L’obésité et le diabète de type 2 (DT2) sont des pathologies métaboliques associées à des perturbations de l’homéostasie glucidique et énergétique. Les enterohormones sont des acteurs importants de la regulation des mécanismes perturbés lors de ces pathologies. Parmi ces enterohormones, le GLP-1, sécrété par les cellules entéroendocrines de type L suite à un repas, permet d’amplifier la sécrétion d’insuline par les cellules β-pancréatiques et de diminuer la prise alimentaire. L’objectif de ma thèse a été de caractériser le rôle du récepteur nucléaire HNF-4γ dans l’homéostasie énergétique et la fonction endocrine de l’intestin.A l’aide d’un modèle murin d’invalidation totale et constitutive du facteur de transcription HNF-4γ, notre équipe a mis en évidence que l’absence de HNF-4γ induit une amélioration de la tolérance au glucose grâce à une augmentation du nombre de cellules L et de la quantité plasmatique de GLP-1 en réponse au glucose. L’ensemble de ces données démontre pour la première fois un rôle de HNF-4γ dans l’homéostasie glucidique via une modulation du lignage enteroendocrine spécifique du GLP-1 et suggère que son absence pourrait protéger les souris de l’établissement d’un DT2.Par ailleurs, la perte d’expression de HNF-4γ confère une protection vis-à-vis de la prise de poids et de l’intolérance au glucose normalement induites par six semaines d’un régime riche en lipides et en fructose grâce une perte énergétique accrue dans les fécès essentiellement due à une malabsorption des acides gras.En conclusion, cette étude met en exergue le rôle du récepteur nucléaire intestinal HNF-4γ dans la fonction enteroendocrine et la susceptibilité à l’obésité et au DT2. / Obesity and type 2 diabetes (T2D) are metabolic pathologies associated with glucose and energy homeostasis perturbations. Enterohormones are important players in the regulation of the mechanisms disturbed during these pathologies. Among these enterohormones, GLP-1, secreted by enteroendocrine L cells in response to a meal, potentiates insulin secretion by pancreatic β cells and inhibits food intake. The aim of my thesis was to characterize the role of the nuclear receptor HNF-4γ in the energy homeostasis and the endocrine function of the intestine.By using a total and constitutive HNF-4γ knock-out mouse model, our team has highlighted that the loss of hnf-4γ induces an improved glucose tolerance. This effect is due to an increased GLP-1 cell number and GLP-1 plasma levels in response to glucose. All together these data demonstrate for the first time a role of HNF-4γ in glucose homeostasis through a modulation of the enteroendocrine lineage specific for GLP-1 and suggest that its absence could protect mice from the T2D establishment.The loss of HNF-4γ protects mice from body weight gain and glucose intolerance normally induced by six weeks of a high-fat/high-fructose diet demonstrating its involvement in obesity and T2D. HNF-4γ -/- mice are protected from obesity by a greater energy loss in faeces mainly due to lipid malabsorption. These results demonstrate that HNF-4γ is necessary for the intestinal fatty acids uptake.In conclusion, this study highlights the role of the intestinal nuclear receptor HNF-4γ in enteroendocrine function and susceptibility to obesity and T2D.

(EN) Obesity and type 2 diabetes mellitus (T2DM) are among metabolic disease with increasing incidence and prevalence. Last decade has been devoted to intensive research focused on pathophysiological mechanisms underlying development of these diseases. Besides environmental factors, lifestyle and amount and composition of food, adipose tissue is a key player in the pathogenesis of obesity and its metabolic complications including insulin resistance (IR) and T2DM. Primary aim of our work was to evaluate the role of recently discovered adipokine omentin and the role of mitochondrial dysfunction in subcutaneous adipose tissue (SCAT) and in peripheral monocytes (PM) in patients with obesity and T2DM with respect to the development of insulin resistance and diabetes. A total number of 118 subjects enrolled in the study were divided into three groups: patients with obesity and T2DM (T2DM group), obese non-diabetics (OB) and healthy lean subjects as a control group (KO). Study subjects underwent several types of interventions - 2 to 3 weeks of very-low calorie diet (VLCD, energy intake 600 kcal per day), regular physical activity program or bariatric surgery (laparoscopic sleeve gastrectomy, LSG). Results indicate that low serum omentin concentrations may contribute to development of obesity-associated...

