First phase insulin response in children with islet autoantibodies : results from the Finnish Type 1 Diabetes Prediction and Prevention study

Type 1 diabetes results from the deficiency of insulin secretion from the pancreatic beta cells. The preclinical period of type 1 diabetes is characterized by the appearance of islet autoantibodies in the peripheral blood and appearance of two or more autoantibodies is highly predictive of clinical type 1 diabetes. The aim of this thesis was to investigate beta cell function in children from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. The DIPP study screens newborns for class II HLA associated risk for type 1 diabetes and follows children regularly. One or more intravenous glucose tolerance tests (IVGTTs) were performed for children who had developed islet autoantibodies. In progressors a declined first phase insulin response (FPIR) to glucose was observed 4-6 years prior to diagnosis as compared to non-progressors. Furthermore, in the age dependent comparison children progressing to T1D had lower FPIR than non-progressors throughout the whole childhood and this difference increased over time. When the association between FPIR and class II HLA was studied, it was observed that the class II HLA association was secondary to the appearance of autoantibodies. Declining pattern of FPIR was associated with multiple autoantibodies irrespective of class II HLA risk. Genetic variants outside the class II HLA region were, however, associated with the longitudinal pattern of FPIR. This study showed that in children that progress to clinical T1D the beta cell secretory capacity is reduced years before the onset of the disease. KEYWORDS: type 1 diabetes, beta cell function, insulin, glucoseEnsivaiheen insuliinivaste autovasta-ainepositiivilla lapsilla. Tuloksia suomalaisesta tyypin 1 diabeteksen ennustamis- ja ehkäisy (DIPP) –tutkimuksesta Tyypin 1 diabetes johtuu haiman betasolujen insuliinin erityksen puutteesta. Prekliinisenä aikana ennen tyypin 1 diabetesta perifeeriseen verenkiertoon ilmaantuu autovasta-aineita haiman saarekesoluja vastaan. Tyypin 1 diabeteksen riski on selkeästi lisääntynyt, kun lapselle on ilmaantunut kaksi tai useampi erilaista autovasta-ainetta. Tämän väitöskirjan tarkoituksena oli tutkia betasolujen toimintaa suomalaisen DIPP-tutkimuksen lapsilla. Yksi tai useampi suonensisäinen sokerirasituskoe tehtiin lapsille, joille oli ilmaantunut autovasta-aineita. Ensimmäisessä työssä tutkittiin glukoosin aineenvaihduntaa terveillä ja tyypin 1 diabetekseen sairastuvilla lapsilla. Sairastuvilla ensivaiheen insuliinivaste oli laskenut jo 4-6 vuotta ennen diagnoosia. Lisäksi iän mukaisessa vertailussa sairastuvilla lapsilla ensivaiheen insuliinivaste pysyi matalana koko lapsuuden ja ero ryhmien välillä kasvoi iän myötä. Kun tutkittiin luokan II HLA alueen ja ensivaiheen insuliinivasteen välisiä yhteyksiä, havaittiin, että yhteys johtui autovasta-aineista. Ajan myötä heikkenevä insuliinivaste oli yhteydessä kahden tai useamman autovasta-aineen esiintymiseen riippumatta luokan II HLA genotyyppiin liittyvästä riskistä. Muiden luokan II HLA alueen ulkopuolisten geneettisten varianttien ja insuliinivasteen välillä löytyi kuitenkin yhteyksiä. Tämä tutkimus osoitti, että lapsilla, jotka sairastuvat tyypin 1 diabetekseen betasolujen kyky erittää insuliinia on vähentynyt jo vuosia ennen kliinistä diagnoosia

Molecular and Cellular Markers in Skeletal Muscle Damage after Acute Voluntary Exercise Containing Eccentric Muscle Contractions

