La déficience partielle en lipoprotéine lipase (LPLD) est associée à une augmentation du risque cardiométabolique chez les hommes et les femmes. L’adiponectine, le syndrome métabolique et la ménopause sont des modulateurs importants de ce risque. L’objectif de cette étude était d’évaluer la contribution de l’adiponectine au profil de risque cardiométabolique de femmes porteuses de variants dans le gène LPL connus pour être associés avec la LPLD. L'échantillon étudié comprenait 568 femmes d'origine canadienne-française, dont 127 avec une LPLD et 441 non LPLD (contrôles). L'influence de l'adiponectine sur le risque associé à la LPLD a été évaluée en utilisant des analyses de régression multiples prenant en compte l’influence du statut ménopausique, des variables anthropométriques, du bilan lipidique, de la glycémie à jeun et du tabagisme. Les résultats montrent que les niveaux d'adiponectine étaient significativement plus faibles dans les groupes LPLD. La contribution des valeurs faibles d’adiponectine au profil de risque cardiométabolique des sujets LPLD était indépendante du statut ménopausique et de toutes les autres covariables étudiées. Cela suggère que l'adiponectine contribue au profil de risque cardiométabolique chez les femmes porteuses d’une mutation connue pour être associée avec la LPLD. / The cardiovascular risk significantly increases after menopause. Lipoprotein lipase (LPL) is a key enzyme in the metabolism of triglyceride (TG)-rich lipoproteins which contributes to cardiometabolic homeostasis. Adiponectin is an adipocytokine which also influences the cardiometabolic status. The objective of this study was to evaluate the contribution of plasma adiponectin to the cardiometabolic status of women carrying loss-of-function LPL gene variants (LPLD). A total of 568 French Canadian women (127 LPLD and 441 controls) were included. The association of plasma adiponectin with LPLD was assessed using multiple regression models. Cardiometabolic covariates included anthropometrics, lipids (TG, HDL-C, LDL-C, apo B), fasting glucose and smoking. Mean plasma adiponectin concentration was significantly lower in women with LPLD. Women carrying loss-of function LPL gene mutations also presented a significantly higher risk of coronary artery disease. In conclusion, these results suggest that low plasma adiponectin significantly contributes to the cardiometabolic risk profile of postmenopausal women carrying loss-of-function LPL gene mutations, independently of anthropometrics, lipids and other covariates.

The effects of peptides derived from β-lactoglobulin and α-lactalbumin on metabolic syndrome were studied. α-lactalbumin and β-lactoglobulin were hydrolyzed with trypsin, alcalase, flavourzyme, or a combination of alcalase and flavourzyme and fractionated. Angiotensin coverting enzyme inhibition of the < 1 kDa fraction of alcalase hydrolyzed β-lactoglobulin was 95 %. Antioxidant activity of the < 1 kDa fraction of β-lactoglobulin hydrolyzed with a combination of alcalase and flavourzyme was 18 %. Stimulated adipocytes incubated with the < 1 kDa fraction of β-lactoglobulin hydrolyzed with either trypsin or alcalase produced 30 pg/mL of interleukin 6. Adiponectin and glucose transporter type 4 secretions increased 1.1 and 0.86 fold respectively during incubation with the < 1 kDa fraction of β-lactoglobulin hydrolyzed with a combination of alcalase and flavourzyme. Results indicate that β-lactoglobulin peptides formed with alcalase and a combination of alcalase and flavourzyme influence markers associated with metabolic syndrome and may be useful as functional foods or nutraceuticals.

