INTRODUÇÃO: A diabetes mellitus tipo 2 (DM) é uma doença metabólica caracterizada pela presença de hiperglicemia crônica. Estudos prévios demonstraram que pacientes com pré-diabetes (PDM) têm uma história natural de progressão para DM. A neuropatia diabética é a complicação mais comum da DM e avanços recentes na neurofisiologia clínica trouxeram um refinamento das técnicas de avaliação. Entre estas estão à resposta cutânea simpática (SSR) e o teste sensorial quantitativo (QST). Biomarcadores como Enolase Neurônio-Específica (NSE) e a Proteína S100-Beta (S100B) vem sendo descritos por muitos autores como associados a danos em células do sistema nervoso. OBJETIVO: O objetivo deste estudo é avaliar parâmetros neurofisiológicos e compará-los com achados clínicos e bioquímicos (S100B e NSE) em pacientes com DM, PDM e controles saudáveis. MÉTODOS: Pacientes dos ambulatórios de Neurologia e Endocrinologia foram randomizados em um estudo transversal. Os participantes foram submetidos a uma bateria de testes clínicos e neurofisiológicos que englobaram condução nervosa, Onda-F, SSR e QST. Níveis séricos de NSE e S100B foram quantificados através de ensaio ELISA (Enzyme-linked immunosorbent assay). RESULTADOS: A avaliação clínica e os estudos de condução nervosa e Onda-F foram similares nos grupos estudados. Já os limiares QST calor (QSTc) e QST dor (QSTd) foram significativamente elevados nos pacientes PDM e DM com relação aos controles (P<0.05 para todas as comparações). No entanto, estes parâmetros não foram capazes de distinguir pacientes DM vs. PDM (P >0.1 para todas as comparações). O SSR foi capaz de diferenciar o grupo DM do controle (P <0,01) embora não tenha mostrado diferença entre os grupos PDM e controle (P = 0,6). Não houve diferença entre os níveis de S100B (P = 0.6) e NSE (P = 0.2) entre os grupos DM, PDM e controles. CONCLUSÃO: O QST e SSR são testes úteis para a avaliação de pacientes com diferentes graus de tolerância a glicose. Este estudo não encontrou diferenças entre os biomarcadores NSE e S100B em indivíduos com DM e PDM. / BACKGROUND: Type 2 diabetes mellitus (DM) is a metabolic disease characterized by the presence of chronic hyperglycemia. Previous studies demonstrated that patients with prediabetes states (PDM) have a natural history of progression to DM. Neuropathy is the most common and disabling complication of diabetes and recent advances in neurophysiology have enabled a refinement of neurophysiological diagnostic techniques such as sympathetic skin response (SSR) and quantitative sensory testing (QST). Biomarkers like Neuron-specific Enolase (NSE) and S100- Beta Protein (S100B) has been described for many authors as associated with damage at nervous system cells and are related with severity of injury as well as clinical outcomes. OBJECTIVE: The aim of this study is to evaluate neurophysiological findings and compare them with clinical and biochemical findings (S100B and NSE) in patients with DM, PDM and healthy controls. METHODS: Patients at the outpatient Neurology and Endocrinology service were randomized in a cross-sectional study. Participants underwent a battery of clinical and neurophysiological tests that encompassed nerve conduction studies, F-wave, SSR and QST. ELISA (enzyme-linked immunosorbent assay) were perform to quantify serum levels of NSE and S100B. RESULTS: There were no difference regarding clinical evaluation, nerve conduction studies and F-wave were between groups. The QST thresholds of warm (QSTw) and QST pain (QSTp) were significantly elevated in patients with PDM and DM compared to controls (P <0.05 for all comparisons). However, these parameters were not able to distinguish among DM and PDM (P > 0.1 for all comparisons). The SSR was able to differentiate DM from control group (P <0.01) but did not show difference between PDM and control groups (P = 0.6). There was no difference on levels of S100B (P = 0.6) and NSE (P = 0.2) between the DM, PDM and control groups. CONCLUSION: The QST and SSR are useful tests to evaluating patients with different degrees of glucose tolerance. This study found no differences between biomarkers NSE and S100B in subjects with DM and PDM.

