Abstract Type 2 diabetes can be prevented if the impaired glucose tolerance is found. Oral glucose tolerance test is needed in clinical practise for that but it is expensive and inconvenient. Obesity, hypertension, dyslipidemia and hypertension in pregnancy are factors often found in persons with type 2 diabetes. When there are more than one factor in same person the risk of type 2 diabetes multiplies. The purpose of this study was to investigate the prevalence of abnormal glucose metabolism and risk factors of type 2 diabetes in middle aged Finnish population in Savitaipale municipality and develop a method to screen abnormal glucose metabolism in primary health care. It was also studied the correlation of blood pressure and body mass index during pregnancy and abnormal glucose metabolism in later life. The study population was 1561 people born 1933–1956. 77,5% participated and 1097 people of them not having known abnormal glucose metabolism were taken to the cross-sectional study to develop the screening method. All 325 women who have had childbirth and files of that were taken to the prospective pregnancy cohort study. Information was collected with interview, measurements, laboratory research and from childbirth files. According the World Health Organisation criteria 1999 the prevalence of diabetes was 8,7% in men and 7,4% in women, previously undiagnosed 3,9% and 3,1%. Every fourth had abnormal glucose metabolism (men 23,2%, women 23,5%). The prevalence of obesity, hypertension, use of long-term antihypertensive medication and dyslipidemia (only in women) was higher among those, who had abnormal glucose metabolism. Logistic models were made for the classified risk factors. The model (AUC 0.718 for men, 0.761 for women) containing age, gender, waist circumference, systolic blood pressure and use of long-term antihypertensive medication was as good as model containing in addition family history of diabetes, smoking habits, serum lipids and long-term use of lipid lowering medication. Risk score tables were made from classified risk factors to evaluate the probability of the abnormal glucose metabolism. The blood pressure level and body mass index in pregnancy correlated independently with abnormal glucose metabolism in later life, blood pressure also adjusted with body mass index. Hypertension in pregnancy or after delivery correlated with abnormal glucose metabolism adjusted with body mass index. Hypertension in pregnancy doubled the risk of abnormal glucose metabolism in later life adjusted for body mass index in pregnancy and hypertension in later life. This information is important in prevention of type 2 diabetes. / Tiivistelmä Tyypin 2 diabetesta voidaan estää, mikäli heikentynyt glukoosinsieto tunnistetaan. Siihen tarvitaan glukoosirasituskoetta, jota on pidetty kalliina ja hankalana toteuttaa. Lihavuus, kohonnut verenpaine, dyslipidemia ja raskausdiabetes ovat tyypin 2 diabeteksen riskitekijöitä ja niiden ryvästyminen samaan henkilöön lisää diabetekseen sairastumisen todennäköisyyttä. Tyypin 2 diabeteksen riskitekijöiden ja poikkeavan glukoosiaineenvaihdunnan määrää ja raskauden aikaisen verenpaineen yhteyttä myöhemmin ilmaantuvaan poikkeavaan glukoosiaineenvaihduntaan tutkittiin 1933–1956 syntyneessä savitaipalelaisessa väestössä. Tavoitteena oli kehittää perusterveydenhuoltoon soveltuva poikkeavan glukoosiaineenvaihdunnan seulontamenetelmä. Kohdejoukosta (n = 1561) osallistui 77,5 %, joista 1097:llä henkilöllä ei tiedetty olevan diabetesta. Heistä kerättiin tietoa haastattelulla, mittauksilla ja laboratoriotutkimuksilla sekä äitiysneuvolakorteista. Raskausaineistoon ja takenevaan kohorttitutkimukseen otettiin kaikki ne 325 naista, myös diabeetikot, joista raskaudesta oli tiedot käytettävissä. Diabetesta sairasti 8,7 % miehistä ja 7,4 % naisista, aiemmin diagnosoimattomia oli 3,9 % ja 3,1 %. Poikkeava