The increase in the NTPDase and 5'-nucleotidase enzymatic activities, in patients with diabetes and hypertension, unchained the investigation of the possible mechanisms involved in the alterations in ectonucleotidases activities. The oxidative stress level and also the answer of the antioxidant systems were evaluated in patients with type 2 diabetes, hypertension and type 2 diabetes with associated hypertension. The interference of the glucose concentration was evaluated in the enzymatic activity of the ectonucleotidases, serum cholinesterase and also antioxidant enzymes. The curves in vitro demonstrated that the increase in enzymatic activity was proportional to the elevation in the glucose concentrations, demonstrating a direct interference of the hyperglycemia. The increase in the NTPDase expression demonstrated an important correlation with adenine nucleotide ATP and ADP hydrolyze in patients with diabetes and associated hypertension. The increment in markers of oxidative stress and antioxidant systems levels in patients with diabetes and associated hypertension seems to be related with a compensatory mechanism to prevent oxidative damages. Low serum acid ascorbic levels increase exposes to oxidative damages in patients with diabetes and associated hypertension, resultant of the increase in reactive oxygen species generation. The increment in the serum cholinesterase activity can be potentially related with glycemia levels and lipid metabolism in patients with diabetes and associated hypertension. The medicines administered to the patients did not alter the enzymatic responses in the analyzed groups. Therefore, there were a possible interference of the diabetes and hypertension in the catalytic mechanism of the serum cholinesterase enzyme. Data obtained in the studies permit to suggest that high blood glucose levels constitute one of the principal factors capable to promote alterations in the enzymatic responses in patients with diabetes and associated hypertension. / O aumento na atividade enzimática da NTPDase e 5'-nucleotidase, em pacientes com diabetes e hipertensão, desencadeou a investigação dos possíveis mecanismos envolvidos nas alterações na atividade das ectonucleotidases. O nível de estresse oxidativo e também a resposta dos sistemas antioxidantes foram avaliados em pacientes com diabetes tipo 2, hipertensão e diabetes tipo 2 com hipertensão associada. A interferência da concentração de glicose foi avaliada na atividade enzimática das ectonucleotidases, colinesterase sérica e também das enzimas antioxidantes. As curvas in vitro demonstraram que o aumento na atividade dos sistemas enzimáticos foi proporcional à elevação nas concentrações de glicose, demonstrando uma interferência direta da hiperglicemia. O aumento na expressão da enzima NTPDase demonstrou uma importante correlação com a hidrólise dos nucleotídeos de adenina ATP e ADP em pacientes com diabetes e hipertensão associada. O incremento nos níveis de marcadores de estresse oxidativo e dos sistemas antioxidantes, em pacientes com diabetes e hipertensão associada, parecem estar relacionados com um mecanismo compensatório para prevenir o dano oxidativo. Os baixos níveis de ácido ascórbico sérico aumentam a exposição dos pacientes, com diabetes e hipertensão associada, aos danos oxidativos resultantes do aumento na geração de espécies reativas de oxigênio. O aumento na atividade da enzima colinesterase sérica, em pacientes com diabetes e hipertensão associada, pode estar potencialmente relacionado com os níveis de glicemia e com o metabolismo dos lipídios. Os medicamentos administrados aos pacientes não alteraram as respostas enzimáticas nos grupos analisados. Portanto, houve uma possível interferência do diabetes e da hipertensão no mecanismo catalítico da colinesterase sérica. Os dados obtidos nos estudos permitem sugerir que os elevados níveis de glicose sangüínea constituem um dos principais fatores capazes de promover alterações nas respostas enzimáticas em pacientes diabéticos e com hipertensão associada.