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Item A Gut-Centric Model of Metabolic Homeostasis(Journal Of Diabetes Science and Technology, 2023-01-13) Rajagopalan, Harith; Lopez-Talavera, Juan Carlos; Klonoff, David C.; Cherrington, Alan D.Modern changes in diet and lifestyle have led to an explosion of insulin resistance and metabolic diseases around the globe which, if left unchecked, will become a principal driver of morbidity and mortality in the 21st century. The nature of the metabolic homeostatic shift within the body has therefore become a topic of considerable interest. While the gut has long been recognized as an acute nutrient sensor with signaling mechanisms to the other metabolic organs of the body, its role in regulating the body's metabolic status over longer periods of time has been underappreciated. Recent insights from bariatric surgery and intestinal nutrient stimulation experiments provide a window into the adaptive role of the intestinal mucosa in a foregut/hindgut metabolic balance model that helps to define metabolic parameters within the body-informing the metabolic regulation of insulin resistance versus sensitivity, hunger versus satiety, energy utilization versus energy storage, and protection from hypoglycemia versus protection from hyperglycemia. This intestinal metabolic balance model provides an intellectual framework with which to understand the distinct roles of proximal and distal intestinal segments in metabolic regulation. The model may also aid in the development of novel disease-modifying therapies that can correct the dysregulated metabolic signals from the intestine and stem the tide of metabolic diseases in society.Item Efficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overload(Frontiers in Physiology, 2019-08-13) Hwang, Hyun Seok; Baldo, Marcelo P.; Rodriguez, Jose Pindado; Faggioni, Michela; Knollmann, Bjorn C.Background: The dual Na+ and cardiac Ca2+-release channel inhibitor, Flecainide (FLEC) is effective in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by mutations in cardiac Ca2+ -release channels (RyR2), calsequestrin (Casq2), or calmodulin. FLEC suppresses spontaneous Ca2+ waves in Casq2-knockout (Casq2(-/-) ) cardiomyocytes, a CPVT model. However, a report failed to find FLEC efficacy against Ca2+ waves in another CPVT model, RyR2-R4496C heterozygous mice (RyR2(R)(4496)(C+/-)), raising the possibility that FLEC efficacy may be mutation dependent. Objective: To address this controversy, we compared FLEC in Casq2(-/-) and RyR2(R)(4496)(C+ /-) cardiomyocytes and mice under identical conditions. Methods: After 30 min exposure to FLEC (6 mu M) or vehicle (VEH), spontaneous Ca2+ waves were quantified during a 40 s pause after 1 Hz pacing train in the presence of isoproterenol (ISO, 1 mu M). FLEC efficacy was also tested in vivo using a low dose (LOW: 3 mg/kg ISO + 60 mg/kg caffeine) or a high dose catecholamine challenge (HIGH: 3 mg/kg ISO + 120 mg/kg caffeine). Results: In cardiomyocytes, FLEC efficacy was dependent on extracellular [Ca2+]. At 2 mM [Ca2+], only Casq2(-/-) myocytes exhibited Ca2+ waves, which were strongly suppressed by FLEC. At 3 mM [Ca2+] both groups exhibited Ca2+ waves that were suppressed by FLEC. At 4 mM [Ca2+], FLEC no longer suppressed Ca2+ waves in both groups. Analogous to the results in myocytes, RyR2(R)(4496C)(+/- )mice (n = 12) had significantly lower arrhythmia scores than Casq2(-/-) mice (n = 9), but the pattern of FLEC efficacy was similar in both groups (i.e., reduced FLEC efficacy after HIGH dose catecholamine challenge). Conclusion: FLEC inhibits Ca2+ waves in RyR2(R4496)(C+/-) cardiomyocytes, indicating that RyR2 channel block by FLEC is not mutation-specific. However, FLEC efficacy is reduced by Ca2+ overload in vitro or by high dose catecholamine challenge in vivo, which could explain conflicting literature reports.Item Neuronal and hormonal perturbations in postural tachycardia syndrome (vol 5, 220, 2014)(Frontiers in Physiology, 2019-07-30) Mar, Philip L.; Raj, Satish R.[This corrects the article DOI: 10.3389/fphys.2014.00220.]. http://hdl.handle.net/1803/10006