Le diabète de type 2, défini par une hyperglycémie chronique, résulte d'un déficit de la sécrétion d'insuline et d'une insulinorésistance. Durant le prédiabète qui précède la maladie, la cellule ß pancréatique est capable d'établir une hyperactivité sécrétoire compensatrice de l'insulinorésistance. Les NO synthases neuronales (nNOS) pancréatique et musculaire contrôlent respectivement la sécrétion d'insuline induite par le glucose dans la cellule ß et la force contractile, la captation et l'utilisation du glucose dans les myocytes. Dans le modèle génétique du rat obèse Zucker fa/fa mimant l'état prédiabétique associant un hyperinsulinisme et une insulinorésistance, nous avons retrouvé au niveau de la cellule ß une forte augmentation du complexe entre la nNOS et son inhibiteur endogène PIN (Protein Inhibitor of Neuronal NOS) au niveau des granules de sécrétion d'insuline. Ce complexe, grâce à une interaction accrue avec la myosine V, participe à l'hyperactivité sécrétoire de la cellule ß pancréatique. En effet, des molécules inhibant spécifiquement l'interaction nNOS-PIN permettent de rétablir, chez le rat fa/fa, une sécrétion d'insuline normale. Au niveau musculaire, nous avons observé, dans ce modèle animal, une diminution d'expression de la nNOS sans variation du taux d'ARNm, traduisant une protéolyse accrue de la protéine. L'inhibition de la dégradation protéasomale permet de restaurer l'expression et l'activité catalytique de la nNOS dans le muscle squelettique. Cette perte de fonctionnalité de l'enzyme participerait à l'installation de l'insulinorésistance. Ces travaux ont permis de valider la nNOS comme une cible potentielle pour la prévention du diabète de type 2. / Type 2 diabetes is a chronic disorder defined by chronic hyperglycemia resulting from a deficiency of insulin secretion and an insulin resistance in peripheral tissues and liver. A long lasting silent phase, called prediabetes, precedes the disease and in which pancreatic ß cell is able to improve insulin secretion to compensate for the insulin resistance. The pancreatic and muscular neuronal nitric oxide synthases (nNOS) control respectively glucose-induced insulin secretion in pancreatic ß cell and glucose uptake and utilization in myocytes. In the genetic model of obese Zucker fa/fa rat mimicking the prediabetic state characterized by hyperinsulinemia and insulin resistance, we found a high increase in the amount of the complex between nNOS and its endogenous inhibitor PIN (Protein Inhibitor of Neuronal NOS) at the level of insulin secretory granules within the ß cell. This complex, through an increased interaction with myosin V, participates in the secretory hyperactivity of the pancreatic ß cell, observed in this model of prediabetes. Indeed, molecules that specifically inhibit nNOS-PIN interaction allow to restore a normal insulin secretion in fa/fa rat. In skeletal muscle of this model, we observed a decreased expression of nNOS protein with no change in mRNA levels, suggesting an increased proteolysis of the protein. Inhibition of proteasomal degradation restores the expression and the catalytic activity of nNOS in skeletal muscle. Thus, this loss of functionality of the enzyme could participate in the installation of insulin resistance. This work therefore validated nNOS as a potential target for the prevention of type 2 diabetes.

