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In vielen promisken Paarungssystemen konkurrieren die Männchen einer Gruppe um den Zugang zu fertilen Weibchen. Um es Rivalen zu erschweren, haben sie verschiedene Paarungstaktiken entwickelt. Eine von Vertebraten und Invertebraten oft genutzte Strategie ist das „mate-guarding“. Hier bewacht ein hochrangiges Männchen das fertile Weibchen indem es ständig in dessen Nähe bleibt, wodurch es den Zugang der anderen Männchen stark minimiert. Durch diese Monopolisierung des Weibchens erhöht ein Männchen seinen Reproduktionserfolg und damit zusätzlich die Wahrscheinlichkeit der Vaterschaft. Diese für das Männchen gewinnbringende Strategie birgt jedoch auch energetische Kosten. Solche negativen Verknüpfungen zwischen Kosten und Gewinn, sogenannte „trade-offs“, beeinflussen den Fortpflanzungserfolg ebenso wie die Körperkondition und die Überlebenschance eines Männchens. Haben solche Kosten beispielsweise eine Verschlechterung der körperlichen Verfassung zur Folge, kann sich das negativ auf die Fähigkeiten der Männchen, ein Weibchen zu monopolisieren, auswirken und damit den Vaterschaftserfolg der Männchen mindern. Die mit solch einer Paarungstaktik wie dem „mate-guarding“ einhergehenden Kosten könnten sich auch auf die Entstehung von Strategien zur Partnerwahl bei den Männchen auswirken: Männchen sollten ihre Energie vor allem auf die Reproduktion mit den fittesten Weibchen aufwenden. Um die grundlegenden Faktoren der Partnerwahl sowie die Verteilung des Reproduktionserfolges unter den Männchen („reproductive skew“) besser zu verstehen, müssen die bei der Monopolisierung des Weibchens entstehenden Kosten quantifiziert werden. Primaten sind ein interessantes Taxa um diese Fragen zu untersuchen, da viele Arten in stabilen Mehr-Männchen-Gruppen leben und „mate-guarding“ eine vorteilhafte Taktik ist, die oft von hochrangigen Männchen angewandt wird. Allerdings haben sich bisherige Studien an Primaten auf die Quantifizierung der Futterkosten beschränkt und die Ergebnisse sind bisher sehr widersprüchlich. Unser Verständnis dieser Kosten wird weiterhin durch das Fehlen eines zuverlässigen, nicht-invasiven physiologischen Markers, der den energetischen Zustand von Nicht-Menschenaffen misst, beeinträchtigt. Das Hauptziel dieser Arbeit war es daher, die Kosten des „mate-guarding“ in einer Primatenart, die in Mehr-Männchen-Gruppen lebt wie die Javaneraffen (Macaca fascicularis), zu quantifizieren. Bisherige Ergebnisse zeigen, dass die Alpha-Männchen dieser Primatenart ihre Weibchen weniger monopolisieren als das „Priority of Access-Model“ vorhersagt. Der Monopolisierungserfolg scheint demnach durch die Kosten, die den Männchen durch das „mate-guarding“ entstehen, limitiert zu sein. In Studie 1 der vorliegenden Arbeit habe ich die Eignung von Urin C-Peptiden (UCP, ein Nebenprodukt der Insulinproduktion), als Marker für den Energiestatus von Makakenmännchen, evaluiert. In Studie 2 und 3 quantifizierte ich die energetischen, physiologischen und physischen (z.B. Aggression) Kosten des „mate-guardings“. In der vierten Studie untersuchte ich den Einfluss der Qualität der Weibchen auf die Kosten der des „mate-guardings“ und die Investition der Männchen in dieses Verhalten. Als erstes betrachtete ich den Zusammenhang zwischen den UCP Werten und Indikatoren für den Zustand der körperlichen Verfassung bei frei- und in Gefangenschaft lebender Makaken, um UCP als zuverlässigen Marker für Energiestatus (Studie 1) zu validieren. Die UCP Level waren positiv korreliert mit dem BMI (Body-Mass-Index) sowie mit dem Fettgehalt einer Hautfalte. In einem Experiment, bei dem die Futterzufuhr reduziert wurde, stellte sich heraus, dass UCP Level mit Änderungen des BMI und der geminderten Futterzufuhr kovariiert. Demzufolge ist UCP ein nützlicher Marker um nicht-invasiv intra- und interindividuelle Veränderungen der Körperkondition und des Ernährungszustandes zu ermitteln. Für die weitere Fragestellung beobachtete ich drei freilebende Javaneraffengruppen während zwei Paarungsperioden, in Ketambe, Gunung Leuser National Park in Indonesien. Um ein möglichst umfassendes Bild der potentiellen Kosten des „mate-guarding“ bereitzustellen, kombinierte ich