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Tiivistelmä Tyypin 2 diabeteksen ilmaantuvuus perustuen erityiskorvattavien lääkkeiden käyttöön on laskenut Suomessa koko 2010-luvun, mutta D2D-alueen sairaanhoitopiirien väliset erot ovat säilyneet. Kolmasosa D2D-hankkeessa vuosina 2003–2007 tunnistetuista suuren sairastumisriskin henkilöistä osallistui tarjottuun hoito- ja seurantaohjelmaan. Perusterveydenhuollossa ja myös työterveyshuollossa on herätty torjumaan diabetesta. Väestön diabetestietoisuus on lisääntynyt koko maassa DEHKO-ohjelman, D2D-hankkeen ja FINDRISC-diabeteksen riskitestin laajan käytön myötä. Tuloksellinen tyypin 2 diabeteksen ehkäisy edellyttää sekä korkean riskin että väestötason strategiaan perustuvia toimia ja monialaista yhteistyötä terveyttä edistävien elintapojen edistämiseksi ja omaksumiseksi.

Objective: To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets. Design: Bi-directional Mendelian randomisation study. Setting: Genome-wide association studies from three Finnish cohorts (Northern Finland Birth Cohort 1966, Young Finns Study, or FINRISK study), and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits. Participants: Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits. Interventions: Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits (coronary artery disease, stroke, type 2 diabetes mellitus, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, glycated haemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, triglycerides, C reactive protein, glucose, fasting insulin, and lifetime smoking). Main outcome methods: Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated. Results: Genetic evidence (mendelian randomisation P<0.0011) suggests that higher body mass index, waist circumference, smoking, higher concentrations of lipids, and systolic blood pressure increase circulating concentrations of several inflammatory cytokines and C reactive protein. Evidence

This 36-month study aimed to determine whether exercise intervention added to weight loss treatment in the beginning or at 6 months is effective for weight loss and long-term weight maintenance. A total of 120 obese adults (body mass index >30) were randomly assigned to intensified behavioral modification (iBM), iBM+ additional exercise from 0 to 3 months (CWT1), iBM+ additional exercise from 6 to 9 months (CWT2), and a control group (CON). Questionnaires and measurements were collected at baseline, 3, 9, 24, and 36 months. The intervention consisted of an 12 months intensified weight-loss period followed by a 24 months weight-maintenance period. Eighty (67%) subjects (mean age 46.0 years, BMI 36.2) completed the trial. Compared with the control group, all three intervention groups had significant weight loss during the 36-month intervention period (p < 0.001). The achieved weight loss remained significant at 36 months in the iBM (−6.8%, p < 0.001), the CWT1 (−5.8%, p < 0.001), and the CWT2 group (−3.9%, p < 0.001). The CWT1 group showed significant reduction in waist circumference at 9 months (−11.3 cm, p < 0.001), at 24 months (−8.8 cm, p < 0.001), and at 36 months (−8.7 cm, p < 0.001). Intensified behavioral modification alone and with exercise resulted in clinically significant weight loss and long-term weight maintenance. The addition of exercise at the onset promoted greater reductions in waist circumference. In the treatment of obesity, including severe obesity, more intensive lifestyle interventions with exercise should be incorporated.