INTRODUÇÃO: A diabetes mellitus tipo 2 (DM) é uma doença metabólica caracterizada pela presença de hiperglicemia crônica. Estudos prévios demonstraram que pacientes com pré-diabetes (PDM) têm uma história natural de progressão para DM. A neuropatia diabética é a complicação mais comum da DM e avanços recentes na neurofisiologia clínica trouxeram um refinamento das técnicas de avaliação. Entre estas estão à resposta cutânea simpática (SSR) e o teste sensorial quantitativo (QST). Biomarcadores como Enolase Neurônio-Específica (NSE) e a Proteína S100-Beta (S100B) vem sendo descritos por muitos autores como associados a danos em células do sistema nervoso. OBJETIVO: O objetivo deste estudo é avaliar parâmetros neurofisiológicos e compará-los com achados clínicos e bioquímicos (S100B e NSE) em pacientes com DM, PDM e controles saudáveis. MÉTODOS: Pacientes dos ambulatórios de Neurologia e Endocrinologia foram randomizados em um estudo transversal. Os participantes foram submetidos a uma bateria de testes clínicos e neurofisiológicos que englobaram condução nervosa, Onda-F, SSR e QST. Níveis séricos de NSE e S100B foram quantificados através de ensaio ELISA (Enzyme-linked immunosorbent assay). RESULTADOS: A avaliação clínica e os estudos de condução nervosa e Onda-F foram similares nos grupos estudados. Já os limiares QST calor (QSTc) e QST dor (QSTd) foram significativamente elevados nos pacientes PDM e DM com relação aos controles (P<0.05 para todas as comparações). No entanto, estes parâmetros não foram capazes de distinguir pacientes DM vs. PDM (P >0.1 para todas as comparações). O SSR foi capaz de diferenciar o grupo DM do controle (P <0,01) embora não tenha mostrado diferença entre os grupos PDM e controle (P = 0,6). Não houve diferença entre os níveis de S100B (P = 0.6) e NSE (P = 0.2) entre os grupos DM, PDM e controles. CONCLUSÃO: O QST e SSR são testes úteis para a avaliação de pacientes com diferentes graus de tolerância a glicose. Este estudo não encontrou diferenças entre os biomarcadores NSE e S100B em indivíduos com DM e PDM. / BACKGROUND: Type 2 diabetes mellitus (DM) is a metabolic disease characterized by the presence of chronic hyperglycemia. Previous studies demonstrated that patients with prediabetes states (PDM) have a natural history of progression to DM. Neuropathy is the most common and disabling complication of diabetes and recent advances in neurophysiology have enabled a refinement of neurophysiological diagnostic techniques such as sympathetic skin response (SSR) and quantitative sensory testing (QST). Biomarkers like Neuron-specific Enolase (NSE) and S100- Beta Protein (S100B) has been described for many authors as associated with damage at nervous system cells and are related with severity of injury as well as clinical outcomes. OBJECTIVE: The aim of this study is to evaluate neurophysiological findings and compare them with clinical and biochemical findings (S100B and NSE) in patients with DM, PDM and healthy controls. METHODS: Patients at the outpatient Neurology and Endocrinology service were randomized in a cross-sectional study. Participants underwent a battery of clinical and neurophysiological tests that encompassed nerve conduction studies, F-wave, SSR and QST. ELISA (enzyme-linked immunosorbent assay) were perform to quantify serum levels of NSE and S100B. RESULTS: There were no difference regarding clinical evaluation, nerve conduction studies and F-wave were between groups. The QST thresholds of warm (QSTw) and QST pain (QSTp) were significantly elevated in patients with PDM and DM compared to controls (P <0.05 for all comparisons). However, these parameters were not able to distinguish among DM and PDM (P > 0.1 for all comparisons). The SSR was able to differentiate DM from control group (P <0.01) but did not show difference between PDM and control groups (P = 0.6). There was no difference on levels of S100B (P = 0.6) and NSE (P = 0.2) between the DM, PDM and control groups. CONCLUSION: The QST and SSR are useful tests to evaluating patients with different degrees of glucose tolerance. This study found no differences between biomarkers NSE and S100B in subjects with DM and PDM.

