Dramatic increase in serum trypsinogens, SPINK1 and hCG beta in aortic surgery patients after hypothermic circulatory arrest

The concentrations of several diagnostic markers have been found to increase dramatically in critically ill patients with a severe disturbance of normal physiological homeostasis, without indication of the diseases they are normally associated with. To prevent false diagnoses and inappropriate treatments of critically ill patients, it is important that the markers aiding the selection of second-line treatments are evaluated in such patients and not only in the healthy population and patients with diseases the markers are associated with. The levels of trypsinogen isoenzymes, the trypsin inhibitor serine peptidase inhibitor Kazal type 1 (SPINK1), hCG and hCG beta, which are used as pancreatitis and cancer markers, were analyzed by immunoassays from serum samples of 17 adult patients who have undergone surgery of the ascending aorta during hypothermic circulatory arrest (HCA) with optional selective cerebral perfusion. Highly elevated levels of trypsinogen-1, -2 and -3, SPINK1 and hCG beta were observed in patients after HCA. This was accompanied by increased concentrations of S100 beta and NSE. In conclusion, this study highlights the importance of critically evaluating the markers used for aiding selection of second line of treatments in critically ill patients.Peer reviewe

Palmitate and oleate exert differential effects on insulin signalling and glucose uptake in human skeletal muscle cells

Saturated fatty acids are implicated in the development of insulin resistance, whereas unsaturated fatty acids may have a protective effect on metabolism. We tested in primary human myotubes if insulin resistance induced by saturated fatty acid palmitate can be ameliorated by concomitant exposure to unsaturated fatty acid oleate. Primary human myotubes were pretreated with palmitate, oleate or their combination for 12 h. Glucose uptake was determined by intracellular accumulation of [H-3]-2-deoxy-d-glucose, insulin signalling and activation of endoplasmic reticulum (ER) stress by Western blotting, and mitochondrial reactive oxygen species (ROS) production by fluorescent dye MitoSOX. Exposure of primary human myotubes to palmitate impaired insulin-stimulated Akt-Ser(473), AS160 and GSK-3 beta phosphorylation, induced ER stress signalling target PERK and stress kinase JNK 54 kDa isoform. These effects were virtually abolished by concomitant exposure of palmitate-treated myotubes to oleate. However, an exposure to palmitate, oleate or their combination reduced insulin-stimulated glucose uptake. This was associated with increased mitochondrial ROS production in palmitate-treated myotubes co-incubated with oleate, and was alleviated by antioxidants MitoTempo and Tempol. Thus, metabolic and intracellular signalling events diverge in myotubes treated with palmitate and oleate. Exposure of human myotubes to excess fatty acids increases ROS production and induces insulin resistance.Peer reviewe

Skeletal muscle proteomes reveal downregulation of mitochondrial proteins in transition from prediabetes into type 2 diabetes

Skeletal muscle insulin resistance is a central defect in the pathogenesis of type 2 diabetes (T2D). Here, we analyzed skeletal muscle proteome in 148 vastus lateralis muscle biopsies obtained from men covering all glucose tolerance phenotypes: normal, impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and T2D. Skeletal muscle proteome was analyzed by a sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics technique. Our data indicate a downregulation in several proteins involved inmitochondrial electron transport or respiratory chain complex assembly already in IFG and IGT-muscles, with most profound decreases observed in T2D. Additional phosphoproteomic analysis reveals altered phosphorylation in several signaling pathways in IFG, IGT, and T2D muscles, including those regulating glucose metabolic processes, and the structure of muscle cells. These data reveal several alterations present in skeletalmuscle already in prediabetes and highlight impairedmitochondrial energy metabolism in the trajectory from prediabetes into T2D.Peer reviewe

Metabolic milieu associates with impaired skeletal characteristics in obesity

High leptin concentration, low-grade inflammation, and insulin resistance often coexist in obese subjects; this adverse metabolic milieu may be the main culprit for increased fracture risk and impaired bone quality seen in patients with type 2 diabetes. We examined the associations of leptin, hs (high sensitivity)-CRP and insulin resistance with bone turnover markers (BTMs) and bone characteristics in 55 young obese adults (median BMI 40 kg/m(2)) and 65 non-obese controls. Mean age of the subjects was 19.5 +/- 2.5 years (mean +/- SD). Concentrations of leptin, adiponectin, hs-CRP, MMP-8 and TIMP-1, fasting plasma glucose and insulin (to calculate HOMA), BTMs (BAP, P1NP, CTX-1, and TRAC5b) were measured. Bone characteristics were determined with pQCT at radius and tibia, and with DXA for central sites. Leptin, hs-CRP and HOMA correlated inversely with BTMs: the partial coefficients were 1.5-1.9 fold higher in males than in females. After adjusting for age, BMI, and other endocrine factors, leptin displayed an independent effect in males on radial bone mass (p = 0.019), tibial trabecular density (p = 0.025) and total hip BMD (p = 0.043), with lower densities in males with high leptin. In females, the model adjusting for age, BMI, and other endocrine factors, revealed that hs-CRP had independent effects on radial bone mass (p = 0.034) and lumbar spine BMD (p = 0.016), women with high hs-CRP having lower values. Partial correlations of adiponectin and TIMP-1 with bone characteristics were discrepant; MMP-8 showed no associations. In conclusion, in young obese adults and their controls, leptin, hs-CRP and HOMA associate inversely with BTMs and bone characteristics. Leptin appears to be the key independent effector in males, whereas hs-CRP displayed a predominant role in females.Peer reviewe