The effects of peptides derived from β-lactoglobulin and α-lactalbumin on metabolic syndrome were studied. α-lactalbumin and β-lactoglobulin were hydrolyzed with trypsin, alcalase, flavourzyme, or a combination of alcalase and flavourzyme and fractionated. Angiotensin coverting enzyme inhibition of the < 1 kDa fraction of alcalase hydrolyzed β-lactoglobulin was 95 %. Antioxidant activity of the < 1 kDa fraction of β-lactoglobulin hydrolyzed with a combination of alcalase and flavourzyme was 18 %. Stimulated adipocytes incubated with the < 1 kDa fraction of β-lactoglobulin hydrolyzed with either trypsin or alcalase produced 30 pg/mL of interleukin 6. Adiponectin and glucose transporter type 4 secretions increased 1.1 and 0.86 fold respectively during incubation with the < 1 kDa fraction of β-lactoglobulin hydrolyzed with a combination of alcalase and flavourzyme. Results indicate that β-lactoglobulin peptides formed with alcalase and a combination of alcalase and flavourzyme influence markers associated with metabolic syndrome and may be useful as functional foods or nutraceuticals.

Ο λιπώδης ιστός είναι πλέον ένα ενδοκρινές όργανο το οποίο εκκρίνει ένα μεγάλο αριθμό βιοδραστικών μεσολαβητών που στοχεύουν σε όργανα μεταβολικής σημασίας όπως ο εγκέφαλος, το ήπαρ, οι σκελετικοί μύες και το ανοσοποιητικό σύστημα, ρυθμίζοντας την ομοιόσταση, την αρτηριακή πίεση, το μεταβολισμό των λιπιδίων και της γλυκόζης, την φλεγμονή και την αθηροσκλήρυνση. Η αντιπονεκτίνη κύρια πρωτεΐνη παραγόμενη από τον λιπώδη ιστό δρα προστατευτικά στην ανάπτυξη ινσουλινοαντίστασης, φλεγμονής και αθηρωμάτωσης. Η παχυσαρκία και κυρίως η κεντρική παχυσαρκία συνδέεται με την εμφάνιση πολλών νοσογόνων καταστάσεων. Στο σπλαχνικό λίπος εκκρίνεται TNF-α από τα λιποκύτταρα και τα μακροφάγα του στρώματος, ο οποίος καταστέλλει την παραγωγή και την δράση της αντιπονεκτίνης δρώντας ευωδοτικά στην ανάπτυξη του μεταβολικού συνδρόμου. Μελετήσαμε τις διαφορές της έκφρασης της αντιπονεκτίνης και του TNF-α σε σπλαχνικό και υποδόριο λιπώδη ιστό με τη μέθοδο της έμμεσης ανοσοϊστοχημείας σε τρεις ομάδες ασθενών: υγιείς, παχύσαρκους υγιείς και σε παχύσαρκους με μεταβολικό σύνδρομο και Σ.Δ. / Adipose tissue, besides of its energy producting role, is now considered as an endocrine organ which releases numerous cytokines and adipokines. Adipose tissue crosstalks with immune, cardiovascular reproductive and other systems. In obesity (BMI>30) the adipocytes become hypertrophic, loosing their normal activity and increasing the risk of appearence of the Metabolic Syndrome (a cluster of risk factors which may lead to Coronary Artery Disease). Adiponectin is an adipokine which plays pivotal role protecting from Diabetes Melitus t. 2 and inflammation. In obesity, the level of serrum adiponektin is remarkably low. TNF-α is a multifunctional cytokine released mostly from the immune cells. Central obesity (waist circumference >102cm) is characterized of a low grade inflammation combined with decreased secretion of TNF-α from adipocytes and stroma cells of visceral adipose tissue. In central obesity TNF-α acts against insulin leading to the appearance of insulin resistance and M.S. In our study we examined the different levels of secretion of adiponectin and TNF-α from the adipocytes of subcutaneous and visceral fat between three categories of patients: a) Controls, b) Obese without central obesity M.S. and c) Obese with M.S.

