal physiology, as it is the first peptide designated as a hormone. During the last century since its first discovery, the hormonal effects of secretin in the gastrointestinal tract were extensively studied, and its principal role in the periphery was found to stimulate exocrine secretion from the pancreas. Recently, a functional role of secretin in the brain has also been substantiated, with evidence suggesting a possible role of secretin in embryonic brain development. Given that secretin and its receptors are widely expressed in multiple tissues, this peptide should therefore exhibit pleiotrophic functions throughout the body. The present article reviews the current knowledge on the central and peripheral effects of secretin as well as its therapeutic uses.

Partial reversal of phencyclidine-induced impairment of prepulse inhibition by secretin.

BACKGROUND: Secretin is a "gut-brain" peptide whose neural function is as yet poorly understood. Several clinical studies have reported modestly increased social interaction in autistic children following intravenous secretin administration. Very recently secretin also was administered to schizophrenic patients and found to increase social interaction in some individuals. METHODS: In light of this finding, we assessed the ability of secretin to reverse phencyclidine- (PCP) induced impairment in prepulse inhibition (PPI), a leading animal model of sensorimotor gating deficits in schizophrenia. RESULTS: Similar to atypical antipsychotics, secretin (1, 3, 10, 30, and 100 microg/kg) partially and dose-dependently reversed the PCP-induced deficit in PPI without significantly affecting baseline startle when administered intraperitoneally (IP) 10 minutes following IP administration of PCP (3 mg/kg). CONCLUSIONS: This finding may be relevant to observations of antipsychotic efficacy of secretin in schizophrenic patients as well as our previous report that systemically administered secretin is capable of modulating conditioned fear, even at quite low doses.

Intravenous secretin for autism spectrum disorder.

BACKGROUND: Secretin is a gastro-intestinal hormone which has been presented as an effective treatment for autism based on anecdotal evidence. OBJECTIVES: To determine if intravenous secretin:1. improves the core features of autism (social interaction, communication and behaviour problems); 2. improves the non-core aspects of behaviour or function such as self injurious behaviour;3. improves the quality of life of affected individuals and their carers; 4. has short term and long term effects on outcome; 5. causes harm. SEARCH STRATEGY: Results of electronic searches of CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, ERIC, HealthStar and Sociofile (1998 - March 2005) were independently examined by two authors. Reference lists of trials and reviews were searched; experts and trialists were contacted to find unpublished studies. SELECTION CRITERIA: Randomised controlled trials of intravenous secretin comparing secretin with a placebo treatment in children or adults diagnosed with autism spectrum disorders, where at least one standardised outcome measure was reported. DATA COLLECTION AND ANALYSIS: Fourteen studies met inclusion criteria. All outcome data were continuous. Where trials used cross-over designs, analysis was conducted on results from first treatment phase, allowing combined analysis with parallel design trials. Where standardised assessment tools generated scores as outcome measures, comparisons were made between means of these scores. Where baseline means were reported, differences between treatment and control were determined to assess possible bias. Where mean change from baseline was reported, this was used in preference to post-treatment scores for meta-analyses or forest plots. As meta-analysis was possible for only one outcome (Childhood Autism Rating Scale), it was impossible to use sensitivity or subgroup analyses to assess impact of study quality, clinical differences in the intervention, or clinically relevant differences between groups, such as age or presence of gastrointestinal symptoms. MAIN RESULTS: Twenty-five established standardised outcome measures were reported to assess core features of autism, communication, behaviour, visio-spatial skills, affect and adverse events within fourteen included studies. No more than four studies used any one outcome measure similarly. Outcomes were reported between three and six weeks. RCTs of efficacy of secretin in autism have not shown improvements for core features of autism. AUTHORS' CONCLUSIONS: There is no evidence that single or multiple dose intravenous secretin is effective and as such it should not currently be recommended or administered as a treatment for autism. Further experimental assessment of secretin's effectiveness for autism can only be justified if methodological problems of existing research can be overcome.

Novel treatments for autistic spectrum disorders.

In no area of developmental pediatric practice is there more controversy regarding the choice of treatment than related to children with autistic spectrum disorders (ASD). Complementary and alternative medical therapies (CAM) are often elected because they are perceived as treating the cause of symptoms rather than the symptoms themselves. CAM used for autism can be divided by proposed mechanism: immune modulation, gastrointestinal, supplements that affect neurotransmitter function, and nonbiologic intervention. Secretin as a therapy for autism is discussed as an example of how a clinical observation rapidly grew to a widespread treatment before well-designed studies demonstrated absence of effect. The plausibility for behavioral effect was not substantiated by clinical studies. CAM used for treatment of autism is examined in terms of rationale, evidence of efficacy, side effects, and additional commentary. Families and clinicians need access to well-designed clinical evidence to assist them in choice of therapies.

Randomized controlled trial of transdermal secretin on behavior of children with autism.

Previous trials of secretin for the treatment of autism have utilized a single or double dose administered intravenously. This is a report of a double-blind, randomized, controlled crossover trial of transdermally applied secretin in 15 children diagnosed with autism or pervasive developmental delay. Secretin or placebo was applied daily, in ointment form, to the backs of the children in randomized, successive 4 week periods with an intermediate 6 week washout period. Behavioral outcomes were measured by parents and teachers using the Autism Treatment Evaluation Checklist. Overall, there were no statistically significant differences in speech, sociability, sensory, and health scores for treatment versus placebo periods. In addition, there were no differences in such scores for children with a history of diarrhea. Severity of autism was significantly greater at baseline in children receiving concomitant medications. Improvement in speech was found during the treatment phase of the trial (p=0.0479 for secretin versus placebo) only in children not using other medications.