zum einen meine durchgeführten Verhaltensbeobachtungen der Männchen, den Aufenthalt der Männchen in den Bäumen und sexuelle Interaktionen der Männchen mit den Weibchen. Zum anderen ermittelte ich GPS-Daten der Wanderungsdistanz, non-invasive Indikatoren für physiologischen Stress (faecal glucocorticoid, fGC), den Energiestatus (UCP) und bewertete die Verfügbarkeit von Früchten. Insgesamt konnten 2088 Fokusstunden, 331 Urin- und 771 Kotproben gesammelt und analysiert werden. Zudem wurden jeden Monat 360 Fruchtbäume begutachtet. In Studie 2 konnte ich zeigen, dass „mate-guarding“ die Parameter der Energieaufnahme und des Energieverbrauches reduziert. Dies hatte jedoch keine signifikanten Auswirkungen auf den gesamten Energiestatus (UCP Level) eines Männchens. Dieses Ergebnis weist auf ein ausbalanciertes Verhältnis von Energieaufnahme und Energieverbrauch der Männchen während des „mate-guardings“ hin. In Studie 3 konnte ich nachweisen, dass die Männchen während des „mate-guardings“, höhere fGC Werte aufwiesen. Dieser Wert wurde jedoch durch die Zeit, die Männchen in Vigilanz investieren, moduliert. „Mate-guarding” erhöhte einerseits die Vigilanzzeit eines Männchens und andererseits auch die Aggressionsrate der Männchen. Alpha-Männchen waren das ganze Jahr über gestresster als andere Männchen, unabhängig von Paarungskonkurrenz. Dies suggeriert, dass erhöhte Glucocorticoidlevel während des „mate-guarding“ den Männchen helfen ihre energetische Homöostase aufrechtzuerhalten, jedoch könnte dies Langzeitkosten darstellen, die bei lang anhaltender Belastung zu chronischem Stress führen können. Die Kombination dieser physiologischer Kosten und dem Verletzungsrisiko, dass mit Aggressionen einhergeht, könnte die Möglichkeit eines Alphamännchens ein Weibchen zu monopolisieren minimieren und damit auch Einfluss auf die Verteilung des Reproduktionserfolges der Männchen in einer Gruppe haben. In Studie 4 konnte ich zeigen, dass männliche Javaneraffen einige der Kosten des „mate-guarding“ reduzieren können indem sie gezielt Weibchen mit hohem reproduktiven Wert bewachen, da sie dann geringere fGC Werte haben. Darüber hinaus passten Männchen ihre Investition in „mate-guarding“ an, indem sie aufmerksamer und aggressiver waren wenn sie hochrangige Weibchen oder Weibchen mit denen sie starke Bindungen formten, bewachten. Diese Ergebnisse bestätigen, dass Männchen nicht nur hochwertige Weibchen auswählen, sondern diese auch länger und besser monopolisieren. In meiner Arbeit konnte ich die Kosten, die „mate-guarding“ für die Männchen einer Primatenart mit sich bringt, aufzeigen und hervorheben wie diese Kosten die Verteilung des Reproduktionserfolges unter den Männchen in der Gruppe beeinflusst. Auf Grundlage meiner Ergebnisse schlage ich vor, dass männliche Javaneraffen eine „unvollständige Weibchenmonopolisierungs-Strategie“ entwickelt haben, bei der sie die Kosten des „mate-guarding“ reduzieren indem sie Weibchen selektiv nach deren Reproduktionsqualität wählen und Weibchen mit geringerer Qualität weniger gründlich monopolisieren. Diese unvollständige Weibchenmonopolisierung könnte eine entscheidende Komponente des Energiemanagements von Alphamännchen sein, die ihnen erlaubt ganzjährig adäquat auf versuchte Rangübernahmen zu reagieren und somit ihre Amtszeit zu verlängern und die damit einhergehenden Fitnessvorteile zu erhalten. Beim Vergleich meiner Ergebnisse mit anderen Säugetier-Taxa, diskutiere ich in meiner Arbeit weiterhin die Beziehung zwischen den Kosten des „mate-guarding“ und der Verteilung des Reproduktionserfolges der Männchen in der Gruppe, die durch 1) reproduktive Saisonalität, 2) Energie-Management-Strategien der Männchen, 3) Errungenschaft eines hohen Ranges in der Gruppe und 4) der Sozialstruktur, moduliert sein kann. Zukünftige Studien, die die Kosten der Paarungstaktiken der Männchen untersuchen, sollten die Komplexität des Reproduktionsaufwandes, den Männchen investieren, bedenken. Diese Investitionen scheinen nicht ausschließlich auf die reproduktive Phase im Jahr beschränkt zu sein, sondern können sich über das ganze Jahr verteilen und spiegeln sich in Form der Konkurrenz zwischen Männchen in Bezug auf Rangstatus und sozialen Interaktionen wider.