Οι λιποκίνες αποτελούν πρωτεϊνικά προϊόντα του λιπώδους ιστού με αυτοκρινείς, παρακρινείς και ενδοκρινείς δράσεις που εμπλέκονται στην παθογένεια της καρδιαγγειακής νόσου. Η τοπική παραγωγή λιποκινών, ειδικά από τον περιαγγειακό λιπώδη ιστό, μπορεί να επηρεάσει τη φυσιολογία και την παθολογία των αγγείων. Το ενδοκανναβινοειδές σύστημα σχετίζεται με τη ρύθμιση της ενδοκρινούς λειτουργίας του λιπώδους ιστού, αλλά και με την παθογένεια της αθηροσκλήρωσης. Μελετήσαμε την έκφραση της αντιπονεκτίνης, της βισφατίνης, της λεπτίνης και των νεότερων λιποκινών χεμερίνης και βασπίνης, καθώς και του υποδοχέα ενδοκανναβινοειδών CB1 σε ανθρώπινο περιαορτικό και επικαρδιακό λιπώδη ιστό, καθώς και τη συσχέτισή τους με την αορτική και τη στεφανιαία αθηροσκλήρωση. Εφαρμόστηκε ανοσοϊστοχημική χρώση για τις λιποκίνες και τον CB1 σε δείγματα ανθρώπινου περιαορτικού, περιστεφανιαίου και επικαρδιακού λίπους της κορυφής της καρδιάς. Οι αθηροσκληρωτικές βλάβες στο παρακείμενο αγγειακό τοίχωμα αξιολογήθηκαν με βάση την κατάταξη του AHA. Οι λιποκίνες εκφράστηκαν στον περιαγγειακό και επικαρδιακό λιπώδη ιστό της κορυφής και – με εξαίρεση την αντιπονεκτίνη – στα αγγειακά λεία μυικά κύτταρα και στα αφρώδη κύτταρα των αθηροσκληρωτικών βλαβών. Ο CB1 εκφράστηκε στον περιαορτικό και επικαρδιακό λιπώδη ιστό, καθώς και στα αορτικά και στεφανιαία αγγειακά λεία μυικά κύτταρα. Η αορτική αθηροσκλήρωση συσχετίστηκε θετικά με την έκφραση της χεμερίνης, της βασπίνης, της βισφατίνης και της λεπτίνης στο περιαορτικό λίπος. Η στεφανιαία αθηροσκλήρωση συσχετίστηκε θετικά με την έκφραση της χεμερίνης και της βασπίνης στο περιστεφανιαίο λίπος. Η έκφραση της αντιπονεκτίνης στο λιπώδη ιστό συσχετίστηκε αρνητικά τόσο με την αορτική όσο και με τη στεφανιαία αθηροσκλήρωση. Η έκφραση λιποκινών στον επικαρδιακό λιπώδη ιστό της κορυφής δε συσχετίστηκε με την αθηροσκλήρωση. Επίσης, η έκφραση του CB1 δε συσχετίστηκε με την αορτική ή με τη στεφανιαία αθηροσκλήρωση. Συμπερασματικά, παρατηρήθηκε: α) διαφορετικό προφίλ έκφρασης της αντιπονεκτίνης, βισφατίνης, λεπτίνης, χεμερίνης, βασπίνης και του CB1 στον περιαορτικό, περιστεφανιαίο και επικαρδιακό λιπώδη ιστό της κορυφής, β) συσχέτιση των λιποκινών, αλλά όχι του CB1, με την αορτική ή και με τη στεφανιαία αθηροσκλήρωση, με χαρακτηριστικό τρόπο για κάθε λιποκίνη. Η τοπική παραγωγή λιποκινών ενδεχομένως επηρεάζει ποικιλοτρόπως την αθηροσκληρωτική διαδικασία σε διαφορετικές θέσεις. / Adipokines are protein products of adipose tissue with autocrine, paracrine and endocrine actions, which have been implicated in the pathogenesis of cardiovascular disease. Locally produced adipokines, especially by periadventitial adipose tissue, may affect vascular physiology and pathology. The endocannabinoid system has also been implicated in the pathogenesis of atherosclerosis and in adipose tissue endocrine function regulation. We investigated the expression of adiponectin, visfatin, leptin and novel adipokines chemerin and vaspin, as well as CB1 endocannabinoid receptor, in human periaortic and epicardial adipose tissue, as well as their correlation to aortic and coronary atherosclerosis. Standard immunohistochemical staining for the adipokines and CB1 was performed on samples of human periaortic, pericoronary and apical epicardial adipose tissue. Atherosclerotic lesions of the adjacent vascular wall were assessed using the AHA classification. Adipokines were expressed in periadventitial and apical epicardial adipose tissue and - except for adiponectin - in vascular smooth muscle cells and foam cells in atherosclerotic lesions. CB1 was expressed in periaortic and epicardial adipose tissue, as well as in aortic and coronary vascular smooth muscle cells. Aortic atherosclerosis was positively correlated with chemerin, vaspin, visfatin and leptin periaortic fat expression. Coronary atherosclerosis was positively correlated with chemerin and visfatin pericoronary fat expression. Adipose tissue adiponectin expression was negatively correlated to atherosclerosis in both locations. Expression of adipokines in apical epicardial fat was not associated to atherosclerosis. CB1 expression was not correlated with either aortic or coronary atherosclerosis. Our results show: a) a different expression pattern of adiponectin, visfatin, leptin, chemerin, vaspin and CB1 in periaortic, pericoronary and apical epicardial adipose tissue, b) a correlation of these adipokines - but not CB1 - with either aortic or coronary atherosclerosis or both in a pattern characteristic for each adipokine and suggest that locally produced adipokines might differently affect the atherosclerotic process in different locations.

