INTRODUÇÃO: a ação dos hormônios contrarreguladores da insulina na cetoacidose diabética tem sido estudada desde a década 1970-80, e é sabido que seus níveis elevados, aumentando a resistência à insulina, têm papel importante na gênese da CAD. Leptina e ghrelina foram mais recentemente associadas à homeostase da glicose, no entanto, seu papel na CAD ainda é controverso. Os objetivos deste estudo foram: avaliar as alterações nas concentrações séricas de leptina e ghrelina presentes ao diagnóstico da CAD durante os primeiros três dias de seu tratamento e após a estabilização completa do quadro, as correlações com a insulina e outros contrarreguladores, comparando com indivíduos saudáveis. MÉTODOS: foram analisados 25 episódios de cetoacidose diabética em 22 pacientes admitidos no setor de emergência pediátrica de um hospital terciário em São Paulo, Brasil, entre março de 2010 e julho de 2013. Os episódios de cetoacidose foram manejados com reposição endovenosa de fluidos e eletrólitos e análogos de ação ultrarrápida de insulina subcutânea intermitente. Amostras para glicose, insulina, leptina, ghrelina, GH, cortisol e catecolaminas foram obtidas no momento da admissão (T0), durante o tratamento da cetoacidose (após 2, 4, 6, 12, 24 e 72 horas) e em um momento estável após a alta (TE). Os dados foram analisados utilizando-se os testes ANOVA ou Kruskal-Wallis para a comparação de variáveis contínuas durante o tratamento, Teste t de Student ou Mann Whitney para a comparação entre pacientes e grupo controle, e testes de Pearson ou Spearman para correlação entre as variáveis; p < 0.05 foi considerado significativo. RESULTADOS: observamos três fases distintas (a): o diagnóstico de CAD (T0) em que prevalecem hiperglicemia, insulinopenia e elevação de hormônios contrarreguladores; nesse momento, as concentrações de leptina foram menores que no grupo controle, provavelmente relacionadas à insuficiência de energia, estado hipercatabólico e elevação dos hormônios contrarreguladores; as concentrações de ghrelina foram menores que no grupo controle, apesar do hipercatabolismo, da hipoinsulinemia e da hiperglucagonemia, todas situações que fisiologicamente elevariam seus níveis, possivelmente devido à hiperglicemia marcante do momento; (b) durante o tratamento da CAD (T2 a T72): com redução gradual da glicemia até T24, elevação gradual da insulina, redução de glucagon, GH, cortisol e norepinefrina; nesse período, ocorreu elevação gradual da leptina após o início do tratamento com insulina, que atingiu níveis comparáveis ao GC no T72; redução da ghrelina (T4 menor que T72), provavelmente inibida pela hiperglicemia e por doses suprafisiológicas de insulina; e (c) após a resolução da CAD (TE): com hiperinsulinização; GH, cortisol e norepinefrina comparáveis ao GC, glucagon reduzido em relação ao GC, possivelmente supresso pelos altos níveis de insulina; as concentrações de leptina foram maiores que em T0 e comparáveis ao GC; os níveis de ghrelina, comparáveis ao diagnóstico e durante o tratamento da CAD, ainda significativamente menores que no GC, provavelmente influenciados pela hiperglicemia, hiperinsulinemia e baixos níveis de glucagon. CONCLUSÕES: as concentrações de leptina diminuídas ao diagnóstico de CAD tornam-se semelhantes em pacientes com DM1 estáveis em relação a indivíduos saudáveis, podendo ser um marcador de hipercatabolismo. As concentrações de ghrelina permaneceram baixas durante todo o estudo em pacientes diabéticos, independentemente da descompensação / INTRODUCTION: The role of glucoregulatory hormones in diabetic ketoacidosis have been investigated since 1970-80s and the elevation of growth hormone, cortisol and norepinephrine reduce the sensitivity to insulin. Leptin and Ghrelin have more recently been shown to regulate glucose and insulin metabolism; however, their functions in DKA are still controversial. The aims of this study were to analyze leptin, ghrelin and their relationships with other glucoregulatory hormones on diagnosis of diabetic ketoacidosis, during the first 72 hours of treatment and after recovery compared with healthy subjects. METHODS: We examined 25 DKA episodes in 22 patients who were admitted to the pediatric emergency department of a tertiary hospital in São Paulo, Brazil, from March 2010 to July 2013. These episodes were managed with fluids and electrolytes replacement and intermittent subcutaneous fast-acting insulin analogues. Samples for blood glucose, insulin, leptin, ghrelin, GH, cortisol, and catecholamines were obtained on admission (T0), during treatment (after 2, 4, 6, 12, 24 and 72 hours) and after discharge (TS). The control group (CG) was comprised by 21 healthy subjects, who submitted a single blood sample. Data were analyzed by ANOVA or Kruskal-Wallis to compare continuous variables during treatment, student t-test or Mann Whitney for comparisons between patients and controls, and Pearson or Spearman correlations between variables; p < 0.05 was considered to be significant. RESULTS: we observed three distinct phases: (a) on diagnosis of DKA (T0) where hyperglycemia, insulinopenia, and elevated glucoregulatory hormones prevail; leptin concentrations were lower than CG at this moment, probably related to energy insufficiency, hypercatabolic state, and elevated glucoregulatory hormones; ghrelin concentrations were lower than CG at this moment, despite hypercatabolism, hypoinsulinemia and hyperglucagonemia, situations that physiologically would increase them, possibly related to marked hyperglycemia at T0; (b) during DKA treatment (T2 to T72): with gradual reduction of blood glucose until T24, gradual rise of insulin; reduction of glucagon, GH, cortisol and norepinephrine. Leptin levels rises gradually after the start of insulin treatment and is comparable to control group at T72; reduction of ghrelin (T4 lower than T72), possibly inhibited by hyperglycemia and supraphysiological doses of insulin, all lower than CG; and (c) After DKA (TS), in an outpatient setting: with marked hyperinsulinization, GH, cortisol and norepinephrine were comparable to CG. Glucagon was lower than CG, possibly suppressed by high insulin levels; leptin was higher than T0 and comparable to CG; ghrelin levels were comparable to all samples during DKA treatment, and still significantly lower than CG, probably influenced by hyperglycemia, hyperinsulinemia and low glucagon levels. CONCLUSIONS: Low leptin levels were a marker of hypercatabolic state, with normalization of its concentrations with DKA resolution. Ghrelin was low in diabetic patients independent of metabolic derangements

L’addiction à l’alimentation (AA) est un concept ancien, mais encore sujet de controverses qui toucherait 18 à 24 % des obèses. Dans cette thèse, nous nous sommes intéressés aux intrications entre régulations du comportement alimentaire, addiction et AA, afin de mieux comprendre les mécanismes liés à la désinhibition de la prise alimentaire. Notre travail a conduit à plusieurs résultats : 1) Une revue de la littérature a permis de montrer l’existence d’interaction étroite entre les niveaux de régulation du comportement alimentaire et comment AA pourrait en être un exemple de dérégulation. 2) Une étude de cohorte a permis de démontrer l’existence de caractéristiques cliniques communes entre addictions et AA et celle d’un probable transfert d’addiction de la nicotine vers l’alimentation. 3) Sur le plan expérimental, nous avons montré qu’il existe des perturbations des ondes P300 et N200, dans l’obésité et la désinhibition alimentaire, proches de celles observées dans les addictions. 4) Enfin, nos résultats suggèrent le rôle potentiel de la ghréline comme marqueur de risque de trouble du comportement alimentaire. Ce travail ouvre des perspectives sur le plan expérimental, avec la suggestion de groupes contrôles plus pertinents ; cliniques, avec la création d’un potentiel test de dépistage rapide ; thérapeutiques, avec la mise en place d’un essai thérapeutique par tDCS / Food addiction (FA) is an old concept, but still subject to controversy. It affects 18 to 24% of obese people. In this thesis, we are interested in overlaps between food behavior regulation, addiction and FA, in order to better understand the mechanisms linked to food intake disinhibition. Our work leads to several results: 1) A review of the literature has shown the existence of close interaction between eating behavior regulation levels and how FA could be an example of their disturbance. 2) A cohort study demonstrated the existence of common clinical features between addiction and FA and a probable addiction transfer from nicotine to food. 3) From an experimental point of view, we have shown that there are disturbances of P300 and N200 ERP, in obesity and food disinhibition, close to those observed in addictions. 4) Finally, our results suggest the potential role of ghrelin as a marker for eating disorders increased risk. This work opens experimental perspectives, with the suggestion of more relevant control groups; clinical perspectives, with the creation of a screening tool; therapeutics perspectives, with the establishment of a therapeutic trial by tDCS