glukoosiaineenvaihdunta oli joka neljännellä. Lihavuutta, kohonnutta verenpainetta, verenpainelääkkeen käyttöä ja naisilla dyslipidemiaa oli enemmän niillä, joilla oli poikkeava glukoosiaineenvaihdunta. Tutkimuksessa luotiin luokitelluista muuttujista logistisia malleja. Malli, johon muuttujiksi valittiin ikä, sukupuoli, vyötärön ympärys, systolinen verenpaine ja verenpainelääkkeen käyttö, todettiin yhtä hyväksi (miesten ROC -käyrän AUC 0.718, naisten 0.761) ennustamaan heikentynyt glukoosinsieto ja diabetes kuin malli, johon lisäksi valittiin suvun diabetes, tupakointi, rasva-arvoja ja lipidilääkityksen käyttö. Muuttujista tehtiin taulut, joista voi nähdä poikkeavan glukoosiaineenvaihdunnan todennäköisyyden. Raskauden aikainen verenpaine ja painoindeksi olivat yhteydessä myöhemmin ilmaantuvaan poikkeavaan glukoosiaineenvaihduntaan, samoin loppuraskauden verenpaine painoindeksillä vakioituna. Raskaudessa todettu kohonnut verenpaine oli, mutta raskauden aiheuttama kohonnut verenpaine ei ollut, yhteydessä myöhemmin ilmaantuvaan poikkeavaan glukoosiaineenvaihduntaan painoindeksistä riippumatta, samoin loppuraskauden diastolinen verenpaine seulonnan diastolisesta verenpaineesta riippumatta. Raskaudessa tai sen jälkeen todettu kohonnut verenpaine kaksinkertaisti poikkeavan glukoosiaineenvaihdunnan riskin loppuraskauden painoindeksistä tai seulonnassa todetusta kohonneesta verenpaineesta riippumatta. Kahdella helposti mitattavalla muuttujalla voidaan päätellä glukoosirasituskokeen tarve. Diabetesta ehkäistäessä on tärkeä tietää, että raskauden kohonnut verenpaine ja ylipaino lisäävät myöhempää poikkeavaa glukoosiaineenvaihduntaa.

Objetivo: Determinar potenciales factores de riesgo para diabetes mellitus gestacional (DMG). Métodos: Estudio de casos y controles realizado en el Hospital Alberto Sabogal mediante recolección de historias clínicas del 2009 a 2014. Se define como caso las gestantes con diagnóstico de DMG mediante una prueba de tolerancia oral a la glucosa (PTOG), previa glucosa en ayunas anormal y control a la gestante sin valores indicativos de DMG. Las variables de interés fueron paridad, antecedente de cesáreas, abortos y recién nacido con mayor peso. Modelos de regresión logística fueron calculados para estimar odd ratios (OR) e intervalos de confianza al 95% (IC95%). Resultados: Se incluyeron 84 casos y 336 controles. En el modelo multivariado, la multiparidad incrementó el riesgo de DMG (OR= 3,54; IC95% 1,55 – 8,14). También, antecedente de abortos, a partir del segundo aborto (OR= 3,40, IC95% 1,55 – 7,44) y cesáreas previas (1 cesárea OR= 3,5 IC95% 1,89 – 6,47 y 2+ cesáreas OR=8,35 IC95% 3,50 – 19,95). La multiparidad, dos o más abortos y mayor número de cesáreas son factores de riesgo para DMG. / Objectives: To identify risk factors for gestational diabetes mellitus (GDM). Methods: A case-control study was performed in Alberto Sabogal Hospital, collecting medical records from 2009 to 2014. A case was defined as a pregnant women diagnosed with GDM by an oral glucose tolerance test (OGTT) after an abnormal fasting glucose and control was defined as a pregnant women without GDM indicative values. The study outcome was GDM. The variables of interest were multiparity, previous cesarean section, abortions, newborn with the greatest weight. Logistic regression were used to calculate the odds ratio (OR) and a confidence interval of 95% (IC95%). Results: 84 cases and 336 controls were included. In the multivariate model, multiparity increased risk of GDM (OR= 3.54, 95% CI 1.55 to 8.14). As well history of abortions, from the second abortion (OR= 3.40, 95% CI 1.55 to 7.44) and previous cesarean section are also related (cesarean section 1 OR= 3.5 95% CI 1.89 to 6.47 and 2+ cesarean OR= 8.35 95% CI 3.50 to 19.95). Multiparity, two or more abortions, a biggest number of cesarean sections are GDM risk factors.