Orientador: Angelina Zanesco / Banca: Edson Antunes / Banca: Cláudia Cavaglieri / Banca: Rodrigo Pauli / Banca: Maria Andréia Delbin / Resumo: O período de pós-menopausa tem sido associado com maior risco para o ganho de peso e acúmulo de gordura abdominal em mulheres o que pode levar à alta incidência de doenças cardiometabólicas. O exercício físico promove efeitos benéficos sobre esses transtornos. Até o presente momento não foram encontrados na literatura estudos avaliando o efeito do treinamento intervalado em variáveis relacionadas à saúde da mulher. Assim a adiponectina tem sido estudada em diferentes estados patológicos, porém poucos estudos existem avaliando os níveis plasmáticos de adiponectina em mulheres na pós-menopausa. Além disso, o risco de doença cardiovascular aumenta após a menopausa, o qual pode estar relacionado com a resistência à insulina e à rigidez arterial que é um significante preditor da aterosclerose. Portanto, o objetivo deste trabalho foi avaliar o efeito do treinamento físico aeróbio intervalado, por doze semanas, sobre as alterações nas concentrações plasmáticas de nitrito/nitrato e adiponectina em mulheres na pós-menopausa. Foram selecionadas vinte e três mulheres com idade de 55±5 anos, na pós-menopausa, com sobrepeso. As voluntárias foram submetidas a treinamento aeróbio intervalado que foi composto por três ciclos de 10 minutos de duração (totalizando 30 min/sessão) divididos em três momentos: 4 min a 60% da FCreserva; 4 min a 70% da FCreserva; e 2 min com 80% da FCreserva, que consistiu em um treinamento de três dias por semana durante doze semanas; a intensidade foi reajustada na 6ª semana do período de treinamento. Foram realizadas avaliações antropométricas (Índice de Massa Corpórea e Circunferência Abdominal), hemodinâmicas (Pressão Arterial Sistólica, Pressão Arterial Diastólica e Frequência Cardíaca), e cardiorespiratórias com o teste de uma milha, para mensurar a potência aeróbia. As concentrações plasmáticas de ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Post menopause period has been associated with increased risk for weight gain and accumulation of abdominal fat in women which can lead to high incidence of cardiometabolic disease. On the other hand, physical exercise promotes beneficial effects on this disorder. Regarding the influence of intermittent physical exercise on the cardio-metabolic parameters in women after menopause, no studies exist at the present time. Therefore, the purpose of this study was to evaluate the effect of aerobic interval training for twelve (12) weeks, on the plasma nitrite/nitrate and adiponectin levels in postmenopausal women. Twenty-three overweight women were selected with mean age of 55 ± 5 years old. They were submitted to aerobic training intervals consisting of twelve (12) weeks, with a frequency of three sessions per week during 30 minutes of aerobic exercise intensity between 60% and 80% heart rate reserve. The training program was adjusted at 6-week. Anthropometric data were evaluated (body mass index and waist circumference) and hemodynamics parameters (systolic blood pressure, diastolic blood pressure, heart frequency). One mile walking test was also performed to evaluate the cardio-respiratory capacity at the initial and final time of the study. Plasma nitrite/nitrate and adiponectin levels were determined. All data was analyzed before and after aerobic exercise. Our data show that postmenopausal women present a significant reduction in waist circumference (3.8%) without changing in body mass index. The exercise protocol was effective in reducing diastolic blood pressure by 6.7% as well as the time to perform the one mile walking test (3.8%) indicating an improvement in physical fitness. Moreover, there was an increase in VO2max values (baseline: 25.1 ± 0.8, trained: 26.5 +0.9 ml / kg / min) approximately 5.5%, p <0.002. Similarly, plasma adiponectin levels after intermittement aerobic ... (Complete abstract click electronic access below) / Doutor