Das Equine Metabolische Syndrom (EMS) beschreibt einen Cluster von metabolischen Störungen, die durch Adipositas, Insulinresistenz und Hufrehe im Zusammenhang stehen. Ziel dieser Arbeit war es, den Einfluss einer achtwöchigen oralen Supplementierung von Chrom, Metformin beziehungsweise von einer Kombination aus Chrom und Metformin auf die Insulinsensitivität und die Glukosetoleranz bei adipösen Pferden und Ponys zu untersuchen. Für diese Studie standen 24 Pferde und Ponys (14,4 ± 3,87 Jahre, 14 Stuten und 10 Wallache) mit Adipositas, Insulinresistenz und Hufrehe zur Verfügung. Während der achtwöchigen Versuchsphase bekamen die Tiere eine Heuration (1,5 kg Heu/100 kg Körpermasse (KM)) und zweimal täglich das ihnen zugewiesene Supplement (Chrom: 25 µg/kg KM, Metformin: 15 mg/kg KM, Chrom+Metformin: 25 µg/kg KM Chrom + 15 mg/kg KM Metformin in jeweils 25 g Grünmehl/100 kg KM) verabreicht. Eine vierte Gruppe erhielt als Placebo 25 g Grünmehl/100 kg KM ohne Supplement. Vor Versuchsbeginn und nach Versuchsende durchliefen die Pferde und Ponys, an zwei aufeinanderfolgenden Tagen, nach jeweils einer zwölfstündigen Fastenperiode einen kombinierten Glukose-Insulin-Toleranztest (KGIT) zur Bestimmung der Insulinsensitivität und einen oralen Glukose-Toleranz-Test (OGTT) zur Bestimmung der Glukoseabsorption und -toleranz. Im Verlauf des Versuchszeitraums konnte bei den Pferden ein durchschnittlicher Gewichtsverlust von 2,77 ± 2,99 % verzeichnet werden (Behandlung p > 0,05). Beim OGTT zeigte sich keine signifikante Veränderung der Glukose- und Insulinreaktionen zwischen Versuchsbeginn und Versuchsende. Die Seruminsulinmaximalwerte der mit Metformin und der mit Chrom+Metformin supplementierten Gruppen waren nach der Versuchszeit numerisch gesunken (Metformin Versuchsbeginn: 452 ± 642 µU/ml, Versuchsende: 202 ± 121 µU/ml; Chrom+Metformin Versuchsbeginn: 388 ± 347 µU/ml, Versuchsende: 342 ± 164 µU/ml, Behandlung p > 0,05). Im KGIT zeigten sich bei den Glukosewerten keine signifikanten Unterschiede zwischen den einzelnen Behandlungsgruppen und zwischen den Werten vor Versuchsbeginn und nach Versuchsende. Die Seruminsulinkonzentrationen lagen im KGIT vor Versuchsbeginn bei allen Probanden zum Zeitpunkt Minute 45 über 100 µU/ml. Somit gelten alle Versuchsteilnehmer per definitionem als insulinresistent. Nach den acht Wochen Supplementierung befanden sich beim KGIT zum Zeitpunkt Minute 45, mit Ausnahme eines Probanden aus der Chrom+Metformin-Gruppe, alle Seruminsulinwerte weiterhin >100 µU/ml. Somit sind die übrigen 23 Pferde und Ponys weiterhin als insulinresistent einzustufen. Weder Chrom, noch Metformin oder die Kombination von Chrom+Metformin konnte in den hier im Versuch angewandten Dosierungen die Insulinsensitivität und Glukosetoleranz der erkrankten Pferde und Ponys verbessern.:1 Einleitung 1 2 Literaturübersicht 2 2.1 Das Equine Metabolische Syndrom (EMS) 2 2.1.1 Definition 2 2.1.1.1 Adipositas 3 2.1.2 Diagnostische Methoden 6 2.1.3 Beeinflussung der Insulinresistenz und der Adipositas 12 3 Material und Methode 23 3.1 Versuchsziel 23 3.2 Versuchsaufbau 23 3.3 Vorversuch 23 3.4 Versuchstiere 24 3.5 Versuchsdurchführung 24 3.5.2 Fütterung 25 3.5.3 Gruppeneinteilung 26 3.5.4 Oraler Glukosetoleranztest vor und nach der Supplementierungsphase 26 3.5.5 Kombinierter Glukosetoleranztest vor und nach der Supplementierungsphase 27 3.5.6 Scoring 28 3.5.7 Wägung 29 3.6 Analysen 29 3.6.1 Vorversuch 29 3.6.2 Hauptversuch 30 3.7 Statistik 31 4 Ergebnisse 33 4.1 Einschlusskriterien 33 4.2 Hauptversuch 34 4.2.1 Gesundheitszustand der Pferde und Ponys 34 4.2.2 Gewichtsentwicklung der Pferde und Ponys 35 4.2.4 Blutparameter 36 5 Diskussion 54 5.1 Kritik der Methoden 54 5.2 Diskussion der Ergebnisse 58 5.2.1 Effekte der vier verschiedenen Supplementierungen auf die Insulinsensitivität 58 5.3 Abschließende Betrachtung 61 6 Zusammenfassung 63 7 Summary 65 8 Literaturverzeichnis 67 9 Anhang 79

