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

Résumé L’augmentation de l’espérance de vie chez les patients atteints de fibrose kystique (FK) entraine une augmentation de la prévalence des anomalies de tolérance au glucose, soit l’intolérance au glucose (IGT) et le diabète (DAFK). En dépit du fait, que les anomalies de la tolérance au glucose soient associées à un mauvais prognostic, l’origine de ces troubles n’est pas encore clairement établie. Notre objectif était d’examiner le rôle de l’insulinopénie et de la résistance à l’insuline dans la détérioration de la tolérance au glucose dans une cohorte prospective observationelle patients FK non diabétique. Nos résultats démontrent une réduction marquée de la phase précoce de la sécrétion de l’insuline ainsi qu’une augmentation de l’aire sous la courbe de la glycémie (AUC) chez tous les groupes de patients. Nous avons aussi démontré qu’une variation de la sensibilité à l’insuline joue un rôle prépondérant dans les changements de catégorie de tolérance au glucose dans cette population. Finalement, il semblerait que l’augmentation de l’AUC du glucose et la réduction de la phase précose de la sécrétion d’insuline sont des meileurs prédicateurs du status clinique que les catégories de tolérance au glucose. Il existe plusieurs indices pour évaluer la sécrétion d’insuline et pourtant aucun n’a été validé chez les patients FK. Nous avons examiné la validité des index de la sécrétion de l’insuline dérivés de l’hyperglycémie provoquée par voie orale (HGPO) ainsi que des valeurs à jeun par rapport au test de référence. Alors que la plupart des index calculés à partir de l’HGPO corrèlent significativement avec les valeurs du test de référence, cela n’est pas le cas pour les index calculés à partir des valeurs à jeun. La validation de ces index nous permet d’évaluer la sécrétion de l’insuline prospectivement dans notre cohorte de FK à partir de l’HGPO, est un test recommandé pour le dépistage du DAFK. Les recommandations nutritionnelles suggèrent aux patients FK une diète comprenant environ 40% de lipides afin d’éviter la malnutrition. Nous avons examiné le profil lipidique des patients FK diabétiques et non diabétiques après une HGPO et un repas hyperlipidique (RT). Nos résultats démontrent que la FK est associée à des augmentations de l’excursion glycémique lors de l’HGPO ou d’un RT comparativement aux témoins. Cependant, le RT provoque 1) une plus faible excursion glycémique comparativement à l’HGPO ; 2) une meilleure suppression de la production hépatique de glucose et 3) l’excursion lipidique postprandiale des patients FK reste normale. Il est donc peu probable que les anomalies de la sécrétion de l’insuline par les cellules  soient secondaires à une lipotoxicité. Nous avons aussi examiné les taux d’adiponectine, une hormone sécrétée par le tissu adipeux et pouvant moduler l’action de l’insuline. Les niveaux d’adiponectine corrèlent négativement avec plusieurs facteurs présents chez les patients FK incluant l’IGT, l’inflammation et une adiposité centrale en dépit d'un faible poids corporel. Les patients FK ne présentaient aucune altération des taux d’adiponectine malgré la présence d’une résistance à l’insuline, une inflammation sub-clinique et de l’IGT. La FK apparaît donc comme une condition où il existe une discordance entre les taux d’adiponectine et la résistance à l’insuline ou l’inflammation. En conclusion la prévalence de l’IGT est élevée dans cette population caractérisée par une excursion glycémique anormalement plus élevée, due principalement à une altération de la sécrétion de l’insuline exacerbée par une résistance à l’insuline. Mots clés : Adiponectine, Hyperglycémie par voie oral (HGPO), intolérance au glucose, fibrose kystique, diabète, résistance à l’insuline, sécrétion de l’insuline. / Abstract Abnormal glucose tolerance is a frequent co-morbidity in cystic fibrosis patients (CF), and is associated with a worse prognosis. However, the most pertinent factors to predict the clinical status and the physiopathology of glucose intolerance remain unclear. The aim of this study was to investigate the roles of impaired insulin secretion and insulin resistance in the progression of glucose intolerance from the normal state up to diabetes (CFRD) using an ongoing prospective observational cohort of non-diabetic CF patients. We demonstrated that CF patients displayed a reduced first phase insulin secretion across glucose tolerance categories (normal; intolerance and CFRD). Moreover, variation in insulin resistance has a significant impact on glucose tolerance in this population. Finally, early in the course of the disease, increased glucose area under the curve (AUC) and reduced first phase insulin secretion are better predictors of clinical status than conventional glucose tolerance categories. Numerous indices to evaluate insulin