Adiponectin is an adipose-derived protein (adipocytokine) that is secreted by adipose tissue. It has insulin-sensitizing, anti-inflammatory and cardio-protective properties, and is thought to be protective against obesity-related diseases such as type 2 diabetes. Humans and cats are two species that commonly develop type 2 diabetes associated with insulin resistance, impaired beta cell function and spontaneous islet amyloid deposition. The domestic cat (Felis catus) has recently been proposed as an animal model for human type 2 diabetes. However, little is known about the physiology of adiponectin in cats. Therefore, we set out to investigate the association of adiponectin profiles with dietary carbohydrate intake, feeding, body weight, fat mass, and insulin sensitivity in healthy young adult cats (n=32; 2-4 years old; gender ratio 1:1; body condition 4-5/9). Cats were fed a moderate carbohydrate diet (37% ME) at maintenance energy requirements for four weeks. Cats were then assigned to either receive a low (19% ME) or high (52% ME) carbohydrate diet and fed at maintenance energy requirements for another four weeks, followed by ad-libitum feeding for eight weeks to facilitate weight gain. Adiponectin profiles including total circulating adiponectin and its distribution [low molecular weight (LMW) and high molecular weight (HMW) adiponectin], and proportion of adiponectin that is HMW (SA) were measured by ELISA and velocity sedimentation using sucrose gradients, followed by Western blotting, respectively. We demonstrated inter-animal variation in total adiponectin concentration at baseline (0.6 to 15.0 g/mL), with the adiponectin present in both LMW and HMW forms. Feeding with a high carbohydrate diet for four weeks at maintenance energy requirements resulted in increased total adiponectin concentration, which was associated with an increased concentration of LMW adiponectin. In contrast, feeding with a low carbohydrate diet for four weeks at maintenance energy requirements resulted in increased concentration of HMW adiponectin, decreased LMW adiponectin concentration, and increased SA, without a change in total adiponectin concentration. In cats fed the high carbohydrate diet, total adiponectin and HMW adiponectin concentrations become lower at six hours after feeding, as compared to the fasting concentrations. This phenomenon was not observed in cats fed a low carbohydrate diet, indicating a diet-dependent postprandial effect. There was no effect of gender on any of the adiponectin profiles in cats. Unlike other studies in humans and mice in which adiponectin concentrations decreased as fat mass increased, our data indicate that a moderate weight gain achieved by ad libitum feeding of a low carbohydrate diet for eight weeks correlated with increased adiponectin concentrations. Total adiponectin concentration (mirrored by HMW adiponectin) was positively correlated with body weight gain and fat mass gain (but not absolute fat mass) in our overweight cats. Furthermore, the fat mass-related increases in plasma adiponectin over eight weeks correlated with insulin sensitivity (higher adiponectin concentration corresponded to greater insulin sensitivity in overweight cats). These data hint at the possibility that in overweight animals, adiponectin is similar to other adipokines that rise concomitantly with increased of moderate fat mass gain and thus increases insulin sensitivity. Overall, the knowledge in this study therefore provides useful information to veterinarians and cat food manufacturers, and forms a foundation for future studies to extend our knowledge of adiponectin in cats. Data gathered in cats may also be applicable to humans and could therefore inform research using cats as an animal model of human obesity and type 2 diabetes.

