Type 1 diabetes (T1D) results from a loss of functional insulin-producing pancreatic beta cells. The etiology of T1D is poorly understood, but the detection of infiltrating inflammatory cells in the pancreas and circulating autoantibodies has led to the common notion that an autoimmune process plays a central role in the pathogenesis of the disease. The aim of this doctoral thesis was to assess various aspects of the immunopathology of type 1 diabetes. To this purpose, studies have been conducted on pancreatic material from the Network for Pancreatic Organ Donors with Diabetes (nPOD) collection, the Nordic Network for Islet Transplantation, and the Diabetes Virus Detection (DiViD) study. Paper I is a study on pancreatic tissue from organ donors with varying duration of T1D as well as non-diabetic donors and subjects with other types of diabetes, in which persistent expression of glucose transporters was shown on the beta cell membrane despite several years of T1D. Glucose transporter 1 was also confirmed as the predominant glucose transporter on human pancreatic islets. In paper II, we report on signs of inflammation in the exocrine but not in the endocrine pancreas in non-diabetic organ donors with diabetes-related autoantibodies, suggesting that diabetes-associated autoantibodies can occur in response to unspecific pancreatic lesions. Paper III aimed to characterize the T cell-infiltration of pancreatic islets in material from recent-onset T1D patients. Insulitis was shown in all subjects, but with distinct differences in expression analysis of T- and B cell activation to cell-mediated allorejected kidney transplant. Also Paper IV was conducted on material from recent-onset cases and showed increased islet glucagon content, in combination with a reduced number of islets but sustained mean islet size. Together, these results provide expansion of our knowledge of the immunopathology in T1D, and will hopefully assist in bringing us towards a deeper understanding of T1D aetiology and eventually an effective cure.

Diabetes mellitus affects nearly 300 million people in the world. The development of diabetes is caused by dysfunction or by reduction of insulin-producing β-cells that are part of the endocrine pancreas. Therefore, the most critical step for understanding the pathophysiology of diabetes and for restoring lost β cells is the identification of molecular cues that specify the cellular phenotype in the pancreas. This work is based on the hypothesis that the transcription factor NEUROD1 is a key factor for the development of the pancreas and for the maintenance of endocrine tissue function. Neurod1 conditional KO mutants (Neurod1CKO) were generated using the Cre-loxP system by crossing floxed Neurod1 mice with Isl1-Cre line. Immunohistochemical analyses of the pancreas at embryonic day 17.5 and postnatal day 0 showed that the deletion of Neurod1 negatively affected the development, organization of endocrine tissue, and total mass of pancreatic endocrine cells. To better understand molecular changes, quantitative PCR was used to analyse mRNA expression in the developing pancreas at the age of embryonic day 14.5 and postnatal day 1. Genes important for the development and function of the pancreas have been selected for the study of expression changes. These analyses showed changes in expression of genes...

BACKGROUND: Pancreatic cancer is one of the most lethal cancers. Despite enhanced understanding of the disease, the 5-year survival rate remains 8% due to the late stage of diagnosis and a lack of effective treatment options. Early detection of precancerous lesions, such as intraductal papillary mucinous neoplasms (IPMNs), is a strategy to prevent pancreas cancer related death. Standard qualitative imaging assessment cannot reliably distinguish between benign and malignant branch duct intraductal papillary mucinous neoplasms (BD-IPMNs). A more consistent risk prediction method is needed to inform clinical decision making such that patients with benign cysts may be spared from unnecessary surgical resection. OBJECTIVE: To assess whether a BD-IPMN malignancy risk prediction model which demonstrated strong potential on preoperative computed tomography (CT) images would show similar results on magnetic resonance imaging (MRI). METHODS: 19 pathologically proven BD-IPMN patients with preoperative contrast-enhanced CT and MRI and were included in the study. Five radiomics features were extracted from the portal-venous phase CT and MR images of the largest cyst. Associations between radiomics features extracted from CT and MR were assessed using Pearson correlations. RESULTS: Of the five radiomics features, average-weighted eccentricity (AWE) was most strongly correlated between imaging modalities in all patients (n=19, r=0.46, 95% CI=0.001-0.75, p=0.05), low-risk patients (r=0.63, 95% CI=0.09-0.88, p=0.028), and patients with a solid component or mural nodule (r=0.66, 95% CI=-0.32-0.96, p=0.15). However, when two outliers within the dataset were removed from analysis, AWE no longer correlated between MR and CT. None of the other radiomics features displayed significant correlations between the modalities. CONCLUSIONS: The CT-based risk prediction model cannot be applied to MR data suggesting that a new model should be created from MRI data alone. / 2021-06-17T00:00:00Z

