IL-1 Receptor Antagonist (IL-1Ra) Levels and Management of Metabolic Disorders

Low-grade inflammation is a major player in obesity and the metabolic syndrome predicting development of type 2 diabetes (T2DM). The interleukin-1 receptor antagonist (IL-1Ra) is a vital and natural anti-inflammatory factor and mediator in glucose homeostasis disturbances. The predictive role is independent of multiple confounders, and elevated levels appear few years before T2DM. The role of IL-1Ra is important for accumulated risk factors, dysregulated metabolism and glucose homeostasis, and dietary interventions. Longitudinal and cross-sectional population study cohorts have enabled the approximation of IL-1Ra limit values for metabolic dysregulation and guide further analysis as a potential biomarker. The limit value of IL-1Ra is reaching 400 pg/mL with prediabetes and before T2DM. However, subjects with metabolic syndrome are suggested to have lower limit values, especially among men. Future research may evaluate the role of IL-1Ra in actual glucose homeostasis together with routine fasted laboratory tests, such as glucose and C-reactive protein (CRP) instead of the oral glucose tolerance test. The significance of intermediate low IL-1Ra levels in metabolic abnormalities should be further analyzed. It is possible to specify the impact of multiple lifestyle and metabolic parameters together with age and sex. IL-1Ra could be studied in multiple approaches including interventional studies of metabolic diseases

Associations of interleukin-1 (IL-1) gene variation and IL-1 receptor antagonist phenotypes with immunological responses, metabolic dysregulation and type 2 diabetes