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Diabetes mellitus is a metabolic disease characterized by hyperglycemia due defective or deficient response to insulin secretion. Type 2 diabetes mellitus (Type 2 DM) is therefore associated with a general activation of the innate immune system, in which there is a chronic, cytokine-mediated state of low-grade inflammation. Dipeptidyl peptidase IV (DPP-IV) is a cell-surface protease that bind with Adenosine deaminase (ADA) and both enzymes act in the lymphocytes proliferation and citokyne production. Vitis vinifera is a plant that has been studied due its pharmacology effects including the hypoglycemic properties. Thus, the aim of this study is to evaluate some inflammatory biomarkers, the ADA and DPP-IV activities in type 2 DM and investigate the effects of aqueous grape seed extract from Vitis vinifera (cv. Merlot) (GSE) in the ADA and DPP-IV activities in lymphocytes submitted to different glucose concentrations, in vitro. In the manuscript I, in lymphocytes, we observed a decrease in CD26 expression, an increase in ADA and n-acetil-β-d-glucosaminidase (NAG) activities in type 2 DM patients when compared to controls, while the gamma-glutamyl tranferase (GGT) and DPP-IV activities did not show differences between the groups. Moreover, the NAG activity demonstrated a positive correlation with ADA activity and a negative, with CD26 expression. GGT activity was positively correlated with waist circumference and body mass index (BMI), in type 2 DM. In the manuscript II, we observed we observed an increase in ADA activity when lymphocytes were exposure to the high concentration (100mM) of glucose and GSE prevented this increase in ADA activity. In serum, in the manuscript I, we showed an increase in ADA activity and in C reactive protein (CRP) levels in type 2 DM. Furthermore, the levels of CRP in diabetics were positively correlated with waist circumference and BMI. The GGT and DPP-IV activities did not show alterations between the groups, but in type 2 DM the DPP-IV activity was positively correlated with glicated hemoglobin. We concluded that, glucose might stimulated the ADA activity in the same time that it cause decrease in CD26 expression, in lymphocytes. Moreover, GSE prevents the ADA activation in presence of glucose possible due its hypoglycemic properties. / O diabetes melito (DM) é uma desordem metabólica caracterizada por hiperglicemia em virtude de resposta defeituosa ou deficiente à secreção de insulina. O DM tipo 2 (DM 2) está associado com a ativação do sistema imune, no qual há uma inflamação de baixo grau mediada por citocinas. A dipeptidil peptidase IV (DPP-IV, CD26) é uma protease multifuncional e na superfície celular ela encontra-se ligada a adenosina deaminase (ADA). Ambas estão envolvidas na proliferação de linfócitos e na produção de citocinas inflamatórias. A Vitis vinifera é uma planta que tem sido estudada devido suas propriedades farmacológicas, dentre essas, por apresentar efeitos hipoglicêmiantes. Desta forma, o objetivo deste estudo foi avaliar biomarcadores inflamatórios, a atividade da ADA e da DPP-IV em pacientes com DM 2, e verificar o efeito do extrato aquoso de sementes de Vitis vinifera (cv. Merlot) sobre a atividade da ADA e da DPP-IV em linfócitos expostos a diferentes concentrações de glicose, in vitro. Em linfócitos, no manuscrito I observamos uma diminuição na expressão do CD26, um aumento na atividade da ADA e da n-acetil-β-d-glicosaminidase (NAG) em pacientes com DM 2 em relação aos controles, enquanto que a atividade da gamaglutamil transferase (GGT) e da DPP-IV não se alterou. Também, a atividade da NAG linfocitária em pacientes com DM 2 mostrou-se positivamente relacionada com a atividade da ADA e negativamente com a expressão do CD26 e a atividade da GGT mostrou-se positivamente relacionada à circunferência abdominal e ao IMC. Já no manuscrito II, observamos um aumento na atividade da ADA quando os linfócitos forma expostos a 100mM de glicose e este aumento foi atenuado quando, expostos a glicose e extrato aquoso de sementes de Vitis vinifera. Em soro, no manuscrito I, observamos um aumento na atividade da ADA e também nos níveis de proteína C reativa (PCR) em pacientes com DM 2. Além disso, os níveis de PCR em diabéticos mostraram-se positivamente correlacionados com a circunferência abdominal e o índice de massa corporal (IMC) desses pacientes. A atividade da GGT e da DPP-IV não mostraram diferenças entre os grupos. No entanto, a atividade da DPP-IV sérica mostrou-se correlacionada com os níveis de hemoglobina glicada nos pacientes com DM 2. Conclui-se que, a glicose possa estimular a atividade da ADA ao mesmo tempo em que provoca uma redução da expressão do CD26 em linfócitos. Além disso, o extrato aquoso de sementes de Vitis vinifera é capaz de impedir a ativação da atividade da ADA em presença de glicose possivelmente devido suas propriedades hipoglicemiantes.