Motivation: The prevalence of cardiovascular dysfunction, especially hypertension, in Africans has increased dramatically over the past few decades. Despite considerable in~ depth studies, cardiovascular diseases remain the leading cause of morbidity and mortality. Further escalations are predicted, especially in developing countries such as South Africa, if measures are not taken to combat the trend. Numerous cardiovascular risk factors have been investigated within African-Americans as well as Caucasians. However, it is not known to what extent African-Americans and Africans from South Africa are comparable. Therefore, it is essential to investigate risk factors and their possible contributory role in the high susceptibility of cardiovascular dysfunction in the black South African population. Aim: To investigale potential risk factors and their possible involvement and association with the high prevalence of cardiovascular dysfunction within the black South African population. Methodology: Manuscripts presented in Chapters 2, 3 and 4 made use of the data obtained from the cross-sectional SAfrEIC (The South African study regarding the influence of Sex, age and ethnicity on insulin sensitivity and Cardiovascular function) study. The study group included 756 asymptomatic, apparently healthy African men and women as well as Caucasian men and women, recruited from the North West Province, South Africa. Anthropometric and cardiovascular measurements were taken as well as their lipid profiles, fasting insulin levels, and uric acid and adiponectin levels. Independent t-tests, analyses of variance (ANOVA) and analyses of covariance (ANCOVA) were used for comparison of variables between groups to determine significant differences. Partial correlations coefficients were used to show association between variables while adjusting for confounders. Multiple analyses of covariance (MANCOVA) were performed to compare variables between the groups, whilst adjusting for relevant confounders. Stepwise multiple and single regression analyses were also used to determine and confirm the most significant associations between variables. All subjects gave informed consent in writing and the Ethics Committee of the NorthWest University approved the study, The reader is referred to the "Materials and Methods" section of Chapters 2, 3 and 4 for a more elaborate description of the subjects, study design and analytical methods used in each paper. Results and conclusions of the individual manuscripts *Results from Chapter 2 revealed significantly lower uric acid levels for African men compared to Caucasian men, Despite these lower levels. the association between uric acid and blood pressure is more pronounced within the African men. The strong positive relationship between uric acid and blood pressure might be explained by uric acid's independent relationship with vascular resistance, Uric acid also revealed a positive association with triglycerides in both the African and Caucasian men. These results suggest that uric acid per se can act as a risk factor in the development of cardiovascular dysfunction in African men, *Results from Chapter 3 showed opposing changes in insulin secretion for African men and Caucasian men with increasing age. Whereas insulin levels increased in Caucasian men with progressive age, insulin levels in African men tended to decrease with ageing. Additionally, the insulin-blood pressure relationship within African men revealed opposite results as to what was expected. While the Caucasian men revealed a more positive association between insulin and blood pressure within the younger individuals, older individuals revealed a negative association between insulin and blood pressure, This implies that the vasoconstrictory actions of insulin seem to dominate in young individuals while the vasodilatory actions of insulin take over in older individuals, The turnaround probably acts as a counter protective mechanism against age-related cardiovascular dysfunction. On the contrary, despite decreased insulin secretion in older African men, they exhibit a more positive association between insulin and blood pressure, whereas younger subjects showed a more negative association, These results might suggest dissociation between insulin and blood pressure, Insulin per se might, therefore, not act as a risk factor, but rather the lack of insulin-mediated vasodilatory effects as observed within younger Africans. *Results from Chapter 4 contradicted the notion found in the literature that age-related increase in adiponectin levels are due to impaired renal function. Although the results from this chapter confirmed a Significant association between renal function (estimated creatinine clearance) and adiponectin levels a multiple regression model revealed insulin resistance (HOMA-IR) as the major contributor to adiponectin levels. Adiponectin levels increased with progressive ageing only in the Africans. No such change was observed for the Caucasians. This might be due to development of functional adiponectin resistance or perhaps due to a decline in pancreatic cell mass with ageing. In conclusion, the cardiovascular profile of Africans seems to be more detrimentally affected compared to Caucasians. Results from this study have elucidated on the associations and potential involvement of possible risk factors including, uric acid, insulin, C-peptide, as well as adiponectin, with regards to the high prevalence of cardiovascular dysfunction within the black South African population. / Thesis (Ph.D. (Physiology))--North-West University, Potchefstroom Campus, 2010.

Motivation: The prevalence of cardiovascular dysfunction, especially hypertension, in Africans has increased dramatically over the past few decades. Despite considerable in~ depth studies, cardiovascular diseases remain the leading cause of morbidity and mortality. Further escalations are predicted, especially in developing countries such as South Africa, if measures are not taken to combat the trend. Numerous cardiovascular risk factors have been investigated within African-Americans as well as Caucasians. However, it is not known to what extent African-Americans and Africans from South Africa are comparable. Therefore, it is essential to investigate risk factors and their possible contributory role in the high susceptibility of cardiovascular dysfunction in the black South African population. Aim: To investigale potential risk factors and their possible involvement and association with the high prevalence of cardiovascular dysfunction within the black South African population. Methodology: Manuscripts presented in Chapters 2, 3 and 4 made use of the data obtained from the cross-sectional SAfrEIC (The South African study regarding the influence of Sex, age and ethnicity on insulin sensitivity and Cardiovascular function) study. The study group included 756 asymptomatic, apparently healthy African men and women as well as Caucasian men and women, recruited from the North West Province, South Africa. Anthropometric and cardiovascular measurements were taken as well as their lipid profiles, fasting insulin levels, and uric acid and adiponectin levels. Independent t-tests, analyses of variance (ANOVA) and analyses of covariance (ANCOVA) were used for comparison of variables between groups to determine significant differences. Partial correlations coefficients were used to show association between variables while adjusting for confounders. Multiple analyses of covariance (MANCOVA) were performed to compare variables between the groups, whilst adjusting for relevant