secretion have been proposed, but their validity has not been explored in cystic fibrosis (CF). The aim of this study was to validate surrogate indices of insulin secretion calculated from fasting values or the oral glucose tolerance test (OGTT) in CF patients against the gold standard, the intravenous glucose tolerance test (IVGTT). This is an essential step to study the physiopathological role of defective insulin secretion in the development of CFDR in large cohort. We showed that all insulin secretion indices correlated significantly with the IGVTT in control individuals. However, while OGTT-derived indices correlated significantly with the gold standard test in all CF groups, this was not the case for fasting-derived indices. Since the OGTT is required on a regular basis in CF patients to screen for CFRD, OGTT-derived indices should be used to evaluate insulin secretion. Abnormal insulin secretion combined with recommended high fat intake could be associated with dysregulation of glucose and lipid metabolisms in CF patients. Thus, the second objective was to examine postprandial glucose and lipid profiles during an OGTT and a standardized high-fat test meal (TM) in CF patients. CF patients presented higher glucose excursion compared to controls after the OGTT and TM. This excursion was significantly reduced in both amplitude and length during the TM for CF patients. In addition, control and CF patients presented similar profiles for both triglycerides and fatty acids. These results exclude lipotoxicity as a major player in ß cell defect for these patients. Circulating adiponectin levels are negatively associated with glucose intolerance, inflammation and central adiposity. Since these conditions are common in CF patients, we examined whether adiponectin values are altered in this population. CF patients did not show any changes in adiponectin levels despite insulin resistance, glucose intolerance and sub-clinical inflammation. Thus, CF appears to be one of the rare conditions in which discordance between adiponectin values and insulin resistance or inflammation is evident. In conclusion, CF patients are characterized by a high prevalence of glucose abnormalities due to an insulin secretion defect but also the contribution of insulin resistance. Key words: Adiponectin, Cystic fibrosis, diabetes, glucose intolerance, Oral glucose tolerance test, insulin resistance, insulin secretion.

The prevalence of childhood obesity and Type 2 Diabetes Mellitus (T2DM) has increased during recent decades. T2DM is accompanied with functional changes in the islets of Langerhans, which can be identified early in the pathogenesis. The aim of this thesis was to explore how metabolic changes caused by obesity early in life relate to islet function prior to overt T2DM. To address this, Uppsala Longitudinal Study of Childhood Obesity (ULSCO) was established (paper I). Initially, the association between palmitate and insulin secretion was investigated using a translational approach with obese and lean normoglycemic juveniles and isolated human islets (paper II). Secondly, dynamics of islet-hormones insulin and glucagon, and gut-hormones glucagon like-peptide 1 (GLP-1) and glicentin (paper III) and magnetic resonance imaging of pancreatic fat fraction (PFF) (paper IV) were studied in association to glucose tolerance and beta-cell function. Finally, a novel method of analysing shape features of oral glucose tolerance test (OGTT) curves was introduced and evaluated (paper V). Obese subjects had high prevalence of prediabetes and metabolic syndrome (MetS) (paper I). In obese pre-pubertal children with elevated palmitate levels, hyperinsulinemia was observed (paper II). In contrast, obese pubertal adolescents with similar palmitate levels showed moderate insulin levels during OGTT with delayed first phase insulin response. To explore mechanisms for these variations, isolated human islets were exposed to palmitate for different time periods in vitro. After 2 days accentuated insulin response was observed. Impaired beta-cell function and apoptosis were evident after 7 days, however. Hyperglucagonemia and disturbed GLP-1 and glicentin levels were associated with obesity and glycaemic status, with fasting glicentin being predictive of prediabetes (paper III). Furthermore, PFF was increased in obese subjects and associated to MetS and visceral adipose tissue, but not to beta-cell function (paper IV). OGTT curves were converted into geometric centres, centroids, which correlated with differences in glucose tolerance (paper V). In conclusion, the islet function in obese children was associated with elevated levels of palmitate, but not pancreatic fat. Fasting palmitate and glicentin levels, as well as centroid analyses of OGTT curves, could potentially identify obese children at risk of prediabetes and subsequent T2DM.

