Studies on microcirculation in insulin resistance

The overall aim of this thesis was to investigate the microcirculation in insulin resistance, with focus on the expression of endothelin-1, through a translational approach. Specific aims: 1) Investigate if circulating endothelin-1 levels predicts incident coronary heart disease events. 2) To assess if sex differences modify endothelin-1 as a predictor of type 2 diabetes. 3) To investigate if microvascular insulin resistance impairs insulin delivery to the subcutaneous adipose tissue and skeletal muscle. 4) To investigate if acute administration of the PDE-5 inhibitor tadalafil induces positive vascular, metabolic and anti-inflammatory effects in type 2 diabetes. 5) To further elucidate the molecular action of tadalafil in tumour necrosis factor-α (TNF-α) stimulated human endothelial cells. Principal findings: The population-based cohort in Vara-Skövde was investigated for paper I-II. During baseline cardiovascular risk factors and endothelin-1 were assessed and incident coronary heart disease (CHD) was followed-up during a 10-year period (paper I). Endothelin-1 levels had a predictive value for incident CHD in women, but not in men. A randomly selected subgroup was investigated in a follow-up after 10 years, and impaired glucose tolerance (IGT) and T2D was documented for paper II. Here, higher quartiles of endothelin-1 at baseline were associated with IGT/T2D at follow-up in women. Paper III investigates microvascular aspects of insulin resistance using microdialyis; participants with T2D and age-matched healthy controls were studied after an oral glucose load. Participants with T2D had decreased delivery of insulin to adipose tissue, and a blunted subcutaneous adipose tissue blood flow compared with controls. In paper IV, T2D participants received either placebo or tadalafil (20 mg) before a mixed meal in a randomized controlled trial. Tadalafil increased forearm blood flow, glucose uptake and capillary recruitment, and blunted a postprandial increase of endothelin-1. In paper V, the effects of tadalafil were studied in an experimental setting using TNF-α stimulated endothelial cells. Tadalafil treatment decreased expression of c-Jun N-terminal kinase (JNK) phosphorylation as well as reduced gene expression and secretion of endothelin-1. Conclusions: This thesis shows that (i) endothelial dysfunction precedes IGT/T2D and CHD, and that endothelin-1 may pose as a risk factor for women, (ii) delivery of insulin from the circulation to subcutaneous adipose tissue is impaired in participants with T2D, and that participants with T2D exhibit a blunted postprandial blood flow response, (iii) acute administration of tadalafil induces positive vascular and metabolic effects in the postprandial state in T2D, and tadalafil decrease gene expression of endothelin-1 in cultured endothelial cells by decreasing activation of JNK

Bayesiansk flernivåanalys för att undersöka variationen i elevers trygghet i skolan : En studie baserad på enkäten Om mig