Résumé : La résistance à l’insuline est un facteur de risque important pour le développement du diabète de type 2. Un désordre au niveau du métabolisme postprandial, qui se manifeste par une diminution relative du stockage des acides gras (AG) dans les tissus adipeux, mène à un débordement plasmatique des AG et à leur canalisation dans les tissus maigres tels que le cœur, le foie et les muscles squelettiques sous forme de dépôts ectopiques. Ce phénomène, connu sous le nom de lipotoxicité, se développe dans un contexte de balance énergétique positive chronique favorisée par la consommation alimentaire excessive ainsi que la sédentarité et peut varier entre les hommes et les femmes. Plusieurs études démontrent que le changement des habitudes de vie peut corriger ces désordres métaboliques. Notre laboratoire a développé une méthode unique pour étudier le métabolisme des AG de façon non invasive à l’aide d’un traceur radioactif, l’acide 14(R,S)-fluoro-6-thia-heptadécanoïque ([indice supérieur 18]F-FTHA), un analogue des acides gras à longue chaines utilisé en tomographie par émission de positrons. Nos études antérieures ont démontré que chez les sujets intolérants au glucose (IG+) on observe des niveaux de captage des AG dans le myocarde plus élevés associés à une fraction d’éjection du ventricule gauche ainsi qu’un volume d'éjection systolique diminués. À la suite d’une intervention d’un an axée sur les habitudes de vie des sujets IG+, on note une diminution du captage des AG dans le myocarde ainsi qu’une amélioration des paramètres de la fonction cardiaque. Cependant, chez des sujets IG+ ayant suivi une restriction calorique d’une semaine sans modifications de leur niveau d’activité physique, nous avons observé une augmentation du captage des AG dans le myocarde en parallèle avec une diminution de la fraction d’éjection du ventricule gauche. La restriction calorique, l’activité physique et la perte de poids influencent le métabolisme des substrats énergétiques et la fonction cardiaque chez les IG+, mais le sexe biologique est aussi un facteur important qui agit sur ces derniers. Le captage élevé des AG par le cœur chez les hommes est expliqué par des niveaux de chylomicrons plus élevés alors que chez les femmes il est associé à l’obésité. Bien que nos études ne nous ont pas permis de faire un lien entre les habitudes de vie des sujets IG+ et les anomalies métaboliques observées en période postprandiale chez ces sujets ni d’identifier quels changements dans leurs habitudes de vie ont contribué aux améliorations métaboliques dans le myocarde, elles nous ont amenées à redéfinir nos outils méthodologiques pour mieux étudier les habitudes de vie et de prendre en considération les différences entre les hommes et les femmes dans nos études futures. / Abstract : Insulin resistance is a major risk factor for the development of type 2 diabetes. Abnormalities in postprandial metabolism, which are characterized by a relative decrease in fatty acid storage capacity in adipose tissue leading to fatty acid spillover into the systemic circulation, give rise to ectopic fat deposition in non adipose tissues such as the heart, the liver and skeletal muscles. This phenomenon, commonly referred to as lipotoxicity, arises within the context of a chronic positive energy balance which is the direct result of excessive food consumption together with decreased energy expenditure and may be different in men and women. Many studies have shown, however, that metabolic abnormalities are reversible with changes in lifestyle habits. Our laboratory has developed a unique non-invasive method to study dietary fatty acid (DFA) metabolism using a radioactive tracer, 14(R,S)-[[superscript 18]F]-fluoro-6-thia-heptadecanoic acid ([superscript 18]F-FTHA), a long-chain fatty acid analogue, in combination with positron emission tomography. Our previous work demonstrated that patients with impaired glucose tolerance (IGT+) display an increase in myocardial DFA partitioning associated with a decreased left ventricular ejection fraction and stroke volume. Following a one-year lifestyle intervention regimen in IGT+ subjects, a reduction in myocardial DFA uptake as well as an improvement in cardiac function parameters was observed. However, IGT+ subjects who participated in a short-term caloric restriction while maintaining their usual level of physical activity, experienced an increase in myocardial DFA partitioning in parralel with a decreased left ventricular ejection fraction. Caloric restriction, physical activity and weight loss all have an impact on energy substrate metabolism and cardiac function in IGT+ patients, but gender is a major determinant as well. Increased myocardial DFA uptake in men is driven largely by elevated circulating chylomicron-TG levels whereas in women it appears to be associated with obesity. Although it was not possible for us to establish a link between IGT+ patients’ lifestyle habits and the postprandial metabolic abnormalities that they display nor to identify which lifestyle changes contributed to the metabolic improvements in the heart observed after the intervention, our studies helped redefine our methodological tools for assessing lifestyle parameters and underlined the importance of considering gender differences in our future studies.

