Mechanisms of activation of mouse and human enteroendocrine cells by nutrients.

OBJECTIVE: Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. DESIGN AND RESULTS: mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators. CONCLUSIONS: Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes.

A case report of atrial fibrillation in early adulthood: dig deeper.

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia, which is often associated with underlying risk factors and undiagnosed conditions, including congenital heart disease. Atrial septal defects (ASDs) come to mind, albeit arrhythmias usually present later in life. We present herewith a young patient with cor triatriatum sinister (CTS), with some delay in establishing the diagnosis, following new onset AF in early adulthood. Case summary: A 31-year-old man presented with pre-syncope and coryzal symptoms and was newly diagnosed with AF in the context of an intercurrent viral illness. After treatment with oral anticoagulation and successful outpatient cardioversion, he was discharged from cardiology review. Two years later he re-presented with exercise intolerance and a 12-lead electrocardiogram revealing recurrence of AF. Subsequent investigation with transthoracic echocardiography revealed the underlying congenital cardiac defect of CTS, together with an ASD and patent foramen ovale. After corrective surgery, which involved membrane resection, a Cox-maze procedure and ASD closure, sinus rhythm was restored and at follow-up the patient had returned to baseline function. Discussion: Young patients presenting with new onset AF should undergo thorough cardiovascular assessment to identify treatable causes and reversible risk factors. Cor triatriatum sinister is a rare congenital anomaly that may present in adulthood and give rise to symptomatic AF. Surgical correction including a Cox-maze procedure in our patient resulted in restoration of sinus rhythm and a return of the patient's baseline functional status and improved quality of life.

Chronic thromboembolic pulmonary hypertension following long-term peripherally inserted central venous catheter use.

A 36-year-old woman presented with recurrent pulmonary emboli (PE) despite oral anticoagulation. She was a type I diabetic with severe gastroparesis requiring insertion of multiple long-term peripherally inserted central catheters (PICC) over a 10-year period. Imaging at presentation demonstrated a PICC-associated mobile mass in the right atrium and signs of pulmonary hypertension (PH). She was thrombolyzed and fully anticoagulated, and diabetic management without PICC strongly recommended. PH persisted, however, and she developed chronic thromboembolic pulmonary hypertension (CTEPH), for which successful pulmonary endarterectomy (PEA) surgery led to symptomatic and hemodynamic improvement. This was the first case of CTEPH reported related to long-term PICC use outside the setting of malignant disease, and a novel observation that the PEA specimen contained multiple plastic fragments. Long-term PICC placement increases the risk of CTEPH, a life-threatening, albeit treatable, complication.