Situé dans le noyau suprachiasmatique (SCN) de l’hypothalamus, l'horloge principale contrôle les rythmes des processus comportementaux et métaboliques chez les mammifères. Par exemple, les rythmes quotidiens de veille-sommeil, d'alimentation-jeûne, de glycémie, de tolérance au glucose et de sensibilité à l'insuline sont régulés par l'horloge SCN. La lumière est le synchroniseur principal du SCN, même si de nombreux facteurs autres que la lumière, tels que l'éveil comportemental ou des facteurs métaboliques, peuvent également moduler la phase ou la période des SCN. L'objectif de cette thèse était d'étudier différents aspects des interactions entre l'éveil comportemental, les rythmes circadiens et le métabolisme du glucose. Dans la première partie, nous avons déterminé l'action centrale du Gastrin-Releasing Peptide (GRP), un neuropeptide synthétisé dans le SCN, sur le métabolisme du glucose. Nos résultats indiquent qu’une injection icv de GRP induit une hyperglycémie prolongée. Nous avons également montré qu’une privation de sommeil à court terme conduit à une détérioration de la tolérance au glucose. Dans la deuxième partie, nous avons démontré que l'éveil comportemental induit par la privation de sommeil ou une injection de caféine améliore l’entraînement photique de l'horloge SCN chez un rongeur diurne : le rat roussard du Soudan, Arvicanthis ansorgei. Ces réponses circadiennes chez une espèce diurne qui sont opposées à celles précédemment mises en évidence chez les rongeurs nocturnes pourraient avoir des applications biomédicales. / Located in the hypothalamic suprachiasmatic nucleus (SCN), the master clock generates rhythms of behavioural and metabolic processes in mammals. For example, daily rhythms of sleep-wake, fasting-feeding, plasma glucose concentration, glucose tolerance and insulin sensitivity are regulated by the SCN clock. Light is the primary synchronizer of SCN pacemaker though many light-independent factors such as behavioural arousal and metabolic cues also have phase and period resetting properties. The aim of thesis was to study different aspects of the interactions between behavioural arousal, circadian rhythms and glucose metabolism. In the first part, we extended the study of brain control of glucose metabolism by investigating the central action of gastrin-releasing peptide (GRP), a neuropeptide synthesized in the SCN, on glucose metabolism. Our result indicates that central GRP induces long-lasting hyperglycemia. We also showed that acute sleep deprivation leads to impaired glucose tolerance. In the second part, we demonstrated that behavioural arousal induced by sleep deprivation or caffeine treatment enhances photic-entrainment of the SCN clock in the diurnal Sudanian grass rat, Arvicanthis ansorgei. These circadian responses in a diurnal species are opposite to the earlier findings in nocturnal rodents and may have biomedical applications.

The worldwide prevalence of obesity has increased severely in recent decades. Obese people have risk of developing insulin resistance, type 2 diabetes, dyslipidemia, cardiovascular disease, metabolic syndrome (MS) and cancer. In addition, obesity has been related to oxidative changes and a low-grade chronic inflammation that initially affects adipose tissue and later the others organs and systems. Guarana (Paullinia cupana) is a native plant from the Amazon, Brazil which has bioactive compounds that appear to act in energy metabolism, oxidative and inflammatory processes. However, epidemiological studies about guaraná consumption effect are still incipient. Thus, this study investigated the in vivo effect of habitual intake of guarana on the individuals health, observing the occurrence of obesity, type 2 diabetes and MS, as well as the markers associated with these diseases, as well as their behavior in experiments in vitro. In a first case-control study included 637 elderly were divided among those who habitually drank guaraná (GI: n = 421) and those who did not ingest the plant (NG, n = 239). The prevalence of hypertension, obesity and MS was lower in GI, than in the NG. In addition, in GI women were observed