Le but de ce travail était de déterminer les effets de la pratique d'activité physique sur le phénotype osseux et l'adiposité médullaire en cas d'insuffisance pondérale selon deux approches complémentaires, chez l'humain et chez les souris. La première étude a été menée sur 24 femmes normo-pondérées et 13 femmes en sous-poids âgées entre 20 et 35 ans. Cette étude a montré que les femmes en sous-poids présentent une faible masse osseuse au niveau du corps entier, rachis lombaire et col fémoral et une altération de la géométrie du col fémoral par rapport aux femmes normo-pondérées, et un score de l'os trabéculaire sur la limite inférieure de la normale. La VO₂ₘₐₓ (L/min) était parmi les principaux déterminants des paramètres osseux chez les jeunes femmes quel que soit leur indice de masse corporelle. Les résultats de cette première étude suggèrent que l'augmentation de la VO₂ₘₐₓ (L/min) sont essentiels pour prévenir la perte osseuse chez les jeunes femmes en sous-poids. La deuxième étude a été menée sur des souris femelles jeunes adultes soumises à un exercice physique volontaire dans une roue combinée à une restriction alimentaire (restriction de 50% de l'apport ad libitum) pendant 15 et 55 jours. Cette étude a démontré que la perte pondérale liée à la restriction alimentaire présente des répercussions négatives sur l'os cortical avec peu d'effets néfastes sur l'os trabéculaire et est associée à une augmentation du nombre des adipocytes médullaires dès 15 jours de restriction. Cette étude a également démontré que l'exercice physique volontaire dans une roue ne protège pas contre les modifications de l'architecture osseuse et l'accumulation de l'adiposité médullaire liées à la restriction alimentaire. Parce que la ghréline est apparue comme régulateur potentiel de l'adiposité médullaire, la troisième étude a été menée sur des souris femelles jeunes adultes dépourvues du récepteur de la ghréline (Growth Hormone Secretagogue Receptor, Ghsr-/-) soumises à une restriction alimentaire (restriction de 50% de l'apport ad libitum) combinée à un exercice physique volontaire dans une roue de 21 jours. Cette étude a démontré que la ghréline est un médiateur clé de l'expansion de l'adiposité médullaire associée à la restriction alimentaire suite à l'activation du GHSR et que la restriction alimentaire est nécessaire pour révéler certaines différences dans la microarchitecture osseuse associée à l'invalidation du GHSR. / The aim of this work was to determine the effects of physical activity on bone phenotype and bone marrow adiposity in underweight conditions using two complementary approaches, on human and on mice. The first study was conducted on 24 normal weight women and 13 underweight women aged 20-35 years. This study showed that underweight women have appropriately lower bone mass at the whole body, lumbar spine and femoral neck and altered femoral neck geometry compared to normal weight women, and a trabecular bone score on the lower limit of normal. VO₂ₘₐₓ (L/min) was considered as strong determinant of bone parameters in young adult women regardless of their body mass index. The results of this first study suggest that increasing VO₂ₘₐₓ (L/min) is essential to prevent bone loss in underweight young women. The second study was conducted on young adult female mice subjected to voluntary wheel running and food restriction (50% of ad libitum intake) during 15 and 55 days. This study demonstrated that weight loss related to food restriction has a negative impact on cortical bone with few adverse effects on trabecular bone and is associated with an increase in the number of bone marrow adipocytes already after 15 days of restriction. This study also showed that voluntary wheel running exercise does not protect against changes in bone architecture and accumulation of bone marrow adiposity related to food restriction. Because ghrelin appeared as a potential regulator of bone marrow adiposity, the third study was conducted on young adult mice lacking the ghrelin receptor (Growth Hormone Secretagogue Receptor, Ghsr-/-) subjected to voluntary wheel running and food restriction (50% of ad libitum intake) during 21 days. This study demonstrated that ghrelin is a key mediator of food restriction - associated bone marrow adiposity expansion through activation of GHSR and that food restriction is necessary to reveal some differences in bone microarchitecture associated to GHSR invalidation.