The prevalence of obesity is increasing worldwide despite a rise in therapeutic interventions to address this epidemic. However, there is a dearth of evidence-based non-surgical treatment guidelines for severe obesity. The aim of this three-year randomized, controlled trial was to elucidate the role of physical activity (PA) in the treatment of severe obesity. First, we studied the association of lifelong PA, aerobic fitness, and cardiac autonomic function by heart rate variability in severely obese adults. Secondly, we investigated the long-term effects of a three-month intensified behavioral modification (iBM) with exercise on glucose tolerance. Thirdly, we aimed to find out whether the timing of the exercise implemented at the weight loss phase of the intervention affects weight loss and waist circumference reduction (WC) from baseline. Finally, we evaluated whether a three-month exercise intervention combined with iBM has long-term effects on weight loss, weight maintenance, and reduction of WC over a three-year follow-up. 120 volunteers (mean BMI 36.8) were randomized into three intervention groups and a control group. All intervention groups were offered intensified behavioral weight loss guidance. According to previous studies, weight loss often stops and re-weighting begins after six months of intervention; we thus added exercise to the protocol of one group right at the beginning of the intervention and to another group after six months. Supervised three-month heart rate-controlled exercise training was implemented as circuit weight training. The weight loss period lasted 12 months, and the weight maintenance period lasted 24 months. Lifetime physical activity and aerobic fitness were positively associated with cardiac autonomic function. During the trial, iBM alone and combined with exercise led to clinically significant weight loss and long-term weight control. Increasing exercise right at the beginning of the weight loss period reduced abdominal, Tiivistelmä Lihavuus yleistyy huolimatta erilaisten hoitomuotojen kehittymisestä. Vaikean lihavuuden hoitamiseen on vain vähän tutkitusti vaikuttavia ei-leikkauksellisia vaihtoehtoja. Tämän tutkimuksen tavoitteena oli selvittää fyysisen aktiivisuuden roolia vaikean lihavuuden hoidossa. Ensimmäiseksi tutkimme elinaikaisen fyysisen aktiivisuuden ja aerobisen kunnon yhteyksiä sykevaihtelulla mitattuun sydämen autonomiseen säätelyyn vaikeasti lihavilla aikuisilla. Toisessa osatyössä selvitimme 3 kuukauden liikuntaharjoittelun ja tehostetun elintapaohjauksen pitkäaikaisia yhteisvaikutuksia sokeriaineenvaihduntaan. Kolmannessa osatyössä selvitimme, vaikuttaako painonpudotusvaiheessa toteutetun liikuntaharjoittelun ajoitus painonpudotukseen ja vyötärönympärykseen. Lopuksi tutkimme, vaikuttaako elintapaohjaukseen yhdistetty 3 kuukauden harjoittelu pitkällä aikavälillä painonpudotukseen, painonhallintaan ja vyötärönympärykseen kolmen vuoden seurannan aikana. 120 vapaaehtoista aikuista (keskimääräinen BMI 36,8) satunnaistettiin kolmeen interventioryhmään ja kontrolliryhmään. Kaikille interventioryhmien jäsenille tarjottiin tehostettua elintapaohjausta painonpudotukseen. Aiempien interventiotutkimusten perusteella painonlasku usein pysähtyy 6 kuukauden kohdalla. Tämän vuoksi sisällytimme interventioprotokollaan liikuntaharjoittelun yhdelle ryhmälle heti intervention alussa ja toiselle ryhmälle 6 kuukauden kohdalla aloittamisesta. Ohjattu 3 kuukauden liikuntaharjoittelu toteutettiin sykeohjattuna kiertoharjoitteluna. Painonpudotusvaihe kesti 12 kuukautta ja painonhallintavaihe 24 kuukautta. Elinikäinen fyysinen aktiivisuus ja aerobinen kunto olivat positiivisesti yhteydessä sydämen autonomiseen säätelyyn. Tehostettu elintapaohjaus yksin ja yhdessä liikuntaharjoittelun kanssa johti kliinisesti merkittävään painonpudotukseen ja pitkäaikaiseen painonhallintaan. Liikunnan lisääminen heti painonpudotuksen alussa pienensi keskivartalolihavuutta, edisti painonhallintaa ja paransi soke

Purpose: The aim of this study was to describe the clinical ocular surface characteristics in a population-based sample of Finnish elderly people. Methods: This cross-sectional study included 601 subjects (335 females, 266 males) born between the years 1933–1956 and living in Savitaipale, Finland. Ocular surface health was evaluated using a comprehensive set of diagnostic tests. Previous dry eye (DE) diagnosis and history of drug treatment of DE were also recorded. Differences between sexes were estimated with Wilcoxon rank sum test and Fisher’s exact test. Results: Overall, 10% and 33% of people displayed signs of DE and ocular surface disease (OSD), respectively, and 30% had been previously diagnosed with DE and 36% used some form of drugs for DE. Men displayed more severe signs of meibomian gland dysfunction, blepharitis and conjunctival redness (p < 0.001), while women had higher scores in corneal staining (p = 0.005) and OSD Index (p < 0.001). Conclusion: Signs of OSD and DE are common among the Finnish elderly population. However, the diagnosis is affected by the diagnostic criteria used and significant differences exist between sexes. Although women were more frequently diagnosed with DE and OSD and experienced more ocular surface irritation, men had more often lid and meibomian gland-related issues. The current diagnostic criteria of DE pose a risk of misclassifying men, who commonly display less severe symptoms in comparison with women yet exhibit more severe clinical signs associated especially with the lid margin.