<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>

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.

Résumé L’augmentation de l’espérance de vie chez les patients atteints de fibrose kystique (FK) entraine une augmentation de la prévalence des anomalies de tolérance au glucose, soit l’intolérance au glucose (IGT) et le diabète (DAFK). En dépit du fait, que les anomalies de la tolérance au glucose soient associées à un mauvais prognostic, l’origine de ces troubles n’est pas encore clairement établie. Notre objectif était d’examiner le rôle de l’insulinopénie et de la résistance à l’insuline dans la détérioration de la tolérance au glucose dans une cohorte prospective observationelle patients FK non diabétique. Nos résultats démontrent une réduction marquée de la phase précoce de la sécrétion de l’insuline ainsi qu’une augmentation de l’aire sous la courbe de la glycémie (AUC) chez tous les groupes de patients. Nous avons aussi démontré qu’une variation de la sensibilité à l’insuline joue un rôle prépondérant dans les changements de catégorie de tolérance au glucose dans cette population. Finalement, il semblerait que l’augmentation de l’AUC du glucose et la réduction de la phase précose de la sécrétion d’insuline sont des meileurs prédicateurs du status clinique que les catégories de tolérance au glucose. Il existe plusieurs indices pour évaluer la sécrétion d’insuline et pourtant aucun n’a été validé chez les patients FK. Nous avons examiné la validité des index de la sécrétion de l’insuline dérivés de l’hyperglycémie provoquée par voie orale (HGPO) ainsi que des valeurs à jeun par rapport au test de référence. Alors que la plupart des index calculés à partir de l’HGPO corrèlent significativement avec les valeurs du test de référence, cela n’est pas le cas pour les index calculés à partir des valeurs à jeun. La validation de ces index nous permet d’évaluer la sécrétion de l’insuline prospectivement dans notre cohorte de FK à partir de l’HGPO, est un test recommandé pour le dépistage du DAFK. Les recommandations nutritionnelles suggèrent aux patients FK une diète comprenant environ 40% de lipides afin d’éviter la malnutrition. Nous avons examiné le profil lipidique des patients FK diabétiques et non diabétiques après une HGPO et un repas hyperlipidique (RT). Nos résultats démontrent que la FK est associée à des augmentations de l’excursion glycémique lors de l’HGPO ou d’un RT comparativement aux témoins. Cependant, le RT provoque 1) une plus faible excursion glycémique comparativement à l’HGPO ; 2) une meilleure suppression de la production hépatique de glucose et 3) l’excursion lipidique postprandiale des patients FK reste normale. Il est donc peu probable que les anomalies de la sécrétion de l’insuline par les cellules  soient secondaires à une lipotoxicité. Nous avons aussi examiné les taux d’adiponectine, une hormone sécrétée par le tissu adipeux et pouvant moduler l’action de l’insuline. Les niveaux d’adiponectine corrèlent négativement avec plusieurs facteurs présents chez les patients FK incluant l’IGT, l’inflammation et une adiposité centrale en dépit d'un faible poids corporel. Les patients FK ne présentaient aucune altération des taux d’adiponectine malgré la présence d’une résistance à l’insuline, une inflammation sub-clinique et de l’IGT. La FK apparaît donc comme une condition où il existe une discordance entre les taux d’adiponectine et la résistance à l’insuline ou l’inflammation. En conclusion la prévalence de l’IGT est élevée dans cette population caractérisée par une excursion glycémique anormalement plus élevée, due principalement à une altération de la sécrétion de l’insuline exacerbée par une résistance à l’insuline. Mots clés : Adiponectine, Hyperglycémie par voie oral (HGPO), intolérance au glucose, fibrose kystique, diabète, résistance à l’insuline, sécrétion de l’insuline. / Abstract Abnormal glucose tolerance is a frequent co-morbidity in cystic fibrosis patients (CF), and is associated