En production animale, notamment dans les filières bovines, il est dun intérêt économique daugmenter la quantité dhormone de croissance dans la circulation sanguine. La ghréline est un peptide principalement produit au niveau de la paroi stomacale. Ce ligand endogène au GHSR stimule la sécrétion hypophysaire de lhormone de croissance. Peptide orexigène, la ghréline est impliquée dans les mécanismes relatifs au maintien de lhoméostasie énergétique. Dans loptique daméliorer les performances animales, deux approches de la ghréline ont été effectuées. La première approche consiste en létude des gènes bovins codant pour la ghréline (bGHRL) et son récepteur (bGHSR). Ces deux gènes ont été respectivement localisés sur BTA 22 et BTA 1. Quatorze polymorphismes ont été détectés sur ces deux gènes et trois dentre eux affectent la structure primaire du GHSR bovin. Des associations, à différents niveaux de signification, entre certains de ces 14 sites polymorphiques et des traits de production et de conformation ont été mis en évidence au sein dun groupe de 127 taureaux Holstein sur base de leurs descendances directes présentes en Région Wallonne. La seconde approche aborde les effets dune immunisation passive contre la ghréline sur des rats mâles en croissance en comparaison à celles contre la leptine et la cholécystokinine. Lors dune alimentation équilibrée, le traitement envers la ghréline sur ces rats na pas influencé la croissance et lingestion par rapport aux animaux témoins. Des effets ont été observés entre les différentes immunomodulations au niveau des paramètres de croissance, dingestion et endocrinologiques. Les présents résultats invitent à de nouvelles investigations des gènes bGHRL et bGHSR sur des données relatives à dautres populations/races bovines et de limmunomodulation de la ghréline lors de conditions dexpérimentation différentes (alimentation déséquilibrée, stade physiologique, espèce, etc.). Ces investigations pourraient être valorisées en sélection et production animale mais également en médecine tant humaine que vétérinaire.

Pancreatic endocrine tumors and gastrointestinal stromal tumors are rare. Evidence regarding prognostic factors, and in the former also treatment, is scarce. We evaluated the survival and prognostic factors in a consecutive series of 324 patients with pancreatic endocrine tumors treated at a single institution. Radical surgery, WHO classification, TNM stage, age and Ki67 ≥2% emerged as independent prognostic factors. Having a non-functioning tumor was not an independent prognostic marker, and neither was hereditary tumor disease. We present the first evaluation of the newly proposed TNM staging system for these patients. A separate analysis of well-differentiated neuroendocrine carcinomas is reported, suggesting tumor size ≥5cm and Ki67 ≥2% as negative prognostic markers in this group. The first 36 patients with advanced neuroendocrine tumors treated with temozolomide at our clinic were evaluated. The median time to progression was seven months. Fourteen percent showed partial regression and 53% stabilization of disease. Side effects were generally mild. Investigation of O6-methylguanine DNA methyltransferase revealed a low expression in a subset of tumors. Four out of five patients responding to treatment had tumors with low expression. Concomitant expression of the orexigen ghrelin and its receptor in pancreatic endocrine tumors is demonstrated. No significant difference in mean plasma ghrelin between patients and controls were found, but elevated plasma ghrelin was seen in five patients. We provide the first report of expression of ghrelin and its receptor in gastrointestinal stromal tumors. Concomitant expression was frequent, indicating the presence of an autocrine loop. The tumors also expressed the neuroendocrine marker synaptic vesicle protein 2. Together, these findings are suggestive of neuroendocrine features.