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias. Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.Peer reviewe

Perustulon työllisyysvaikutukset : Asiantuntijahaastatteluihin ja verrannollisiin esimerkkeihin perustuva arvio

Perustuloon kohdistuu suuria odotuksia työllisyyden, työhön kannustamisen ja työn vastaanottamisen sekä työvoiman kysynnän ja tarjonnan suhteen. Hyötyvätkö perustulosta pienituloiset, työttömät, epävakaissa työsuhteissa työskentelevät, mikroyrittäjät vai palvelualojen työnantajat ja kolmannen sektorin toimijat? Koska perustulosta ei ole konkreettisia esimerkkejä tai empiirisiä tuloksia, ei näihin kysymyksiin ole myöskään tutkimuksiin perustuvaa vastausta. Perustulon työllisyysvaikutuksia voidaan arvioida vain epäsuorasti ja ennakoiden. Tämän selvityksen tavoitteena oli kartoittaa olemassa olevaa tutkimustietoa ja arvioida sen perusteella perustulon mahdollisia työllisyysvaikutuksia. Olemme lisäksi tehneet asiantuntijahaastatteluja ja selvittäneet, miten TE-toimistojen, kuntien ja kolmannen sektorin toimijat arvioivat perustuloa ja sen vaikutusta työvoimapolitiikan toimeenpanoon ja työllisyyspalvelujen kehittämistarpeisiin. Olemme haastatelleet myös itsensä työllistäjiä (freelance toimittajia) ja pyrkineet sitä kautta saamaan selville, miten perustulo vaikuttaisi heidän toimeentuloonsa ja työssäkäyntiin. Kirjallisuuskatsauksessa selvitimme minimitulojärjestelmistä ja minimipalkoista saatuja kokemuksia eri maista. Vaikka esimerkit eivät ole suoraan verrattavissa perustuloon, ne auttavat kuitenkin hahmottamaan monia sellaisia kysymyksiä, joita liittyy perustulon työllisyysvaikutuksiin, kuten työvoiman kysyntään ja rekrytointiin sekä työvoiman tarjontaan ja mahdollisuuteen tai haluun vastaanottaa lyhytkestoisia ja pienipalkkaisia työtehtäviä. Esimerkit auttavan ymmärtämään myös sitä, miten perustulo voi vaikuttaa makrotalouden tasolla tiettyjen toimialojen kehitykseen. Tutkimuksen toisessa osassa selvitettiin perustulon mahdollisia vaikutuksia työvoimapolitiikan toimeenpanoon. Suurin osa TE-toimistojen, kuntien ja kolmannen sektorin asiantuntijoista suhtautui myönteisesti perustuloon, vaikka kriittisiäkin näkemyksiä esitettiin erityisesti perustulon vastikkeettomuuteen liittyen. Haastateltavat olivat yksimielisiä siitä, että nykyinen sosiaali- ja työttömyysturvajärjestelmä on liian monimutkainen aiheuttaen byrokratialoukkuja, ja että työn vastaanottamisen kannustavuutta tulisi lisätä. Keinoista tai perustulon mallista, joka parhaiten poistaisi näitä esteitä, oli erilaisia näkemyksiä. Kiinnostavaa oli myös se, että perustulon käyttöönoton nähtiin edellyttävän rinnalleen ennaltaehkäisevien palvelujen kehittämistä. Ennaltaehkäiseviä palveluja tulisi olla sosiaali- ja terveyspalveluissa, vapaa-ajan palveluissa sekä työllistymistä ja sosiaalista osallisuutta tukevissa palveluissa. Nuorille työnhakijoille asiantuntijat halusivat perustuloon liitettävää seurantaa ja palvelujen aktiivista tarjoamista. Tutkimuksen kolmannessa osiossa selvitettiin perustulon mahdollisia vaikutuksia itsensä työllistäjien työhön ja toimeentuloon. Haastattelujen perusteella perustulo voisi tuoda vakautta ja turvaa itsensä työllistäjille tyypilliseen epäsäännölliseen toimeentuloon luomalla perusturvan. Perustulo voisi helpottaa etenkin niiden itsensä työllistäjien taloudellista tilannetta, joilla ei tulojen pienuuden tai elämäntilanteen vuoksi ole mahdollisuutta kasvattaa säästöpuskuria taloudellisesti huonompien kuukausien varalle. Nykyisellään sosiaaliturvajärjestelmän ei koettu tuovan turvaa tulojen vaihteluun. Vaikka selvityksen tuloksia voi pitää vain alkukartoituksena, ja sen ulkopuolelle jäi monia tärkeitä asioita, niin se kuitenkin avaa ja konkretisoi kiinnostavalla monia perustulon työllisyysvaikutuksiin liitettyjä kysymyksiä

Urocortin 3 overexpression reduces ER stress and heat shock response in 3T3-L1 adipocytes

The neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1 alpha) and attenuated inflammation (TNF alpha) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 mu M of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis.Peer reviewe