confounders. Stepwise multiple and single regression analyses were also used to determine and confirm the most significant associations between variables. All subjects gave informed consent in writing and the Ethics Committee of the NorthWest University approved the study, The reader is referred to the "Materials and Methods" section of Chapters 2, 3 and 4 for a more elaborate description of the subjects, study design and analytical methods used in each paper. Results and conclusions of the individual manuscripts *Results from Chapter 2 revealed significantly lower uric acid levels for African men compared to Caucasian men, Despite these lower levels. the association between uric acid and blood pressure is more pronounced within the African men. The strong positive relationship between uric acid and blood pressure might be explained by uric acid's independent relationship with vascular resistance, Uric acid also revealed a positive association with triglycerides in both the African and Caucasian men. These results suggest that uric acid per se can act as a risk factor in the development of cardiovascular dysfunction in African men, *Results from Chapter 3 showed opposing changes in insulin secretion for African men and Caucasian men with increasing age. Whereas insulin levels increased in Caucasian men with progressive age, insulin levels in African men tended to decrease with ageing. Additionally, the insulin-blood pressure relationship within African men revealed opposite results as to what was expected. While the Caucasian men revealed a more positive association between insulin and blood pressure within the younger individuals, older individuals revealed a negative association between insulin and blood pressure, This implies that the vasoconstrictory actions of insulin seem to dominate in young individuals while the vasodilatory actions of insulin take over in older individuals, The turnaround probably acts as a counter protective mechanism against age-related cardiovascular dysfunction. On the contrary, despite decreased insulin secretion in older African men, they exhibit a more positive association between insulin and blood pressure, whereas younger subjects showed a more negative association, These results might suggest dissociation between insulin and blood pressure, Insulin per se might, therefore, not act as a risk factor, but rather the lack of insulin-mediated vasodilatory effects as observed within younger Africans. *Results from Chapter 4 contradicted the notion found in the literature that age-related increase in adiponectin levels are due to impaired renal function. Although the results from this chapter confirmed a Significant association between renal function (estimated creatinine clearance) and adiponectin levels a multiple regression model revealed insulin resistance (HOMA-IR) as the major contributor to adiponectin levels. Adiponectin levels increased with progressive ageing only in the Africans. No such change was observed for the Caucasians. This might be due to development of functional adiponectin resistance or perhaps due to a decline in pancreatic cell mass with ageing. In conclusion, the cardiovascular profile of Africans seems to be more detrimentally affected compared to Caucasians. Results from this study have elucidated on the associations and potential involvement of possible risk factors including, uric acid, insulin, C-peptide, as well as adiponectin, with regards to the high prevalence of cardiovascular dysfunction within the black South African population. / Thesis (Ph.D. (Physiology))--North-West University, Potchefstroom Campus, 2010.

A correta classificação do tipo de DM leva mais precocemente ao tratamento adequado e atualmente é dividida em 4 categorias: DM tipo 1, DM tipo 2, Outros tipos e Diabete Gestacional. O DM tipo 1 é geralmente auto-imune, surge em geral antes dos 20 anos de idade e é dependente de insulina para impedir a cetoacidose. O DM tipo 2 é responsável por mais de 90% dos casos, acontece em geral após os 45 anos, com história familiar e associado à síndrome metabólica. Na categoria “outros tipos”, o Maturity Onset Diabetes of the Young (MODY) é um subtipo que inicia abaixo dos 25 anos, não-dependente de insulina e apresenta herança dominante. No entanto, apesar da classificação definir essas categorias através de características peculiares, pode existir uma sobreposição de quadros, principalmente no DM que inicia no adulto jovem. Assim, novos sistemas de classificação têm sido propostos, empregando a presença da auto-imunidade (anticorpos) e índices de função de célula β (peptídeo-C) para definir a patogênese e nomenclatura mais específicas. O objetivo desta revisão é descrever e analisar o desempenho destas ferramentas diagnósticas na classificação do DM. Os anticorpos evidenciam a auto-imunidade do DM 1. O IAA (insulin auto-antibody) está presente quando o início do DM se dá, principalmente, antes dos 5 anos de idade e o anti- GAD (glutamic acid decarboxylase) tem seu melhor desempenho nos indivíduos com início da doença acima dos 20 anos, sendo o teste que permanece positivo por mais tempo. A medida do peptídeo-C avalia a reserva pancreática de insulina e deve ser realizada com glicemia entre 70-200 mg/dl. A medida após estímulo é a mais estudada e <1,5 ng/ml define o paciente como DM 1. O estímulo com refeição mista é o recomendado pela ADA, mas o teste com 1 mg de glucagon é mais simples e igualmente acurado. Dados em relação à utilização da classificação baseada na medida de diferentes anticorpos dirigidos ao pâncreas classificação A (anticorpos) e β (peptídeo-C) pode ser adotada como um método acurado, relativamente simples e preciso de classificação de DM. / The correct classification of DM type leads to earlier appropriate treatment and is currently divided into 4 categories: type 1 DM, type 2 DM, Other types and Gestational DM. Type 1 DM is generally autoimmune, it usually appears before the age of 20 years, and depends on insulin to prevent ketoacidosis. Type 2 DM accounts for over 90% of the cases, it usually occurs after the age of 45, with a family history and metabolic syndrome. In the category “other types”, Maturity Onset Diabetes of the Young (MODY) is a subtype that begins before the age of 25, is non-insulin dependent and presents a dominant heritage. However, although the classification defines these categories through peculiar characteristics, there may be superimposed pictures, especially in the case of DM which begins in the young adult. Thus, new classification systems have been proposed, using the presence of autoimmunity (antibodies) and β cell (C-peptide) indexes to define the pathogenesis and more specific nomenclatures. The purpose of this review is to describe and analyze the performance of these diagnostic tools in the classification of DM. The presence of antibodies show the autoimmunity of type 1 DM. IAA (insulin auto-antibody) is present mainly before the age of 5 years, and anti-GAD (glutamic acid decarboxylase) performs best in individuals who begin the disease above the age of 20, and its test remains positive longest. The C-peptide measure evaluates the pancreatic reserve of insulin and should be performed with a glycemia between 70-200 mg/dl. Post-stimulus measuring is more widely studied and <1.5 ng/ml defines the patient as DM1. Stimulation with a mixed meal is recommended by ADA, but the test with 1 mg of glucagon is simpler and just as effective. Data on classification A (antibodies), β (Cpeptide) suggest that it may be adopted as an effective, relatively simple and precise method for DM classification.