Tesis por compendio de publicaciones / La gran preocupación que existe actualmente alrededor del peso corporal, está colaborando a la proliferación de innumerables dietas de adelgazamiento entre las personas “no satisfechas con su peso”. En este sentido hemos estudiado la obesidad desde un punto de vista cronobiológico, para poder dilucidar la importancia que tiene la alteración circadiana de ciertos ritmos biológicos en la ganancia de peso o la no pérdida del mismo. El acúmulo de grasa corporal y el grado de lipogénesis en el tejido adiposo podría ser diferente a distintas horas del día, ingiriendo las mismas calorías. A su vez uno de los aspectos más interesantes, es poder conseguir una caracterización cronobiológica de cada individuo, establecer mejoras en las terapias de comportamiento alimentario, introducir nuevos índices que permitan detectar pacientes de riesgo y poder establecer pautas alimentarias y hábitos de vida individualizados que ayuden a estos pacientes a alcanzar la meta de peso propuesta. / The great controversy now there about body weight, is collaborating with the proliferation of countless diets among people "not satisfied with their weight." In this sense, we have studied obesity from a chronobiological viewpoint, to elucidate the importance of the alteration of circadian biological rhythms in weight gain or no loss. The accumulation of body fat and the degree of lipogenesis in adipose tissue may be different n accordance with the time of day, even eating the same calories. In turn one of the most interesting aspect, is to be able to characterize the individual chronobiology of each patient, establish improved therapies feeding behavior, introducing new indices to detect patients at risk and to establish dietary patterns and lifestyle habits that help these patients to achieve the proposed weight goal.

Le récepteur X des farnésoïdes (FXR) fait partie de la superfamille des récepteurs nucléaires et agit comme un facteur de transcription suite à la liaison d’un ligand spécifique. Le récepteur FXR, activé par les acides biliaires, joue un rôle essentiel dans le métabolisme des lipides et du glucose en plus de réguler l’homéostasie des acides biliaires. Notre laboratoire a récemment mis en évidence une nouvelle voie de régulation du récepteur PPARγ en réponse au récepteur de la ghréline. En effet, la ghréline induit l’activation transcriptionnelle de PPARγ via une cascade de signalisation impliquant les kinases Erk1/2 et Akt, supportant un rôle périphérique de la ghréline dans les pathologies associées au syndrome métabolique. Il est de plus en plus reconnu que la cascade métabolique impliquant PPARγ fait également intervenir un autre récepteur nucléaire, FXR. Dans ce travail, nous montrons que la ghréline induit l’activation transcriptionnelle de FXR de manière dose-dépendante et induit également la phosphorylation du récepteur sur ses résidus sérine. En utilisant des constructions tronquées ABC et CDEF de FXR, nous avons démontré que la ghréline régule l’activité de FXR via les domaines d’activation AF-1 et AF-2. L’effet de la ghréline et du ligand sélectif GW4064 sur l’induction de FXR est additif. De plus, nous avons démontré que FXR est la cible d’une autre modification post-traductionnelle, soit la sumoylation. En effet, FXR est un substrat cellulaire des protéines SUMO-1 et SUMO-3 et la sumoylation du récepteur est ligand-indépendante. SUMO-1 et SUMO-3 induisent l’activation transcriptionnelle de FXR de façon dose-dépendante. Nos résultats indiquent que la lysine 122 est le site prédominant de sumoylation par SUMO-1, quoiqu’un mécanisme de coopération semble exister entre les différents sites de sumoylation de FXR. Avec son rôle émergeant dans plusieurs voies du métabolisme lipidique, l’identification de modulateurs de FXR s’avère être une approche fort prometteuse pour faire face à plusieurs pathologies associées au syndrome métabolique et au diabète de type 2. / The farnesoid X receptor (FXR) is a ligand-activated transcription factor within the nuclear receptor superfamily. FXR is activated by bile acids and plays a crucial role in the regulation of glucose and lipid metabolism and in bile acid homeostasis. Our group has recently identified the contribution of the ghrelin receptor in the regulation of the nuclear receptor PPARγ. Indeed, ghrelin triggers transcriptional activation of PPARγ through a concerted signaling cascade involving Erk1/2 and Akt kinases. These results support the peripheral actions of ghrelin in diseases associated with the metabolic syndrome. It is recognized that there is interplay between PPARγ metabolic cascade and FXR. Here, we demonstrate that ghrelin promotes FXR transcriptional activity in a dose-dependent manner and also promotes its phosphorylation on serine residues. By using truncated ABC and CDEF constructs of FXR, we found that ghrelin induces FXR activity through the AF-1 and AF-2 activation domains. The ghrelin-induced FXR activity is additive to the induction by the selective agonist GW4064. Also, we demonstrate that FXR is the target of sumoylation, another post-translational modification. In particular, FXR is modified by SUMO-1 and SUMO-3 in a ligand-independent manner. SUMO-1 and SUMO-3 promote dose-dependent transcriptional activity of FXR. Our results show that lysine 122 is the prevalent site of sumoylation by SUMO-1, though a compensation mechanism seems to exist between the various sumoylation sites of FXR. With its emerging role in several metabolic cascades, identification of FXR modulators represents a promising approach for the treatment of the metabolic syndrome and type 2 diabetes.