Diabetes Mellitus tipo 2 e demência são doenças altamente prevalentes na população idosa. Estudos têm evidenciado que o DM 2 está associado com perda cognitiva e um elevado risco tanto para demência vascular quanto para demência do tipo Alzheimer. Idosos com tolerância à glicose diminuída também apresentam perda cognitiva, sendo que a hiperinsulinemia parece explicar o déficit cognitivo nesses pacientes. Objetivos: Avaliar em pacientes idosos diabéticos e com tolerância à glicose diminuída a presença de alterações cognitivas comparados aos normais e uma possível associação com resistência insulínica, síndrome metabólica, marcadores inflamatórios e adiponectina. E diagnosticar entre os pacientes com alteração cognitiva aqueles com demência através da avaliação neuropsicológica. Pacientes e Métodos: Foram estudados 140 pacientes com idades entre 65 e 86 anos, sendo 107 do sexo feminino e 33 do sexo masculino classificados em 3 grupos conforme TOTG: tolerância à glicose normal (52), tolerância à glicose alterada (42) e DM (46). Os pacientes foram avaliados antropometricamente e realizada dosagem de glicemia, hemoglobina glicada, colesterol total e frações, insulina, adiponectina, TNF-alfa e IL-6. Realizados testes de rastreio cognitivo, através do mini-exame do estado mental, teste do relógio e fluência verbal. Os pacientes com baixo desempenho passaram por avaliação neuropsicológica. Resultados: os grupos foram comparáveis em relação à idade, gênero e escolaridade. Não encontramos diferença estatística entre os grupos em relação à presença de HAS, IMC e cintura abdominal. A prevalência de dislipidemia e síndrome metabólica foi maior nos pacientes com intolerância à glicose e diabetes. Os pacientes com resistência insulínica, definida pelo HOMA-IR, tiveram maiores níveis de IL-6 e TNF-a e menor adiponectinemia. Nos testes de triagem, 42 sujeitos apresentaram desempenho abaixo do esperado para idade e escolaridade e destes 33 apresentaram alteração cognitiva. Não houve diferença estatística entre os pacientes com alteração cognitiva e os normais, em relação à resistência insulínica, adiponectina e marcadores inflamatórios. Pacientes com alteração cognitiva apresentaram significantemente menor funcionalidade, prejuízo na memória imediata e de evocação, no reconhecimento da lista de palavras e na memória lógica de Wescheler. Conclusões: Não observamos nos pacientes idosos diabéticos e com tolerância à glicose diminuída maior presença de alterações cognitivas em comparação aos normais. Pacientes diagnosticados com comprometimento cognitivo leve e demência não apresentaram diferenças dos normais em relação à presença da resistência insulínica, síndrome metabólica e marcadores inflamatórios / Introduction: Type 2 Diabetes (T2D) and dementia are highly prevalent diseases among the elderly population. Studies have been evincing that type 2 diabetes are associated with cognitive impairment and also shows a high risk for vascular dementia and for Alzheimers disease. Studies suggest that elderly people with impaired glucose tolerance (IGT) present cognitive loss, and the hyperinsulinemia seems to explain the cognitive deficit in those patients. Objective: To evaluate the presence of cognitive alterations compared to the normal and a possible association of insulin resistance (IR), metabolic syndrome (MS), inflammatory markers and adiponectin in T2D elderly and IGT; to diagnose dementia among patients with cognitive alteration by neuropsychological examination. Patient and Methods: 140 patients with ages between 65 and 86 years were studied 107 of whom were women and classified in 3 groups according to GTT: Normal glucose tolerance (NGT), IGT and T2D. Anthropometric measurements and analyses of glucose and insulin, A1c, total cholesterol and fractions, adiponectin, TNF-alpha and IL-6, were performed in this patients. Cognitive function was measured by mini-mental state examination, clock drawing and verbal fluency test. The patients with cognitive impairment were submitted to neuropsychological battery. Results: The groups were comparable in relation to age, gender and level of education. We did not find statistical differences among the groups in relation to the presence of HA, BMI, waist and inflammatory markers. The presence of MS and IR was increased in the IGT and T2D groups. Patients with IR had high IL-6 and TNF-a and low adiponectin. In the neuropsychological battery, 42 subjects were below the expected for their age and level of education, and, of these, 33 presented cognitive alteration. There was not statistical significance among patients with cognitive deficit the presence of insulin resistance measured by HOMA-IR, adiponectin and inflammatory markers. Patients with cognitive impairment showed poorer performance in immediate and delayed recall of a word list, recognition test and Weschelers memory logic. Conclusion: T2D and IGT were not associated with impaired cognitive function. No difference in insulin resistance, metabolic syndrome, and inflammatory markers has been seen between normal patients and patients with impairment cognitive