A correta classificação do tipo de DM leva mais precocemente ao tratamento adequado e atualmente é dividida em 4 categorias: DM tipo 1, DM tipo 2, Outros tipos e Diabete Gestacional. O DM tipo 1 é geralmente auto-imune, surge em geral antes dos 20 anos de idade e é dependente de insulina para impedir a cetoacidose. O DM tipo 2 é responsável por mais de 90% dos casos, acontece em geral após os 45 anos, com história familiar e associado à síndrome metabólica. Na categoria “outros tipos”, o Maturity Onset Diabetes of the Young (MODY) é um subtipo que inicia abaixo dos 25 anos, não-dependente de insulina e apresenta herança dominante. No entanto, apesar da classificação definir essas categorias através de características peculiares, pode existir uma sobreposição de quadros, principalmente no DM que inicia no adulto jovem. Assim, novos sistemas de classificação têm sido propostos, empregando a presença da auto-imunidade (anticorpos) e índices de função de célula β (peptídeo-C) para definir a patogênese e nomenclatura mais específicas. O objetivo desta revisão é descrever e analisar o desempenho destas ferramentas diagnósticas na classificação do DM. Os anticorpos evidenciam a auto-imunidade do DM 1. O IAA (insulin auto-antibody) está presente quando o início do DM se dá, principalmente, antes dos 5 anos de idade e o anti- GAD (glutamic acid decarboxylase) tem seu melhor desempenho nos indivíduos com início da doença acima dos 20 anos, sendo o teste que permanece positivo por mais tempo. A medida do peptídeo-C avalia a reserva pancreática de insulina e deve ser realizada com glicemia entre 70-200 mg/dl. A medida após estímulo é a mais estudada e <1,5 ng/ml define o paciente como DM 1. O estímulo com refeição mista é o recomendado pela ADA, mas o teste com 1 mg de glucagon é mais simples e igualmente acurado. Dados em relação à utilização da classificação baseada na medida de diferentes anticorpos dirigidos ao pâncreas classificação A (anticorpos) e β (peptídeo-C) pode ser adotada como um método acurado, relativamente simples e preciso de classificação de DM. / The correct classification of DM type leads to earlier appropriate treatment and is currently divided into 4 categories: type 1 DM, type 2 DM, Other types and Gestational DM. Type 1 DM is generally autoimmune, it usually appears before the age of 20 years, and depends on insulin to prevent ketoacidosis. Type 2 DM accounts for over 90% of the cases, it usually occurs after the age of 45, with a family history and metabolic syndrome. In the category “other types”, Maturity Onset Diabetes of the Young (MODY) is a subtype that begins before the age of 25, is non-insulin dependent and presents a dominant heritage. However, although the classification defines these categories through peculiar characteristics, there may be superimposed pictures, especially in the case of DM which begins in the young adult. Thus, new classification systems have been proposed, using the presence of autoimmunity (antibodies) and β cell (C-peptide) indexes to define the pathogenesis and more specific nomenclatures. The purpose of this review is to describe and analyze the performance of these diagnostic tools in the classification of DM. The presence of antibodies show the autoimmunity of type 1 DM. IAA (insulin auto-antibody) is present mainly before the age of 5 years, and anti-GAD (glutamic acid decarboxylase) performs best in individuals who begin the disease above the age of 20, and its test remains positive longest. The C-peptide measure evaluates the pancreatic reserve of insulin and should be performed with a glycemia between 70-200 mg/dl. Post-stimulus measuring is more widely studied and <1.5 ng/ml defines the patient as DM1. Stimulation with a mixed meal is recommended by ADA, but the test with 1 mg of glucagon is simpler and just as effective. Data on classification A (antibodies), β (Cpeptide) suggest that it may be adopted as an effective, relatively simple and precise method for DM classification.