The use of adult hepatic stem cells for the treatment of diabetes, based both on the close embryological association of the pancreas and liver, and on a putative shared tissue stem cell, has been proposed by a number of studies. This study investigated the capacity of hepatic oval cells to differentiate into pancreatic endocrine cells in the presence of pancreatic mesoderm. The GaIN model of hepatic injury was used to induce oval cell activation in Male Sprague-Dawley rats. A viable and significant oval cell population could not however, be isolated and propagated in culture. In order to continue experimentation, a PHeSC-A2 cell line, derived from normal adult porcine liver, was cultured with quail pancreatic mesoderm in the GFRM-Ham s F12.ITS culture system. Cells demonstrating positive immulocalization of the pancreatic markers, insulin and glucagon, were identified as PHeSC-A2-derived, by visual assessment of their nuclear morphology. Techniques used to confirm these results and preclude the derivation of the pancreatic endocrine cells from pancreatic endodermal contamination, proved ineffectual. The tentative results obtained in this study have lead to the following postulations: firstly, the PHeSC-A2 cell line may possess a higher level of potentiality than previously demonstrated; secondly, this potential may be due to the shared embryological origins of the pancreas and liver, and thirdly, permissive signaling from pancreatic mesoderm may have the capacity to induce the differentiation of hepatic oval cells into pancreatic endocrine cells. Further research is required to confirm the results obtained in this study and to substantiate the aforementioned propositions.

Les pertes de la fonction et de la masse des cellules beta pancréatiques jouent un rôle central dans le diabète de type 2 (DT2). Les beta-arrestines 1 et 2 (ARRB1 et ARRB2), sont impliquées dans la sécrétion et/ou la survie des cellules beta pancréatiques.Dans une première étude, afin de caractériser précisément la fonction d’ARRB1 dans les cellules beta pancréatiques, nous avons eu pour objectif de générer des souris invalidées spécifiquement dans ces cellules en utilisant le système Cre/lox sous le contrôle du promoteur Ins1. Des études avaient été publiées à partir des deux lignées Ins1Cre-/+ et Arrb1f/f. Nous avons généré et travaillé sur les souris Arrb1f/f :Ins1Cre-/+. Le phénotype des souris Arrb1f/f :Ins1Cre-/+ était faible et surtout non reproductible comparé aux souris Arrb1f/f :Ins1Cre-/- utilisées comme témoins. Le faible niveau d’expression d'Arrb1 dans les cellules beta et le manque d'anticorps spécifique pour l'immunocytochimie ont rendu difficile la vérification de l'absence d'expression de ARRB1 dans ces cellules. Après séquençage du gène modifié Arrb1 des souris “floxées“, nous avons pu montrer que l'insertion du premier site loxP avait induit un décalage du cadre de lecture introduisant un codon stop et, par conséquent, la non-expression du gène Arrb1. Étant donné que les souris Arrb1 “floxées“ utilisées comme témoins étaient déjà knockout (KO), le projet utilisant ces souris a dû être arrêté.Notre équipe a rapporté l'implication d'ARRB2 dans la régulation de la masse des cellules bêta pancréatique, mais son rôle dans la signalisation du récepteur du Glucagon-Like Peptide-1 (GLP-1R), une cible thérapeutique majeure du DT2, n'avait pas encore été exploré.Nous avons montré, dans une deuxième étude, une meilleure tolérance orale au glucose ainsi qu’une augmentation de la sécrétion d’insuline chez les souris Arrb2 KO par rapport aux souris témoins sur les îlots en présence des concentrations physiologiques circulantes de GLP-1. Ceci est corrélé à une production d’AMPc et un recrutement de la PKA plus élevés dans les cellules beta Arrb2 KO. A l’inverse, l’activation des kinases ERK1/2 est diminuée indiquant un recrutement majeur des ERK1/2 par ARRB2 au GLP-1R. En parallèle, j’ai montré que les taux de ARRB1 et ARRB2 des îlots pancréatiques sont altérés par des conditions diabétogènes et diabétiques. Mes résultats démontrent clairement un rôle critique de ARRB2 dans la signalisation du GLP-1R. Un défaut d’expression de la protéine pourrait participer au déficit des mécanismes de compensation de la masse fonctionnelle des cellules beta conduisant au DT2. / The loss of function and mass of pancreatic beta-cells play a central role in type 2 diabetes (T2D). Beta-arrestin 1 and 2 (ARRB1 and ARRB2) are involved in insulin secretion and/or beta-cell survival. In a first study, in order to characterize the role of ARRB1 in beta-cells, we aimed to invalidate the Arrb1 gene