Introdução: O diabetes melito pós-transplante (DMPT) é uma complicação comum em transplantados renais e está associada a desfechos desfavoráveis. Tanto a adiponectina como a quimiocina ligante 5 (CCL5) têm relação com o metabolismo da glicose, o que permite supor que polimorfismos nesses genes possam levar ao desenvolvimento de DMPT. Objetivo: Verificar a associação dos polimorfismos do gene da adiponectina e da CCL5 com DMPT em transplantados renais caucasianos. Métodos: Trata-se de um estudo caso-controle aninhado a uma coorte de transplantados renais do Hospital de Clínicas de Porto Alegre (HCPA). Duzentos e setenta transplantados renais caucasianos (83 com DMPT e 187 sem DMPT), com pelo menos um ano de transplante, foram incluídos no estudo. Pacientes com diabetes melito pré-transplante e com múltiplos transplantes de órgãos foram excluídos. O diagnóstico de DMPT foi realizado através dos critérios da Associação Americana de Diabetes. Dados sócio-demográficos e clínicos foram coletados. A genotipagem dos polimorfismos 276G/T (rs1501299) do gene da adiponectina e dos polimorfismos rs2280789 e rs3817665 do gene da CCL5 foi realizada pela técnica de discriminação alélica por PCR (polymerase chain reaction) em tempo real. O estudo foi aprovado pelo Comitê de Ética em Pesquisa do HCPA e todos os pacientes assinaram o Termo de Consentimento Livre e Esclarecido. Resultados: O genótipo TT do polimorfismo 276G/T do gene da adiponectina foi mais frequente nos pacientes com DMPT do que naqueles sem diabetes, em comparação aos genótipos GG/GT (modelo recessivo; p=0,031). O genótipo TT foi identificado como fator de risco independente para o DMPT em transplantados renais caucasianos, no modelo ajustado para as variáveis: idade no momento do transplante, índice de massa corporal pré-transplante e uso de tacrolimus (TT vs. GG/GT, HR=1,88 IC95% 1,03-3,45, p=0,041). Não houve diferença na distribuição dos genótipos e alelos dos polimorfismos rs2280789 e rs3817655 do gene da CCL5 entre os pacientes com e sem DMPT. Conclusões: O polimorfismo 276G/T do gene da adiponectina está associado ao DMPT em transplantados renais caucasianos. / Background: New onset diabetes after transplantation (NODAT) is an increasingly recognized complication of kidney transplantation that is associated with poor outcomes. Both adiponectin and chemokine ligand 5 (CCL5) are related to glucose metabolism, allowing hypothesize that genetic variation in their genes can lead to development of NODAT. Objective: To investigate the association between adiponectin and CCL5 genes polymorphisms with NODAT in Caucasian kidney transplant recipients. Methods: This nested case-control study was undertaken within a cohort of kidney transplant recipients from Hospital de Clínicas de Porto Alegre, Southern Brazil. Two hundred seventy Caucasian kidney transplant recipients (83 with NODAT and 187 without NODAT) with at least one year of transplantation were included in this study. Patients with pretransplant diabetes mellitus and multi-organ transplantation were excluded. NODAT diagnosis was determined by American Diabetes Association criteria. Demographic and clinical data were collected. Subjects were genotyped for 276G/T adiponectin gene polymorphism and rs2280789 and rs3817655 CCL5 gene polymorphisms by real-time PCR (polymerase chain reaction). This study was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre and all subjects received adequate information about this study and gave informed consent. Results: The TT genotype of 276G/T adiponectin gene polymorphism was significantly more frequent in NODAT than non-NODAT patients, compared to GG/GT genotypes (recessive model; p=0.031). TT genotype was identified as an independent risk factor for NODAT in Caucasian kidney transplant recipients, after adjusting for age at transplantation, pretransplant BMI and tacrolimus usage (TT vs. GG/GT, HR=1.88 95%CI 1.03-3.45, p=0.041). There were no differences in genotype and allele distributions of rs2280789 and rs3817655 CCL5 gene polymorphisms between NODAT and non-NODAT groups. Conclusions: The 276G/T adiponectin gene polymorphism is associated with NODAT in Caucasian kidney transplant recipients.