Aim: The aim of this study was to explore whether active participation in a longitudinal birth cohort study is associated with study participants’ health behaviour and well-being. Methods: The subjects of this study were part of the Northern Finland Birth Cohort 1966. The follow-up data were collected through clinical examinations and questionnaires when the cohort members were 1, 14, 31 and 46 years old. In this study, cohort participation activity was divided into three categories: active, semiactive and least active. Results: The total number of study participants who participated in the 46-year follow-up on both the survey and clinical trials was 6392, of which 66.5% (n=4268) participated actively in the cohort study. A total of 67.6% were female (p<0.001). Of the participants, 23.7% (n=1519) were semiactive and 9.5% (n=605) were the least active. Women who participated least actively experienced statistically significantly more depressive symptoms and poorer health, were more dissatisfied with their lives and had more addiction problems. In men, there was not a statistically significant association between participation activity and these well-being variables other than addiction problems and mental health. Conclusions: The findings indicate that participation activity is associated with better self-reported health and well-being, especially among women. With this knowledge, people can be encouraged to participate in longitudinal health research and, at the same time, may improve their own health and quality of life.

The purpose of this study was to examine and compare the associations between albuminuria and fasting (FPG), 1 h post-load (1 h PG) and 2 h post-load plasma glucose (2 h PG) in an oral glucose tolerance test (OGTT). A total of 496 people free of known diabetes (mean age 72 years) participated in the examinations including the OGTT with plasma glucose measurements at 0, 1, and 2 h and levels of HbA1c. Albuminuria was determined by the urinary albumin-to-creatinine ratio and was defined as ≥3.0 mg/mmol. Compared with those without albuminuria, participants with albuminuria had significantly higher 1 h PG and 2 h PG levels, but not FPG or HbA1c levels. An elevated 1 h PG increased the estimated odds ratio of albuminuria more than three times in people with prediabetic 1 h PG (8.6–11.5 mmol/L: OR 3.60; 95% CI 1.70–7.64) and diabetic 1 h PG (≥11.6 mmol/L: OR 3.05; 95% CI 1.29–7.23). After adjusting for blood pressure and age, the association of elevated 1 h PG with albuminuria remained significant. Prediabetic or diabetic FPG, 2 h PG, or HbA1c did not have a statistically significant association with albuminuria. These findings suggest that 1 h PG seems to be the best glycemic parameter and is useful in recognizing persons with an elevated risk of early kidney disease due to hyperglycemia.