In den vorliegenden Studien wurde der Fragestellung nachgegangen, wie sich unterschiedliche Fütterungsprotokolle während der Aufzuchtperiode auf den peripartalen Energie- und Fettstoffwechsel und die Insulinsensitivität von Färsen auswirken. Besonderes Augenmerk lag dabei auf der Frage, ob der „Revised Quantitative Insulin Sensitivity Check Index“ (RQUICKI) bei Färsen sinnvoll angewendet werden kann, um eine Aussage hinsichtlich der Insulinsensitivität zu treffen. Auch mögliche Auswirkungen auf das Konzeptionsalter, den Kalbeverlauf, die Milchleistung und die postpartale Morbidität wurden untersucht. Aus 46 Kälbern der Rasse Deutsche Holstein wurden drei Fütterungsgruppen gebildet. Gruppe 1 (n = 18) wurde gemäß den Richtlinien der GfE energetisch optimal gefüttert (Kontrollgruppe), Gruppe 2 (n = 14) wurde intensiv und Gruppe 3 (n = 14) restriktiv gefüttert. Im Abstand von zwei Wochen wurden die Tiere jeweils gewogen. Aus den vorliegenden Daten wurde die durchschnittliche tägliche Körpermassezunahme berechnet. Außerdem wurde zehn, sechs, drei und eine Woche vor der Kalbung sowie zwei Wochen nach der Kalbung die Rückenfettdicke (RFD) sonografisch bestimmt. Weiterhin wurden das Alter bei erfolgreicher Konzeption, Kalbeverlauf sowie Daten der Kälber, Milchleistungsprüfungsdaten und Rastzeit erfasst. Vor und nach der Kalbung wurde aus der Vena caudalis mediana Blut entnommen. Aus dem Serum wurden die Konzentrationen der folgenden Parameter bestimmt: Insulin, Insulin-like growth factor 1 (IGF-1), Glukose, freie Fettsäuren (FFS), Bilirubin, Cholesterol, Harnstoff, Betahydroxybutyrat (BHB) sowie Gesamteiweiß. Erkrankungen im postpartalen Zeitraum, wie Endometritis, Mastitis, Stoffwechselstörungen, Erkrankungen des Bewegungsapparates sowie Zyklusstörungen wurden ebenfalls in die Studien miteinbezogen. Zur Bestimmung der Insulinsensitivität wurde das Rechenmodell „Revised Quantitative Insulin Sensitivity Check Index“ (RQUICKI) verwendet. Unter Einbeziehung der Serumkonzentrationen von Glukose, Insulin und FFS lautete die Formel RQUICKI = 1/[log (Glukose) + log (Insulin) + log (FFS)]. Ein niedriger Index-Wert bedeutet eine verminderte Insulinsensitivität. Die intensiv aufgezogenen Tiere der Gruppe 2 zeigten mit 13,3 ± 1,0 Monaten ein signifikant (p = 0,003) früheres Konzeptionsalter im Gegensatz zu den Tieren der beiden anderen Gruppen (Gruppe 1: 16,0 ± 1,5 Monate; Gruppe 3: 17,7 ± 1,4 Monate). Eine Woche ante partum wiesen die Tiere der Gruppe 2 eine signifikant (p = 0,022) höhere RFD auf als die Tiere der beiden anderen Gruppen. Der RQUICKI korrelierte eine Woche ante partum signifikant negativ mit der RFD (r = -0,573; p = 0,003). RQUICKI war bei den Tieren der Gruppe 2 eine Woche ante partum signifikant (p < 0,05) niedriger als bei den Tieren der anderen Gruppen. In allen drei Gruppen konnten am dritten Tag post partum die niedrigsten Index-Werte nachgewiesen werden. Aus den errechneten Index-Werten lässt sich für Färsen für die Zeitpunkte eine Woche ante partum sowie vier Wochen post partum ein Referenzbereich von RQUICKI = 0,40 ± 0,04 ableiten. Um den dritten Laktationstag liegt bei Färsen der Referenzbereich von RQUICKI = 0,34 ± 0,02. Die intensiv aufgezogenen Färsen zeigten insgesamt mit 85,7 % die höchste Anzahl an Komplikationen bei der Kalbung, der Unterschied war statistisch allerdings nicht zu sichern. Die unterschiedliche Fütterung wirkte sich weder auf das Geschlecht der Kälber noch auf deren Geburtsgewicht aus. Signifikante Unterschiede (p < 0,05) ergaben sich bei den Serumkonzentrationen von Insulin, IGF-1, FFS und Cholesterol ante partum sowie den Bilirubin- und FFS-Konzentrationen 28 Tage post partum. Es konnten keine statistisch signifikanten Unterschiede bei den Konzentrationen von Glukose, Harnstoff, BHB und Totalprotein ermittelt werden (p > 0,05). Beim Vergleich der 305-Tage-Milchleistung wiesen die Tiere der Gruppe 2 die niedrigste Milchleistung auf. Eine signifikant (p = 0,039) höhere Inzidenz von postpartalen Zyklusstörungen war bei den Tieren der Gruppe 2 erkennbar. Eine Woche ante partum korrelierte RQUICKI signifikant negativ (r = -0,509, p = 0,008) mit dem Auftreten von Zyklusstörungen post partum. Die Untersuchungen haben gezeigt, dass durch die Fütterungsintensität während der Aufzuchtperiode die Zuchtreife, der peripartale Energie- und Fettstoffwechsel einschließlich der Insulinsensitivität, die Milchleistung sowie die postpartale Fertilität beeinflusst werden. Aus der intensiven Aufzucht resultieren eine frühere Zuchtreife, höhere Rückenfettdicken, eine gesteigerte peripartale Lipolyse einschließlich reduzierter Insulinsensitivität, eine verminderte Milchleistung und eine schlechtere Fertilität. / The aim of these studies was to investigate how different diets during the rearing period influence peripartal energy and fat metabolism as well as insulin sensitivity of heifers. Special attention was paid to the question if the „Revised Quantitative Insulin Sensitivity Check Index“ (RQUICKI) could be used to estimate insulin sensitivity in heifers. Possible influences on age at first breeding, calving, milk yield and postpartal morbidity were analysed as well. Furthermore, the aim of this investigation was to prove, if different diets at rearing influence the peripartal insulin sensitivity of heifers. 