specifically in these cells using the Cre/lox system under the control of the Ins1 promoter. Studies had been published with both Ins1Cre-/+ and Arrb1f/f lines. We generated Arrb1f/f:Ins1Cre-/+ mice. The phenotype of Arrb1f/f :Ins1Cre-/+ mice was weak with a lack of reproducibility compared to Arrb1f/f :Ins1Cre-/- mice used as controls. The low expression level of Arrb1 in beta-cells and the lack of specific antibody for immunocytochemistry made it difficult to verify the absence of expression of ARRB1 in these cells. After sequencing the modified Arrb1 gene of the “floxed” mice, we observed that the insertion of the first loxP site induced a shift in the reading frame introducing a stop codon and, consequently, the non-expression of the Arrb1 gene. Since the “floxed“ Arrb1 mice used as controls were already knockout (KO), the project using these mice was stopped.Our team has reported the involvement of ARRB2 in the regulation of beta-cell mass, but its role in Glucagon-Like Peptide-1 (GLP-1) receptor signaling, a major therapeutic target for T2D, remained to be explored. In a second study, we showed a better glucose tolerance and an increase in insulin secretion from isolated islets in Arrb2KO compared to control mice in the presence of physiological circulating concentrations of GLP-1. This was correlated with higher cAMP production and PKA activation in Arrb2KO beta-cells. By contrast, the activation of ERK1/2 kinases was decreased indicating a major recruitment of ERK1/2 by ARRB2 to GLP-1R. In parallel, we showed that the expression levels of ARRB1 and ARRB2 in pancreatic islets were altered in diabetogenic and diabetic conditions. My results clearly demonstrate a critical role of ARRB2 in GLP-1R singaling which could impact the function, maintenance and plasticity of beta-cell mass in response to GLP-1. A lack of expression of ARRB2 could participate in the deficit of compensatory mechanisms of the functional beta-cell mass leading to T2D.

O projeto teve como objetivo avaliar o efeito do uso de enzimas exógenas sobre os grânulos de zimógenos no pâncreas. O projeto foi dividido em três experimentos, sendo o experimento I para avaliação do uso da protease via ração nas dosagens de 50, 100 e 150% das recomendações do fabricante. O experimento II, foi realizado avaliando-se o uso da enzima amilase nas dosagens de 50, 100 e 150% das recomendações do fabricante e o experimento III foi realizado avaliando-se as dosagens de amilase, amilase + fitase, protease e protease + fitase sobre os grânulos de zimógenos. Em cada experimento, foi utilizado delineamento inteiramente casualizado sendo um total de nove tratamentos com oito repetições. Aos 21 e 42 dias de idade, as aves foram sacrificadas por deslocamento cervical para coleta e processamento do pâncreas para análise histopatológica e posterior análise pelo programa Image Pro Plus&reg;. Este programa permitiu a mensurar a porcentagem dos grânulos de zimógenos nas imagens obtendo-se um índice matemático da presença dos grânulos de zimógenos no pâncreas, o qual pode ser avaliado estatisticamente e submetidos a regressão polinomial os experimentos I e II e ao teste de Tukey o experimento III. Uma redução significativa (P<0,05) com efeito quadrático na presença dos grânulos de zimógenos pode ser observada nos experimentos I e II. O experimento III apresentou diferença estatística (P<0,05) entre o uso de fitase 100% + Protease 100% quando comparado com o controle. / This research project was conducted in the poultryhouse of the Faculty of Veterinary Medicine USP - Department of Nutrition and Animal Production, Pirassununga Site. Thus, this present study aimed to evaluate the effect of exogenous enzymes on the zymogenes granules of pancreas. It was performed three experimental trials; the first experiment has evaluated the addition of 50, 100 and 150% of protease manufactory recommendation in the feed. The trial two was conducted to evaluate the addition of 50, 100 and 150% of amylase manufactory recommendation in feed, and the experiment three was conducted to evaluated the addition of amylase, amylase + phytase, protease and protease + phytase in the feed on the zymogens granules. Each experiment was designed totally randomized with a total of nine treatments with eight replicates each. The birds were killed by cervical dislocation at days 21 e 42 to collect the pancreas for histopathology analysis followed by the Image Pro Plus&reg; program analysis, this program allowed to transform the image into a mathematic number, which could be used in statistical analysis. At the experiments I and II, the statistical analysis were conducted by the polynomial regression method and the experiment three was evaluated by Tukey test. A significant reduction (P<0,05) with quadratic effect was observed on the zymogens granules at the experiments I and II. The experiment III show a significant difference between the treatment with phytase 100% + Protease 100% and the control group.