<p>Insulin release from single islets of Langerhans is pulsatile. The secretory activities of the islets in the pancreas are coordinated resulting in plasma insulin oscillations. Nutrients amplitude-regulate the insulin pulses without influencing their frequency. Diabetic patients show an abnormal plasma insulin pattern, but the cause of the disturbance remains to be elucidated. Ithe present thesis the influence of the cytoplasmic calcium concentratio([Ca²⁺]_i) and cell metabolism on pulsatile insulin release was examined in single islets of Langerhans from <i>ob/ob</i>-mice. Glucose stimulation of insulin release involves closure of ATP-sensitive K⁺ channels (K_ATP channels), depolarization, and Ca²⁺ influx in β-cells. In the presence of 11 mM glucose, pulsatile insulin secretion occurs in synchrony with oscillations i[Ca²⁺]_i. When [Ca²⁺]_i is low and stable, e.g. under basal conditions, low amplitude insulin pulses are still observed. When [Ca²⁺]_i is elevated and non-oscillating, e.g. when the β-cells are depolarized by potassium, high amplitude insulin pulses are observed. The frequency of the insulin pulses under these conditions is similar to that observed when [Ca²⁺]_i oscillations are present. By permanently opening or closing the K_ATP channels with diazoxide or tolbutamide, respectively, it was investigated if glucose can modulate pulsatile insulin secretion when it does not influence the channel activity. Under these conditions, [Ca²⁺]_i remained stable whereas the amplitude of the insulin pulses increased with sugar stimulation without change in the frequency. Metabolic inhibition blunted but did not prevent the insulin pulses. The results indicate that oscillations in metabolism can generate pulsatile insulin release when [Ca²⁺]_i is stable. However, under physiological conditions, pulsatile secretion is driven by oscillations in metabolism and [Ca²⁺]_i, acting in synergy.</p>

<p>The aim of this thesis was to examine different approaches to support the self-care of persons with Type 2 diabetes, with special reference to practical, social, and sexual aspects of women's self-management. The methods to elucidate this comprised: evaluating a new model for diabetes patient education; designing a model to analyse the role of social networks in women's diabetes; conducting individual and focus group interviews for deeper understanding of the social and sexual aspects of diabetes; and collecting questionnaire data as a complement to the above.</p><p>The experience-based educational program led by pharmacists was found to improve participants' subjective control over diabetes and to provide important emotional support and encouragement to continue self-care. Metabolic control as measured by HbA_1c temporarily improved. The social network model elucidated potential mechanism leading to conflict of disease and social demands in women's diabetes. Qualitative analysis of the focus group interviews pointed to the role of guilt, shame, and social taboo in connection with the women's diabetes and sexuality.</p><p>Borderland is the metaphor I have chosen to describe the space between the traditional health care system and the everyday self-care of people with chronic disease. Using Borderland as a framework, a future model for diabetes management, anchored in our own and other's findings, is outlined and the concept of "Disease Manager Role" is introduced. The vision of a self-care support center in Borderland addresses such issues as accessibility, continuity, equitable provider-user relations, shared care plans, and strengthening social support.</p>

<p>Most human traits and common diseases have a complex genetic makeup involving more than one gene. The work presented in this thesis investigates standing body height and the common disease type 2 diabetes mellitus (T2DM). In study I we analyzed two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene that had been shown to be associated with T2DM. Analysis was performed in the ULSAM population cohort of ~1500 males. We were able to replicate the association to type 2 diabetes and in addition to that we made a novel find, showing association between the risk alleles and increased proinsulin levels. In study II we analyzed four genes identified to be associated with T2DM in a genome-wide association study. We analyzed SNPs in these genes in the ULSAM population cohort and found an association between SNPs in the HHEX gene and insulin responses and insulin levels. </p><p>The aim of studies III-V was to identify genes affecting normal variation in standing body height. Using a candidate gene approach in study III, 17 genes were screened in the ULSAM population cohort using SNPs. A suggestive association of the ESR1 gene with height was found and confirmed as significant in males from the PIVUS population cohort. In study IV, as a part of the GenomEUtwin project, we performed genetic fine mapping of a linked locus for body height on the X-chromosome. By analyzing 1377 SNPs in 780 Finnish twins, we mapped a region spanning 65kb of this locus with linkage to body height in males. This region contains the GPC3 and PHF6 genes that have known connections to syndromes were standing body height is affected. In study V significant linkage and association to standing body height in males was found for the COL1A11 gene, using population cohorts from Finland and Iceland. </p>