46 German Holstein calves were randomly divided in three groups. Group 1 (n = 18) was fed with an optimal diet (control group) based on recommendations of the German Society of Nutrition Physiology, group 2 (n = 14) was fed with a highly-concentrated diet and group 3 (n = 14) got a low-concentrated diet. In intervals of two weeks the heifers were weighed. With the obtained data the averaged daily weight gain was computed. In addition, ten, six, three and one week ante partum as well as two weeks post partum the backfat thickness (BFT) was measured ultrasonographically. Age at first breeding, calving, data of the calves, milk yield and interval to first service post partum were recorded, too. Before and after calving blood samples were taken from the Vena caudalis mediana. The concentrations of the following parameters were measured in blood serum: Insulin, insulin-like growth factor 1 (IGF-1), glucose, free fatty acids (FFA), bilirubin, cholesterol, urea, betahydroxybutyrat (BHB) as well as total protein. Furthermore, postpartal diseases like endometritis, mastitis, metabolic disorders, limb diseases and fertility disorders were included. To determine insulin sensitivity a mathematic model called “Revised Quantitative Insulin Sensitivity Check Index” (RQUICKI) was used. Serum concentrations of glucose, insulin and FFA were included in the formula RQUICKI = 1/[log (glucose) + log (insulin) + log (FFA)]. A low index value represents a decreased insulin sensitivity. Intensive reared heifers of group 2 reached age at first breeding (13.3 ± 1.0 months) significant (p = 0.003) earlier than heifers of the other both groups (group 1: 16.6 ± 1.5 months; group 3: 17.7 ± 1.4 months). One week ante partum heifers of group 2 showed significant (p = 0.022) higher BFT than heifers of the other groups. At the same timepoint, RQUICKI correlated significant negative with the BFT (r = -0.573; p = 0.003). In heifers of group 2, RQUICKI was significant lower (p < 0.05) one week ante partum than in heifers of the other groups. In all groups, the index values were lowest three days post partum. Based on the received index values reference ranges for RQUICKI in heifers can be proposed. One week ante partum as well as four weeks post partum the reference range for RQUICKI can be defined as RQUICKI = 0.40 ± 0.04. Three days after calving the reference range can be defined as RQUICKI = 0.34 ± 0.02. The intensive reared heifers show with an overall of 85.7 % the most difficulties at calving, but this was statistically not different. The different diets didn’t influence neither the sex of the calves nor their birth weight. Ante partum, serum concentrations of Insulin, IGF-1, FFA and cholesterol differed significantly (p < 0.05) as well as serum concentrations of bilirubin and FFA differed on day 28 post partum. No significant differences could be determined in serum concentrations of glucose, urea, BHB and total protein (p > 0.05). Heifers of group 2 showed the lowest 305-day milk yield. The incidence of postpartal ovarian diseases was significantly (p = 0.039) higher in heifers of group 2. A significant negative correlation (r = -0.509, p = 0.008) existed between RQUICKI ante partum and the incidence of postpartal ovarian diseases. In conclusion, different diets during the rearing period influence age at first breeding, peripartal energy and fat metabolism including insulin sensitivity, milk yield as well as postpartal fertility. An intensive rearing results in an earlier age at first breeding, increased BFT, enhanced peripartal lipolysis as well as reduced insulin sensitivity, decreased milk yield and poorer fertility.