Pancreatic cancer is one of the most devastating human cancers with the lowest survival rate among 24 commonly diagnosed cancers. It is the seventh and the sixth leading cause of cancer-related deaths in the world and Hong Kong respectively. The current pancreatic cancer treatment options, have limited efficacy and undesirable side effects. Because of the high mortality rate and unsatisfactory treatment outcome, it is necessary to develop new strategies for pancreatic cancer therapy. / In human, an abundant arginine reserve is known to be crucial for tumor cell proliferation. Arginine is a semi-essential amino acid because most of the somatic cells can re-synthesize it from other metabolites like citrulline in urea cycle. However, arginine auxotrophy is observed in certain tumors, such as hepatocarcinoma, melanoma and sarcoma, where restriction or depletion of arginine will lead to tumor death. Further studies have found that deficiency in either argininosuccinate synthetase 1 (ASS1) or ornithine transcarbamylase (OTC) expression contributes to arginine auxotrophy in these tumors. These findings implicated the potential of using arginine deprivation as a novel pancreatic cancer treatment strategy. / PEG-BCT-100 is a pegylated recombinant human arginase that metabolizes arginine into urea and ornithine. This study examined the preclinical anti-tumor efficacy of PEG-BCT-100 and the underlying mechanism in pancreatic cancer. Six pancreatic cancer cell lines AsPC-1, BxPC-3, CFPAC-1, Capan-2, MIA PaCa-2 and Panc10.05 were used as in vitro cell model. Cell growth was either completely stopped or dramatically reduced in arginine-free medium, suggesting pancreatic cancer cells were arginine auxotrophic. The protein and mRNA expression levels of the ASS1, OTC and argininosuccinate lyase (ASL), which are enzymes involved in arginine, were studied. The results showed that ASL was highly expressed in all cell lines, suggesting it is not an essential regulator in arginine auxotrophy in pancreatic cancer. On the other hand, ASS1 was only detected in BxPC-3 and CFPAC-1, while OTC was undetectable in all cell lines in both mRNA and protein levels. The effect of PEG-BCT-100 was illustrated via cell cycle progression, cell proliferation and viability. Single drug effect combining PEG-BCT-100 with other anti-tumor drugs, such as 5-FU and gemcitabine, was further explored. Synergistic effect of PEG-BCT-100 and gemcitabine under combination of PEG-BCT-100 and gemcitabine was observed in CFPAC-1 and MIA PaCa-2. Overexpression of OTC and ASS1 decreased the sensitivity of towards PEG-BCT-100 significantly. Taken together, OTC deficiency is a potential indicative marker for the sensitivity of arginine depletion treatment in pancreatic cancer. / 胰腺癌是最具毀滅性的人類癌症之一，在二十四種常見的癌症中，它有着最低的存活率。儘管不在發病率最高的十種癌症中，胰腺癌仍舊是世界第七大致死癌症，以及香港第六大致死癌症。手術治療，放射治療，以及化學藥物治療是現今常用的胰腺癌治療手段，但是這些療法不是限制繁多，就是收效甚微，並常常伴有強烈的副作用。由於胰腺癌具有很高的致死率以及缺乏有效的治療方法，所以新的治療策略亟待開發。 / 於人類而言，精氨酸是一種半必需氨基酸，因爲它可以通過尿素循環中的其他代謝產物，如鳥氨酸以及瓜氨酸，重新合成。然而，精氨酸缺陷出現在多種腫瘤中，像肝癌，黑色素瘤，以及血癌。限制或者減少精氨酸的供應會導致這些腫瘤死亡。除此之外，腫瘤細胞的快速生長也依賴於充足的精氨酸。進一步的研究表明，在這些腫瘤中，精氨琥珀酸合成酶1（ASS1）或者鳥氨酸氨甲醯基轉移酶（OTC）的任意一個缺乏都會導致精氨酸缺陷。本文將探討將剝奪精氨酸作爲一種新策略來治療胰腺癌的可行性。 / PEG-BCT-100又名金氨素，是一種聚乙二醇化重組人精氨酸酶，它可以催化精氨酸分解爲尿素和鳥氨酸。我們研究了PEG-BCT-100在胰腺癌細胞中的抗癌效果以及探討了與其相關的作用機理。在我們的研究中，AsPC-1, BxPC-3, CFPAC-1, Capan-2, MIA PaCa-2以及Panc10.05這六個細胞株用作體外的細胞模型。