Objetivo: Avaliar a influência de diferentes ambientes intrauterinos na concentração de hormônios no leite materno e sua relação com o peso da criança nos primeiros seis meses de vida. Materiais e Métodos: Trata-se de um de estudo de coorte prospectivo de uma amostra de recém-nascidos a termo da cidade de Porto Alegre. O recrutamento dos pares mãe-bebê ocorria 24 a 48 horas após o parto e os sujeitos incluídos em um dos cinco grupos: Diabetes, Hipertensão, Tabagistas, Pequenos para Idade Gestacional (PIG) e Controle. O colostro foi coletado no pós-parto e o leite maduro no 1º mês. Foram quantificadas as concentrações de Leptina, Adiponectina e Insulina pelo método ELISA. O peso e a estatura das mães e das crianças foram obtidos em todas as entrevistas Resultados: A concentração dos hormônios diminuiu com a maturação do leite materno com diferença estatística do colostro para o leite maduro para leptina no PIG (p=0,05) e Insulina nos grupos PIG (p=0,012) e Controle (p=0,041). O grupo PIG diferiu estatisticamente do Controle na concentração de leptina no 1M (p=0,045). O peso dos recém-nascidos PIG foi inferior aos outros grupos no nascimento e na alta hospitalar, mantendo-se diferente aos 15 dias do diabetes e controle, e, apenas do controle, no 1º mês. A partir dessa entrevista, a média de peso do PIG foi semelhante aos outros grupos indicando um catch up precoce avaliado pela diferença de escore-Z de peso para idade (>0,67). Tanto a leptina (r=-0,295; p=0,03) quanto a insulina (r=0,262; p=0,047) do leite maduro se correlacionaram com o ganho de peso da criança no 1º mês. Conclusões: A concentração dos hormônios no leite materno dos cinco grupos é semelhante ao nascimento, mas diminui do colostro para o leite maduro. A leptina e a insulina tem redução estatisticamente significativa no grupo PIG. O estudo demonstra uma antecipação metabólica do leite materno sobre a condição de PIG, relacionando-se com a possibilidade de um catch up precoce no primeiro mês de vida desses lactentes. / Objective: To evaluate the influence of different intrauterine environments on breast milk hormones concentration and its relationship with infant weight up to 6 months. Material and Methods: This is a thematic, prospective and longitudinal term born cohort from Porto Alegre, Brazil. Mother-infant pairs were recruited 24 to 48 hours after birth and then included in one of five groups: diabetes, hypertension, smoking, mothers of Small for Gestational Age (SGA) and controls. Colostrum was collected at 24h postpartum and mature milk 1 month later. Breast milk leptin, adiponectin and insulin were determined by ELISA. In all interviews mother and infant weight and height were obtained. Results: Adipokines levels decreased according to milk maturation with statistical difference in leptin from colostrum to mature milk in SGA group (p=0.05) and insulin in SGA (p=0.012) and control (p=0.041) groups. SGA differed statistically from control at colostrum in leptin concentration (p=0,045). SGA had low maternal BMI means values in all measurements reflecting in lower leptin and insulin concentration. SGA infant weight was statistically different from all groups at born and at discharge keeping different from diabetes and control at 15 days postpartum and only from control at 1 month. After, the weight mean of SGA was similar from others groups indicating an early catch up. Both, leptin (r=-0.295; p=0.03) and insulin (r=0.262; p=0.047) at 1 month were correlated with infant weight gain at 1 month. Conclusion: Breast milk hormones are similar at birth in all groups but the concentration decreases from colostrum to mature milk. SGA had a significant reduction in leptin and insulin concentration. This study demonstrates breast milk metabolic anticipation on SGA, probably is related to early catch up at 1 month of life.