As the prevalence of vitamin D deficiency continues to grow, mounting evidence supporting its link with chronic disease strengthens suggesting vitamin D’s candidacy in the prevention and treatment of multiple disease states and their complications. Dietary guidelines, however, do not take sun exposure into account. The present study sought to explore the impact of sun exposure on vitamin D status (serum 25(OH)D), and identify other significant determinants of serum levels which may have the greatest effects on overall health. Participants (n = 34) were pre-menopausal women aged 18 to 50 years (mean age 39 ± 6 years), who had their blood drawn at a local pathology lab and a follow-up appointment at a health assessment lab for the collection of other measurements. Mean serum 25(OH)D level was 64 ± 18 nmol/L, and mean dietary vitamin D intake was approximately 327 ± 229 IU/day. Although 82% of participants were below the RDA guidelines (600 IU/day for females ages 9-50 years) for dietary vitamin D intake, only 32% had serum 25(OH)D levels < 50 nmol/L (the recommended level of sufficiency for bone health) reflecting deficiency. While serum 25(OH)D levels were significantly correlated to dietary vitamin D intake (r = 0.42, p = 0.0139), it is reasonable to assume that participants obtained adequate vitamin D from sun exposure. Fasting serum insulin levels were significantly, positively correlated with BMI (r = 0.83, p < 0.0001), and sun exposure index (Body Surface Area x Minutes of Direct Sunlight) was significantly, positively correlated with serum 25(OH)D levels (fall weekend SEI: r = 0.47, p = 0.0059; spring weekend SEI: r = 0.43, p = 0.0135; average weekend SEI: r = 0.43, p = 0.013; and average overall SEI: r = 0.39, p = 0.0247). Reported sun exposure appeared to be least during winter weekdays and the most during summer weekends. Regression analysis was used to determine the strongest predictors of serum 25(OH)D levels, which were found to be sun exposure, dietary vitamin D intake, skin reflectance, age, BMI, and ethnicity (R2 = 0.58 , p = 0.0031), demonstrating that simple questionnaires, such as those employed in this study, can help to predict serum 25(OH)D status and thus be considered in the future treatment of vitamin D deficiency.

Background and Aims: During positive energy balance, excess lipid storage in subcutaneous adipose tissue (SAT) is associated with increased lipolysis. Elevated circulating fatty acid (FA) concentrations from both SAT lipolysis and dietary fat intake may result in visceral adipose tissue (VAT) accumulation, impairment of glucose metabolism, altogether increasing obesity-associated metabolic risks. We aimed to test the hypothesis that FA composition of red blood cell total phospholipids (RBC-TPL) and SAT is associated with body fat centralisation (VAT/SAT ratio) and insulin sensitivity (SI) in black South African women with obesity. Methods: Participants’ (n = 41) body fat composition and distribution, SI, and RBC-TPL, abdominal and gluteal SAT (gSAT) FA composition (gas-liquid chromatography) were measured. Results: RBC-TPL contained higher proportions of saturated fatty acids (SFAs) than SAT (p < 0.001), which were associated with lower SI (p < 0.05). Mono-unsaturated fatty acids (MUFAs) and stearoyl-CoA desaturase-1 (SCD1)-16 were lower, while poly-unsaturated fatty acids (PUFAs), and delta-5 and delta-6 desaturase indices were higher in RBC-TPL than SAT (p < 0.001). Interestingly, FA profiles differed between SAT depots with higher SFAs and lower MUFAs, SCD1-16 and SCD1-18 indices in abdominal compared to gluteal SAT (p < 0.01). In both SAT depots, higher SFAs and lower PUFAs (n-3 and n-6) correlated with lower VAT/SAT ratio; and lower PUFAs (n-3 and n-6) and higher total MUFA correlated with higher SI. Conclusion: Our findings confirm the relationships between the FA composition of RBC-TPL and SAT and metabolic risk in black women with obesity, which are dependent on both the FA class, and the tissue type/blood compartment in which they are distributed.