Type 2 diabetes (T2D) is a common metabolic disorder characterized by elevated glucose levels. Recognizing people at high risk for T2D allows interventions that may delay or prevent the development of T2D and diabetes-related complications. The previously accepted methods for identifying these people are fasting plasma glucose (FPG), two-hour post-load glucose (2-h PG) in an oral glucose tolerance test (OGTT) and glycated hemoglobin A1c (HbA1c). However, one-hour post-load glucose (1-h PG) in an OGTT has risen in interest for its high predictive value for future T2D at an even earlier time point than the currently used methods. The aim of this thesis was to investigate the ability of 1-h PG to predict T2D and cardiovascular diseases as well as to evaluate the association between 1-h PG and other diabetic complications including retinopathy signs and albuminuria. The value of 1-h PG measurement was compared with current diagnostic methods. Four Finnish study populations were used for the analyses of the present thesis. The results revealed that 1-h PG was a better predictor of T2D and cardiovascular outcomes than FPG or 2-h PG, also improving the explanatory power of the traditional cardiovascular risk models. Elevated 1-h PG was related to retinopathy signs, while FPG, 2-h PG and HbA1c were not. Both prediabetic ( 8.6 mmol/L) and diabetic ( 11.6 mmol/L) 1-h PG levels were independently associated with albuminuria, but no such an association was seen in FPG, 2-h PG and HbA1c. Furthermore, the 2-h PG did not provide any benefit in addition to FPG and 1-h PG in the prediction of T2D and cardiovascular outcomes or in the detection of albuminuria. In conclusion, these findings indicate that the use of 1-h PG improves the predictability of T2D and cardiovascular diseases and the detection of retinopathy signs and albuminuria. Together with previous findings, these results indicate that the use of 1-h PG and shortened 1-h OGTT seems reasonable to consider in the, Tiivistelmä Tyypin 2 diabetes on yleinen aineenvaihduntasairaus, johon liittyy kohonnut verensokeri. Suuressa sairastumisriskissä olevien potilaiden tunnistaminen on tärkeää, jotta tyypin 2 diabeteksen sekä siihen liittyvien komplikaatioiden kehittymistä voidaan ennaltaehkäistä. Aikaisemmin hyväksytyt menetelmät suuressa sairastumisriskissä olevien potilaiden tunnistamiseksi ovat paastoverensokeri, glukoosirasituskokeen 2 tunnin glukoosi ja glykohemoglobiini A1c (HbA1c). Glukoosirasituskokeen 1 tunnin glukoosi on herättänyt viime aikoina kiinnostusta, sillä sen on havaittu ennustavan hyvin tulevaa tyypin 2 diabetesta jopa varhaisemmassa vaiheessa kuin nykyisin käytössä olevat menetelmät. Tämän väitöskirjan tavoitteena oli tutkia 1 tunnin glukoosiarvon kykyä ennustaa tyypin 2 diabetesta ja sydän- ja verisuonitauteja sekä arvioida 1 tunnin glukoosiarvon yhteyttä retinopatiamuutoksiin ja albuminuriaan. Yhden tunnin glukoosiarvoa verrattiin nykyisiin käytössä oleviin diagnostisiin menetelmiin. Tässä väitöskirjassa hyödynnettiin neljää suomalaista väestöpohjaista aineistoa. Tutkimustulokset osoittivat, että 1 tunnin glukoosiarvo on parempi tyypin 2 diabeteksen sekä sydän- ja verisuonitapahtumien ennustaja kuin paastoglukoosi tai 2 tunnin glukoosi, ja se parantaa myös perinteisten sydän- ja verisuonitautien riskimallien selitysastetta. Retinopatiamuutokset olivat yhteydessä kohonneeseen 1 tunnin glukoosiarvoon, mutta eivät paastoarvoihin, 2 tunnin arvoihin tai HbA1c:hen. Sekä prediabeettinen ( 8.6 mmol/l) että diabeettinen ( 11.6 mmol/l) 1 tunnin glukoosiarvo olivat itsenäisesti yhteydessä albuminuriaan, mutta vastaavaa yhteyttä ei todettu paastoglukoosille, 2 tunnin glukoosille tai HbA1c:lle. Kahden tunnin glukoosiarvo ei myöskään parantanut paastoglukoosin ja 1 tunnin glukoosin lisänä tyypin 2 diabeteksen tai sydän- ja verisuonitapahtumien ennustettavuutta eikä albuminurian tunnistettavuutta. Tutkimustulosten perusteella 1 tunnin glukoosiarvon käyttö parantaa tyypin 2

The amount of physical activity decreases and sedentary time increases with aging, predisposing older adults to increased risk of type 2 diabetes and cardiovascular diseases. The aims of this study were to evaluate the associations between accelerometer-measured physical activity and sedentary time with glucose metabolism, cardiovascular risk and mortality in older adults. In 2013–2015, population-based sample of older adults (n = 714) participated in the Oulu45 cohort study at age of 67–70 years. Physical activity and sedentary time were measured with wrist-worn Polar Active accelerometer based activity monitor for two weeks. Participants’ underwent an oral glucose tolerance test and risk of cardiovascular diseases was estimated with Framingham risk score. The data for all-cause mortality were identified from the Digital and Population Data Services Agency, Finland after an average of 6.2 years follow-up. Four physical activity profiles were identified. In more active profiles, prevalence of glucose metabolism disorders, 120 min glucose and insulin values in oral glucose tolerance test were lower compared with the less active profiles. In older adults with central obesity, even light physical activity and avoiding sedentary time were associated with improved glucose metabolism and decreased insulin resistance. Both light and moderate to vigorous physical activity were associated with lower risk of cardiovascular diseases. High sedentary time was associated with increased cardiovascular risk. Low sedentary time and high time spent in light physical activity were associated with lower mortality. Based on these results, a higher amount of physical activity, at any intensity level, and avoidance of sedentary time were associated with reduced risk of type 2 diabetes, cardiovascular diseases and mortality in older adults. Especially overweight older adults should be encouraged to increase their physical activity and to avoid being sedentary., Tiivistelmä Vähäinen fyysisen aktiivisuuden määrä ja runsas paikallaanoloaika lisäävät riskiä sairastua tyypin 2 diabetekseen sekä sydän- ja verisuonisairauksiin. Tämän tutkimuksen tavoitteina oli selvittää kiihtyvyysanturilla mitatun kevyen, kohtuukuormitteisen ja raskaan fyysisen aktiivisuuden sekä paikallaanolon yhteyttä iäkkäiden henkilöiden sokeriaineenvaihduntaan sekä sydän- ja verisuonisairauksien ja kuoleman riskiin. Väestöpohjaisen Oulu45-kohorttitutkimuksen aineisto (n = 714) kerättiin vuosina 2013–2015, ja tutkittavat olivat iältään 67–70-vuotiaita. Tutkittavien fyysinen aktiivisuus ja paikallaanolo mitattiin kahden viikon ajan ranteessa pidettävällä kiihtyvyysanturiin perustuvalla Polar Active -aktiivisuusmittarilla. Tutkittaville tehtiin sokerirasituskoe ja heidän sydän- ja verisuonisairauksien riskiään arvioitiin Framinghamin riskipisteillä. Kuolleisuustiedot kerättiin Digi- ja väestötietovirastosta keskimäärin 6,2 vuoden seuranta-ajan jälkeen. Tutkimuksessa tunnistettiin iäkkäistä neljä liikkujaprofiilia. Profiililtaan fyysisesti aktiivisilla oli harvemmin sokeriaineenvaihdunnan häiriöitä ja matalammat 120 minuutin glukoosi- ja insuliiniarvot sokerirasituskokeessa. Kevyt fyysinen aktiivisuus ja vähäisempi paikallaanoloaika tehostivat etenkin keskivartalolihavien iäkkäiden sokeriaineenvaihduntaa ja vähensivät insuliiniresistenssiä. Sekä kevyt, että kohtuukuormitteinen ja raskas fyysinen aktiivisuus vähensivät sydän- ja verisuonisairauksien riskiä, kun taas runsas paikallaanoloaika lisäsi riskiä. Runsaampi kevyt fyysinen aktiivisuus ja vähäinen paikallaanoloaika pienensivät kuoleman riskiä. Tämän väitöskirjan tulosten perusteella vähäinenkin fyysinen aktiivisuus on paikallaanoloa parempi vaihtoehto iäkkäiden henkilöiden sokeriaineenvaihdunnan ja sydänterveyden edistämiseksi. Erityisesti keskivartalolihavia iäkkäitä tulisi rohkaista lisäämään liikkumista ja vähentämään paikallaanoloa.

