It is known that the circadian rhythm in hepatic phosphoenolpyruvate carboxykinase expression (a limiting catalytic step of gluconeogenesis) and hepatic glucose production is maintained by both daily oscillation in autonomic inputs to the liver and night feeding behavior. However, increased glycemia and reduced melatonin (Mel) levels have been recently shown to coexist in diabetic patients at the end of the night period. In parallel, pinealectomy (PINX) is known to cause glucose intolerance with increased basal glycemia exclusively at the end of the night. The mechanisms that underlie this metabolic feature are not completely understood. Here, we demonstrate that PINX rats show night-time hepatic insulin resistance characterized by reduced insulin-stimulated RAC-α serine/threonine-protein kinase phosphorylation and increased phosphoenolpyruvate carboxykinase expression. In addition, PINX rats display increased conversion of pyruvate into glucose at the end of the night. The regulatory mechanism suggests the participation of unfolded protein response (UPR), because PINX induces night-time increase in activating transcription factor 6 expression and prompts a circadian fashion of immunoglobulin heavy chain-binding protein, activating transcription factor 4, and CCAAT/enhancer-binding protein-homologous protein expression with Zenith values at the dark period. PINX also caused a night-time increase in Tribble 3 and regulatory-associated protein of mammalian target of rapamycin; both were reduced in liver of PINX rats treated with Mel. Treatment of PINX rats with 4-phenyl butyric acid, an inhibitor of UPR, restored night-time hepatic insulin sensitivity and abrogated gluconeogenesis in PINX rats. Altogether, the present data show that a circadian oscillation of UPR occurs in the liver due to the absence of Mel. The nocturnal UPR activation is related with night-time hepatic insulin resistance and increased gluconeogenesis in PINX rats.

Melatonin is a hormone synthesized in the pineal gland, which modulates several functions within the organism, including the synchronization of glucose metabolism and glucose-stimulated insulin secretion (GSIS). Melatonin can mediate different signaling pathways in pancreatic islets through two membrane receptors and via antioxidant or pro-oxidant enzymes modulation. NADPH oxidase (NOX) is a pro-oxidant enzyme responsible for the production of the reactive oxygen specie (ROS) superoxide, generated from molecular oxygen. In pancreatic islets, NOX-derived ROS can modulate glucose metabolism and regulate insulin secretion. Considering the roles of both melatonin and NOX in islets, the aim of this study was to evaluate the association of NOX and ROS production on glucose metabolism, basal and GSIS in pinealectomized rats (PINX) and in melatonin-treated isolated pancreatic islets. Our results showed that ROS content derived from NOX activity was increased in PINX at baseline (2.8 mM glucose), which was followed by a reduction in glucose metabolism and basal insulin secretion in this group. Under 16.7 mM glucose, an increase in both glucose metabolism and GSIS was observed in PINX islets, without changes in ROS content. In isolated pancreatic islets from control animals incubated with 2.8 mM glucose, melatonin treatment reduced ROS content, whereas in 16.7 mM glucose, melatonin reduced ROS and GSIS. In conclusion, our results demonstrate that both basal and stimulated insulin secretion can be regulated by melatonin through the maintenance of ROS homeostasis in pancreatic islets.

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Introdução: Os órgãos tendinosos de Golgi (OTG) são receptores sensoriais localizados na junção miotendínea e conectados em série com as fibras musculares. Sua função no controle motor em humanos ainda não está elucidada. Objetivos: Relatar a fisiologia do OTG e seu envolvimento em distúrbios do tônus e na percepção da força, bem como sua interação com outros sistemas envolvidos no controle motor. Métodos: A revisão da literatura foi realizada no período de 1964 até os dias atuais. O estudo foi baseado em artigos experimentais e de revisão além de capítulos de livros-textos. Resultados: O OTG é inervado por axônio aferente (af) Ib que dispara sempre que há tensão no músculo, inibindo, através de um interneurônio (IN) inibitório Ib, o neurônio motor que está gerando a força. Além disso, os neurônios motores antagonistas são facilitados através de duas sinapses por um IN excitatório Ib. Os estímulos convergem ao IN Ib das mais variadas fontes, incluindo vários af periféricos e estímulos excitatórios e inibitórios suprassegmentares. Conclusão: O OTG atua juntamente com o fuso muscular na regulação do tônus e da complacência musculares; está envolvido na mediação da propriocepção e possui um papel importante no ritmo locomotor normal.

Fatores neurotróficos como possível estratégia terapêutica na regeneração do tecido nervoso: Revisão sistemática Neurotrophic factors as a possible therapeutic strategy in nervous tissue regeneration: A systematic review

Título da Tese: Papel da melatonina na regulação da ritmicidade circadiana de tecidos periféricos envolvidos com o metabolismo energético: avaliação do perfil diário da expressão dos genes relógio (clock genes).

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