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The last few years have seen dramatic advances in genomics, including the discovery of a large number of non-coding and antisense transcripts. This has revolutionised our understanding of multifaceted transcript structures found within gene loci and their roles in the regulation of development, neurogenesis and other complex processes. The recent and continuing surge of knowledge has prompted researchers to reassess and further dissect gene loci. The ghrelin gene (GHRL) gives rise to preproghrelin, which in turn produces ghrelin, a 28 amino acid peptide hormone that acts via the ghrelin receptor (growth hormone secretagogue receptor/GHSR 1a). Ghrelin has many important physiological and pathophysiological roles, including the stimulation of growth hormone (GH) release, appetite regulation, and cancer development. A truncated receptor splice variant, GHSR 1b, does not bind ghrelin, but dimerises with GHSR 1a, and may act as a dominant negative receptor. The gene products of ghrelin and its receptor are frequently overexpressed in human cancer While it is well known that the ghrelin axis (ghrelin and its receptor) plays a range of important functional roles, little is known about the molecular structure and regulation of the ghrelin gene (GHRL) and ghrelin receptor gene (GHSR). This thesis reports the re-annotation of the ghrelin gene, discovery of alternative 5’ exons and transcription start sites, as well as the description of a number of novel splice variants, including isoforms with a putative signal peptide. We also describe the discovery and characterisation of a ghrelin antisense gene (GHRLOS), and the discovery and expression of a ghrelin receptor (growth hormone secretagogue receptor/GHSR) antisense gene (GHSR-OS). We have identified numerous ghrelin-derived transcripts, including variants with extended 5' untranslated regions and putative secreted obestatin and C-ghrelin transcripts. These transcripts initiate from novel first exons, exon -1, exon 0 and a 5' extended 1, with multiple transcription start sites. We used comparative genomics to identify, and RT-PCR to experimentally verify, that the proximal exon 0 and 5' extended exon 1 are transcribed in the mouse ghrelin gene, which suggests the mouse and human proximal first exon architecture is conserved. We have identified numerous novel antisense transcripts in the ghrelin locus. A candidate non-coding endogenous natural antisense gene (GHRLOS) was cloned and demonstrates very low expression levels in the stomach and high levels in the thymus, testis and brain - all major tissues of non-coding RNA expression. Next, we examined if transcription occurs in the antisense orientation to the ghrelin receptor gene, GHSR. A novel gene (GHSR-OS) on the opposite strand of intron 1 of the GHSR gene was identified and characterised using strand-specific RT-PCR and rapid amplification of cDNA ends (RACE). GHSR-OS is differentially expressed and a candidate non-coding RNA gene. In summary, this study has characterised the ghrelin and ghrelin receptor loci and demonstrated natural antisense transcripts to ghrelin and its receptor. Our preliminary work shows that the ghrelin axis generates a broad and complex transcriptional repertoire. This study provides the basis for detailed functional studies of the the ghrelin and GHSR loci and future studies will be needed to further unravel the function, diagnostic and therapeutic potential of the ghrelin axis.