lower levels of total cholesterol, LDL-cholesterol and AOPP (products of advanced protein oxidation). The men in this group showed lower values of waist circumference. In a second study, we used an in vivo protocol for evaluation the guaraná effect on inflamatory markers levels. Peripheral blood mononuclear cells (PBMCs) were treated with and without guaraná (5 g/ml), besides glucose (15 mM) and insulin (1 mU/ml). Were also evaluates the citokyne plasma levels in subjects suplemented with guaraná (90 mg/day) for 14 days. Both the in vitro and in vivo analyses demonstrated a decrease in the proinflammatory cytokines: IL-1β, IL-6, TNF-, IFN- and an increase in antiinflammatory IL-10. The results demonstrate the protective guaraná effect against obesity, hypertension and MS, as well as his performance on the oxidative and inflammatory processes associated with these. / A prevalência mundial da obesidade tem aumentado consideravelmente, nas últimas décadas. Os indivíduos obesos apresentam riscos de desenvolvimento de resistência à insulina, diabetes tipo 2, dislipidemia, doenças cardiovasculares, síndrome metabólica (SM) e câncer. Além disso, a obesidade tem sido relacionada a alterações oxidativas e a uma inflamação crônica de baixo grau que atinge inicialmente o tecido adiposo e posteriormente o organismo de forma sistêmica. O guaraná (Paullinia cupana) é uma planta nativa da Amazônia, que possui compostos bioativos que parecem atuar no metabolismo energético, oxidativo e inflamatório. Entretanto, estudos epidemiológicos sobre as consequências do seu consumo na saúde humana são ainda incipientes. Sendo assim, este trabalho avaliou o efeito in vivo da ingestão habitual de guaraná pelos indivíduos testados, observando a ocorrência de obesidade, diabetes tipo 2 e SM, bem como o comportamento in vitro dos marcadores bioquímicos e inflamatórios associados a essas doenças. Em um primeiro estudo caso-controle foram incluídos 637 idosos divididos no grupo dos que ingeriam guaraná habitualmente (GI: n = 421) e dos que não ingeriam a planta (NG: n = 239). A prevalência de hipertensão, obesidade e SM foi menor no grupo GI do que no NG. Além disso, nas mulheres foram observados níveis mais baixos de colesterol total, LDL-colesterol e AOPP (produtos de oxidação proteica avançada) no grupo GI. Já os homens desse grupo mostraram menores valores de circunferência abdominal. Em um segundo estudo, foi utilizado um protocolo in vitro para avaliação do efeito do guaraná nos níveis de marcadores inflamatórios. Células mononucleares periféricas (PBMCs) foram tratadas com e sem guaraná (5 g/ml), além de glicose (15 mM) e insulina (1 mU/mL). Foram avaliados ainda, in vivo, os níveis plasmáticos de citocinas em indivíduos saudáveis suplementados com guaraná (90 mg/dia) durante 14 dias. Tanto no ensaio in vitro, como no in vivo foi observada uma diminuição nos níveis das citocinas pró-inflamatórias: IL-1β, IL-6, TNF- e IFN- e aumento da anti-inflamatória IL-10. Os resultados deste trabalho demonstram o efeito protetor do guaraná contra a obesidade, hipertensão e SM, bem como sua atuação nas rotas oxidativas e inflamatórias associadas a esses processos.

Résumé confidentiel / Résumé confidentiel

Abstract Type 2 diabetes is increasing overall in the world and is mostly associated with Western lifestyle including replete, unhealthy diet, sedentary life style and growing obesity. In the future the highest prevalence will be seen among older people due to longer life expectancy and changes in demography. Because diabetes is associated with increased morbidity, especially from cardiovascular causes, and a shortened life expectancy, an important aspect in the older population is the impact of diabetes on health related quality of life (HRQoL) and development of disability. To measure HRQoL we have many valid instruments, one of them the widely used RAND-36 survey. The 2-hour glucose value is important in screening subjects at high risk for diabetes, but it is time consuming and costly. Recently, 1-hour post load glucose has aroused interest in the prediction of diabetes. Few studies have focused on the