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Type 2 diabetes is a complex chronic metabolic disorder characterized by hyperglycemia associated with a relative deficiency of insulin secretion and a reduced response of target tissues to insulin. Considerable efforts have been put into the development of models describing the glucose-insulin system. The best known is Bergman’s “minimal” model for glucose, which is estimating glucose concentrations using fixed insulin concentrations as input. However, due to the involved feedback mechanisms, simultaneous modeling of both entities would be advantageous. This is particularly relevant if the model is intended to be used as a predictive tool. The mechanism-based glucose-insulin model presented in this thesis is able to simultaneously describe glucose and insulin profiles following a wide variety of clinical provocation experiments, such as intravenous and oral glucose tolerance tests, clamp studies and sequential meal tests over 24 hours. It consists of sub-models for glucose, labeled glucose and insulin kinetics. It also incorporates control mechanisms for the regulation of glucose production, insulin secretion, and glucose uptake. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed in NONMEM. Even if this model is a crude representation of a complex physiological system, its ability to represent the main processes of this system was established by identifying: 1) the difference in insulin secretion and insulin sensitivity between healthy volunteers and type 2 diabetics, 2) the action of incretin hormones after oral administration of glucose, 3) the circadian variation of insulin secretion and 4) the correct mechanism of action of a glucokinase activator, a new oral antidiabetic compound acting on both the pancreas and the liver. These promising results represent a proof of concept of a mechanistic drug-disease model that could play an important role in the clinical development of anti-diabetic drugs.

Os extratos de média polaridade de sete indivíduos de Piper solmsianum coletados em diferentes localidades foram analisados por cromatografia líquida de alta eficiência para se verificar diferenças quantitativas na concentração relativa de apiol, dilapiol, miristicina, grandisina, elemicina, isoelemicina e lignana tetraidrofurânica rel- (7R, 8R, 7\'R, 8\'R)-3,4,3\',4\'-dimetilenodioxi-5,5\'-dimetoxi-7,7\'-epoxilignana. Todos os perfis cromatográficos consistiam de apenas dois, três ou quatro picos majoritários. O(s) composto(s) majoritário(s) era(m) distinto(s) de planta para planta, e em um dos espécimes o pico predominante não era nenhum dos sete metabólitos secundários avaliados. Estudaram-se as variações diárias e anuais em três espécimes de uma população selvagem de P. solmsianum localizada na Reserva da CUASO, em São Paulo. A grandisina apresentou teores máximos no início da noite e teores mínimos no início da manhã. Apiol/dilapiol apresentou variação circadianas evidentes apenas em dois indivíduos, sendo que em um deles o teor máximo ocorreu por volta das oito horas da noite, e no outro, o teor máximo ocorreu por volta das cinco horas da manhã. A variação sazonal mostrou pequena amplitude de oscilação. Em dois espécimes o máximo teor de apiol/dilapiol e grandisina ocorreu no verão. No terceiro espécime não se observou variação periódica anual. / The crude extracts of seven individuals of Piper solmsianum collected in different places were analyzed by high efficiency liquid chromatography (HPLC) in order to determine changes in the relative content of apiol, dillapiol, myristicin, grandisin, elemicin, isoelemicin, and tetrahydrofuran lignan rel-(7R,8R,7R,8R)-3,4,3,4- dimethylenedioxy-5,5-dimethoxy-7,7-epoxylignan. All chromatographic profiles consisted of two, three or four major peaks with significant qualitative and quantitative differences. Major components were different from plant to plant and in one specimen an component different from the seven metabolites observed in most cases. The leaf extracts from three wild specimens of P. solmsianum collected at CUASO Reserve, showed annual and diurnal variations in apiol/dillapiol and grandisin relative concentrations. Three plants presented circadian variation with maximum content of grandisin late afternoon, and minimum content in the dawn. Apiol/dillapiol displayed clear circadian variation in two individuals, but without synchrony between phases. The maximum content was observed and in a second specimen around 8 p.m., and in the another specimen, the maximum content occur was observed at 5 a.m. The seasonal variation showed small amplitude of oscillation and in two individuals the maxima contents of apiol/dillapiol and grandisin were observed in summer