Objectives: The EZSCAN is a non-invasive device that, by evaluating sweat gland function, may detect subjects with type 2 diabetes mellitus (T2DM). The aim of the study was to conduct a systematic review and meta-analysis including studies assessing the performance of the EZSCAN for detecting cases of undiagnosed T2DM. Methodology/Principal findings: We searched for observational studies including diagnostic accuracy and performance results assessing EZSCAN for detecting cases of undiagnosed T2DM. OVID (Medline, Embase, Global Health), CINAHL and SCOPUS databases, plus secondary resources, were searched until March 29, 2017. The following keywords were utilized for the systematic searching: type 2 diabetes mellitus, hyperglycemia, EZSCAN, SUDOSCAN, and sudomotor function. Two investigators extracted the information for meta-analysis and assessed the quality of the data using the Revised Version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. Pooled estimates were obtained by fitting the logistic-normal random-effects model without covariates but random intercepts and using the Freeman-Tukey Arcsine Transformation to stabilize variances. Heterogeneity was also assessed using the I2 measure. Four studies (n = 7,720) were included, three of them used oral glucose tolerance test as the gold standard. Using Hierarchical Summary Receiver Operating Characteristic model, summary sensitivity was 72.0% (95%CI: 60.0%– 83.0%), whereas specificity was 56.0% (95%CI: 38.0%– 74.0%). Studies were very heterogeneous (I2 for sensitivity: 79.2% and for specificity: 99.1%) regarding the inclusion criteria and bias was present mainly due to participants selection. Conclusions: The sensitivity of EZSCAN for detecting cases of undiagnosed T2DM seems to be acceptable, but evidence of high heterogeneity and participant selection bias was detected in most of the studies included. More studies are needed to evaluate the performance of the EZSCAN for undiagnosed T2DM screening, especially at the population level.

Prevalence of obesity and associated diseases like type 2 diabetes has increased rapidly during last years. These diseases closely relate to each other. Obesity leads to insulin resistence, which directly precedes type 2 diabetes. Metformin is the most prescribed medicament for type 2 diabetic patients and insulin resistant people. It improves glucose tolerance and insulin resistance. Enzyme AMP-activated protein kinase (AMPK) is strogly involved in metformin action. The latest studies using transgenic models lacking AMPK suggest, that notable part of mechanisms involved in metformin action is independent on AMPK. n-3 polyunsaturated fatty acids (n-3 PUFA), namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are abundant in sea fish, have beneficial effects on metabolism. These fatty acids lower plasma lipids and exert cardioprotective effects. n-3 PUFA also prevent development of insulin resistence and type 2 diabetes in rodents. The aim of this thesis was to characterise acute effects of metformin on glucose homeostasis, impact of short term diet intervention with diet rich in n-3 PUFA on metformin action and the role of insulin stimulated signalling pathways and AMPK. Results suggest that early effect of metformin is dose dependent and that single dose of metformin...