effect of the age of onset of diabetes and how it effects on the HRQoL at an older age. The aim of this study was to investigate the risk factors for future diabetes in men healthy in midlife; the interest was especially focused on 1-hour post load glucose. The other objective was to estimate the HRQoL in men who develop diabetes at an old age. The present prospective study is based on the Helsinki Businessmen Study originally consisting of 3.490 men, born in 1919–1934 and followed since the 1960´s. All the men had socioeconomically similar status and belonged to the highest social group. The extensive baseline examinations were conducted in 1974, when the men were in midlife, mean age 48. At that time the men´s health, medication and cardiovascular risk factors were observed and self-related health (SRH) was rated on a five-step scale. The men who were healthy without medications were included in the follow-up group. The men were later investigated with postal questionnaires (1985/86, 2000, 2002/03, 2007). In 2000, at mean age of 73, the HRQoL of the survivors was examined using the RAND-36 instrument and was replicated in 2002/03, 2005 and 2007. Development of diabetes was evaluated using the National Drug Reimbursement register and self-reported diabetes in questionnaires. Baseline 1-hour post-load blood glucose and weight gain from the age of 25 to midlife predicted future diabetes, and especially a combination of 1-hour glucose >8.9 mmol/L and body mass index (BMI) of ≥30 was associated with a 10.1-fold increase of diabetes risk independently of cardiovascular risk factors. Men with late-onset of diabetes (age >75) tented to be healthier in midlife. Diabetes did not affect the HRQoL until after diabetes onset. According to the evaluation in 2000, three RAND-36 scales, i.e. physical functioning, general health and social functioning, worsened already after 0–4 years from diabetes onset but did not deteriorate thereafter. There was no consistent impact on mental health. In conclusion, this study demonstrates that in men, who develop diabetes later in old age, cardiovascular risk factors in midlife and elevated 1-hour post-load glucose and weight gain up to midlife are important predictors for future diabetes. Developing diabetes exerts clear effects on HRQoL, measured with RAND-36 very early after diagnosis, but affects only some of the domains. / Tiivistelmä Tyypin 2 diabetes on lisääntymässä maailmanlaajuisesti ja on suurelta osin yhteydessä länsimaisen elämäntyylin yleistymiseen. Keskeisimpinä tekijöinä ovat muuttunut, yltäkylläinen ruokavalio, vähentynyt fyysinen aktiivisuus ja niiden myötä lihavuuden lisääntyminen. Diabeteksen lisääntyminen näyttäisi olevan suurinta yli 65-vuotiaiden keskuudessa. Tähän vaikuttavat mm. eliniän pidentyminen ja väestörakenteen muutokset. Diabetesta sairastavien riski sairastua ja kuolla sydän- ja verisuonisairauksien komplikaatioihin on suurempi kuin ei-diabeetikoilla ja sairauksien myötä toimintakyky sekä elämänlaatu heikkenevät. Henkilön oma arvio hyvinvoinnista on tärkeä mittari. Elämänlaadun luotettava mittaaminen on tullut mahdolliseksi testattujen kysymyssarjojen myötä. Yksi laajasti käytetty mittari on RAND-36. Diabetesriskissä olevien henkilöiden löytämiseksi on käytetty 2-tunnin glukoosirasitustestiä, joka on aikaa vievä. Viimeaikoina onkin herännyt kiinnostus glukoosirasituksen jälkeistä yhden tunnin sokeriarvoa kohtaan. Useimmat tyypin 2 diabetekseen liittyvät tutkimukset ovat keskittyneet työikäiseen väestöön, minkä vuoksi tutkimuksia vanhemmalla iällä puhjenneesta diabeteksesta ja sen vaikutuksesta elämänlaatuun on vähemmän. Tämän tutkimuksen tarkoituksena oli selvittää keski-iän riskitekijöitä, jotka ennustavat tulevaa tyypin 2 diabetesta myöhemmällä iällä. Yhtenä tutkimuskohteena oli yhden tunnin glukoosirasituksen jälkeinen sokeriarvo. Myöhemmällä iällä puhjenneen diabeteksen merkitystä elämänlatuun kartoitettiin RAND-36-mittarilla. Tutkimusaineistona oli ns. Helsingin Johtajatutkimuksen mieskohortti, jota on seurattu 1960-luvulta alkaen. Kaikki miehet (n=3.490) olivat alkuaan terveitä, vuosina 1919–1934 syntyneitä