The upstream proinflammatory interleukin-1 (IL-1) cytokines, together with a naturally occurring IL-1 receptor antagonist (IL-1Ra), play a significant role in several diseases and physiologic conditions. The IL-1 proteins affect glucose homeostasis at multiple levels contributing to vascular injuries and metabolic dysregulations that precede diabetes. An association between IL-1 gene variations and IL-1Ra levels has been suggested, and genetic studies have reported associations with metabolic dysregulation and altered inflammatory responses. The principal aims of this study were to: 1) examine the associations of IL-1 gene variation and IL-1Ra expression in the development and persistence of thyroid antibodies in subacute thyroiditis; 2) investigate the associations of common variants in the IL-1 gene family with plasma glucose and insulin concentrations, glucose homeostasis measures and prevalent diabetes in a representative population sample; 3) investigate genetic and non-genetic determinants of IL-1Ra phenotypes in a cross-sectional setting in three independent study populations; 4) investigate in a prospective setting (a) whether variants of the IL-1 gene family are predictors for clinically incident diabetes in two population-based observational cohort studies; and (b) whether the IL-1Ra levels predict the progression of metabolic syndrome to overt diabetes during the median follow-up of 10.8 and 7.1 years. Results from on patients with subacte thyroiditis showed that the systemic IL-1Ra levels are elevated during a specific proinflammatory response and they correlated with C-reactive protein (CRP) levels. Genetic variation in the IL-1 family seemed to have an association with the appearance of thyroid peroxidase antibodies and persisting local autoimmune responses during the follow-up. Analysis of patients suffering from diabetes and metabolic traits suggested that genetic IL-1 variation and IL-1Ra play a role in glucose homeostasis and in the development of type 2 diabetes. The coding IL-1 beta SNP rs1143634 was associated with traits related to insulin resistance in cross-sectional analyses. Two haplotype variants of the IL-1 beta gene were associated with prevalent diabetes or incident diabetes in a prospective setting and both of these haplotypes were tagged by rs1143634. Three variants of the IL-1Ra gene and one of the IL-1 beta gene were consistently identified as significant, independent determinants of the IL-1Ra phenotype in two or three populations. The proportion of the phenotypic variation explained by the genetic factors was modest however, while obesity and other metabolic traits explained a larger part. Body mass index was the strongest predictor of systemic IL-1Ra concentration overall. Furthermore, the age-adjusted IL-1Ra concentrations were elevated in individuals with metabolic syndrome or diabetes when compared to those free of metabolic dysregulation. In prospective analyses the systemic IL-1Ra levels were found as independent predictors for the development of diabetes in people with metabolic syndrome even after adjustment for multiple other factors, including plasma glucose and CRP levels. The predictive power of IL-1Ra was better than that of CRP. The prospective results also provided some evidence for a role of common IL-1 alpha promoter SNP rs1800587 in the development of type 2 diabetes among men and suggested that the role may be gender specific. Likewise, common variations in the IL-1 beta coding region may have a gender specific association with diabetes development. Further research on the potential benefits of IL-1Ra measurements in identifying individuals at high risk for diabetes, who then could be targeted for specific treatment interventions, is warranted. It has been reported in the recent literature that IL-1Ra secreted from adipose tissue has beneficial effects on glucose homeostasis. Furthermore, treatment with recombinant human IL-1Ra has been shown to have a substantial therapeutic potential. The genetic results from the prospective analyses performed in this study remain inconclusive, but together with the cross-sectional analyses they suggest gender-specific effects of the IL-1 variants on the risk of diabetes. Larger studies with more extensive genotyping and resequencing may help to pinpoint the exact variants responsible and to further elucidate the biological mechanisms for the observed associations. This would improve our understanding of the pathways linking inflammation and obesity with glucose and insulin metabolism.Interleukiini-1 (IL-1) sytokiiniperhe on voimakas tulehdusvasteen laukaisija sekä säätelijä