Diabetes Mellitus tipo 2 e demência são doenças altamente prevalentes na população idosa. Estudos têm evidenciado que o DM 2 está associado com perda cognitiva e um elevado risco tanto para demência vascular quanto para demência do tipo Alzheimer. Idosos com tolerância à glicose diminuída também apresentam perda cognitiva, sendo que a hiperinsulinemia parece explicar o déficit cognitivo nesses pacientes. Objetivos: Avaliar em pacientes idosos diabéticos e com tolerância à glicose diminuída a presença de alterações cognitivas comparados aos normais e uma possível associação com resistência insulínica, síndrome metabólica, marcadores inflamatórios e adiponectina. E diagnosticar entre os pacientes com alteração cognitiva aqueles com demência através da avaliação neuropsicológica. Pacientes e Métodos: Foram estudados 140 pacientes com idades entre 65 e 86 anos, sendo 107 do sexo feminino e 33 do sexo masculino classificados em 3 grupos conforme TOTG: tolerância à glicose normal (52), tolerância à glicose alterada (42) e DM (46). Os pacientes foram avaliados antropometricamente e realizada dosagem de glicemia, hemoglobina glicada, colesterol total e frações, insulina, adiponectina, TNF-alfa e IL-6. Realizados testes de rastreio cognitivo, através do mini-exame do estado mental, teste do relógio e fluência verbal. Os pacientes com baixo desempenho passaram por avaliação neuropsicológica. Resultados: os grupos foram comparáveis em relação à idade, gênero e escolaridade. Não encontramos diferença estatística entre os grupos em relação à presença de HAS, IMC e cintura abdominal. A prevalência de dislipidemia e síndrome metabólica foi maior nos pacientes com intolerância à glicose e diabetes. Os pacientes com resistência insulínica, definida pelo HOMA-IR, tiveram maiores níveis de IL-6 e TNF-a e menor adiponectinemia. Nos testes de triagem, 42 sujeitos apresentaram desempenho abaixo do esperado para idade e escolaridade e destes 33 apresentaram alteração cognitiva. Não houve diferença estatística entre os pacientes com alteração cognitiva e os normais, em relação à resistência insulínica, adiponectina e marcadores inflamatórios. Pacientes com alteração cognitiva apresentaram significantemente menor funcionalidade, prejuízo na memória imediata e de evocação, no reconhecimento da lista de palavras e na memória lógica de Wescheler. Conclusões: Não observamos nos pacientes idosos diabéticos e com tolerância à glicose diminuída maior presença de alterações cognitivas em comparação aos normais. Pacientes diagnosticados com comprometimento cognitivo leve e demência não apresentaram diferenças dos normais em relação à presença da resistência insulínica, síndrome metabólica e marcadores inflamatórios / Introduction: Type 2 Diabetes (T2D) and dementia are highly prevalent diseases among the elderly population. Studies have been evincing that type 2 diabetes are associated with cognitive impairment and also shows a high risk for vascular dementia and for Alzheimers disease. Studies suggest that elderly people with impaired glucose tolerance (IGT) present cognitive loss, and the hyperinsulinemia seems to explain the cognitive deficit in those patients. Objective: To evaluate the presence of cognitive alterations compared to the normal and a possible association of insulin resistance (IR), metabolic syndrome (MS), inflammatory markers and adiponectin in T2D elderly and IGT; to diagnose dementia among patients with cognitive alteration by neuropsychological examination. Patient and Methods: 140 patients with ages between 65 and 86 years were studied 107 of whom were women and classified in 3 groups according to GTT: Normal glucose tolerance (NGT), IGT and T2D. Anthropometric measurements and analyses of glucose and insulin, A1c, total cholesterol and fractions, adiponectin, TNF-alpha and IL-6, were performed in this patients. Cognitive function was measured by mini-mental state examination, clock drawing and verbal fluency test. The patients with cognitive impairment were submitted to neuropsychological