Made available in DSpace on 2015-07-22T20:49:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-06-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Em pacientes com diabetes mellitus tipo 1 (DM1) foram observadas respostas normais ou aumentadas de GH apos estimulos. O eixo hipotalamo- hipofiseadrenal tem sido menos estudado. A ghrelina e um secretagogo de GH que tambem aumenta os niveis de ACTH e de cortisol, de forma semelhante ao GHRP-6. Nao existem estudos sobre os efeitos da ghrelina em pacientes com DM1. O objetivo do presente trabalho foi avaliar as respostas do GH, ACTH e cortisol a ghrelina e ao GHRP-6 em 9 pacientes com DM1 (HbA1c: 11.7 } 1,3%; media } SE) e em 9 individuos normais. A liberacao de GH induzida por GHRH tambem foi estudada. A media dos niveis basais de GH (ƒÊg/L) foi maior nos pacientes com DM1 (3.5 } 1.2) do que nos controles (0.6 } 0.3). Analisando AASC GH (ƒÊg/L.120min), nao foram observadas diferencas significantes entre os diabeticos (ghrelina: 3.148 } 427; GHRP-6: 1428 } 299; GHRH: 885 } 184) e os controles (ghrelina: 3228 } 1036 ; GHRP-6: 1271 } 217; GHRH: 643 } 178). Em ambos os grupos, a liberacao de GH induzida pela ghrelina foi maior do que apos GHRP-6 e GHRH. Houve uma tendencia (p = 0.055) a elevacao dos niveis de cortisol basal (ƒÊg/dL) nos pacientes com DM1 (11.7 } 1.5) comparado aos controles (8.2 } 0.8). Nao foram observadas diferencas significantes nos valores de AASC cortisol (ƒÊg/dL.90min) entre os grupos apos ghrelina (DM1: 303 } 106; controles: 467 } 86) e GHRP-6 (DM1: 135 } 112; controles: 187 } 73). A media de valores basais de ACTH (pg/mL) foi semelhante nos diabeticos (19.9 } 3.4) e nos controles (14.5 } 2.3). Nao foram observadas diferencas nos valores de AASC ACTH (pg/mL.90min) entre os grupos apos ghrelina (DM1: 1372 } 771; controles: 1394 } 327) e GHRP-6 (DM1: 257 } 291; controles: 423 } 211). Em resumo, os pacientes com DM1 tem resposta normal do GH a ghrelina, GHRP-6 e GHRH. A liberacao de ACTH e cortisol apos ghrelina e GHRP-6 tambem e semelhante aos controles. Nossos resultados sugerem que a hiperglicemia cronica do DM1 nao interfere com a liberacao de GH, ACTH e cortisol estimulada por estes peptideos. / In type 1 diabetes mellitus (T1DM), GH responses to provocative stimuli are normal or exaggerated while the hypothalamic-pituitary-adrenal axis has been less studied. Ghrelin is a GH-secretagogue which also increases ACTH and cortisol levels, similarly to GHRP-6. Ghrelin Ls effects in patients with T1DM have not been evaluated. We, therefore, studied GH, ACTH and cortisol responses to ghrelin and GHRP-6 in 9 patients with T1D1 (HbA1c: 11.7 }1.3%; mean }SE) and 9 control subjects. GHRH- induced GH release was also evaluated. Mean basal GH levels (Rg/L) were higher in T1DM (3.5 }1.2) than in controls (0.6 }0.3). Analyzing ƒ¢AUC GH values (Rg/L.120min), no significant differences were observed in T1DM (ghrelin: 3148 }427; GHRP-6: 1428 }299; GHRH: 885 }184) compared to controls (ghrelin: 3228 }1036; GHRP-6: 1271 }217; GHRH: 643 }178). In both groups, ghrelin-induced GH release was higher than after GHRP-6 and GHRH. There was a trend (p=0.055) to higher mean basal cortisol values (Rg/dL) in T1DM (11.7 }1.5) compared to controls (8.2 }0.8). No significant differences were seen in ƒ¢AUC cortisol values (Rg/dL.90min) in both groups after ghrelin (DM1:303 }106; controls: 467 }86) and GHRP-6 (DM1:135 }112; controls: 187 }73). Mean basal ACTH values (pg/mL) were similar in T1DM (19.9 }3.4) and controls (14.5 }2.3). No differences were seen in ƒ¢AUC ACTH levels (pg/mL.90min) in both groups after ghrelin (DM1:1372 }771; controls: 1394 }327) and GHRP-6 (DM1: 257 }291; controls: 423 }211). In summary, patients with T1DM have normal GH responsiveness to ghrelin, GHRP-6 and GHRH. ACTH and cortisol release after ghrelin and GHRP-6 is also similar to controls. Our results suggest that chronic hyperglycemia of T1DM does not interfere with GH, ACTH and cortisol releasing mechanisms stimulated by these peptides. / TEDE / BV UNIFESP: Teses e dissertações