RESUMO
Diabetes is a common and significant co-morbidity in cystic fibrosis (CF). The pathogenesis of cystic fibrosis related diabetes (CFRD) is incompletely understood. Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis. We determined the structure of the endocrine pancreas in fetal, newborn and older CF and non-CF pigs and assessed endocrine pancreas function by intravenous glucose tolerance test (IV-GTT). In fetal pigs, pancreatic insulin and glucagon density was similar between CF and non-CF. In newborn and older pigs, the insulin and glucagon density was unchanged between CF and non-CF per total pancreatic area, but increased per remnant lobular tissue in CF reflecting exocrine pancreatic loss. Although fasting glucose levels were not different between CF and non-CF newborns, CF newborns demonstrated impaired glucose tolerance and increased glucose area under the curve during IV-GTT. Second phase insulin secretion responsiveness was impaired in CF newborn pigs and significantly lower than that observed in non-CF newborns. Older CF pigs had elevated random blood glucose levels compared with non-CF. In summary, glycaemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycaemia developed over time. Functional changes in CF pig pancreas were not associated with a decline in islet cell mass. Our results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.
Assuntos
Glicemia , Fibrose Cística/metabolismo , Diabetes Mellitus/metabolismo , Intolerância à Glucose , Insulina/metabolismo , Animais , Fibrose Cística/complicações , Fibrose Cística/patologia , Diabetes Mellitus/patologia , Ensaio de Imunoadsorção Enzimática , Teste de Tolerância a Glucose , Insulina/sangue , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/fisiologia , Pâncreas/metabolismo , Pâncreas/patologia , SuínosRESUMO
Our objective was to summarize the available literature on the use of preoperative esophagogastroduodenoscopy (EGD) and its impact on management and/or postoperative outcomes in pediatric patients undergoing metabolic and bariatric surgery. We performed a search using PubMed in February 2023 for articles examining EGD and any clinical correlation in pediatric patients undergoing bariatric surgery. Search results were manually reviewed and included in the study if they examined findings of EGD done prior to bariatric surgery and were excluded if they were not primarily done in pediatric or adolescent patients. Our search yielded 549 distinct articles, with a total of four articles remaining after applying inclusion and exclusion criteria. All four studies were retrospective. A total of 244 patients were studied, with an age range of 9-25 years. Of the patients whose respective findings were reported, 21/150 patients (14%) had esophagitis, 55/150 (37%) had gastritis, 55/244 (23%) had Helicobacter pylori, and 18/150 (12%) had duodenitis. There were a total of 60 findings that changed medical management, and one that changed surgical management. A high proportion of positive EGD findings that changed medical management was evident, and one study suggested that mucosal inflammation may be a prognostic indicator for postoperative weight loss. However, there is a paucity of data examining the utility of routine EGD prior to bariatric surgery, specifically in pediatric patients, and more studies are therefore needed to construct the evidence basis for guidelines.
RESUMO
Pancreatic disease has onset in utero in humans with cystic fibrosis (CF), and progresses over time to complete destruction of the organ. The exact mechanisms leading to pancreatic damage in CF are incompletely understood. Inflammatory cells are present in the pancreas of newborn pigs with CF (CF pigs) and humans, which suggests that inflammation may have a role in the destructive process. We wondered whether tissue inflammation and genes associated with inflammatory pathways were increased in the pancreas of fetal CF pigs [83 to 90 days gestation (normal pig gestation is ~114 days)] and newborn pigs. Compared with fetal pigs without CF (non-CF pigs), in fetal CF pigs, the pancreas exhibited patchy inflammation and acinar atrophy, with progression in distribution and severity in neonatal CF pigs. Large-scale transcript profiling revealed that the pancreas in fetal and newborn CF pigs exhibited significantly increased expression of proinflammatory, complement cascade, and profibrotic genes when compared with fetal and newborn non-CF pigs. Acinar cells exhibited increased apoptosis in the pancreas of fetal and newborn CF pigs. α-Smooth muscle actin and transforming growth factor ß1 were increased in both fetal and newborn CF pig pancreas, suggesting activation of profibrotic pathways. Cell proliferation and mucous cell metaplasia were detected in newborn, but not fetal, CF pigs, indicating that they were not an initiator of pathogenesis but a response. Proinflammatory, complement cascade, proapoptotic, and profibrotic pathways are activated in CF pig pancreas, and likely contribute to the destructive process.