Abstract Background: The objective of the study was to investigate the association of neck circumference (NC) to parameters of glucose homeostasis compared to classical anthropo- metric parameters of lean and obese children. Methods: Three dimensional (3D)-body scanning quan- tified anthropometric (height, weight, NC, hip/waist circumference, BMI) and metabolic parameters (fasting plasma glucose [FPG], insulin, HbA1c, oGTT, HOMA-IR) were determined cross-sectionally in 1542 participants (5–18 years). the strongest association to glucose metabolism para- meters was found for waist circumference (WC), except for FPG and 2h-postload glucose. In multiple linear regres- sion analyses, NC provided additional benefit beyond classical anthropometric indices to describe impairment of glucose homeostasis. Conclusions: We suggest that NC is comparable or addi- tive to established anthropometric parameters but might not be superior to them. However NC is simple to measure, reproducible and may be considered in clinical practice as an additional measurement tool.:Inhalt I Abkürzungsverzeichnis 1. Einführung in die Thematik 1.1. Einleitung und Definition 1.2. Zielsetzung der Arbeit 1.3. wissenschaftlicher Hintergrund 1.4. LIFE Child 2. Publikation Zusammenfassung der Arbeit Literaturverzeichnis Darstellung wissenschaftlicher Beitrag Erklärung über die eigenständige Abfassung der Arbeit Danksagung

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Während der Schwangerschaft vollziehen sich im Körper der Frau verschiedene Adaptionsmechanismen, um eine bestmögliche Versorgung für das heranwachsende Kind zu gewährleisten. Bei fortschreitender Gravidität entwickelt sich eine physiologische Insulinresistenz. Gelingt es den maternalen Betazellen des Pankreas‘ nicht, diese zu kompensieren, kann eine diabetische Stoffwechsellage bis hin zur Ausbildung eines Gestationsdiabetes (GDM) entstehen. Adipozytokine beeinflussen direkt lokale und periphere metabolische, endokrinologische sowie immunologische Prozesse. Inwieweit sie in der Gravidität eine Rolle spielen, ist bislang nicht hinreichend geklärt. In verschiedenen Studien wurde eine Beziehung zwischen den Fettgewebshormonen und der Glukosetoleranz in der Schwangerschaft nachgewiesen. Im Rahmen dieser Dissertation sollte eine Analyse zur Glukosetoleranz und zu Adipozytokinserumspiegeln bei Frauen unmittelbar nach der Entbindung vorgenommen werden. Ergebnisse oraler Glukosetoleranztests von gesunden Frauen 24 Stunden postpartal (n=65) wurden mit denen einer nicht-schwangeren, gesunden Kohorte (n=30) verglichen. Maternale und neonatale anthropometrische Daten wurden in Zusammenhang zu Adipozytokinen gestellt. Im Vergleich zu Frauen mit normaler Glukosetoleranz (NGT) postpartal konnten in dieser Studie signifikant verminderte Blutglukose – sowie nüchtern – Proinsulinspiegel in der nicht-schwangeren Kontrollgruppe nachgewiesen werden, wohingegen die nüchtern-C-Peptidspiegel erhöht waren. Weiterhin zeigten sich postpartal signifikant niedrigere Adiponektin-, aber höhere sOB-R- (soluble leptin receptor) sowie Leptinspiegel der NGT-Mütter im Vergleich zur Kontrollgruppe. Zusätzlich konnte eine Beziehung zwischen Adipozytokinserumspiegeln und Parametern der Glukosetoleranz bzw. Adipositas demonstriert werden. Daraus lässt sich die These ableiten, dass Frauen in der frühen Phase nach der Entbindung ähnliche biochemische Konstellationen wie beim metabolischen Syndrom, der gestörten Glukosetoleranz oder bei Störungen des Adipozytokinsystems aufweisen.:Bibliographische Beschreibung Abkürzungsverzeichnis 1 Einführung in die Thematik 1.1 Kohlenhydratstoffwechsel in der Schwangerschaft 1.1.1 Adipozytokine 1.1.1.2 Adiponektin 1.1.1.2 Leptin und der lösliche Rezeptor (sOB-R)1.1.1 1.2 Promotionsprojekt - Ziel und Fragestellung 1.2.3 Hintergrund und Fragestellung 1.2.3 Methoden 1.2.3 Ergebnisse 2 Publikation 3 Zusammenfassung und Interpretation der Arbeit 4 Literatur I Erklärung über das eigenständige Abfassen der Arbeit II Publikation III Dank