Background: The number of skin cancer is increasing rapidly. However, little is known about the risk factors of skin cancer in older persons. Our objectives were to determine the risk factors for skin cancer or its precursors in an older population. More specifically, to study the association of new skin cancers with previous skin cancer, sex, age, Fitzpatrick’s skin type, history of outdoor work and socioeconomic status (SES). Methods: In this retrospective cross-sectional study of a large, well documented historical cohort data set a total body skin examination (TBSE) was performed for 552 participants aged between 70 and 93 years by dermatologists. The information gathered was augmented with health register data and self-reported data. The associations between skin cancer and its risk factors were studied by using the logistic regression analyses. Results: According to the TBSE skin cancer/precursor was present in 25.5% of participants and was more common in males than in females (34.5% vs 20.2%, p < 0.001). Previous skin cancer increased the risk of subsequent skin cancer 2.6-fold (OR 2.56, 95% CI 1.43–4.55) and male sex nearly 2-fold (1.97, 95% CI 1.26–3.08). Specific risk factors for the first occurrence of skin cancer were male sex and outdoor work. There was also association between skin cancer and age and socioeconomic status. Conclusions: TBSE is recommend for physicians treating older persons to allow early recognition of skin cancers or their precursors. Older males need particularly close attention.

Aims: Rates of parental separation have increased dramatically in recent decades. We evaluated the association of individuals’ childhood family structure with their somatic health over 46 years of follow-up. Methods: Data were drawn from the Northern Finland Birth Cohort, an ongoing project in which 12,058 participants born in 1966 have been followed from their 24th gestational week. Based on information supplied at age 14 years, family structure was categorised as ‘single-parent family’ and ‘two-parent family’. The anthropometric information, data from blood samples and medical history were collected from postal questionnaires and clinical examinations routinely performed at the ages of 31 and 46 years. Results: The study population comprised a total of 10,895 individuals; 85% (n=9253) were offspring of two-parent families and 15% (n=1642) of single-parent families. Type 2 diabetes (P=0.032) or prediabetes (P=0.007), psychoactive drug problems (P<0.001) and sexually transmitted diseases (P<0.001) were more common in the single-parent family group than in the participants from two-parent families. In addition, among men back diseases (P=0.002), and among women hypertension (P=0.003) and ovary infection (P=0.024) were more frequent in individuals affected by parental death than in those from two-parent families. Conclusions: Our results indicate the association of childhood family structure with offspring morbidity during 46 years’ follow-up. The lifetime morbidity was observed to be higher among offspring from a single-parent family compared to two-parent family offspring. Public and scientific concern about the consequences of parental separation on the offspring’ health exist, therefore support from healthcare professionals and society is warranted.