A correta classificação do tipo de DM leva mais precocemente ao tratamento adequado e atualmente é dividida em 4 categorias: DM tipo 1, DM tipo 2, Outros tipos e Diabete Gestacional. O DM tipo 1 é geralmente auto-imune, surge em geral antes dos 20 anos de idade e é dependente de insulina para impedir a cetoacidose. O DM tipo 2 é responsável por mais de 90% dos casos, acontece em geral após os 45 anos, com história familiar e associado à síndrome metabólica. Na categoria “outros tipos”, o Maturity Onset Diabetes of the Young (MODY) é um subtipo que inicia abaixo dos 25 anos, não-dependente de insulina e apresenta herança dominante. No entanto, apesar da classificação definir essas categorias através de características peculiares, pode existir uma sobreposição de quadros, principalmente no DM que inicia no adulto jovem. Assim, novos sistemas de classificação têm sido propostos, empregando a presença da auto-imunidade (anticorpos) e índices de função de célula β (peptídeo-C) para definir a patogênese e nomenclatura mais específicas. O objetivo desta revisão é descrever e analisar o desempenho destas ferramentas diagnósticas na classificação do DM. Os anticorpos evidenciam a auto-imunidade do DM 1. O IAA (insulin auto-antibody) está presente quando o início do DM se dá, principalmente, antes dos 5 anos de idade e o anti- GAD (glutamic acid decarboxylase) tem seu melhor desempenho nos indivíduos com início da doença acima dos 20 anos, sendo o teste que permanece positivo por mais tempo. A medida do peptídeo-C avalia a reserva pancreática de insulina e deve ser realizada com glicemia entre 70-200 mg/dl. A medida após estímulo é a mais estudada e <1,5 ng/ml define o paciente como DM 1. O estímulo com refeição mista é o recomendado pela ADA, mas o teste com 1 mg de glucagon é mais simples e igualmente acurado. Dados em relação à utilização da classificação baseada na medida de diferentes anticorpos dirigidos ao pâncreas classificação A (anticorpos) e β (peptídeo-C) pode ser adotada como um método acurado, relativamente simples e preciso de classificação de DM. / The correct classification of DM type leads to earlier appropriate treatment and is currently divided into 4 categories: type 1 DM, type 2 DM, Other types and Gestational DM. Type 1 DM is generally autoimmune, it usually appears before the age of 20 years, and depends on insulin to prevent ketoacidosis. Type 2 DM accounts for over 90% of the cases, it usually occurs after the age of 45, with a family history and metabolic syndrome. In the category “other types”, Maturity Onset Diabetes of the Young (MODY) is a subtype that begins before the age of 25, is non-insulin dependent and presents a dominant heritage. However, although the classification defines these categories through peculiar characteristics, there may be superimposed pictures, especially in the case of DM which begins in the young adult. Thus, new classification systems have been proposed, using the presence of autoimmunity (antibodies) and β cell (C-peptide) indexes to define the pathogenesis and more specific nomenclatures. The purpose of this review is to describe and analyze the performance of these diagnostic tools in the classification of DM. The presence of antibodies show the autoimmunity of type 1 DM. IAA (insulin auto-antibody) is present mainly before the age of 5 years, and anti-GAD (glutamic acid decarboxylase) performs best in individuals who begin the disease above the age of 20, and its test remains positive longest. The C-peptide measure evaluates the pancreatic reserve of insulin and should be performed with a glycemia between 70-200 mg/dl. Post-stimulus measuring is more widely studied and <1.5 ng/ml defines the patient as DM1. Stimulation with a mixed meal is recommended by ADA, but the test with 1 mg of glucagon is simpler and just as effective. Data on classification A (antibodies), β (Cpeptide) suggest that it may be adopted as an effective, relatively simple and precise method for DM classification.

The main purpose of this thesis was to examine the relationship of pre-diagnostic circulating levels of sex-steroids (androgens and estrogens), sex hormone binding globuline (SHBG), insulin-like growth factor-I (IGF-I), IGF binding proteins (BP) and C-peptide (as a marker of pancreatic insulin secretion) with risk of ovarian and endometrial cancer. Additionally, the interrelationships of body mass index (BMI), sex-steroids, IGF-I and IGFBP-3 were examined. Two case-control studies were nested within 3 prospective cohort studies centered in New York (USA), Umeå (Sweden) and Milan (Italy). The ovarian study included 132 cancer cases. The endometrial study included 166 cancer cases in the IGF-I and C-peptide component and 124 postmenopausal cases in the sex-steroids component. For each case, two controls matching the case for cohort, age, menopausal status and date at recruitment were selected. In total 286 and 315 controls were included in the ovarian and endometrial cancer studies, respectively. Odds ratios (OR) and their 95% confidence intervals (CI) for cancer risk associated with increasing hormone concentrations were estimated by conditional logistic regression. The cross-sectional analysis was based on anthropometric and hormonal data from 620 controls selected for the two nested case-control studies. There was no association of prediagnostic androstenedione, testosterone, DHEAS, SHBG or estrone with ovarian cancer risk in the whole study population or in women who were pre- or postmenopausal at blood donation. In the premenopausal group, risk appeared to increase with increasing androstenedione (OR (95% CI) for the highest tertile: 2.35 (0.81-6.82), p=0.12). There was no association of IGF-I, IGFBP-1, 2, 3 or C-peptide concentrations with risk of ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at an early age (&lt;55), circulating IGF-I was directly and strongly associated with risk (OR (95% CI): 4.74 (1.20-18.7), p&lt;0.05 for the highest IGF-I tertile). In the endometrial study, previous observations were confimed that elevated circulating estrogens and androgens and decreased SHBG increase risk of developing endometrial malignancy after menopause. Multivariate ORs (95% CI) for endometrial cancer for quartiles with the highest hormone levels were: 4.13 (1.76-9.72), p&lt;0.001 for estradiol; 3.67 (1.71-7.88), p=0.001 for estrone; 2.15 (1.05-4.40), p&lt;0.04 for androstenedione; 1.74 (0.88-3.46), p=0.06 for testosterone; 2.90 (1.42-5.90), p&lt;0.01 for DHEAS and 0.46 (0.20-1.05), p&lt;0.01 for SHBG. Prediagnostic IGF-I, IGFBP-1, -2 and –3 were not related to risk of endometrial cancer in the whole study population. In postmenopausal women, levels of IGFBP-1 were inversely related to risk with an OR for the highest quartile of 0.36 (0.13-0.95), p&lt;0.05. Endometrial cancer risk increased with increasing levels of C-peptide (p&lt;0.01), up to an OR of 4.40 (1.65-11.7) for the highest quintile after adjustment for BMI and other confounders. The cross-sectional analyses showed that in both pre- and postmenopausal women SHBG decreased with increasing BMI. In the postmenopausal group, estrogens, testosterone and androstenedione increased with BMI, while the association with IGF-I was non-linear, the highest mean IGF-I concentration being observed in women with BMI between 24 and 25. In postmenopausal women, IGF-I was positively related to androgens, inversely correlated with SHBG, and was not correlated with estrogens. In conclusion, elevated pre-diagnostic sex-steroids, IGF-I or C-peptide increase risk of developing ovarian and endometrial cancer. BMI influences the circulating levels of these hormones, especially after menopause.