with a worse prognosis. However, the most pertinent factors to predict the clinical status and the physiopathology of glucose intolerance remain unclear. The aim of this study was to investigate the roles of impaired insulin secretion and insulin resistance in the progression of glucose intolerance from the normal state up to diabetes (CFRD) using an ongoing prospective observational cohort of non-diabetic CF patients. We demonstrated that CF patients displayed a reduced first phase insulin secretion across glucose tolerance categories (normal; intolerance and CFRD). Moreover, variation in insulin resistance has a significant impact on glucose tolerance in this population. Finally, early in the course of the disease, increased glucose area under the curve (AUC) and reduced first phase insulin secretion are better predictors of clinical status than conventional glucose tolerance categories. Numerous indices to evaluate insulin secretion have been proposed, but their validity has not been explored in cystic fibrosis (CF). The aim of this study was to validate surrogate indices of insulin secretion calculated from fasting values or the oral glucose tolerance test (OGTT) in CF patients against the gold standard, the intravenous glucose tolerance test (IVGTT). This is an essential step to study the physiopathological role of defective insulin secretion in the development of CFDR in large cohort. We showed that all insulin secretion indices correlated significantly with the IGVTT in control individuals. However, while OGTT-derived indices correlated significantly with the gold standard test in all CF groups, this was not the case for fasting-derived indices. Since the OGTT is required on a regular basis in CF patients to screen for CFRD, OGTT-derived indices should be used to evaluate insulin secretion. Abnormal insulin secretion combined with recommended high fat intake could be associated with dysregulation of glucose and lipid metabolisms in CF patients. Thus, the second objective was to examine postprandial glucose and lipid profiles during an OGTT and a standardized high-fat test meal (TM) in CF patients. CF patients presented higher glucose excursion compared to controls after the OGTT and TM. This excursion was significantly reduced in both amplitude and length during the TM for CF patients. In addition, control and CF patients presented similar profiles for both triglycerides and fatty acids. These results exclude lipotoxicity as a major player in ß cell defect for these patients. Circulating adiponectin levels are negatively associated with glucose intolerance, inflammation and central adiposity. Since these conditions are common in CF patients, we examined whether adiponectin values are altered in this population. CF patients did not show any changes in adiponectin levels despite insulin resistance, glucose intolerance and sub-clinical inflammation. Thus, CF appears to be one of the rare conditions in which discordance between adiponectin values and insulin resistance or inflammation is evident. In conclusion, CF patients are characterized by a high prevalence of glucose abnormalities due to an insulin secretion defect but also the contribution of insulin resistance. Key words: Adiponectin, Cystic fibrosis, diabetes, glucose intolerance, Oral glucose tolerance test, insulin resistance, insulin secretion.

Σκοπός της μελέτης ήταν: (1) να προσδιοριστεί η συχνότητα της διαταραχής ανοχής στη γλυκόζη (IGT) και του σακχαρώδη διαβήτη τύπου II (ΣΔII) σε παχύσαρκα παιδιά και εφήβους στην Ελλάδα και (2) να καθοριστεί εάν οι συγκεντρώσεις γλυκόζης και ινσουλίνης νηστείας μπορούν να προβλέψουν τη διαταραχή ανοχής στη γλυκόζη (IGT)) στα παιδιά αυτά σε σχέση με τα επίπεδα της λεπτίνης, της γκρελίνης, της αδιπονεκτίνης και της σωματομεδίνης, και την έκκριση της αυξητικής ορμόνης (GH) και της θυρεοειδοτρόπου ορμόνης (TSH) κατά τη διάρκεια του 24ωρου μαζί με την ημερήσια έκκριση της κορτιζόλης. Έγινε καμπύλη σακχάρου (OGTT) μαζί με επίπεδα ινσουλίνης σε 117 παχύσαρκα παιδιά και εφήβους 12,1  2,7 ετών και μελετήθηκαν τα επίπεδα της λεπτίνης, της γκρελίνης, της αδιπονεκτίνης και της σωματομεδίνης (IGF-I) κατά τη δοκιμασία ανοχής στη γλυκόζη (OGTT). Επίσης, μελετήθηκαν τα επίπεδα της 24ωρης έκκρισης της GH και της TSH και της ημερήσιας έκκρισης της κορτιζόλης. Χρησιμοποιήθηκαν οι δείκτες HOMA-IR και ο ινσουλινογόνος δείκτης για την εκτίμηση της αντίστασης της ινσουλίνης και της λειτουργίας των β κυττάρων, αντίστοιχα. 