There is a wide variation in the development and course of erectile dysfunction (ED) in men, which confirms the need for prospective studies. We conducted a cross-sectional analysis among the general male population at the baseline (n = 359) and in a follow-up survey (n = 218) 12 years later. The prospective 12-year study included 189 men. ED was assessed using the International Index of Erectile Function questionnaire. The mean age of the participants was 62.0 years at the baseline, while at the 12-year follow-up it was 71.6 years. The crude prevalence of ED was 61.6% at the baseline and 78.9% at the follow-up, and the prevalence tended to increase with age. All of the men aged 75 years or more had at least mild ED. The incidence of ED in every thousand person years was 53.5. A total of 54.5% of the men experienced ED progression, while 39.2% reported no changes in erectile function, and 6.3% experienced ED regression during the 12-year study. The likelihood of ED progression was higher in the older compared with younger age group (odds ratio, OR 5.2 (95% CI: 1.1–26.2)), and the likelihood of ED regression was lower among men with increased depression symptoms (OR 0.3 (95% CI: 0.1–0.6)) and among men with a decreased interest in their sexual life (OR 0.1 (95% CI: 0.0–0.6)). Lifestyle factors such as the consumption of alcohol and smoking were not significantly associated with ED.

Background: Endurance exercise training promotes the catabolism of branched-chain amino acids (BCAAs) in skeletal muscles. We have previously shown that mitochondrial DNA (mtDNA) haplogroups J and K are markers of low responders in endurance training. In this paper, we hypothesize that BCAA catabolism is a surrogate marker of lower respiratory chain activity attributed to these haplogroups. We evaluated whether exercise-induced changes in amino acid concentrations differ between subjects harbouring mtDNA haplogroups J or K and those with non-JK haplogroups. Methods: Finnish male conscripts (N = 633) undertook the 12-min Cooper running test at the beginning and end of their military service. The intervention during the service mainly included endurance aerobic exercise and sports-related muscle training. Concentrations of seven amino acids were analysed in the serum using a high-throughput ¹H NMR metabolomics platform. Total DNA was extracted from whole blood, and restriction fragment analysis was used to determine mtDNA haplogroups J and K. Results: The concentrations of the seven amino acids were higher following the intervention, with the exception of phenylalanine; interestingly, the increase in the concentrations of three BCAAs was larger in subjects with haplogroup J or K than in subjects with non-JK haplogroups (p = 0.029). MtDNA haplogroups J and K share two common nonsynonymous variants. Structural analysis based on crystallographic data on bovine complexes I and III revealed that the Leu18 variant in cytochrome b encoded by m.14798T > C may interfere with ubiquinone binding at the Qi site in complex III. Conclusions: The increase in the concentrations of serum BCAAs following exercise intervention differs between subjects harbouring mtDNA haplogroup J or K and those harbouring non-JK haplogroups. Lower response in endurance training and difference in exercise-induced increase in the concentrations of serum BCAAs suggest decreased respiratory cha

Background: Epidemiological and experimental evidence has linked chronic inflammation to cancer aetiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomisation (MR) analysis. Methods: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian, and prostate), and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12,906 for endometrial to 133,384 for breast cancer). Results: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95% CI 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85) and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer aetiolog

Aims: To examine the association of physical activity (PA) and sedentary time (ST) with glucose metabolism according to waist circumference (WC) in older people. Methods: A population-based sample of 702 individuals (aged 67–70 years) wore wrist-worn accelerometers for two weeks and underwent an oral glucose tolerance test. The associations between moderate-to-vigorous (MVPA) and light (LPA) PA, ST, and glucose metabolism across the tertiles of WC were analysed using general linear regression. Results: Among highest WC tertile, LPA negatively associated with fasting insulin (β = − 0.047, 95% CI − 0.082 to − 0.012), HOMA-IR (β = − 0.098, 95% CI − 0.184 to − 0.012), and HOMA-β (β = − 3.367, CI − 6.570 to − 0.783). ST associated with 120 min glucose (β = 0.140, CI 0.021 to 0.260). Among lowest WC tertile, MVPA negatively associated with 30 min insulin (β = − 0.086, 95% CI − 0.168 to − 0.004) and 120 min insulin (β = − 0.160, 95% CI − 0.257 to − 0.063) and positively associated with Matsuda index (β = 0.076, 95% CI 0.014 to 0.139). Light PA negatively associated with 120 min insulin (β = − 0.054, 95% CI − 0.104 to − 0.005). Conclusion: With the limitation of the cross-sectional study, reducing ST and increasing LPA may be beneficial for glucose metabolism among abdominally obese older adults. Lean older adults could benefit more from increasing MVPA.