爲了評估PEG-BCT-100治療胰腺癌的可行性，我們首先調查了精氨酸對胰腺癌細胞的重要性。通過將這些胰腺癌細胞培養在有精氨酸供應和沒有精氨酸供應的完全培養基中，我們發現剝奪精氨酸能完全停止或者極大地減少了胰腺癌細胞的生長。這說明了這些胰腺癌細胞也都是精氨酸營養缺陷型的細胞。通過蛋白印跡和實時定量聚合酶鏈式反應實驗，我們進一步研究了精氨酸代謝相關基因在這些胰腺癌細胞中的表達水平。結果表明，精氨琥珀酸裂解酶（ASL）在全部的六條細胞系中都有被檢測到。ASS1只出現在BxPC-3和CFPAC-1中。然而在全部的細胞中，無論是蛋白質水平還是mRNA水平，OTC都沒有被檢測到。緊接着，我們研究了PEG-BCT-100在胰腺癌細胞活力，細胞增殖，細胞週期以及細胞凋亡等方面的影響。結果表明，PEG-BCT-100可以從多個方面抑制胰腺癌細胞。我們還嘗試探索了PEG-BCT-100與其他胰腺癌治療藥物在胰腺癌細胞中的聯合使用效果。然後發現PEG-BCT-100與吉西他滨（gemcitabine）聯合使用具有協同效果。最後，我們構建了四種不同表達類型的MIA PaCa-2細胞模型：（ASS1-/OTC-）, (ASS1-/OTC+), (ASS1+/OTC-)以及(ASS1+/OTC+)。接着我們測試了PEG-BCT-100在這些細胞模型中的效果。結果表明，同時在MIA PaCa-2細胞中表達ASS1和OTC可以明顯地提高其對PEG-BCT-100的抗性，單表達其中一個基因對PEG-BCT-100的抗性也有些許提高，但效果不如雙表達明顯。 / 總而言之，對於胰腺癌細胞而言，精氨酸是必不可少的。PEG-BCT-100有很明顯的胰腺癌效果。在胰腺癌中，OTC的表達情況可以作爲預估PEG-BCT-100治療效果的重要生物標誌。 / Deng, Haohao. / Thesis M.Phil. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 111-117). / Abstracts also in Chinese. / Title from PDF title page (viewed on 14, October, 2016). / Deng, Haohao. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Chan Wai-Pong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (leaves 114-135). / Abstracts in English and Chinese. / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- General review of pancreas --- p.1 / Chapter 1.2 --- The renin-angiotensin system (RAS) --- p.4 / Chapter 1.3 --- Tissue RAS --- p.12 / Chapter 1.4 --- Hypoxia and RAS --- p.21 / Chapter 1.5 --- Pancreatitis and RAS --- p.25 / Chapter 1.6 --- Aim of study --- p.27 / Chapter Chapter 2 --- Method / Chapter 2.1 --- Experimental animals and rat models --- p.30 / Chapter 2.2 --- Immunohistochemistry --- p.33 / Chapter 2.3 --- Semi-quantitative reverse transcriptase-polymase chain reaction (RT-PCR) --- p.37 / Chapter 2.4 --- Western blot analysis --- p.41 / Chapter 2.5 --- "Standard curve, quantitative competitive RT-PCR (SC-QC-RT-PCR)" --- p.45 / Chapter 2.6 --- Data analysis --- p.48 / Chapter Chapter 3 --- Result / Chapter 3.1 --- Existence of a local RAS in the rat pancreas --- p.49 / Chapter 3.2 --- Effect of chronic hypoxia on RAS expression in neonatal rat --- p.59 / Chapter 3.3 --- Effect of chronic hypoxia on RAS expression in mature rat --- p.72 / Chapter 3.4 --- Effect of experimental pancreatitis on RAS expression --- p.86 / Chapter Chapter 4 --- Discussion / Chapter 4.1 --- Existence of a local RAS in the rat pancreas --- p.97 / Chapter 4.2 --- Regulation of pancreatic RAS by chronic hypoxia --- p.101 / Chapter 4.3 --- Regulation of pancreatic RAS by pancreatitis --- p.106 / Chapter 4.4 --- Conclusion --- p.111 / Chapter 4.5 --- Further work --- p.112 / Chapter Chapter 5 --- References --- p.114

Les maladies métaboliques sont en pleine expansion dans nos sociétés actuelles et constituent un enjeu de santé publique majeur. Les antécédents familiaux, l'environnement et les habitudes de vie de l'individu vont jouer un rôle dans la susceptibilité à certains de ces désordres métaboliques. Sur la base de données épidémiologiques, un lien a été établi entre environnement durant les premières phases de la vie et survenue de pathologies à l'âge adulte conduisant au concept de DOHaD. L'objectif de ce travail était d'étudier, à partir d'un modèle murin, les conséquences de l'exercice physique quotidien de la mère pendant la gestation ou la lactation sur la composition corporelle, la fonction pancréatique et la gestion des substrats énergétiques de