Assuntos
Fibrose Cística/genética , Fibrose Cística/patologia , Feto/patologia , Inflamação/patologia , Pâncreas/metabolismo , Pâncreas/patologia , Transdução de Sinais/genética , Actinas/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/genética , Proliferação de Células , Proteínas do Sistema Complemento/imunologia , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Progressão da Doença , Feminino , Feto/metabolismo , Perfilação da Expressão Gênica , Inflamação/genética , Pâncreas/imunologia , Gravidez , Sus scrofa , Transcriptoma/genéticaRESUMO
The molecular clock machinery regulates several homeostatic rhythms, including glucose metabolism. We previously demonstrated that Roux-en-Y gastric bypass (RYGB) has a weight-independent effect on glucose homeostasis and transiently reduces food intake. In this study we investigate the effects of RYGB on diurnal eating behavior as well as on the molecular clock and this clock's requirement for the metabolic effects of this bariatric procedure in obese mice. We find that RYGB reversed the high-fat diet-induced disruption in diurnal eating pattern during the early postsurgery phase of food reduction. Dark-cycle pair-feeding experiments improved glucose tolerance to the level of bypass-operated animals during the physiologic fasting phase (Zeitgeber time 2, ZT2) but not the feeding phase (ZT14). Using a clock gene reporter mouse model (mPer2Luc), we reveal that RYGB induced a liver-specific phase shift in peripheral clock oscillation with no changes to the central clock activity within the suprachiasmatic nucleus. In addition, we show that weight loss effects were attenuated in obese ClockΔ19 mutant mice after RYGB that also failed to improve glucose metabolism after surgery, specifically hepatic glucose production. We conclude that RYGB reprograms the peripheral clock within the liver early after surgery to alter diurnal eating behavior and regulate hepatic glucose flux.
Assuntos
Derivação Gástrica , Resistência à Insulina , Camundongos , Animais , Glucose/metabolismo , Derivação Gástrica/métodos , Glicemia/metabolismo , Resistência à Insulina/fisiologia , Comportamento Alimentar , Fígado/metabolismoRESUMO
The pancreas, liver, and gallbladder are commonly involved in cystic fibrosis (CF), and acidic, dehydrated, and protein-rich secretions are characteristic findings. Pancreatic function studies in humans have been done by sampling the jejunal fluid. However, it has been difficult to separately study the function of pancreatic and biliary systems in humans with CF, because jejunal fluid contains a mixture of bile and pancreatic fluids. In contrast, pancreatic and biliary ducts open separately into the porcine intestine; therefore, biliary and pancreatic fluid can be individually analyzed in CF pigs. We studied newborn wild-type (WT) and CF pigs and found that CFTR was localized to the pancreatic ducts. We collected bile and pancreatic fluid and analyzed pancreatic enzymes with activity assays and immunoblot. Pancreatic enzyme expression was significantly decreased in CF compared with WT pigs. The volume and pH of pancreatic fluid were significantly lower and protein concentration was >5-fold higher in CF pigs. Secretin stimulation increased pancreatic fluid volume and pH in WT, but not CF, pigs. Baseline bile volume did not differ between WT and CF pigs, but volume did not increase in response to secretin in CF pigs. Bile pH was lower and protein concentration was twofold higher in CF pigs. These results indicate that pancreatic and biliary secretions are altered in CF pigs. Abnormal pancreatic and biliary secretion in CF may have important implications in disease pathogenesis.
Assuntos
Ductos Biliares/metabolismo , Fibrose Cística/metabolismo , Pâncreas/metabolismo , Amilases/metabolismo , Animais , Ductos Biliares/fisiopatologia , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Modelos Animais de Doenças , Pâncreas/fisiopatologia , Suco Pancreático/metabolismo , Suínos , Tripsina/metabolismoRESUMO
Obesity is a rising medical condition; metabolic and bariatric surgery, mainly sleeve gastrectomy, offers a successful weight loss option which is maintainable. Weight loss is heavily dependent on energy expenditure. Resting energy expenditure (REE) after sleeve gastrectomy has been described in the literature with varying results. In this review, we review all published literature that described REE post sleeve gastrectomy in human. We found that REE goes down after sleeve gastrectomy as the weight loss occurs and REE when adjusted for weight (REE/kg) only goes up significantly in the 2 studies that included youths. REE/kg did not significantly change in studies including adults ages 30 and above. This study is the first that reviews and summarized REE findings post sleeve gastrectomy and more studies are needed especially targeting the pediatric and youth populations.
Assuntos
Cirurgia Bariátrica , Obesidade Mórbida , Adolescente , Adulto , Cirurgia Bariátrica/métodos , Criança , Metabolismo Energético , Gastrectomia/métodos , Humanos , Obesidade Mórbida/cirurgia , Redução de PesoRESUMO
BACKGROUND: Toll-like receptor 4 (TLR4) has been suggested as one of the forefront cross-communicators between the intestinal bacteria and the host to regulate inflammatory signals and energy homeostasis. High-fat diet-induced inflammation is mediated by changes in gut microbiota and requires a functional TLR-4, the deficiency of which renders mice resistant to diet-induced obesity and its associated metabolic dysfunction. Furthermore, gut microbiota was suggested to play a key role in the beneficial effects of Roux-en-Y gastric bypass (RYGB), a commonly performed bariatric procedure. OBJECTIVES: To explore whether TLR4, myeloid differentiation factor 8 (MyD88; 1 of its key downstream signaling regulators) and gut microbiota play an integrative role in RYGB-induced metabolic outcomes. SETTING: Animal- based study. METHOD: We performed RYGB in TLR4 and MyD88 knock-out (KO) mice and used fecal microbiota transplant (FMT) from RYGB-operated animals to these genetic mouse models to address our questions. RESULTS: We demonstrate that RYGB reduces TLR4 expression explicitly in the small and large intestine of C57Blc/6J mice. We also show that TLR4 KO mice have an attenuated glucoregulatory response to RYGB. In addition, we reveal that MyD88 KO mice fail to respond to all RYGB-induced metabolic effects. Finally, fecal microbiota transplant from RYGB-operated mice into TLR4 KO and MyD88 KO naïve recipients fails to induce a metabolic phenotype similar to that of the donors, as it does in wild-type recipients. CONCLUSION: TLR4 and MyD88 are required for RYGB-induced metabolic response that is likely mediated by gut microbiome.