17 ασθενείς (14,5%) είχαν IGT και σε κανένα δε διαγνώστηκε ΣΔII. Τα ποσοστά IGT και ΣΔΙΙ ήταν χαμηλότερα από αυτά μιας πολυεθνικής Αμερικανικής μελέτης. Η διαφορά εντοπίστηκε κυρίως στα προεφηβικά παιδιά (9% έναντι 25,4%), ενώ δεν παρατηρήθηκε διαφορά στους εφήβους (18% έναντι 21%). Ωστόσο, τα ποσοστά IGT ήταν υψηλότερα από αυτά που βρέθηκαν σε άλλες μελέτες από την Ευρώπη. Η γλυκόζη νηστείας, η ινσουλίνη και ο δείκτης HOMA-IR δεν προέβλεψαν την εμφάνιση IGT, όμως, η απόλυτη τιμή της ινσουλίνης στις 2 ώρες της OGTT και ο δείκτης AUCG προέβλεψαν την εμφάνιση IGT. Τα επίπεδα λεπτίνης και γκρελίνης ήταν υψηλότερα στα κορίτσια. Υπήρχε συσχετισμός μεταξύ BMI και λεπτίνης νηστείας, BMI και αδιπονεκτίνης, σωματομεδίνης (IGF-I) και λεπτίνης νηστείας, ενώ δεν υπήρχε καμιά συσχέτιση με τα επίπεδα της κορτιζόλης ή με τα 24ωρα επίπεδα της αυξητικής ορμόνης και της θυρεοειδοτρόπου ορμόνης. Συμπερασματικά, η OGTT φαίνεται να έχει τη δυνατότητα να προβλέψει την IGT, ενώ οι τιμές γλυκόζης και ινσουλίνης νηστείας και οι τιμές του δείκτη HOMA-IR, αν και υψηλότερες στους ασθενείς με IGT και ενδεικτικές για αντίσταση στην ινσουλίνη, δεν μπορούν να προβλέψουν την IGT. / The aims of the present study were: (1) to determine the prevalence of impaired glucose tolerance (IGT) and diabetes mellitus II (DMII) in obese children and adolescents of Greek origin and (2) to study the concentrations of leptin, ghrelin, adiponectin and IGF-I during an oral glucose tolerance test as well as the 24-hour concentrations of growth hormone (GH) and thyrotropin secreting hormone (TSH), and the diurnal secretion of cortisol in these children. A total of 117 obese children and adolescents aged 12.1  2.7 years underwent an oral glucose tolerance test (OGTT) and the concentrations of leptin, ghrelin, adiponectin and IGF-I were studied during the duration of the OGTT in relation to the 24-hour secretion of GH and TSH and the diurnal secretion of cortisol. For the estimation of insulin resistance and beta cell function the homeostatic model assessment (HOMA-IR) and the insulinogenic index, respectively, were used. A total of 17 patients (14.5%) had IGT and none had DMII. The overall prevalence rates of both IGT and DMII observed in the obese children and adolescents were lower than those reported in a recent multiethnic US study. Nevertheless, the difference between the data of this study and those of the US study was mostly due to the prepubertal children (9% vs. 25.4%), while no difference was observed in the pubertal population (18% vs. 21%). The prevalence rates of IGT in this study though, were greater than those reported in other European studies. Fasting glucose, insulin and HOMA-IR values were not predictive of IGT. The absolute value of insulin at 2h of the OGTT combined with the time-integrated glycemia (AUCG) strongly predicted IGT, whereas higher area under the curve for insulin (AUCI) values were found to be protective. Leptin and ghrelin concentrations were higher in the females. There was a correlation found between BMI and fasting leptin, BMI and adiponectin, IGF-I and fasting leptin although there was no correlation found with the GH, TSH or cortisol concentrations. In conclusion, the OGTT seems to be capable of predicting IGT whereas the fasting glucose and insulin concentrations are unable to predict glucose intolerance since HOMA-IR values, although higher in IGT subjects and indicative of insulin resistance, cannot accurately predict IGT.

No description available.