L'obésité est une épidémie mondiale qui augmente le risque de développer un diabète de type 2 ainsi que ses complications. Chez les individus obèses, le tissu adipeux sécrète de grandes quantités d'hormones et de cytokines qui affectent négativement le métabolisme du glucose et des lipides, ce qui provoque l'inflammation et la résistance à l'insuline. L'obésité augmente également l'activité du système rénine-angiotensine (RAS) localement au niveau de différents tissus et de façon systémique dans la circulation. L’angiotensinogène est convertie en angiotensine I par la rénine, ainsi que par la prorénine uniquement quand la prorénine est liée au récepteur de la rénine et prorénine [(P)RR] 1 . Ceci est la voie angiotensine-dépendante (Ang-D) du (P)RR. La liaison de la rénine et de la prorénine avec le (P)RR active également une voie angiotensine-indépendante (Ang-ND), ce qui produit une signalisation intracellulaire comportant la mitogen activated protein kinase (MAPK), la extracellular regulatory kinase 1/2 (ERK1/2), la promyelocytic leukemia zinc finger protein (PLZF) et le tumor necrosis factor alpha (TNF-a). Ceux-ci peuvent provoquer la croissance et la prolifération cellulaire, l'apoptose et la fibrose et pourraient donc être reliés aux dommages tissulaires et aux complications associées à l'obésité 1, 2. Plusieurs effets bénéfiques d’un blocage pharmacologique du (P)RR ont été rapportés tels la prévention du développement d'une fibrose cardiaque et rénale ainsi que la prévention de la néphropathie et de la rétinopathie diabétique. Cependant, les effets du (P)RR dans le tissu adipeux ont été peu étudiés. Par conséquent, notre objectif était d'étudier le rôle du (P)RR dans le développement de l'obésité et de la résistance à l'insuline par : 1) l'administration de HRP (un peptide bloquant l’effet du (P)RR) chez un modèle de souris obèse par l’administration d’une diète riche en gras (HFD), et 2) l’évaluation de souris ayant une délétion (KO) du gène (P)RR spécifiquement dans le tissu adipeux, qui a été généré dans notre laboratoire par la technologie Cre-LoxP. L'expression du gène et de la protéine du (P)RR dans les tissus adipeux était augmentée chez les souris nourries avec une HFD indépendamment du traitement au HRP. Le traitement par le HRP a réduit le poids corporel et la masse adipeuse chez les souris nourries avec une HFD alors qu’une tendance pouvait être observée chez les souris sur diète normale (ND). De façon similaire, les souris (P)RR KO spécifiquement dans le tissu adipeux avaient une réduction du poids corporel et de la masse adipeuse, même sur ND, ce qui suggère fortement l'implication du (P)RR dans le tissu adipeux dans le développement de l'obésité. Le phénotype des souris KO incluait une augmentation de l'activité horizontale uniquement dans leur période active, ce qui pourrait contribuer à augmenter leur métabolisme énergétique et ainsi réduire leur poids corporel et leur masse adipeuse. De plus, les souris KO homozygotes mâles avaient un métabolisme de base plus élevé car nous avons observé une augmentation de la consommation d'oxygène et de la production de dioxyde de carbone pendant leur période active et de sommeil. Cette augmentation du métabolisme pourrait résulter, en partie, d'une augmentation de la thermogenèse comme en témoigne l’expression accrue du gène de brunissement, PRDM16, dans le tissu adipeux péri-rénale de souris mâles KO. Conformément à cela, des résultats récents provenant de notre laboratoire ont également démontré que le HRP pouvait induire du brunissement au niveau du tissu adipeux sous-cutanée 3. Chez les souris traitées avec le HRP, bien que la glycémie eût été similaire aux souris recevant le placebo, l'insuline plasmatique et le rapport insuline/glucose était plus faible indépendamment de la diète. De façon similaire, les souris (P)RR KO avaient une insulinémie et un taux de peptide C plus faibles par rapport aux souris contrôles, sans aucune différence dans les courbes de la glycémie au cours d'un test de tolérance au glucose par voie orale. Les niveaux d'insuline dans l’état basal et stimulé étaient significativement plus faibles chez les souris KO, sans aucune modification du contenu pancréatique en insuline et du ratio insuline/peptide-C, ceci indique donc qu’il n’y a pas eu d’altération du niveau du métabolisme pancréatique de l'insuline. L’augmentation de l'adiponectine plasmatique chez les souris KO pourrait, entre autres, contribuer à une meilleure sensibilité à l'insuline observée. De plus, dans les groupes traités aux HRP, nous avons observé une amélioration du profil d'expression des gènes des transporteurs de glucose GLUT1 et GLUT4, du TNF-alpha, MCP-1, F4/80 et de la leptine dans le tissu adipeux ce qui pourrait contribuer à la meilleure sensibilité à l'insuline. Comme une meilleure sensibilité à l'insuline a été observée chez la souris suite au blocage pharmacologique et à la suppression génétique du (P)RR, ceci suggère que le (P)RR est impliqué dans la régulation de l’homéostasie du glucose. De plus, un taux circulant réduit des triglycérides (TG) a été observé chez les souris traitées au HRP, alors que des niveaux inférieurs de TG ont été trouvés seulement dans les muscles squelettiques chez les souris KO. Ces modifications du métabolisme des lipides et des taux circulants d'adiponectine résultent probablement d'un tissu adipeux plus sain tel que révélé par nos analyses histologiques démontrant une réduction de la taille des