battery. Results: The groups were comparable in relation to age, gender and level of education. We did not find statistical differences among the groups in relation to the presence of HA, BMI, waist and inflammatory markers. The presence of MS and IR was increased in the IGT and T2D groups. Patients with IR had high IL-6 and TNF-a and low adiponectin. In the neuropsychological battery, 42 subjects were below the expected for their age and level of education, and, of these, 33 presented cognitive alteration. There was not statistical significance among patients with cognitive deficit the presence of insulin resistance measured by HOMA-IR, adiponectin and inflammatory markers. Patients with cognitive impairment showed poorer performance in immediate and delayed recall of a word list, recognition test and Weschelers memory logic. Conclusion: T2D and IGT were not associated with impaired cognitive function. No difference in insulin resistance, metabolic syndrome, and inflammatory markers has been seen between normal patients and patients with impairment cognitive

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19892号 / 医博第4141号 / 新制||医||1016(附属図書館) / 32969 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川村 孝, 教授 横出 正之, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

La prévalence du diabète ne cesse d’augmenter et la détection de sujets à risque de développer cette maladie reste une préoccupation importante afin qu’un programme de prévention leur soit proposé. Le dosage de l’HbA1c est utilisé pour l’évaluation de l’efficacité du traitement pris par les diabétiques. Il n’était pas utilisé pour le diagnostic des dysglycémies car les méthodes de ce dosage n’étaient pas standardisées. Actuellement l’IFCC (International Federation of Clinical Chemistry) propose une nouvelle méthode de référence pour cette mesure, et l’OMS (Organisation Mondiale de la Santé) a intégré ce paramètre dans les critères diagnostiques du diabète. but Evaluer la capacité de l’HbA1c à prédire un diabète incident, chercher des seuils, d’HbA1c, de GAJ et de glycémie deux heures (G2H) après un test d’hyperglycémie provoquée par voie orale (HGPO), au delà desquels les sujets sont plus à risque de développer un diabète incident et, enfin, étudier l’influence du tabac sur les variations de ces mesures. Méthodes Pour l’évaluation de la prédiction du diabète et la recherche de seuils, nous avons utilisé les données de l’étude australienne AusDiab, de l’étude danoise Inter99 et de l’étude française D.E.S.I.R. avec plus de 5500, 4500 et 3550 sujets, respectivement. Dans la troisième partie, nous avons utilisé les données du projet DETECT-2 (12 études, 26 000 sujets), ainsi que celles des études françaises D.E.S.I.R. et TELECOM (3700 sujets). Les distributions de l’HbA1c dans les trois premières études étaient différentes, nous avons donc, dans les deux premières parties d’analyses, ajusté les moyennes d’HbA1c à l’inclusion et après le suivi. Nous avons utilisé un modèle logistique pour la comparaison du pouvoir prédictif de l’HbA1c et de GAJ ; l’intervalle de confiance des Odds Ratios (ORs) à été obtenu par bootstrap. Pour rechercher les seuils de prédiction du diabète, nous avons comparé le modèle logistique (avec la variable glycémique) sans seuil au modèle avec seuil. Enfin, nous avons utilisé un modèle linéaire mixte pour évaluer la différence entre les moyennes d’HbA1c, de GAJ et de G2H en fonction du tabagisme, en attribuant un effet aléatoire à la variable ‘centre’. Résultats Avant ajustement des moyennes d’HbA1c, l’incidence du diabète (défini par la prise de traitement antidiabétique, une HbA1c≥6.5% ou une GAJ≥7mmol/l) était de 3.1% dans AusDiab, 2.7% dans Inter99 et 2.5% dans D.E.S.I.R. Les sujets dépistés comme étant diabétiques par l’HbA1c et par la GAJ n’étaient pas toujours les mêmes. L’incidence estimée du diabète augmente bien avec l’augmentation du taux de l’HbA1c et de la GAJ à l’inclusion. Pour chaque critère, l’aire sous la courbe de ROC (Receiver Operating Characteristic) était supérieure à 0.80 témoignant d’une bonne discrimination des deux tests entre les diabétiques incidents et les non diabétiques et le test de Hosmer-Lemeshow témoigne d’une bonne adéquation des modèles utilisés (p>0.05). Dans les trois populations, les ORs qui mesurent l’association entre les taux d’HbA1c et de GAJ et la survenue du diabète étaient presque toujours supérieurs pour l’HbA1c. Les seuils d’HbA1c et de GAJ au-delà desquels les sujets étaient plus à risque de développer un diabète variaient en fonction de la définition