sisältäen luonnollisen tulehdusreaktiota rajoittavan IL-1 reseptorin antagonistin (IL-1Ra) ja on siten merkittävä tekijä useissa eri sairauksissa sekä fysiologisissa tilanteissa. IL-1 proteiinit vaikuttavat sokeriaineenvaihduntaan useilla eri tasoilla ja tulehdusreaktiota voimistavat IL-1 sytokiinit kiihdyttävät verisuonten vauriomekanismeja sekä epäedullisia aineenvaihdunnan säätelymekanismeja edeltäen diabeteksen kehittymistä. Aiemmat tutkimukset ovat viitanneet siihen, että IL-1 perheen geneettinen vaihtelu on yhteydessä periferisestä verestä mitattavissa olevaan IL-1Ra pitoisuuteen. Useat geneettiset tutkimukset ovat myös osoittaneet yhteyden epäedullisten metabolisten säätelymekanismien ja poikkeavan immuunivasteen välillä. ---- IL-1Ra:n mitatut pitoisuudet kohosivat tulehdusreaktiossa ja korreloivat yleisesti käytetyn tulehduksen merkkiaineen C-reaktiivisen proteiinin (CRP) pitoisuuden kanssa. Etenevässä tutkimusasetelmassa IL-1Ra pitoisuuksien havaittiin itsenäisesti ennustavan diabeteksen kehittymistä henkilöillä, joilla lähtötilanteessa oli metabolinen oireyhtymä , riippumatta useista muista tekijöistä kuten esimerkiksi veren sokeripitoisuudesta ja CRP pitoisuuksista. IL-1Ra:n ennusteellinen merkitys oli vahvempi kuin CRP:n. Etenevä tutkimus tuotti viitteellistä näyttöä IL-1 alfa geenin promoottorialueen sekä IL-1 beta geenin koodaavan alueen yleisen yhden emäsparin vaihtelun osuudesta tyypin 2 diabeteksen kehittymisessä miehillä ja havaittu vaikutus saattaa olla sukupuolesta riippuva. Edellä mainitun IL-1 beta geenin yhden emäsparin polymorfismin havaittiin assosioituvan ominaisuuksiin, jotka liittyvät insuliinin verensokeritasoja säätelevän vaikutuksen heikkenemiseen - insuliiniresistenssiin. Vastaavasti kaksi IL-1 beta geenin haplotyyppia assosioituivat diabeteksen ilmaantuvuuteen tai esiintyvyyteen; ja molemmat haplotyypit sisälsivät edellä mainitun IL-1 beta koodaavan alueen harvinaisemman alleelin. Kolme IL-1 reseptoriantagonisti geenin varianttia ja yksi IL-1 beta geenin variantti assosioituivat tilastollisesti merkitsevästi ja useista muista tekijöistä riippumatta IL-1Ra pitoisuuteen kahdessa tai kolmessa tutkimusaineistossa. Geneettisten tekijöiden selitysosuus IL-1Ra ilmiasun vaihtelussa oli kuitenkin melko vaatimaton, sillä ylipaino ja muut metaboliset ominaisuudet selittivät ilmiasun vaihtelua geneettisiä tekijöitä enemmän. Ikävakioidut IL-1Ra tasot olivat korkeampia niillä henkilöillä, joilla todettiin metabolinen oireyhtymä tai diabetes verrattuna niihin joilla näitä aineenvaihduntahäiriöitä ei havaittu. IL-1 geenien vaihtelu näytti myös assosioituvan mitattavien tyreoideaperoksidaasi vasta-ainetasojen kanssa sekä pysyvämpien kilpirauhasen autoimmuunivasteiden kanssa seuranta-aikana. Lisätutkimuksia tarvitaan jatkossa täsmentämään IL-1Ra määritysten potentiaalisia etuja sellaisten henkilöiden tunnistamisessa, joilla on lisääntynyt riski saada diabetes. Tämä voisi auttaa kohdentamaan ehkäisy- ja hoitotoimenpiteet nykyistä paremmin. Aiempien tutkimusten perusteella IL-1Ra:lla näyttäisi olevan edullinen vaikutus glukoositasapainoon sen lisäksi että rasvakudoksen määrä näyttäisi liittyvän sytokiinien tuotantoon. Lisäksi on raportoitu, että IL-1Ra:n lääkkeellinen käyttö tyypin 2 diabeteksen hoidossa parantaa verensokerin tasapainoa melko lyhyen seurantajakson aikana. Nykyisiä isommat tutkimusaineistot, kattavampi geneettinen analytiikka sekä resekvensointi saattavat mahdollistaa merkittävien kausaalisten geneettisten varianttien identifioinnin ja siten selventää taustalla olevia biologisia mekanismeja. Nämä tutkimukset selvittävät edelleen niitä mekanismeja jotka yhdistävät tulehdusreaktiota, liikapainoa ja glukoosi-, ja insuliiniaineenvaihduntaa. Tässä työssä IL-1 geenivarianttien sekä IL-1Ra pitoisuuksien yhteyttä kilpirauhasvasta-aineiden ja vajaatoiminnan esiintymiseen tutkittiin subakuuttia kilpirauhastulehdusta sairastavilla potilailla. Muissa osatöissä tutkittiin edustavassa väestöotoksessa IL-1 geenien yleisten varianttien yhteyttä glukoosi ja insuliinipitoisuuksiin, glukoositasapainon osoittimiin sekä diabeteksen esiintyvyyteen. IL-1Ra ilmiasuun vaikuttavia geneettisiä ja ei-geneettisiä tekijöitä tutkittiin poikkileikkausasetelmassa kolmessa riippumattomassa tutkimusaineistossa. Edelleen kahdessa väestöpohjaisessa kohorttiaineistossa selvitettiin ennustavatko IL-1 geeniperheen variantit kliinisesti havaitun diabeteksen ilmaantuvuutta etenevässä tutkimusasetelmassa sekä ennustavatko IL-1Ra:n pitoisuudet diabeteksen kehittymistä henkilöillä, joilla on todettu metabolinen oireyhtymä. Seuranta-ajat olivat keskimäärin 10.8 ja 7.1 vuotta