<p dir="ltr">The periparturient period involves coordinated physiological adaptations as the dairy cow transitions from a non-lactating to lactating state. The ability of dairy cattle to adapt to the onset of lactation is impacted both by physiological and nutritional factors, and a poor transition can result in reduced productivity and welfare for the animal. Additionally, disease and disorder development are heightened in the transition period, with increased risk for involuntary culling occurring in early lactation. This study aimed to evaluate if the amount of late gestational muscle reserves and prepartum supplementation of branched-chain volatile fatty acids (BCVFA) impacts health and production parameters in multiparous, periparturient dairy cattle. Forty-eight multiparous Holstein dairy cattle were assigned to either a high or low muscle group (HM or LM, respectively) based on their <i>longissimus dorsi</i><i> </i>muscle depth 42 days before expected (BEC). After assignment to group, cattle were then randomly assigned to a control (CON; 80 g/d soyhull pellets as-fed basis) or BCVFA (40 g/d isobutyrate product, 20 g/d isovalerate product, 20 g/d 2-methybutyrate product, fed as calcium salt products on an as-fed basis) treatment, which was top-dressed in the prepartum period only. After parturition, treatment was no longer provided and cattle were fed a common lactating diet. Blood samples, ultrasound images, and feed intake were collected and recorded from 42 BEC through 28 days in milk (DIM), milk yield and composition data was collected from parturition until 28 DIM.</p><p dir="ltr">HM cattle began mobilizing muscle reserves prior to parturition, while LM cattle began to accrete muscle reserves prior to parturition. This difference in prepartum muscle utilization did not impact other body measurements (i.e. body weight or body condition score) between the groups of cows but did result in increased blood glucose concentrations prepartum for HM cows compared with LM. This increase in glucose concentrations is likely due to the increased supply of gluconeogenic precursors as a result of the degradation of muscle tissue. The difference in glucose concentration was not observed postpartum, neither was there a difference in tissue mobilization between the groups postpartum. HM cattle had greater DMI both pre- and postpartum, and produced greater yields of milk, milk fat, milk protein, and milk lactose postpartum compared to the LM group. Despite the increased milk yield, there was no difference in feed efficiency between the groups, as the HM cows consumed more feed. Prepartum supplementation of BCVFA did not impact body measurement changes throughout the entire transition period, but did increase pre- and postpartum DMI, likely due to increased fiber digestibility. The BCVFA treatment increased blood glucose concentrations both pre- and postpartum and reduced milk urea nitrogen concentrations postpartum, likely due to improved nitrogen efficiency. Results show that prepartum supplementation of BCVFA has an improved ruminal carryover effect into early lactation.</p><p dir="ltr">At 14 days BEC and 7 DIM, an intravenous glucose tolerance test (IVGTT) was performed on a sub-set of cows, to evaluate if insulin response could be a mechanism impacting the efficiency and production differences observed between muscle groups and BCVFA supplementation. BCVFA supplementation increased glucose area under the curve in the prepartum period only. No other differences were observed between muscle group or treatment in either the pre- or postpartum period. Because there were no major differences between the cows in response to an IVGTT, we cannot conclude that glucose metabolism is a mechanism to explain differences in production responses observed. IVGTT cannot measure peripheral tissue insulin sensitivity, which is a limitation of this assessment, so our conclusions cannot assess if muscle reserves or BCVFA treatment impact peripheral tissue insulin sensitivity response. These results highlight that the amount of muscle plays a key role in the production responses observed in early lactation and that providing a BCVFA supplement could increase DMI during a period of negative nutrient balance and improve rumen efficiency.</p>