In eccentric muscle contraction, the muscle is lengthening while contracting. For example, in downhill walking, the thigh muscles are contracting eccentrically. It is well known that unaccustomed eccentric exercise causes pain and may lead to inflammation reactions on muscles few days after the exercise. The theme of the present chapter is molecular and cellular markers in skeletal muscle damage after voluntary exercise containing eccentric muscle contractions. The chapter contains three topics: In the first topic, the damaging process followed by regeneration is demonstrated with antibody stainings of connective tissue, plasma membrane, and cytoskeletal proteins. The second topic is infiltration of inflammatory cells in damaged skeletal muscle. Neutrophils are usually the first inflammatory cells mostly present in the injured tissues; however, neutrophils are not present in exercise-induced skeletal muscle damage. Finally, the relationship between skeletal muscle damage and systematic markers, serum creatine kinase and voluntary maximal force production, is described

Comparison of water phase diffusion experiments in laboratory and in situ conditions

In some countries the spent nuclear fuel produced by nuclear power plants will be deposited in crystalline granitic rock formations. In Finland, a repository for the spent nuclear fuel is being built at Olkiluoto. The safety assessment of the repository requires a careful determination of the transport properties of the bedrock. The porosity of the bedrock and the effective diffusion coefficients and distribution coefficients of different radio-nuclides for the bedrock are used as the main parameters in the safety assessment calculations. It has been questioned whether the parameters determined using laboratory experiments can be used to estimate the parameters in the in situ conditions. In this study, laboratory and in situ water phase diffusion experiments (WPDEs) were performed to resolve the issue. In the experiments, the transport of tritiated water (HTO), Cl-36, and Na-22 was studied using similar experimental setups. Mathematical models were constructed and solved to determine the transport parameters from the measured breakthrough curves. On average, the in situ WPDEs resulted in 20 (+/- 6)% smaller porosities and 32 (+/- 10)% smaller effective diffusion coefficients for HTO and Cl-36 than the laboratory WPDEs. It was also found that in veined gneiss, the most dominant rock type of the Olkiluoto bedrock, anion exclusion reduced the retention parameters of Cl-36 compared with those of HTO. Furthermore, the distribution coefficient of Na-22 for veined gneiss was about one order of magnitude smaller in the in situ conditions than in previous laboratory batch sorption experiments. The effects of the results on the safety assessment were evaluated and discussed.Peer reviewe

Reduced beta-cell function in early preclinical type 1 diabetes

Objective: We aimed to characterize insulin responses to i.v. glucose during the preclinical period of type 1 diabetes starting from the emergence of islet autoimmunity. Design and methods: A large population-based cohort of children with HLA-conferred susceptibility to type 1 diabetes was observed from birth. During regular follow-up visits islet autoantibodies were analysed. We compared markers of glucose metabolism in sequential intravenous glucose tolerance tests between 210 children who were positive for multiple (>= 2) islet autoantibodies and progressed to type 1 diabetes (progressors) and 192 children testing positive for classical islet-cell antibodies only and remained healthy (non-progressors). Results: In the progressors, the first phase insulin response (FPIR) was decreased as early as 4-6 years before the diagnosis when compared to the non-progressors (P=0.001). The difference in FPIR between the progressors and non-progressors was significant (P Conclusions: FPIR is decreased several years before the diagnosis of type 1 diabetes, implying an intrinsic defect in beta-cell mass and/or function.Peer reviewe

Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies

A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies, irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39 and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change in FPIR over time was significantly different between those with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932), and IKZF4 (rs1701704) genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR.Peer reviewe

Association between overall diet quality and postmenopausal breast cancer risk in five Finnish cohort studies