Übergewicht, Diabetes oder Fettstoffwechselstörungen sind mit erniedrigten Adiponectinspiegeln assoziiert. Eine Modulation des Adiponectins kann durch genetische und metabolische Gegebenheiten erfolgen. Das Ziel dieser Arbeit war die Analyse von Faktoren, welche die Adiponectinspiegel beeinflussen können, sowie eine Charakterisierung der Oligomerverteilung unter verschiedenen metabolischen Bedingungen. In der MeSyBePo-Kohorte waren die zirkulierenden Adiponectinspiegel mit den Promotorpolymorphismen ADIPOQ -11377 C/G und ADIPOQ -11391 G/A im Adiponectingen assoziiert. Im Hinblick auf die metabolischen Faktoren korrelierte Adiponectin eng mit Parametern des Glukose- und Fettstoffwechsels sowie dem Übergewicht. Innerhalb von hyperinsulinämischen euglykämischen Clamps führte eine akute Hyperinsulinämie zu einer Abnahme der Adiponectinspiegel. Adiponectin zirkuliert im Serum als hochmolekulare (HMW), mittelmolekulare (MMW) und niedrigmolekulare (LMW) Spezies. Mit zunehmendem Körpergewicht konnte eine Verlagerung von HMW-Spezies hin zu den LMW-Spezies beobachtet werden. Durch eine moderate Gewichtsabnahme erhöhten sich die Anteile an HMW- und MMW-Adiponectin wieder. Während sich in Abhängigkeit vom Glukosemetabolismus keine Unterschiede in den Gesamtspiegeln ergaben, wurden bei Personen mit normaler Glukosetoleranz signifikant höhere Anteile an MMW-Adiponectin detektiert als bei Personen mit einem gestörten Glukosestoffwechsel. Insgesamt scheinen die HMW- und MMW-Spezies gegensätzlich zur LMW-Spezies reguliert zu werden. Die Arbeit unterstreicht die wichtige Rolle des Adiponectins im Glukose- und Fettstoffwechsel sowie bei einer Adipositas in vivo. Dabei waren Änderungen der Adiponectinspiegel bei Vorliegen von Insulinresistenz und Adipositas stets mit einer Umverteilung der Oligomerfraktionen verbunden. Vor allem die HMW- und MMW-Spezies des Adiponectins scheinen von entscheidender Bedeutung zu sein. / Experimental data suggest that a dysregulation of adiponectin might be involved in the development of the metabolic syndrome. Adiponectin circulates as a variety of multimeric forms and its concentration was found to be decreased in obesity, type 2 diabetes mellitus, and dyslipidemia. Polymorphisms within the adiponectin gene, as well as the metabolic status, may modulate the adiponectin level. The aim of this work was to evaluate factors that may modulate total adiponectin levels as well as the distribution of its multimeric complexes under specific metabolic conditions. In the caucasian MeSyBePo population, serum adiponectin concentrations were associated with two promoter polymorphisms, ADIPOQ -11377 C/G and ADIPOQ -11391 G/A, respectively. Mean serum adiponectin levels were related to obesity, glucose metabolism, and lipid metabolism. Additionally, hyperinsulinemic euglycemic clamps acutely lowered serum adiponectin concentration. Adiponectin circulates in serum as low-, medium-, and high-molecular-weight complexes (LMW, MMW, and HMW, respectively). Adiponectin oligomer composition was related to BMI, with decreased HMW and MMW fractions in case of high BMI levels. According to this, HMW and MMW adiponectin increased after moderate weight reduction. While total adiponectin levels were comparable between patients with type 2 diabetes and control subjects, a reduction of MMW oligomers was observed in patients with impaired glucose metabolism. Finally, these studies all suggested a differential regulation of HMW and MMW species compared to the LMW fraction. The data presented underline the important role of adiponectin within the glucose- and lipid metabolism as well as in obesity. We showed that modulation of total adiponectin levels in case of insulin resistance or obesity are always accompanied with changes of adiponectin oligomer composition. Thereby the HMW and MMW species seem to play a crucial role in affecting metabolic changes.