Statin treatment, phenotypic frailty and mortality among community-dwelling octogenarian men: the HBS cohort.

BACKGROUND: statin treatment has increased also among people aged 80 years and over, but adverse effects potentially promoting frailty and loss of resilience are frequent concerns. METHODS: in the Helsinki Businessmen Study, men born in 1919-34 (original n = 3,490) have been followed up since the 1960s. In 2011, a random subcohort of home-living survivors (n = 525) was assessed using questionnaires and clinical (including identification of phenotypic frailty) and laboratory examinations. A 7-year mortality follow-up ensued. RESULTS: we compared 259 current statin users (median age 82 years, interquartile range 80-85 years) with 266 non-users (83; 80-86 years). Statin users had significantly more multimorbidity than non-users (prevalencies 72.1% and 50.4%, respectively, P < 0.0001) and worse glucose status than non-users (prevalencies of diabetes 19.0% and 9.4%, respectively, P = 0.0008). However, there was no difference in phenotypic frailty (10.7% versus 11.2%, P = 0.27), and statin users had higher plasma prealbumin level than non-users (mean levels 257.9 and 246.3 mg/L, respectively, P = 0.034 adjusted for age, body mass index and C-reactive protein) implying better nutritional status. Despite morbidity difference, age-adjusted 7-year mortality was not different between the two groups (98 and 103 men among users and non-users of statins, respectively, hazard ratio 0.96, 95% confidence interval 0.72-1.30). CONCLUSIONS: our study suggests that male octogenarian statin users preserved resilience and survival despite multimorbidity, and this may be associated with better nutritional status among statin users.Peer reviewe

Testosterone is associated with insulin resistance index independently of adiposity in women with polycystic ovary syndrome

Objective: To study the associations between androgens, glucose homeostasis, inflammation and statin treatment in women with polycystic ovary syndrome (PCOS). Design and methods: Oral glucose tolerance tests, androgens, hs-CRP and interleukin-1 receptor antagonist (IL-1Ra) were analyzed at baseline and after 6months of atorvastatin (20 mg/d) or placebo treatment in 27 women with PCOS. Results: Testosterone associated with insulin resistance measured with ISIMatsuda independently of BMI, age and SHBG concentrations and the full model, including IL-1Ra, hs-CRP and HDL-C, also showed independency of BMI and waist circumference (p≤.042). Free androgen index (FAI) associated with ISIMatsuda independently of adiposity (p≤.025) but in the full model with waist circumference the association was insignificant. ISIMatsuda decreased with testosterone >1.2nmol/l compared with lower levels at baseline (p=.043) and at six months (p=.003). Accordingly, 30-minute insulin levels were increased with moderately elevated testosterone independently of adiposity (p≤.046). Increased fasting glucose and AUC insulin associated with statin treatment independently of adiposity and the associations attenuated after adjusting for testosterone.  Conclusions: Moderately elevated testosterone concentrations together with obesity-related inflammatory factors modify glucose homeostasis by increasing insulin resistance and early insulin secretion.Peer reviewe

Mykoplasmavirus L2:n genomin subkloonaus pGEM 3 ja pGEM 4 vektoreihin

Syventävä työ ei kirjastoss

Mykoplasmavirus L2:n genomin subkloonaus pGEM 3 ja pGEM 4 vektoreihin

Syventävä työ ei kirjastoss

IL-1 Receptor Antagonist (IL-1Ra) Levels and Management of Metabolic Disorders

Low-grade inflammation is a major player in obesity and the metabolic syndrome predicting development of type 2 diabetes (T2DM). The interleukin-1 receptor antagonist (IL-1Ra) is a vital and natural anti-inflammatory factor and mediator in glucose homeostasis disturbances. The predictive role is independent of multiple confounders, and elevated levels appear few years before T2DM. The role of IL-1Ra is important for accumulated risk factors, dysregulated metabolism and glucose homeostasis, and dietary interventions. Longitudinal and cross-sectional population study cohorts have enabled the approximation of IL-1Ra limit values for metabolic dysregulation and guide further analysis as a potential biomarker. The limit value of IL-1Ra is reaching 400 pg/mL with prediabetes and before T2DM. However, subjects with metabolic syndrome are suggested to have lower limit values, especially among men. Future research may evaluate the role of IL-1Ra in actual glucose homeostasis together with routine fasted laboratory tests, such as glucose and C-reactive protein (CRP) instead of the oral glucose tolerance test. The significance of intermediate low IL-1Ra levels in metabolic abnormalities should be further analyzed. It is possible to specify the impact of multiple lifestyle and metabolic parameters together with age and sex. IL-1Ra could be studied in multiple approaches including interventional studies of metabolic diseases