la descendance à plus ou moins long terme. L'entraînement maternel avant et pendant la gestation est associé à des modifications de la structure et de la fonction du pancréas de la descendance et semble modifier sa gestion des substrats énergétiques à tous les âges. L'exercice de la mère est également associé à une moindre prise de poids de la descendance et limite sa prise de masse grasse lorsqu'elle est soumise à un régime gras et sucré. L'exercice physique de la mère durant la lactation va modifier la composition du lait et la fonction pancréatique de la descendance. Cependant, il est associé à une augmentation du poids corporel de la descendance adulte mais semble la protéger contre l'insulino-résistance induite par la séparation maternelle. La pratique d'un exercice physique quotidien pendant la gestation et/ou la lactation semble donc modifier le développement et la maturation de certains organes (pancréas, tissu adipeux, foie, muscle squelettique) de la descendance ainsi que sa gestion des substrats énergétiques. Les conséquences de cet entraînement maternel sur la descendance vont être plus ou moins bénéfiques selon son âge et selon son environnement nutritionnel. Ce travail de thèse vient compléter les travaux menés dans le cadre des DOHaD et renforce l'idée que l'environnement lors des premières phases de la vie va avoir des conséquences à plus ou moins long terme sur la santé de l'individu. / Prevalence of metabolic diseases is growing up in our modern societies and constitutes a major public health concern. Family history, environment and lifestyle play a role in the susceptibility to several metabolic disorders. Based on epidemiological data, a link has been established between the environment during the first stages of life and diseases occurrence in adulthood leading to the concept of DOHaD. The aim of this work was to study, using a murine model, the effect of daily maternal exercise during gestation or lactation on offspring body composition, pancreatic function and energy substrates handling on a short- and a long-term basis. Maternal training before and during gestation is associated with changes in offspring pancreas structure and function and in energy substrates handling at all ages. Maternal exercise also decreases offspring body weight gain and fat mass gain when exposed to a high-fat/high sucrose diet. Maternal physical exercise during lactation modifies milk composition and offspring pancreatic function. However, it is associated to an increase in offspring body weight in adulthood but seems to protect against the insulin resistance induced by maternal separation. In conclusion, daily physical exercise during gestation and/or lactation modifies offspring organs development and maturation (such as pancreas, adipose tissue, liver, skeletal muscle) and its energy substrates handling. Maternal training consequences on offspring can be either beneficial or deleterious depending on its age and on its nutritional environment. This work is complementary to studies conducted in the framework of the DOHaD concept and strengthens the idea that the environment during the first stages of life will have short- to long-term impacts on the health of the individual.

Li, Chi Han Samson. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 158-175). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.