Insulin release from single islets of Langerhans is pulsatile. The secretory activities of the islets in the pancreas are coordinated resulting in plasma insulin oscillations. Nutrients amplitude-regulate the insulin pulses without influencing their frequency. Diabetic patients show an abnormal plasma insulin pattern, but the cause of the disturbance remains to be elucidated. Ithe present thesis the influence of the cytoplasmic calcium concentratio([Ca2+]i) and cell metabolism on pulsatile insulin release was examined in single islets of Langerhans from ob/ob-mice. Glucose stimulation of insulin release involves closure of ATP-sensitive K+ channels (KATP channels), depolarization, and Ca2+ influx in β-cells. In the presence of 11 mM glucose, pulsatile insulin secretion occurs in synchrony with oscillations i[Ca2+]i. When [Ca2+]i is low and stable, e.g. under basal conditions, low amplitude insulin pulses are still observed. When [Ca2+]i is elevated and non-oscillating, e.g. when the β-cells are depolarized by potassium, high amplitude insulin pulses are observed. The frequency of the insulin pulses under these conditions is similar to that observed when [Ca2+]i oscillations are present. By permanently opening or closing the KATP channels with diazoxide or tolbutamide, respectively, it was investigated if glucose can modulate pulsatile insulin secretion when it does not influence the channel activity. Under these conditions, [Ca2+]i remained stable whereas the amplitude of the insulin pulses increased with sugar stimulation without change in the frequency. Metabolic inhibition blunted but did not prevent the insulin pulses. The results indicate that oscillations in metabolism can generate pulsatile insulin release when [Ca2+]i is stable. However, under physiological conditions, pulsatile secretion is driven by oscillations in metabolism and [Ca2+]i, acting in synergy.

The aim of this thesis was to examine different approaches to support the self-care of persons with Type 2 diabetes, with special reference to practical, social, and sexual aspects of women's self-management. The methods to elucidate this comprised: evaluating a new model for diabetes patient education; designing a model to analyse the role of social networks in women's diabetes; conducting individual and focus group interviews for deeper understanding of the social and sexual aspects of diabetes; and collecting questionnaire data as a complement to the above. The experience-based educational program led by pharmacists was found to improve participants' subjective control over diabetes and to provide important emotional support and encouragement to continue self-care. Metabolic control as measured by HbA1c temporarily improved. The social network model elucidated potential mechanism leading to conflict of disease and social demands in women's diabetes. Qualitative analysis of the focus group interviews pointed to the role of guilt, shame, and social taboo in connection with the women's diabetes and sexuality. Borderland is the metaphor I have chosen to describe the space between the traditional health care system and the everyday self-care of people with chronic disease. Using Borderland as a framework, a future model for diabetes management, anchored in our own and other's findings, is outlined and the concept of "Disease Manager Role" is introduced. The vision of a self-care support center in Borderland addresses such issues as accessibility, continuity, equitable provider-user relations, shared care plans, and strengthening social support.

Most human traits and common diseases have a complex genetic makeup involving more than one gene. The work presented in this thesis investigates standing body height and the common disease type 2 diabetes mellitus (T2DM). In study I we analyzed two single nucleotide polymorphisms (SNPs) in the TCF7L2 gene that had been shown to be associated with T2DM. Analysis was performed in the ULSAM population cohort of ~1500 males. We were able to replicate the association to type 2 diabetes and in addition to that we made a novel find, showing association between the risk alleles and increased proinsulin levels. In study II we analyzed four genes identified to be associated with T2DM in a genome-wide association study. We analyzed SNPs in these genes in the ULSAM population cohort and found an association between SNPs in the HHEX gene and insulin responses and insulin levels. The aim of studies III-V was to identify genes affecting normal variation in standing body height. Using a candidate gene approach in study III, 17 genes were screened in the ULSAM population cohort using SNPs. A suggestive association of the ESR1 gene with height was found and confirmed as significant in males from the PIVUS population cohort. In study IV, as a part of the GenomEUtwin project, we performed genetic fine mapping of a linked locus for body height on the X-chromosome. By analyzing 1377 SNPs in 780 Finnish twins, we mapped a region spanning 65kb of this locus with linkage to body height in males. This region contains the GPC3 and PHF6 genes that have known connections to syndromes were standing body height is affected. In study V significant linkage and association to standing body height in males was found for the COL1A11 gene, using population cohorts from Finland and Iceland.