Os extratos de média polaridade de sete indivíduos de Piper solmsianum coletados em diferentes localidades foram analisados por cromatografia líquida de alta eficiência para se verificar diferenças quantitativas na concentração relativa de apiol, dilapiol, miristicina, grandisina, elemicina, isoelemicina e lignana tetraidrofurânica rel- (7R, 8R, 7\'R, 8\'R)-3,4,3\',4\'-dimetilenodioxi-5,5\'-dimetoxi-7,7\'-epoxilignana. Todos os perfis cromatográficos consistiam de apenas dois, três ou quatro picos majoritários. O(s) composto(s) majoritário(s) era(m) distinto(s) de planta para planta, e em um dos espécimes o pico predominante não era nenhum dos sete metabólitos secundários avaliados. Estudaram-se as variações diárias e anuais em três espécimes de uma população selvagem de P. solmsianum localizada na Reserva da CUASO, em São Paulo. A grandisina apresentou teores máximos no início da noite e teores mínimos no início da manhã. Apiol/dilapiol apresentou variação circadianas evidentes apenas em dois indivíduos, sendo que em um deles o teor máximo ocorreu por volta das oito horas da noite, e no outro, o teor máximo ocorreu por volta das cinco horas da manhã. A variação sazonal mostrou pequena amplitude de oscilação. Em dois espécimes o máximo teor de apiol/dilapiol e grandisina ocorreu no verão. No terceiro espécime não se observou variação periódica anual. / The crude extracts of seven individuals of Piper solmsianum collected in different places were analyzed by high efficiency liquid chromatography (HPLC) in order to determine changes in the relative content of apiol, dillapiol, myristicin, grandisin, elemicin, isoelemicin, and tetrahydrofuran lignan rel-(7R,8R,7R,8R)-3,4,3,4- dimethylenedioxy-5,5-dimethoxy-7,7-epoxylignan. All chromatographic profiles consisted of two, three or four major peaks with significant qualitative and quantitative differences. Major components were different from plant to plant and in one specimen an component different from the seven metabolites observed in most cases. The leaf extracts from three wild specimens of P. solmsianum collected at CUASO Reserve, showed annual and diurnal variations in apiol/dillapiol and grandisin relative concentrations. Three plants presented circadian variation with maximum content of grandisin late afternoon, and minimum content in the dawn. Apiol/dillapiol displayed clear circadian variation in two individuals, but without synchrony between phases. The maximum content was observed and in a second specimen around 8 p.m., and in the another specimen, the maximum content occur was observed at 5 a.m. The seasonal variation showed small amplitude of oscillation and in two individuals the maxima contents of apiol/dillapiol and grandisin were observed in summer

Restless legs syndrome (RLS) is a sensory-motor disorder characterized by abnormal circadian rhythm with an increase in the severity of sensory and motor symptoms at night. Even though many neurological diseases have shown a strong nexus between motor and cognitive symptoms, to date, cognitive functions especially cognitive control in RLS has been poorly understood. Given that cognitive control is a key to leading a self-serving and successful life, including many aspects of employment, social life, and attaining long-term goals, this thesis aimed to examine cognitive control and the underlying mechanisms in RLS. Thalamic gamma aminobutyric acid (GABA), which has been linked to RLS sensory-motor symptoms, also plays an important role in cognitive control. Therefore, the potential relationship between thalamic GABA level and cognitive control in RLS was examined (Study I). RLS patients displayed reduced working memory-based control performances as compared to healthy controls. Elevated thalamic GABA was found to attenuate the observed control deficits in RLS, even though changes in thalamic GABA levels might not be the ultimate causes of these deficits. According to the modulatory effect of thalamic GABA on thalamic activity and thalamo-cortical connectivity, relatively higher GABA levels may have helped RLS patients compensate for their pathological changes such as thalamic hyperactivity and hypoconnectivity, which may underpin the observed control deficits. The critical feature of RLS, abnormal circadian rhythm is thought to be related to nocturnal striatal dopamine deficiency. Concerning the dopaminergic modulation of cognitive control, the circadian variation of cognitive control processes has been investigated (Study II & III). RLS patients displayed reduced attentional control (Study II) and automatic response activation (Study III) at night, which resulted from decreased activation within the extra-striate visual cortex, the superior parietal cortex, and the premotor cortex. As there were no activity changes within the prefrontal cortex, it is likely that cortico-basal ganglia cognitive loops were less prone to RLS. Instead, striatal dopamine deficiency at night may have influenced the cortico-cortical functional connectivity and cortico-basal ganglia motor loops in RLS. These findings not only shed light on the underlying mechanisms of cognitive control, but also advance early clinical treatment possibilities for cognitive changes in RLS patients. Furthermore, recent insights into daytime-related cognition may help patients develop a suitable daytime schedule to minimize the detrimental effects induced by cognitive deficits.