miehiä, jotka kuuluivat ylimpään sosiaaliryhmään. Heidän terveydentilaansa on kartoitettu nykypäiviin saakka. Laajempi perustutkimus tehtiin vuonna 1974, jolloin miehet olivat keski-iässä (48 v). Seurantaan valittiin terveet henkilöt, joilla ei ollut säännöllisiä lääkityksiä. Tällöin kartoitettiin sydän- ja verisuonisairauksien riskitekijöitä, mitattiin glukoosirasituksen jälkeinen yhden tunnin sokeriarvo ja selviteltiin elämäntapoja, minkä lisäksi sen hetkistä itse koettua hyvinvointia mitattiin 5-portaisella asteikolla. Postitse lähetettyjä kyselytutkimuksia on tehty tietyin väliajoin ja aineiston tiedot tähän tutkimukseen on kerätty 31.12.2007 mennessä. Vuonna 2000 kyselytutkimukseen liitettiin elämänlaatumittarina RAND-36-mittarin suomalainen versio. Diabeteksen puhkeamista on seurattu Kelan lääkekorvausrekisteristä sekä itse ilmoitettuna postikyselyiden kautta. Tässä keski-iässä terveessä mieskohortissa tulevan diabeteksen kannalta merkittävimmät ennusteelliset tekijät olivat painon nousu 25-vuoden iästä keski-ikään sekä keski-iässä mitattu glukoosirasituksen jälkeinen yhden tunnin sokeriarvo. Etenkin yhden tunnin sokeriarvo >8.9 mmol/L ja BMI ≥30 nostivat tulevan diabeteksen riskin 10-kertaiseksi. Näillä tekijöillä oli myös vahva yhteys sydän- ja verisuonisairauksien aiheuttamaan kuolleisuuteen. Glukoosirasituksen jälkeisellä yhden tunnin sokeriarvolla näyttäisi olevan merkitystä arvioitaessa tyypin 2 diabetesriskiä tulevaisuudessa, katkaisupisteenä plasman ≥7.8 mmol/L. Elämänlaatua diabetes näytti heikentävän pian diagnoosin jälkeen (0–4 vuotta diagnoosista), mutta sen jälkeen elämänlaatu ei huonontunut oleellisesti. RAND-36 mittarilla mitattuna elämänlaatu heikkeni merkittävästi diabeetikoilla ei-diabeetikoihin verrattuna fyysisen toimintakyvyn, yleisen elämänlaadun ja sosiaalisten toimintojen osa-alueilla, mutta mielenterveyteen diabetes ei näyttänyt vaikuttavan.

Abstract Coronary artery disease (CAD) and type 2 diabetes (T2D) are associated with cardiovascular autonomic dysfunction, which is widely used as a predictor of mortality in cardiovascular diseases. The determinants of autonomic dysfunction in CAD patients with or without T2D are not well known. The aim of this thesis was to examine the determinants of cardiovascular autonomic function in healthy subjects and CAD patients with and without T2D. A second aim was to study the prognostic value of autonomic function in the patient population. A third aim was to study the effects of exercise prescriptions on physical activity and exercise capacity in the patient groups. The association between heart rate (HR) variability and physical activity was examined by means of 24-hour recordings in 45 healthy adults. The determinants and prognostic value of autonomic function, measured by HR recovery, HR variability, and HR turbulence, were assessed in 1060 CAD patients (50% were patients with T2D). Physical activity was measured before and after a six-month exercise prescription in 44 CAD patients without T2D and 39 CAD patients with T2D. In healthy patients, short-term HR variability indexes and the complexity properties of HR were influenced by physical activity, whereas long-term HR variability indexes remained relatively stable at various activity levels, making them robust indexes for assessment of autonomic function during ambulatory conditions. In CAD patients, exercise capacity was the most important determinant of autonomic function in addition to physical activity, age, presence of T2D, and left ventricular systolic function. During a 2-year follow-up, autonomic dysfunction predicted cardiovascular events only in CAD patients with T2D, but did not provide independent prognostic information after multivariate adjustment when high-sensitivity C-reactive protein, a marker of inflammation, remained as an independent predictor. CAD patients with T2D were physically less active than patients without T2D. Exercise prescription promoted a more active lifestyle and improved exercise capacity in both patient groups. In conclusion, cardiovascular autonomic dysfunction in CAD patients with and without T2D is closely