Bakgrund Diabetes typ II är ett globalt och nationellt växande hälsoproblem. Lågkolhydratkost har väckt debatt i samhället, men har enligt studier resulterat i gynnsamma effekter för patientgruppen. Socialstyrelsen rekommenderar måttlig lågkolhydratkost som en av flera primära alternativ till kosthållning för patienter med diabetes typ II. Syfte Att undersöka diabetessjuksköterskors attityd och kunskap gällande lågkolhydratkost vid diabetes typ II. Metod Kvalitativa semi-strukturerade intervjuer med sju diabetessjuksköterskor inom Uppsalas primärvård. Resultat Diabetessjuksköterskorna hade observerat positiva effekter i sitt kliniska arbete av kolhydratreduktion, men ingen sjuksköterska gav måttlig lågkolhydratkost som rekommendation i första hand till patienterna. Farhågor för att lågkolhydratkost, främst orsakat av ett ökat fettintag, skulle kunna resultera i en ökning av risken för hjärt-kärlsjukdom eller andra negativa hälsoeffekter skildrades. Medvetenheten gällande kostrekommendationer och uppdateringen kring aktuell forskning varierade. Slutsats Medvetenhet och kunskap gällande lågkolhydratkost som kosthållning vid diabetes typ II varierade hos diabetessjuksköterskor inom Uppsalas primärvård. Generellt kunde en negativ attityd till lågkolhydratkost urskiljas. För att upprätthålla en evidensbaserad hälso- och sjukvård är det av största vikt att diabetessjuksköterskor får möjlighet att inom arbetsplatsen hålla sig uppdaterade om aktuella forskningsresultat samt att skapa reflektion kring vilken extern och intern påverkan sjuksköterskor kan exponeras för. / Background Diabetes type II is an increasing problem on a national and global scale. Low carbohydrate diets have created debate in today society, all though it has come to show positive effects in studies made on this patient group. In the national guidelines by The National Board of Health and Welfare moderate low-carbohydrate diet is described as a primary diet recommendation for patients with diabetes type II. Aim To investigate the attitude and knowledge of nursing staff towards low-carbohydrate diets as a method for patients with diabetes type II to achieve positive health benefits. Method Qualitative semi-structured interviews with seven nurses in district health centers in Uppsala, Sweden. Result The nursing staff had observed health benefits as a result from low-carbohydrate diets in their daily clinical work with patient suffering from diabetes type II, yet none of the nurses did suggest patients to eat according to this diet. Apprehensions that low-carbohydrate diets, and specifically the increased intake of fat, would contribute to an increased risk of heart disease or cause other harmful bodily effects over a long period of time were described. The awareness of national guidelines and recommendation did vary widely among the nurses. Conclusion Awareness and knowledge regarding a low carbohydrate diet when it comes to patients with diabetes type II ranged with the diabetic nurses in Uppsala Primary Care. Generally, a negative attitude towards low carbohydrate diet could be distinguished. To maintain an evidence-based health care, it is important that diabetes nurses have the opportunity to be updated of current research and to make reflections on what kind of external and internal influences nurses may be exposed to.

Seventeen Cree anti-diabetic herbal medicines and eight Traditional Chinese Medicines have been examined for their potential to cause interactions with drugs, which is considered as a major reason for adverse drug effects. Specifically, the effect of these natural health products was examined on major Phase I drug metabolism enzymes including cytochrome P450, human carboxylesterase-1 and flavin-containing monooxygenases. Several of these natural health products have the potential to cause adverse drug effect through the inhibition of major drug metabolism enzymes. The results indicated that 7 Cree medicines plant extracts inhibited CYP3A4 activity, and 3 of them have been proven to cause potent mechanism-based inactivation of CYP3A4. Seven of eight Traditional Chinese Medicines have been identified as strong CYP3A4 inhibitors; the ethanol extract of Goji has identified as a potent inhibitor for CYP2C9 and 2C19. Goji juice showed universal inhibitory effects on most of the tested enzymes except flavin-containing monooxygenases 3.