Assuntos
Derivação Gástrica , Microbioma Gastrointestinal , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Derivação Gástrica/métodos , Microbioma Gastrointestinal/fisiologia , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Obesidade/cirurgia , Receptor 4 Toll-Like/genéticaRESUMO
BACKGROUND/AIM: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. METHOD: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. RESULTS: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9-a GLP-1 receptor antagonist-worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. CONCLUSIONS: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/biossíntese , Enteropatias/induzido quimicamente , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Receptor do Peptídeo Semelhante ao Glucagon 1/antagonistas & inibidores , Técnica Clamp de Glucose , Intolerância à Glucose/induzido quimicamente , Ibuprofeno/efeitos adversos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and "browning" of visceral mesenteric fat. Consequently, selective splanchnic denervation abolishes all beneficial metabolic outcomes of gastric bypass that involve changes in the endocannabinoid signaling within the small intestine. Furthermore, we demonstrate that administration of rimonabant, an endocannabinoid receptor-1 (CB1) inverse agonist, to obese mice mimics RYGB-specific effects on energy balance and splanchnic nerve activity. On the other hand, arachidonoylethanolamide (AEA), a CB1 agonist, attenuates the weight loss and metabolic signature of this procedure. These findings identify CB1 as a key player in energy regulation post-RYGB via a pathway involving the sympathetic nervous system.
Assuntos
Endocanabinoides/uso terapêutico , Derivação Gástrica/métodos , Sistema Nervoso Simpático/fisiologia , Animais , Endocanabinoides/farmacologia , Feminino , Humanos , Masculino , CamundongosRESUMO
BACKGROUND: Blue Rubber Bleb Nevus Syndrome (BRBNS) is a rare, severe, sporadically occurring disorder characterized by multiple venous malformations. AIMS: To present and analyze a case series of pediatric patients with BRBNS and to describe diagnostic approaches and management options applied. PATIENTS AND METHODS: Multicenter, retrospective study, evaluating the diagnosis and management of children with BRBNS. RESULTS: Eighteen patients diagnosed with BRBNS were included. Cutaneous venous malformations were observed in 78% and gastrointestinal venous malformations in 89%. Lesions were also found in other organs including muscles, joints, central nervous system, eyes, parotid gland, spine, kidneys and lungs. Gastrointestinal lesions were more common in the small intestine than in stomach or colon. The management varied significantly among centers. Endoscopic therapy and surgical therapy alone failed to prevent recurrence of lesions. In younger children and in patients with musculoskeletal or other organ involvement, sirolimus was used with 100% success rate in our series (5 patients treated) although poor compliance with subtherapeutic sirolimus trough levels led to recurrence in a minority. CONCLUSIONS: Considering the multi-organ involvement in BRBNS, diagnosis and management requires a multidisciplinary approach. The treatment includes conservative, medical, endoscopic and surgical options. Prospective multicenter studies are needed to identify the optimal management of this rare condition.
Assuntos
Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Nevo Azul/diagnóstico , Nevo Azul/terapia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/terapia , Criança , Pré-Escolar , Diagnóstico Diferencial , Endoscopia do Sistema Digestório , Feminino , Humanos , Lactente , Comunicação Interdisciplinar , Masculino , Recidiva Local de Neoplasia , Estudos Retrospectivos , Escleroterapia , Sirolimo/uso terapêutico , Malformações Vasculares/diagnóstico , Malformações Vasculares/terapiaRESUMO
Pelvic tumors in adolescent females are very uncommon. While the most common presentation is pelvic discomfort, we report the case of a 14-year-old female presenting with menorrhagia which is an unusual initial complaint for a large pelvic tumor. Adolescent females who present with heavy menstrual bleeding initially undergo assessment to rule out a bleeding disorder. In this case, careful history and physical examination helped in making a quick diagnosis and management. Ultrasound of abdomen showed a huge cystic mass due to serous cystadenoma of the ovary.
RESUMO
Isolation of high-quality RNA from pancreas is challenging because the organ contains large quantities of RNases and undergoes autolysis upon harvest. Here we present a simplified perfusion method of the pancreas using an RNase inhibitor. The technique consistently yields high-quality RNA from stored pancreas samples suitable for molecular biology applications, including quantitative RT-PCR. Yields are comparable to RNA isolated from pancreas immediately, but superior to RNA isolated from stored samples that were snap-frozen or immersed in an RNase inhibitor solution. In addition, when compared to the previously reported in situ ductal perfusion technique, our method does not cause histological artifacts.