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25170号 / 医博第5056号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山本 洋介, 教授 近藤 尚己, 教授 西浦 博 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Résumé : Le diabète gestationnel (DG), qui peut entraîner des conséquences importantes pour la mère et l’enfant, résulte d’un défaut de compensation de la sécrétion d’insuline par rapport à la résistance à l’insuline. Comme la grossesse représente en elle-même un modèle d’augmentation physiologique de la résistance à l’insuline, il est intéressant d’étudier et de caractériser les facteurs qui sont impliqués dans la résistance à l’insuline et, ultimement, dans le DG, chez la femme enceinte. Le Tumor necrosis factor alpha (TNFα) est soupçonné d’être un de ces facteurs, suite aux études effectuées chez les animaux et les populations humaines non enceintes, mais les résultats obtenus en grossesse sont encore controversés. Nous avons émis l’hypothèse que les niveaux circulants de TNFα sont associés au DG et à la résistance à l’insuline dans une large cohorte de femmes enceintes. Nous avons aussi investigué les variations des niveaux de TNFα en réponse à l’hyperglycémie provoquée par voie orale (HGPO) chez des femmes enceintes. Nous avons montré que de hauts niveaux de TNFα étaient liés à une résistance à l’insuline augmentée au 2e trimestre de la grossesse et ce, indépendamment de l’âge, de l’adiposité, de l’âge gestationnel, des triglycérides et des niveaux circulants d’adiponectine dans notre cohorte. De plus, les niveaux de TNFα varient différemment au cours de l’HGPO selon le statut de résistance à l’insuline. En effet, les niveaux de TNFα augmentent à 1h puis diminuent à 2h chez les femmes les plus sensibles à l’insuline, alors qu’ils diminuent tout au long du test chez les femmes les plus résistantes à l’insuline, mais restent en tout temps supérieurs aux niveaux mesurés chez les femmes les plus sensibles à l’insuline. Toutefois, les niveaux de TNFα n’étaient pas différents entre les femmes avec DG et celles normoglycémiques. De façon intéressante, la variation du TNFα pendant l’HGPO chez les femmes DG est similaire à celle chez les femmes avec haute résistance à l’insuline. Ces résultats suggèrent donc que le TNFα est indépendamment associé à la résistance à l’insuline en grossesse et que les voies inflammatoires peuvent contribuer aux dysfonctions glycémiques retrouvées en DG. // Abstract : Gestational diabetes mellitus (GDM), which can exert important impacts on mothers and offspring, results from an imbalance between insulin secretion capacity and insulin resistance. Pregnancy is a state of physiologically increased insulin resistance, providing a unique model to study and characterize biological factors linked to insulin resistance in humans and, ultimately, GDM, in pregnant women. Based on animal studies and analyses in non-pregnant populations, tumor necrosis factor alpha (TNFα) is suspected of being involved in insulin resistance, but results obtained from pregnant populations are still controversial. Our hypothesis was that circulating TNFα would be associated with GDM and insulin resistance in a large cohort of pregnant women. We also investigated dynamic variations of TNFα levels over the course of an oral glucose tolerance test (OGTT) in pregnant women. We showed that higher TNFα levels were associated with higher insulin resistance at 2nd trimester of pregnancy, independent of age, adiposity, gestational age, triglycerides and adiponectin levels in our cohort. Furthermore, TNFα levels varied differently over the course of the OGTT according to insulin resistance status: they rose at 1h and then decreased at 2h in insulin sensitive women, whereas they consistently decreased in insulin resistant women over the course of the test (even though they remained statistically higher than insulin sensitive women’s levels at each time point throughout the OGTT). However, TNFα levels were not different between GDM and non-GDM women. Interestingly, variation of TNFα levels over the course of the OGTT in GDM women followed the same pattern as the variation observed in OGTT in women classified with high insulin resistance. Those results suggest that circulating TNFα is independently associated with insulin resistance in pregnancy and that inflammatory pathways might contribute to glycemic dysregulation observed in GDM.