du diabète incident sauf pour l’HbA1c dans l’étude D.E.S.I.R. (5.3%) et la GAJ dans l’étude AusDiab (5.5mmol/l). Enfin, la moyenne d’HbA1c chez les fumeurs actuels était 0.10%(0.08,0.12) plus élevée que chez ceux qui n’ont jamais fumé ; la moyenne de G2H était -0.44(-0.51,-0.36) moins élevée chez les fumeurs actuels que chez ceux qui n’ont jamais fumé.Conclusion Ces résultats soulignent : 1) l’importance de l’utilisation de l’HbA1c comme critère diagnostique de dysglycémies, 2) la nécessité de mieux explorer les limites inférieures des stades intermédiaires qui précèdent la survenue du diabète, 3) l’importance de prendre en considération les facteurs qui peuvent influencer les taux d’HbA1c / The increasing prevalence of diabetes worldwide makes the detection of people at risk of developing diabetes a major concern, so that they can benefit from diabetes prevention programs. HbA1c is used to evaluate the effectiveness of treatment taken by diabetic patients. HbA1c had not been used to diagnose dysglycemia because the assay methods were not standardized. The International Federation of Clinical Chemistry has proposed a reference method, and in 2011 the World Health Organization included HbA1c as one of the criteria for the diagnosis of diabetes. aims: 1) To evaluate the ability of HbA1c to predict incident diabetes compared with fasting plasma glucose (FPG); 2) to find thresholds for HbA1c, FPG and two hour plasma glucose (G2H) after an oral glucose tolerance test (OGTT) beyond which subjects are more at risk for developing incident diabetes and finally; 3) to study the influence of smoking on HbA1c, FPG and G2H.Methods: Several populations were studied. To evaluate the prediction of diabetes and the search for thresholds, we used data from the Australian study (AusDiab), a Danish study (Inter99) and a French study (D.E.S.I.R.) with respectively more then 5500, 4500 and 3550 participants. In the third part, we used data from the DETECT-2 consortium (12 studies with more than 26 000 men and women) and from two French studies: D.E.S.I.R. and TELECOM (with more than 3700 participants). The distribution of HbA1c in AusDiab, Inter99 and D.E.S.I.R. differed, so in the first two parts of this thesis, we adjusted HbA1c so that all three studies had the same mean HbA1c at baseline and the same mean HbA1c at follow-up. We used a logistic model to quantify the predictive ability of HbA1c and FPG for diabetes, and then derived confidence intervals for the difference in Odds Ratios (ORs) by bootstrap. To search for thresholds to predict incident diabetes, based on HbA1c, FPG and G2H at inclusion, we compared logistic regression models that were linear in the glycaemic variable, without a threshold, with a spline model with a threshold. Linear mixed models with ‘centre’ as a random variable, were used to assess the difference between the means of HbA1c, FPG and G2H in current-, ex- and never-smokers.Results: With unadjusted HbA1c data, the incidence of diabetes (defined by treatment, HbA1c≥6.5% or FPG≥7 mmol/l) was 3.1% in AusDiab, 2.7% in Inter99 and 2.5% in D.E.S.I.R.. Subjects detected as having diabetes by HbA1c and FPG were not always the same. The incidence of diabetes increased with increasing HbA1c and FPG at baseline. For each test, the area under the Receiver Operating Characteristic curve was greater than 0.80, indicating good discrimination for these two measures between those with and without incident diabetes, and the Hosmer-Lemeshow test indicated that the models fitted well (p>0.05). In all three populations, the ORs measuring the association between HbA1c and FPG and the development of diabetes were almost always higher for HbA1c than for FPG. The thresholds of HbA1c and FPG above which the incidence of diabetes were higher, varied according to the definition of incident diabetes - except for HbA1c in D.E.S.I.R. (always 5.3%) and for FPG in AusDiab (always 5.5mmol/l). Finally, in current-smokers, the mean HbA1c was 0.10%(0.08,0.12) higher than in never-smokers; the mean G2H was 0.44( 0.51,-0.36) lower in current-smokers than in never-smokers. Conclusion: The results that we found emphasize: 1) the importance of using HbA1c as a diagnostic criterion for dysglycemia, as those diagnosed diabetic by HbA1c did not have always an FPG ≥ 7 mmol/l, 2) the need to better explore the lower limits of the “pre-diabetic” stage as the thresholds of HbA1c, FPG and 2H-PG that we found were lower than those used in clinical practice, 3) the importance to consider factors that may influence HbA1c and G2H, such as smoking.