related to low exercise capacity and physical activity, which both can be increased by exercise prescriptions. Autonomic dysfunction predicts short-term cardiovascular events only in CAD patients with T2D, but is not as strong an independent predictor as low-grade inflammation. / Tiivistelmä Autonomisen hermoston toiminnan häiriö on yleinen komplikaatio sepelvaltimotaudissa ja tyypin 2 diabeteksessa (T2D), ja sen tiedetään olevan itsenäinen kuolleisuutta ennustava tekijä. Autonomista säätelyä selittäviä tekijöitä ei kuitenkaan tunneta hyvin. Tässä tutkimuksessa selvitettiin autonomisen hermoston toimintaa selittäviä tekijöitä kolmessa ryhmässä: osa tutkittavista oli terveitä, osalla oli sepelvaltimotauti ja T2D, ja osalla pelkästään sepelvaltimotauti. Lisäksi tutkittiin, miten autonominen säätely vaikuttaa sepelvaltimotautipotilaiden ennusteeseen sekä miten liikuntaohjelma vaikuttaa heidän fyysiseen aktiivisuuteensa ja suorituskykyynsä. Sykevaihtelun ja fyysisen aktiivisuuden välistä yhteyttä selvittävään tutkimukseen osallistui 45 tervettä henkilöä. Autonomisen hermoston toimintaa selittäviä tekijöitä ja sen ennustearvoa tutkittiin 1060 sepelvaltimotautipotilaalta, joista puolet sairasti T2D:ta. Näistä potilaista valittiin satunnaisotannalla kuuden kuukauden liikuntaohjelmaan ja fyysisen aktiivisuuden mittauksiin 44 sepelvaltimotautipotilasta, joilla ei ollut T2D:ta, ja 39 potilasta, jotka sairastivat T2D:ta. Terveillä henkilöillä lyhyen aikavälin sykevaihtelumuuttujat olivat yhteydessä fyysiseen aktiivisuuteen, mutta pitkän aikavälin sykevaihtelumuuttujissa tätä yhteyttä ei havaittu. Sepelvaltimotautipotilailla vahvimmiksi autonomista säätelyä selittäviksi tekijöiksi osoittautuivat maksimaalinen suorituskyky, fyysinen aktiivisuus, ikä, T2D ja vasemman kammion ejektiofraktio. Poikkeava autonominen säätely ennusti sydän- ja verisuonitautitapahtumia kahden vuoden seurannan aikana vain T2D:ta sairastavilla sepelvaltimotautipotilailla, mutta sillä ei ollut itsenäistä ennustearvoa, kun vakioitiin muilla riskitekijöillä. Lopulta ainoa huonon ennusteen merkki oli tulehdustilaa kuvaava herkkä CRP. T2D:ta sairastavat sepelvaltimotautipotilaat olivat fyysisesti passiivisempia kuin pelkästään sepelvaltimotautia sairastavat. Yksilöllinen liikuntaohjelma lisäsi korkean intensiteetin fyysistä aktiivisuutta ja paransi suorituskykyä molemmissa potilasryhmissä. Tämän tutkimuksen tulokset osoittavat, että sepelvaltimotautipotilailla autonomisen hermoston toiminnan häiriö on yhteydessä vähäiseen fyysiseen aktiivisuuteen ja heikkoon fyysiseen kuntoon. Molempiin tekijöihin voidaan vaikuttaa positiivisesti liikuntaohjelmalla. Poikkeava autonominen säätely ennustaa lyhyen aikavälin sydän- ja verisuonitautitapahtumia vain T2D:ta sairastavilla sepelvaltimotautipotilailla. Se ei kuitenkaan ole yhtä vahva itsenäinen ennustaja kuin tulehdusta kuvaava herkkä CRP.

Diploma thesis "Vliv řízeného tréninku na habituální pohybovou aktivitu pacientů s diabetes mellitus 2. typu" in the theoretical part deals with Type 2 diabetes (DM2T), its complications and possibilities of its therapy. Emphasis is put on physical activity as the main non-pharmacological mean influencing insulin resistance. The basic health aspects of physical activity, general recommendations and specific sport activities for DM2T patients are mentioned. We also focus on potential risks related to physical exercises. Furthermore, we examine habitual physical activity, meaning energy expenditure in daily activities. The objective of the practical part of this thesis is to determine the level of habitual physical activity of DM2T patients and to show how it is influenced by stationary bicycle exercises. The impact of regular physical activity on the health indicators, physical fitness and anthropometric parameters, is examined. The sample of patients includes 20 individuals with DM2T, who have completed insulin therapy and currently are cured with peroral antidiabetics and regime measures. Pedometer and International Physical Activity Questionnaire (IPAQ) are used in order to monitor habitual physical activity. Powered by TCPDF (www.tcpdf.org)