Endocrine and Metabolic Aspects of Various Sleep Disorders MUDr. Zuzana Vimmerová Lattová Abstract: Recent epidemiological and experimental data suggest a negative influence of shortened or disturbed night sleep on glucose tolerance. However, no comparative studies of glucose metabolism have been conducted in clinical sleep disorders. Dysfunction of the HPA axis may play a causative role in some sleep disorders and in other sleep disorders it may be secondary to the sleep disorder. Moreover, dysfunction of the HPA axis is regarded as a possible causative factor for the impaired glucose sensitivity associated with disturbed sleep. However, data on HPA system activity in sleep disorders are sparse and conflicting. We studied 25 obstructive sleep apnea (OSA) patients, 18 restless legs syndrome (RLS) patients, 21 patients with primary insomnia and compared them to 33 healthy controls. We performed oral glucose tolerance test and assessed additional parameters of glucose metabolism. The dynamic response of the HPA system was assessed by the DEX-CRH-test which combines suppression (dexamethasone) and stimulation (CRH) of the stress hormone system. Compared to controls, increased rates of impaired glucose tolerance were found in OSA (OR: 4.9) and RLS (OR: 4.7), but not in primary insomnia. In addition, HbA1c...

Abstract Type 1 diabetes is considered to be a T cell-mediated autoimmune disease characterized by destruction of the pancreatic beta cells. Its prediction is currently based on diabetes-associated autoantibodies, giving a cumulative risk of 84% during 15 years of follow-up since seroconversion. Prediction of the timing of clinical onset has remained challenging, however. This thesis examines glucose metabolism in autoantibody-positive children with a high risk of developing type 1 diabetes. Out of a total of 14,876 children with an increased genetic risk followed up from birth in the Finnish DIPP study, 567 developed ≥2 autoantibodies during the follow-up and 255 of these (45%) were diagnosed with type 1 diabetes until the end of December 2011. The glucose parameters measured were HbA1c, OGTT and random plasma glucose with 3 to 12 months interval. Seven-day continuous glucose monitoring (CGM) was performed on an age and sex-matched cohort. We showed that rising HbA1c, impaired glucose tolerance in OGTT, random plasma glucose values of ≥7.8mmol/l and potentially CGM can predict type 1 diabetes with a median time to diagnosis of approximately one year. Our results suggest that especially HbA1c and random plasma glucose are cost-effective and improve the prediction of diabetes. These markers may be useful for monitoring the response to treatment in prevention studies. / Tiivistelmä Tyypin 1 diabetesta pidetään T-soluvälitteisenä autoimmuunitautina, joka johtaa haiman beetasolujen tuhoutumiseen. Tyypin 1 diabeteksen ennustaminen perustuu tällä hetkellä diabetekseen assosioituviin vasta-aineisiin, jotka antavat 84% kumulatiivisen riskin 15 vuoden seurannassa. Taudin puhkeamisen ajankohdan ennustaminen on kuitenkin edelleen vaikeaa. Tämä väitöskirja käsittelee glukoosiaineenvaihduntaa vasta-ainepositiivisilla lapsilla, joilla on suurentunut riski sairastua tyypin 1 diabetekseen. Suomalaisessa DIPP-tutkimuksessa vasta-aineiden kehittymistä on seurattu yhteensä 14876 lapselta. Seurannan aikana 567 lasta kehitti ≥2 autovasta-ainetta ja näistä 255 (45%) sairastui tyypin 1 diabetekseen joulukuun loppuun 2011 mennessä. Glukoosiaineenvaihduntaa seurattiin tutkimalla HbA1c, OGTT ja satunnaisia verensokeriarvoja 3-12 kuukauden välein. Ikä ja sukupuolivakioidussa kohortissa tehtiin jatkuvan sokeripitoisuuden seuranta (CGM). Tutkimuksessamme nouseva HbA1c, heikentynyt sokerin sieto OGTT-kokeessa, satunnainen verensokeri ≥7.8 mmol/l ja mahdollisesti CGM ennustavat tyypin 1 diabeteksen puhkeamista. Tulostemme perusteella erityisesti kustannustehokkaat HbA1c ja satunnainen verensokeri parantavat diabeteksen ennustamista. Nämä parametrit saattavat olla hyödyllisiä myös preventiotutkimuksissa hoitovasteen seurannassa.