Associations of overweight and metabolic health with successful aging : 32-year follow-up of the Helsinki Businessmen Study

Background & aims: Prognostic significance of metabolically healthy overweight and obesity (MHO) is under debate. However the relationship between MHO and health-related quality of life (HRQoL) is less studied. We compared successful aging (longevity plus HRQoL) in men with MHO, metabolically healthy normal weight (MHN) and metabolically unhealthy overweight and obesity (MUO). Methods: In the Helsinki Businessmen Study longitudinal cohort, consisting of men born 1919 to 1934. In 1985/86, overweight (BMI >= 25 kg/m(2)) and metabolic health were determined in 1309 men (median age 60 years). HRQoL was assessed using RAND-36/SF-36 in 2000 and 2007, and all-cause mortality retrieved from registers up to 2018. The proportion of men reaching 90 years was also calculated. Results: Of the men, 469 (35.8%), 538 (41.1%), 276 (21.1%), and 26 (2.0%) were MHN, MHO, MUO and MUN, respectively. During the 32-year follow-up, 72.3% men died. With MHN as reference, adjusted hazard ratio with all-cause mortality was 1.08 (95% confidence interval [CI] 0.93 to 1.27) for MHO, and 1.18 (95% CI 0.95 to 1.47) for MUO. During follow-up, 273 men reached 90 years. With MHN as reference, adjusted odds ratio for MHO was 0.82 (95% CI 0.59 to 1.14) and 0.62 (95% CI 0.41 to 0.95) for MUO. Men in MHN group scored generally highest in RAND-36 HRQoL subscales in 2000 and 2007, of those significantly better in Physical functioning, Role physical, Role emotional, Bodily Pain, and General health sub-scales compared to MHO group in 2000. Conclusions: As compared to MHN, MHO in late midlife does not increase mortality, but impairs odds for successful aging. (C) 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.Peer reviewe

Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes

The natural anti-inflammatory protein interleukin-1 receptor antagonist (IL-1Ra) inhibits the activity of IL-1 and is associated with vascular injury and metabolic disorders. We analyzed genetic and nongenetic determinants of the IL-1Ra phenotype. Fifteen haplotype-tagging single nucleotide polymorphisms (SNPs) in the IL-1&alpha; (IL1A), IL-1&beta; (IL1B), and IL-1 receptor antagonist (IL-1RN) genes were determined in the Health 2000 survey (n = 6771) and European myocardial infarction (MI) survivors (n = 972). Three SNPs were genotyped in the FINRISK97 (FR97) study (n = 7222). We found 3 IL1RN variants that were associated with the IL-1Ra phenotype in the study populations and remained significant after Bonferroni correction with increasing significance in meta-analysis (P values for rs3213448,rs315952, rs315949, respectively: 5.5 x 10(-11), 1.5 x 10(-11), and 4.0 x 10(-14)). Minor allele of the rare IL1B variant rs1143642 was associated with decreased IL-1Ra levels in the Health 2000 and FR97 populations, and the association strengthened in the meta-analysis (P = 9.4 x 10(-7)). The proportion of variance explained by the IL1RN variant was larger in MI survivors (5.0%) than in the unselected population (0.5%). Body mass index was the strongest nongenetic predictor of the IL-1Ra phenotype, explaining 11.8% of the variance in Health 2000, 18.1% in FR97, and 25% in MI survivors. In conclusion, 3 IL1RN SNPs and 1 IL1B variant were determining IL-1Ra phenotype independently of body mass index and other metabolic phenotypes. The proportion of phenotypic variation in IL-1Ra explained by the genetic variants was, however, modest compared with the proportion explained by the body mass index