There is limited evidence for any dietary factor, except alcohol, in breast cancer (BC) risk. Therefore, studies on a whole diet, using diet quality indices, can broaden our insight. We examined associations of the Nordic Diet (mNDI), Mediterranean diet (mMEDI) and Alternative Healthy Eating Index (mAHEI) with postmenopausal BC risk. Five Finnish cohorts were combined including 6374 postmenopausal women with dietary information. In all, 8-9 dietary components were aggregated in each index, higher total score indicating higher adherence to a healthy diet. Cox proportional hazards regression was used to estimate the combined hazard ratio (HR) and 95% confidence interval (CI) for BC risk. During an average 10-year follow-up period, 274 incident postmenopausal BC cases were diagnosed. In multivariable models, the HR for highest vs. lowest quintile of index was 0.67 (95 %CI 0.48-1.01) for mNDI, 0.88 (0.59-1.30) for mMEDI and 0.89 (0.60-1.32) for mAHEI. In this combined dataset, a borderline preventive finding of high adherence to mNDI on postmenopausal BC risk was found. Of the indices, mNDI was more based on the local food culture than the others. Although a healthy diet has beneficially been related to several chronic diseases, the link with the etiology of postmenopausal BC does not seem to be that obvious.Peer reviewe

Incidence trends and risk factors of lung cancer in never smokers : Pooled analyses of seven cohorts

The trends in incidence of lung cancer in never smokers are unclear as well as the significance of risk factors. We studied time trends in the incidence and risk factors of lung cancer in never smokers in Finland in a large, pooled cohort. We pooled data from seven Finnish health cohorts from the period between 1972 and 2015 with 106 193 never smokers. The harmonised risk factors included education, alcohol consumption, physical activity, height and BMI. We retrieved incident lung cancers from the nation-wide Finnish Cancer Registry. We estimated average annual percent change (AAPC) and the effects of risk factors on cause-specific hazard ratios (HRs) of lung cancer using Poisson regression. We detected 47 lung cancers in never smoking men (n = 31 859) and 155 in never smoking women (n = 74 334). The AAPC of lung cancer incidence was -3.30% (95% confidence interval [CI]: -5.68% to -0.88%, P = .009) in never smoking men and 0.00% (95% CI: -1.57% to 1.60%, P = .996) in never smoking women. Of the five studied risk factors only greater height in women had a statistically significant increased risk of lung cancer (multivariate HR = 1.84, 95%CI: 1.08 to 3.12). It is plausible that tobacco control measures focused on working places have reduced passive smoking among men more than among women, which could explain the declining trend in lung cancer incidence in never smoker men but not in never smoker women. As tobacco control measures have not been targeted to domestic environments, it is likely that women's exposure to passive smoking has continued longer.Peer reviewe

Incidence trends and risk factors of lung cancer in never smokers : Pooled analyses of seven cohorts

The trends in incidence of lung cancer in never smokers are unclear as well as the significance of risk factors. We studied time trends in the incidence and risk factors of lung cancer in never smokers in Finland in a large, pooled cohort. We pooled data from seven Finnish health cohorts from the period between 1972 and 2015 with 106 193 never smokers. The harmonised risk factors included education, alcohol consumption, physical activity, height and BMI. We retrieved incident lung cancers from the nation-wide Finnish Cancer Registry. We estimated average annual percent change (AAPC) and the effects of risk factors on cause-specific hazard ratios (HRs) of lung cancer using Poisson regression. We detected 47 lung cancers in never smoking men (n = 31 859) and 155 in never smoking women (n = 74 334). The AAPC of lung cancer incidence was -3.30% (95% confidence interval [CI]: -5.68% to -0.88%, P = .009) in never smoking men and 0.00% (95% CI: -1.57% to 1.60%, P = .996) in never smoking women. Of the five studied risk factors only greater height in women had a statistically significant increased risk of lung cancer (multivariate HR = 1.84, 95%CI: 1.08 to 3.12). It is plausible that tobacco control measures focused on working places have reduced passive smoking among men more than among women, which could explain the declining trend in lung cancer incidence in never smoker men but not in never smoker women. As tobacco control measures have not been targeted to domestic environments, it is likely that women's exposure to passive smoking has continued longer.Peer reviewe

Pairwise association of key lifestyle factors and risk of colorectal cancer : a prospective pooled multicohort study