Aims: We describe a 22-year prospective observational population-based study that determined the prevalence and incidence of type 2 diabetes (T2D) and intermediate hyperglycaemia (IH), obesity, hypertension, and disorders of lipid metabolism in a middle-age population in the Finnish municipality of Savitaipale. Methods: 1151 people participated in the baseline survey in 1996–1999, following two follow-up examinations, in 2007–2008 and 2018−2019. Follow-up studies comprised clinical measurements, 2-h oral glucose tolerance test and other biochemistry, questionnaires, and registry data. Results: The prevalence of T2D quadrupled to 27% and the proportion of normoglycemic people decreased from 73% to 44% while IH increased only slightly during the 22-year follow-up. A large proportion of people who died between the surveys were diabetic. The mean body mass index (BMI) did not, whereas mean waist circumference increased significantly, by 5−6 cm (P = 0.001) during the 22 years. Systolic blood pressure increased by 13−15 mmHg from baseline (P = 0.0001) but diastolic blood pressure did not. The mean plasma levels of total and LDL-cholesterol decreased 10.8% and 8.9% in women (P = 0.001), 21.5% and 22.2% in men (P = 0.001), respectively, while HDL-cholesterol and triglycerides remained stable. The proportion of those achieving targets in the treatment of dyslipidaemia increased significantly (P < 0.001). Conclusions: In this 22-year prospective follow-up study of in middle-aged Europeans with high participation rates, the progression of dysglycaemia to overt diabetes with aging was rapid, even without a significant change in BMI.

Aims: This longitudinal study evaluated associations between glucose metabolism and cognitive performance during a 12-year follow-up. Methods: We included 714 subjects, which were followed from the age 55 to 70 years. Using oral glucose tolerance tests the population was classified as normoglycemic (NGT) and based on WHO diagnostic criteria for diabetes and prediabetes. Cognitive performance was assessed with a verbal fluency (category) test and wordlist learning tests of CERAD-nb, a verbal fluency (letter) test, and trail-making tests A and B. Results: Compared to the normal group subjects with long-lasting prediabetes showed significantly greater decline (4.6 versus 2.9 words) on the verbal fluency (category) test (p = 0.041); subjects with long-lasting type 2 diabetes showed significantly greater decline (13 versus 6 s) on the trail making A test (p = 0.021) and on the wordlist learning test (3.3 versus 1.7 words) (p = 0.013); and a combined group of subjects with prediabetes or incident type 2 diabetes showed significantly greater cognitive decline (3.8 versus 2.9 words) in the verbal fluency (category) test (p = 0.039). Conclusion: Prediabetes was associated with cognitive decline during aging. This finding should be incorporated into prevention strategies, because both type 2 diabetes and dementia are increasing world-wide.

Objective: One-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard. Research design and methods: We included 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA1c. We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG ≥11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3). Results: Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%. Conclusions: The 1-h PG of ≥11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes. Prescreening with a diabetes-specific risk calculator to identify high-risk individuals is suggested to decrease the proportion of false-positive cases. Studies including other ethnic groups and assessing complication risk are warranted.

Aims: The Finnish National Diabetes Prevention Program (FIN-D2D) was the first large-scale diabetes prevention program in a primary health care setting in the world. The risk reduction of type 2 diabetes was 69% after one-year intervention in high-risk individuals who were able to lose 5% of their weight. We investigated long-term effects of one-year weight change on the incidence of type 2 diabetes, cardiovascular events, and all-cause mortality. Methods: A total of 10,149 high-risk individuals for type 2 diabetes were identified in primary health care centers and they were offered lifestyle intervention to prevent diabetes. Of these individuals who participated in the baseline screening, 8353 had an oral glucose tolerance test (OGTT). Complete follow-up data during one-year intervention were available for 2730 individuals and those were included in the follow-up analysis. The long-term outcome events were collected from national health registers after the median follow-up of 7.4 years. Results: Among individuals who lost weight 2.5−4.9% and 5% or more during the first year, the hazard ratio for the incidence of drug-treated diabetes was 0.63 (95% CI 0.49−0.81, p = 0.0001), and 0.71 (95% CI 0.56−0.90, p = 0.004), respectively, compared with those with stable weight. There were no significant differences in cardiovascular events or all-cause mortality among study participants according to one-year weight changes. Conclusions: High-risk individuals for type 2 diabetes who achieved a moderate weight loss by one-year lifestyle counseling in primary health care had a long-term reduction in the incidence of drug-treated type 2 diabetes. The observed moderate weight loss was not associated with a reduction in cardiovascular events.