Mutations in the insulin-like growth factor-I (IGF-I) receptor (IGF1R) have been associated with prenatal and postnatal growth retardation. However, little is known about potential effects of mutations in the IGF1R on carbohydrate homeostasis. Methods: We investigated clinical, endocrine and metabolic parameters in four family members carrying a novel IGF1R mutation (p.Tyr387X): an 18-year-old male (index case), his sister and two paternal aunts. Results: All family members showed a variable degree of impairment in prenatal growth, with birth weight standard deviation scores (SDS) between –1.65 and –2.37 and birth length SDS between –1.78 and –3.08. Their postnatal growth was also impaired, with height SDS between –1.75 and –4.86. The index case presented high IGF-I levels during childhood and adolescence and delayed bone age. The index case and his two paternal aunts had impaired glucose tolerance (IGT) associated with a variable degree of alterations in insulin sensitivity and secretion. In contrast, the index case’s sister, who had had IGT during pregnancy, showed normal glucose metabolism but reduced insulin sensitivity. Conclusion: This is the first study showing an association between a novel IGF1R mutation and a variable degree of alterations in prenatal and postnatal growth and in carbohydrate metabolism.

<p>The development of the metabolic syndrome (MetS) and cardiovascular diseases have been suggested to be influenced more by the quality than the amount of dietary fat. The FA composition of serum lipids may be used as biomarkers of dietary fat quality. FAs can, however, also be endogenously synthesized by lipogenic enzymes such as elongases and desaturases. Three desaturases are important in humans: Stearoyl-CoA-desaturase (SCD), ∆6-desaturase (D6D) and ∆5-desaturase (D5D) and surrogate measures of desaturase activities can be estimated as product-to-precursor FA ratios.</p><p>In this thesis, we demonstrated that high SCD, D6D and low D5D estimated activities predicted MetS 20 years later, as well as cardiovascular and total mortality during a maximum of 33.7 years. The relation between D5D and MetS was independent of lifestyle and BMI, while the relation between SCD, D6D and MetS was confounded by BMI. Serum proportions of palmitic (16:0), palmitoleic (16:1) and dihomo-γ-linoleic acids were higher and the serum proportion of linoleic acid (LA) lower at baseline in those individuals who developed MetS. Further, LA was inversely related to mortality, while palmitic, palmitoleic and dihomo-γ-linoleic acids were directly associated with mortality. We also demonstrated that a diet rich in saturated fat “induced” a similar serum FA pattern (including estimated desaturase activities) that was associated with MetS, cardiovascular disease and mortality. We also propose that the SCD ratio [16:1/16:0] might be a novel and useful marker of dietary saturated fat, at least in Western high-fat diets. Finally, genetic variations in the human SCD1 gene were linked to obesity and insulin sensitivity, results that agree with data in SCD1 deficient mice.</p><p>This thesis suggests that dietary fat quality and endogenous desaturation may play a role in the development of metabolic and cardiovascular diseases and the results support current dietary guidelines.</p>

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

The development of the metabolic syndrome (MetS) and cardiovascular diseases have been suggested to be influenced more by the quality than the amount of dietary fat. The FA composition of serum lipids may be used as biomarkers of dietary fat quality. FAs can, however, also be endogenously synthesized by lipogenic enzymes such as elongases and desaturases. Three desaturases are important in humans: Stearoyl-CoA-desaturase (SCD), ∆6-desaturase (D6D) and ∆5-desaturase (D5D) and surrogate measures of desaturase activities can be estimated as product-to-precursor FA ratios. In this thesis, we demonstrated that high SCD, D6D and low D5D estimated activities predicted MetS 20 years later, as well as cardiovascular and total mortality during a maximum of 33.7 years. The relation between D5D and MetS was independent of lifestyle and BMI, while the relation between SCD, D6D and MetS was confounded by BMI. Serum proportions of palmitic (16:0), palmitoleic (16:1) and dihomo-γ-linoleic acids were higher and the serum proportion of linoleic acid (LA) lower at baseline in those individuals who developed MetS. Further, LA was inversely related to mortality, while palmitic, palmitoleic and dihomo-γ-linoleic acids were directly associated with mortality. We also demonstrated that a diet rich in saturated fat “induced” a similar serum FA pattern (including estimated desaturase activities) that was associated with MetS, cardiovascular disease and mortality. We also propose that the SCD ratio [16:1/16:0] might be a novel and useful marker of dietary saturated fat, at least in Western high-fat diets. Finally, genetic variations in the human SCD1 gene were linked to obesity and insulin sensitivity, results that agree with data in SCD1 deficient mice. This thesis suggests that dietary fat quality and endogenous desaturation may play a role in the development of metabolic and cardiovascular diseases and the results support current dietary guidelines.

No description available.