Background Several lifestyle factors are associated with an increased risk of colorectal cancer (CRC). Although lifestyle factors co-occur, in most previous studies these factors have been studied focusing upon a single risk factor or assuming independent effects between risk factors. Aim To examine the pairwise effects and interactions of smoking, alcohol consumption, physical inactivity, and body mass index (BMI) with risk of subsequent colorectal cancer (CRC). Methods and results We used METCA cohort data (pooled data from seven population-based Finnish health behavior survey studies during years 1972-2015) consisting of 171 063 women and men. Participants' smoking, alcohol consumption, physical inactivity and BMI measures were gathered, and participants were categorized into those exposed and those not exposed. The incidence of CRC was modeled by Poisson regression with main and interaction effects of key lifestyle factors. The cohort members were followed-up through register linkage to the Finnish Cancer Registry for first primary CRC case until the end of 2015. Follow-up time was 1715, 690 person years. The highest pairwise CRC risk was among male smokers who had overweight (BMI >= 25 kg/m(2)) (HR 1.75, 95% CI 1.36-2.26) and women who had overweight and consumed alcohol (HR 1.45, 95% CI 1.14-1.85). Overall, among men the association of lifestyle factors and CRC risk was stronger than among women. In men, both having overweight and being a smoker combined with any other adverse lifestyle factor increased CRC risk. Among women, elevated CRC risks were observed for those who were physically inactive and who consumed alcohol or had overweight. No statistically significant interactions were detected between pairs of lifestyle factors. Conclusions This study strengthens the evidence of overweight, smoking, and alcohol consumption as CRC risk factors. Substantial protective benefits in CRC risk can be achieved by preventing smoking, maintaining BMI toPeer reviewe

Lääkevalmisteiden hintakilpailun aktivointi ja väestön odotukset apteekkitoiminnalle

Selvityksen tavoitteena oli tarkastella lääkkeiden hintakilpailua ja väestön odotuksia apteekkitoiminnalle. Tutkimuksissa hintakilpailusta käytettiin Kelan reseptitiedoston ja Kanta-palvelujen reseptiarkiston aineistoja ja laadittiin järjestelmällinen kirjallisuushaku. Suomalaisista apteekkipalvelututkimuksista laadittiin järjestelmällinen kirjallisuushaku. Väestön näkemyksiä apteekkien tehtävistä ja toiminnasta selvitettiin verkkokyselyllä. Geneeristen lääkkeiden markkinat ovat keskittyneet, ja viitehintakautta lyhemmät hintajaksot heikentävät hintakilpailun kannustimia. Biologisia alkuperäislääkkeitä edullisempien biosimilaarien määrääminen uusille potilaille on melko aktiivista, mutta biologisissa lääkkeissä ei ole hintakilpailua. Biologinen substituutio, lääkkeen määräämisen ohjaaminen sekä avohoidon kilpailutetut hankinnat olisivat mahdollisia säästökeinoja. Lääkeneuvonta, koneellinen annosjakelu ja lääkehoidon arviointi ovat tutkituimpia apteekkipalveluja. Palvelujen vaikuttavuudesta ja kustannusvaikuttavuudesta tarvitaan lisää tutkimusta. Väestö on tyytyväinen apteekkien palveluihin sekä itsehoitolääkkeiden hankintaan apteekeista, mutta yksityisyyden suoja koetaan puutteelliseksi. Uusia ja digitaalisia palveluita halutaan käyttöön. Apteekkien lakisääteisten tehtävien ja ammatillisten palveluiden sisältö ja laatu tulisi määritellä laadun arvioinnin mahdollistamiseksi. Julkaisu on päivitetty 5.5.2021, s. 185–189.Tämä julkaisu on toteutettu osana valtioneuvoston selvitys- ja tutkimussuunnitelman toimeenpanoa. (tietokayttoon.fi) Julkaisun sisällöstä vastaavat tiedon tuottajat, eikä tekstisisältö välttämättä edusta valtioneuvoston näkemystä