La T-cadhérine est un récepteur de l'adiponectine, protéine impliquée dans la physiopathologie du diabète. Dans les études d'association pangénomiques, les polymorphismes du gène de la T-cadhérine (CDH13) sont associés aux variations de concentrations d'adiponectine. Le but de notre étude est d'approfondir les relations entre les polymorphismes de CDH13, l'adiponectine circulante, et le risque de diabète et de ses complications. Nous avons sélectionné deux polymorphismes du gène CDH13. Les génotypages ont été effectués dans plusieurs cohortes : D.E.S.I.R., issue de la population générale française, DIABHYCAR, cohorte de sujets atteints du diabète de type 2, et trois cohortes de patients diabétiques de type 1, GENESIS, GENEDIAB et SURGENE. Dans la population générale, les polymorphismes de CDH13 sont associés à l'indice de masse corporelle, à l'HbA1c, au Fatty Liver Index, indice de stéatose hépatique, et aux concentrations plasmatiques d'adiponectine. Dans une étude cas-contrôle entre D.E.S.I.R. et DIABHYCAR, les polymorphismes sont associés au risque de diabète de type 2. Ces associations pourraient être dues aux effets bénéfiques de l'adiponectine. Dans les cohortes de sujets diabétiques de type 1, GENESIS et GENEDIAB, nous avons observé des associations entre les polymorphismes de CDH13, la prévalence et l'incidence de la néphropathie. L'analyse dans l'étude prospective SURGENE confirme ces associations. Le sens des relations observées dans cette étude est en faveur d'un rôle délétère de l'adiponectine dans la néphropathie diabétique. En conclusion, les associations observées pourraient s'expliquer par des variations d'adiponectinémie et suggérer un lien de causalité. / T-cadherin is a receptor of adiponectin, a protein involved in the pathophysiology of diabetes. In genome-wide association studies, T-cadherin gene (CDH13) polymorphisms are associated with adiponectin concentrations. The aim of our study was to deepen the relationship between polymorphisms of CDH13, plasma adiponectin, and the risk of diabetes and its complications. We selected two polymorphisms in CDH13. Genotyping was performed in D.E.S.I.R., cohort drawn from the French general population, DIABHYCAR (subjects with type 2 diabetes) and three cohorts of patients with type 1 diabetes, GENESIS, GENEDIAB and SURGENE. In the general population, CDH13 polymorphisms were associated with body mass index, HbA1c, Fatty Liver Index, an index of hepatic steatosis, and plasma adiponectin. In a case-control study between D.E.S.I.R. and DIABHYCAR, polymorphisms were associated with the risk of type 2 diabetes. These associations with clinical phenotypes could be due to the beneficial effects of adiponectin. In subjects with type 1 diabetes from GENESIS and GENEDIAB, we observed associations between polymorphisms of CDH13 and the prevalence and the incidence of kidney disease. The analysis in the SURGENE prospective study confirmed these associations. The direction of the relationships observed in this study is in favor of a deleterious role of adiponectin in diabetic nephropathy. In conclusion, these associations may be explained by variations in adiponectin and suggest a causal relationship.