According to chapter 5, section 3 of the Swedish School Law (2010: 800), it is written that "The education should be designed in such a way that all pupils are assured of a school environment characterized by safety and education". Today's school students are our future and it is therefore important to analyze puplis’ safety at school. This study investigates whether there is variation between schools, between municipalities and between schools within municipalities in Östergötland regarding pupils' safety at school. This study also investigates which variables that can affect school safety. The reason for this study is to provide a basis for further work to improve puplis’ school safety. The study is based on survey responses from the survey Om mig, which was sent to secondary grade in elementary school and grade 2 in upper secondary school. Data is divided into three parts, where respondents from primary school are in one, respondents from upper secondary school in one and finally one data for the whole of Östergötland, which contains both respondents for elementary school and upper secondary school. The response variable is the question How often do you feel safe at school?, Where students could answer, Always, Often, Sometimes, Rarely or Never. The explanatory variables are variables related to the school and to the student's health, such as trustworthy friend, bullying, stress, support and help developing. In Bilaga1, all of the variables examined are described. This study uses a multilevel logistic regression. Parameters are estimated using Bayesian inferences with noninformative prior distributions. The response variable is converted to a binary variable, where Always and Often was merged, and Sometimes, Rarely and Never was merged. The result showed that there is a small variation in puplis’ safety at school between schools, between municipalities and between schools within municipalities for primary school, upper secondary school and the whole of Östergötland. It was also investigated which variables affect school safety, it proved to be very similar between elementary school and upper secondary school, including bullying, how often students experience good mood at school, and if the students feel that they are treated equally by the teachers have an effect on the puplis’ safety at school.Enligt 5 kapitlet 3 § i skollagen (2010:800) står det skrivet att ”Utbildningen ska utformas på ett sådant sätt att alla elever tillförsäkras en skolmiljö som präglas av trygghet och studiero”. Dagens skolelever är vår framtid och det är därför viktigt att analysera elevers trygghet i skolan. Denna studie undersöker om det finns variation mellan skolor, mellan kommuner samt mellan skolor inom kommuner i Östergötland vad gäller elevers trygghet i skolan. Studien undersöker även vilka variabler som kan ha effekt på tryggheten i skolan. Anledning till att denna studie genomförs är för att ha ett underlag i fortsatt arbete för att förbättra tryggheten i skolan. Studien bygger på enkätsvar från enkäten Om mig, som skickas ut till årskurs 8 i grundskolan samt årskurs 2 på gymnasiet. Datamaterialet är uppdelat i tre delar, där respondenter från grundskolan finns i ett, respondenter från gymnasiet i ett och till sist ett datamaterial för hela Östergötland som innehåller båderespondenter från grundskolan och gymnasieskolan. Responsvariabeln är frågan Hur ofta känner du dig trygg i skolan?, där eleverna kunde svara, Alltid, Ofta, Ibland, Sällan eller Aldrig. Förklaringsvariablerna är variabler som är relaterade till skolan och till elevens hälsa, till exempelpålitlig vän, mobbning, stress, stöd och hjälp att utvecklas. I bilaga 1 finns samtliga undersökta variabler beskrivna. Studien använder sig av en logistisk regression med flera nivåer. Parametrarna skattas med hjälp av Bayesiansk inferens med icke-informativa priorfördelningar. Responsvariabeln kodas om till en binärvariabel, där Alltid och Ofta slås ihop samt Ibland, Sällan och Aldrig slås ihop. Resultatet visade att det finns en liten variation i trygghet mellan skolor, mellan kommuner och mellan skolor inom kommuner, för grundskolan, gymnasiet och för hela Östergötland. Det undersökts även vilka variabler som har effekt på tryggheten i skolan, det visade sig vara väldigt lika mellan grundskolan och gymnasiet där bland annat mobbning, hur ofta eleverna upplever bra stämning i skolan samt om eleverna upplever att de blir rättvist behandlade av lärarna har en effekt på tryggheten i skolan

Endothelin-1 as a predictor of impaired glucose tolerance and type 2 diabetes - A longitudinal study in the Vara-Skövde Cohort

We addressed whether endothelin-1, a marker of endothelial dysfunction, predicts impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in a population study in south-western Sweden. Follow-up after 9.7 years showed an association between circulating endothelin-1 levels at baseline and development of IGT/T2DM in women but not in men

Circulating concentrations of endothelin-1 predict coronary heart disease in women but not in men: a longitudinal observational study in the Vara-Skövde Cohort.

The vasoconstricting peptide endothelin-1 has been proposed to be a marker of cardiovascular disease. Our aim was to investigate whether circulating endothelin-1 levels predict coronary heart disease (CHD) in Sweden

S1 Data -

(XLSX)</p

Gene expression of PAI-1 in subcutaneous adipose tissue of lean, obese and T2D normalized against LRP10.

ANOVA with Bonferroni’s multiple comparisons test. N = 6 for all groups. Abb. PAI-1: Plasminogen Activator Inhibitor -1; T2D: type 2 diabetes.</p

Gene expression levels of PAI-1 in A. platelets compared with reference genes and B. in subcutaneous adipose tissue compared with reference genes.

There were no significant differences in gene expression levels of PAI-1 in platelets between participants with T2D, obese and lean control subjects (T2D n = 6, obese n = 7 and lean control subjects n = 7)(A.). There was a significant difference in gene expression levels of PAI-1 in subcutaneous adipose tissue between lean control subjects and T2D or obese non-diabetic control subjects (T2D n = 7, obese n = 6 and lean control subjects n = 6) * P = 0.003, ** P = 0.038 (B.). Abb. PAI-1: Plasminogen Activator Inhibitor -1; T2D: type 2 diabetes.</p

Platelets in T2D patients compared with obese and lean control subjects.

Platelets in T2D patients compared with obese and lean control subjects.</p

Pool of PAI-1 in A. plasma, B. serum and C. platelets in T2D patients, lean and control participants.

There was a significant increase of plasma PAI-1 in participants with T2D and obese non-diabetic control subjects compared with lean control subjects (T2D n = 6, obese n = 7 and lean control subjects n = 8). * P˂0.001, ** P˂0.001. B. No significant difference in serum PAI-1 between the three groups (T2D n = 6, obese n = 7 and lean control subjects n = 8). C. There was no significant difference in platelet PAI-1 between the three groups (T2D n = 4, obese n = 5 and lean control subjects n = 8). Abb. PAI-1 = plasminogen activator inhibitor -1; T2D = type 2 diabetes.</p