adipocytes chez les souris KO et traitées au HRP 3. Nos résultats démontrent que le (P)RR, en particulier dans le tissu adipeux, est impliqué dans la régulation du poids corporel et de l'homéostasie du glucose probablement par la modulation de la morphologie et de la fonction des adipocytes. Le développement d'une nouvelle stratégie clinique axée sur le blocage du (P)RR pourrait aider à traiter l'obésité et ses pathologies associées telles la résistance à l'insuline et le diabète de type 2. / Obesity is a worldwide epidemic and increases the risk of developing type 2 diabetes and its complications. In obesity, adipose tissue secretes large amounts of hormones and cytokines that negatively regulate glucose and lipid metabolism, causing inflammation and insulin resistance. Obesity also increases the activity of both local (tissue-specific) and circulating renin-angiotensin system (RAS). Angiotensinogen is converted to angiotensin I by renin, whereas prorenin may only do so upon binding to the (pro)renin receptor [(P)RR] 1. This is thus the angiotensin-dependent (Ang-D) pathway of the (P)RR. The binding of renin and prorenin with the (P)RR also activates an angiotensin-independent pathway (Ang-ND), leading to intracellular signaling involving, for instance, the mitogen activated protein kinase (MAPK), the extracellular regulatory kinase ½ (Erk1/2), the promyelocytic leukemia zinc finger protein (PLZF) and tumor necrosis factor alpha (TNF-a) 1, 2. These can produce cell growth and proliferation, apoptosis and fibrosis 1, 2, and as such may contribute to tissue damage and complications associated with obesity. The beneficial effects of pharmacological blockade of the (P)RR include prevention of the development of cardiac and renal fibrosis, as well as of diabetes-associated nephropathy and retinopathy. However, effects of the (P)RR in adipose tissue have been poorly investigated. Hence, our objective was to study the role of the (P)RR in the development of obesity and insulin resistance by: 1) administering HRP (a (P)RR blocker peptide) to mice fed a high-fat diet (HFD), and 2) in knock-out (KO) mice with adipose tissue-specific (P)RR gene deletion, which were generated in our laboratory by cre-loxp technology. (P)RR gene and protein expression in adipose tissue were increased in mice fed a HFD independently of HRP treatment. HRP treatment also reduced mice body weight and fat masses in HFD-fed mice while they only tended to be lower in mice on normal diet (ND). Similarly, the adipose tissue specific (P)RR KO mice had reduced body weight and fat masses, even on ND, and as such confirmed the involvement of adipose tissue (P)RR in the development of obesity. The KO phenotype included increased horizontal activity, only in the dark cycle (active period), which would increase energy expenditure and could contribute to their lower body weight and fat mass. Male hemizygous KO mice had higher basal metabolic rate as they had increased oxygen consumption and carbon dioxide production during both their active and inactive period. This increased basal metabolism may result in part from an increase in thermogenesis as increased “beiging” gene expression, PRDM16, was observed in peri-renal fat of male KO mice. In line with this, recent results from our laboratory have also shown that HRP may induce “beiging” in subcutaneous fat 3. In mice treated with the HRP, although glycemia was similar to placebo treated mice, plasma insulin and the insulin to glucose ratio were lower compared to untreated groups on both HFD or ND. Similarly, (P)RR KO mice had lower plasma insulin and C-peptide levels compared to controls, without any differences in the glycemia curves during an oral glucose tolerance test. Given that the basal and stimulated insulin levels were significantly lower in KO mice, without any changes in total pancreatic insulin content and with similar insulin to C-peptide ratio, this suggests that pancreatic insulin metabolism was not modified. The increased circulating adiponectin levels observed in KO mice may have contributed to the better insulin sensitivity present in the mice. In the HRP treated mice, we observed an improved gene expression profile of glucose transporters GLUT1 and GLUT4, TNF-alpha, MCP-1, F4/80 and leptin in adipose tissue, which may also contribute to the increased insulin sensitivity. Given that better insulin sensitivity was observed in mice with both (P)RR pharmacological blockade and genetic suppression, this suggests that the (P)RR is involved in the regulation of glucose homeostasis. In addition, lower circulating triglycerides (TG) levels were found in mice treated with HRP, whereas lower TG levels were observed only in skeletal muscles in (P)RR KO mice. Put altogether, the lower lipid content and higher plasma adiponectin levels likely result from a healthier fat tissue as revealed by histological analysis which showed a reduction in adipocytes size in KO mice and was recently revealed in HRP treated HFD fed mice 3. Our results demonstrate that the (P)RR, particularly in adipose tissue, is implicated in the regulation of body weight and glucose homeostasis via modulation of adipocytes morphology and function. The development of a new clinical strategy focused on blockade of the (P)RR specifically in adipose tissue could help to treat obesity and its associated pathologies such as insulin resistance and type 2 diabetes.

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.