Made available in DSpace on 2015-07-22T20:49:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-09-29 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Objetivo: determinar se polimorfismos relacionados aos genes codificadores de Adiponectina (+45 e -11377), IL-10 (-1082), IL-6 (-174) e TNFA (-308) estão associados à ocorrência de diabetes gestacional (DG), diabetes mellitus tipo 1 (DM1) e diabetes mellitus tipo 2 (DM2). Além disso, pretendemos avaliar nestes pacientes a expressão destes fatores inflamatórios durante o terceiro trimestre gestacional, considerando o índice de massa corpórea (IMC) pré-gestacional. Métodos: Este estudo teve caráter tipo caso-controle e incluiu 79 pacientes com DG, 26 com DM1, 19 com DM2 e 169 mulheres sem patologia sistêmica ou obstétrica (C), e com história de duas ou mais gestações sem intercorrências como controles. O DNA genômico foi extraído de sangue periférico por método de DTAB/CTAB, e as genotipagens foram realizadas por técnica de PCR-RFLP. Para a análise dos resultados foram aplicados os testes qui-quadrado (χ2), exato de Fischer e Mann-Whitney, tendo sido adotado o nível de significância de p<0,05. Resultados: Não houve associação entre DG, DM1 e DM2 e qualquer um dos polimorfismos analisados. Os níveis séricos de adiponectina foram maiores no grupo controle do que em DG (p=0,0004) e DM2 (p=0,005). As concentrações de adiponectina de gestantes com DM1 também foram maiores do que em DG (p=0,0009) e DM2 (p=0,01). Tais diferenças persistiram considerando-se o IMC pré-gestacional, inclusive quando confrontados gestantes eutróficas ou obesas, entre si. Os níveis de IL-10, IL-6 e TNFA em sobrenadantes de cultura não diferiram entre os grupos C, DG, DM1 e DM2. Conclusões: Não houve associação entre nenhum dos polimorfismos analisados e DG, DM1 e DM2. Os grupos de estudo apresentaram diferenças entre si quanto aos níveis séricos de adiponectina, mas não quanto à produção de IL-10, IL-6 e TNFA. / Background: Adiponectin is involved in glycemic regulation and in the physiopathology of obesity. Adiponectin gene polymorphisms may influence the expression of this molecule. The aims of this study were to assess adiponectin +45 (rs2241766) and -11377 (rs266729) gene polymorphisms and adiponectin serum levels in Brazilian women with gestational diabetes (GD) according to the patients´ prepregnancy body mass index (BMI). Methods: This case-control study involved 79 GD patients and 169 healthy pregnant controls (C) grouped according to BMI (normal < 25 and obese ≥ 25). Genomic DNA was extracted from peripheral blood, and polymorphisms genotyping were obtained by digesting PCR products with the following restriction endonucleases: SmaI (+45) and HhaI (-11377). Adiponectin serum levels were determined by ELISA. Data were analyzed by Mann-Whitney, chi-square or Fisher tests; p<0.05 was considered significant. Results: When both groups were analyzed, adiponectin serum levels were higher in C than in GD women (p=0.0004). Adiponectin serum levels were higher in normal weight versus obese women, both in the C (p=0.01) and in GD (p=0.03) groups, as well as in normal weight C versus normal weight GD (p=0.03) and in obese C compared to obese GD women (p=0.01). Conclusions: Our data suggest that there were no associations between GD and the analyzed gene polymorphisms. There was a significant association between adiponectin -11377 gene polymorphism and adiponectin levels in healthy pregnant women. GD women have decreased adiponectin levels independently of BMI. / FAPESP: 08/55888-8 / TEDE / BV UNIFESP: Teses e dissertações