<p>In patients with diabetes mellitus (DM), acute myocardial infarction (AMI) is a major cause of death. We have studied two populations with respect to the relationship between DM or related glucometabolic disturbances and AMI.</p><p>In the first population, the prevalence of DM and the importance of the glycaemic state for the long-term prognosis in non-diabetic patients were investigated in patients with AMI admitted to the Coronary Care Unite at Västerås Central Hospital.</p><p>In the second population, the prevalence of impaired glucose tolerance (IGT), DM and other metabolic abnormalities was investigated in patients with AMI and without known DM admitted to the Coronary Care Units at Västerås and Karolinska Hospital, Stockholm.</p><p>21% of the patients with AMI had previously known DM and 4% had newly detected DM if diagnosis is based upon fasting blood glucose (F-BG). The glycemic state, measured as HbA1c, at a 5.5 years follow-up was a risk factor for re-infarction and/or death in non-diabetic patients after AMI.</p><p>If an oral glucose tolerance test (OGTT) is performed, 40-45% of all patients with AMI have DM and in addition about 30% have IGT. Both an OGTT and a single post-challenge blood glucose value after 60 minutes performed at hospital discharge, were independent predictors of IGT or DM at follow-up. Insulin resistance, measured by homeostatic model assessment (HOMA-IR), decreased during hospital stay, with no further decrease from hospital discharge to follow-up.</p><p>In summary, the studies in this dissertation have revealed an unexpectedly high prevalence of abnormal glucose tolerance in patients with AMI. The glycaemic state, reflected by HbA1c, in non-diabetic patients after AMI has an impact on the long-term prognosis. Consequently, in all patients with AMI, HbA1c and casual blood glucose should be measured at admission and, at least, F-BG at hospital discharge.</p>

Polycystic ovary syndrome (PCOS) is a complex clinical condition characterized by hyperandrogenism and chronic oligo/anovulation. Infrequent ovulation and metabolic alterations in women with PCOS are associated with subfertility and probably increased miscarriage rates compared with normal fertile women. The overall risk of developing type 2 diabetes and impaired glucose tolerance (IGT) is three- to sevenfold higher in PCOS women, and the onset of glucose intolerance seems to occur at an earlier age than in healthy controls. Women with PCOS also have several risk factors for cardiovascular disease, although it is unclear whether they actually experience more cardiovascular events than other women. Very few studies assessing the long-term reproductive and metabolic consequences in older women with previously confirmed PCOS have been conducted. In this long-term follow-up of women with PCOS, 84 women with a diagnosis of PCOS between 1987 and 1995 and age at the follow-up &gt; 35 years and an age-matched population-based group of control women participated. Data on reproductive outcome, ovarian reserve, endothelial function, insulin sensitivity and beta-cell function were collected. According to our results most women with PCOS had given birth and the rate of spontaneous pregnancies was relatively high. The rate of miscarriages was not increased in PCOS patients and the ultrasound findings together with increased levels of anti-müllerian hormone suggested that their ovarian reserve is superior to women of similar age. PCOS women displayed signs of endothelial dysfunction, but this was largely due to the increased prevalence of independent risk factors for cardiovascular disease such as increased BMI, triglycerides and blood pressures. IGT and type 2 diabetes occurred more often in PCOS women. Free androgen levels and beta-cell function decreased over time whereas insulin sensitivity remained unchanged. Obesity at young age and progressive weight-gain rendered them more prone to be insulin resistant at the follow-up. Beta-cell function was increased in PCOS women in comparison with control subjects but declined over time. Independent of PCOS phenotype at the index assessment and persistence of PCOS symptoms at the follow-up investigation, premenopausal women with PCOS had lower insulin sensitivity and increased beta cell function in comparison with control subjects. Conclusion: The long-term reproductive outcomes of PCOS are similar compared to women with normal ovaries. Although symptoms and androgen levels are normalized over time, women with PCOS continue to display reduced insulin sensitivity and increased beta-cell function and they also have an increased risk of IGT and type 2 diabetes.

In patients with diabetes mellitus (DM), acute myocardial infarction (AMI) is a major cause of death. We have studied two populations with respect to the relationship between DM or related glucometabolic disturbances and AMI. In the first population, the prevalence of DM and the importance of the glycaemic state for the long-term prognosis in non-diabetic patients were investigated in patients with AMI admitted to the Coronary Care Unite at Västerås Central Hospital. In the second population, the prevalence of impaired glucose tolerance (IGT), DM and other metabolic abnormalities was investigated in patients with AMI and without known DM admitted to the Coronary Care Units at Västerås and Karolinska Hospital, Stockholm. 21% of the patients with AMI had previously known DM and 4% had newly detected DM if diagnosis is based upon fasting blood glucose (F-BG). The glycemic state, measured as HbA1c, at a 5.5 years follow-up was a risk factor for re-infarction and/or death in non-diabetic patients after AMI. If an oral glucose tolerance test (OGTT) is performed, 40-45% of all patients with AMI have DM and in addition about 30% have IGT. Both an OGTT and a single post-challenge blood glucose value after 60 minutes performed at hospital discharge, were independent predictors of IGT or DM at follow-up. Insulin resistance, measured by homeostatic model assessment (HOMA-IR), decreased during hospital stay, with no further decrease from hospital discharge to follow-up. In summary, the studies in this dissertation have revealed an unexpectedly high prevalence of abnormal glucose tolerance in patients with AMI. The glycaemic state, reflected by HbA1c, in non-diabetic patients after AMI has an impact on the long-term prognosis. Consequently, in all patients with AMI, HbA1c and casual blood glucose should be measured at admission and, at least, F-BG at hospital discharge.