The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme-labeled immunosorbent assay. Clinical data were collected using a structured questionnaire. Only 39% of patients with genetically verified mitochondrial disease had mitochondrial pathology in their muscle histology. In contrast, biomarkers were elevated in 62% of patients with genetically verified mitochondrial disease. Those with both biomarkers elevated had a muscle manifesting disorder and a defect affecting mitochondrial DNA expression. If at least one of the biomarkers was induced and the patient had a myopathic disease, a mitochondrial DNA expression disease was the cause with 94% probability. Among patients with biomarker analysis and muscle biopsy taken <12 months apart, a mitochondrial disorder would have been identified in 70% with analysis of FGF21 and GDF15 compared to 50% of patients whom could have been identified with muscle biopsy alone. Muscle findings were nondiagnostic in 72% (children) and 45% (adults). Induction of FGF21 and GDF15 suggest a mitochondrial etiology as an underlying cause of a muscle manifesting disease. Normal biomarker values do not, however, rule out a mitochondrial disorder, especially if the disease does not manifest in muscle. We suggest that FGF21 and GDF15 together should be first-line diagnostic investigations in mitochondrial disease complementing muscle biopsy.

Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (nn = 7175) and used Mendelian randomization (MR) to evaluate potential causality (n = 173,480). The results showed evidence for lower Hb levels being associated with lower body mass index, better glucose tolerance and other metabolic profiles, lower inflammatory load, and blood pressure. Expression of the key HIF target genes SLC2A4 and Slc2a1 in skeletal muscle and adipose tissue, respectively, associated with systolic blood pressure in MR analyses and body weight, liver weight, and adiposity in mice. Last, manipulation of murine Hb levels mediated changes to key metabolic parameters. In conclusion, low-end normal Hb levels may be favorable for metabolic health involving mild chronic activation of the HIF response.

We evaluated the survival of a subarctic population and the significance of traditional risk factors for mortality, causes of death and their seasonal variation from the period of 1984–2014. By the end of 2014 (follow-up), 644 (34.4% from 1,869) participants had died (42.1% of cardiovascular causes, 22.4% of neoplastic diseases). The average age at death±SD was 74.6±11.4 years for women (n=284) and 70.2±12.0 years for men (n=360). After adjusting for baseline age, the major risk factors predicting death were male sex (hazard ratio [HR] 1.80; 95% confidence interval [CI] 1.54–2.10), current smoking (HR 1.85; 95% CI 1.58–2.17), obesity (HR 1.75; 95% CI 1.45–2.12), high blood pressure (HR 1.46; 95% CI 1.24–1.72), cardiovascular disease (HR 1.62; 95% CI 1.36–1.93) and depression (HR 1.61; 95% CI 1.21–2.14) at baseline. The most common causes of death and the main risk factors predicting death in this population were the same as reported globally. Lifestyle factors had an important impact in predicting survival. The most common causes of death were the same for men and women. There was no significant difference in overall mortality rate between winter and summer, but cerebrovascular and pulmonary causes of death were more common during winter.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein cholesterol (LDL-C) receptors, and thus regulates the LDL-C levels in the circulation. Type 2 diabetics often have elevated LDL-C levels. However, the functions of PCSK9 in patients with alterations of glu-cose metabolism and statin therapy are still unclear. Method: we investigated a large cohort of 608 subjects, born in 1945 in Oulu, Finland (Oulu Cohort 1945). We studied the effects of PSCK9 lev-els with different glucose tolerances (normal glucose tolerance (NGT), prediabetes (PreDM) or type 2 diabetes (T2D)) with and without statin medication, and analyzed clinical data, NMR metabolomics and PCSK9 plasma levels. Results: PCSK9 plasma levels did not significantly differ between the three groups. Statin therapy significantly increased the PCSK9 levels in NGT, PreDM and T2D groups compared with subjects with no statins. In the NGT group, negative associations between PCSK9 and LDL-C, intermediate-density lipoprotein cholesterol (IDL-C), very low-density lipoprotein cholesterol (VLDL-C), total cholesterol and LDL and IDL triglycerides were observed under statin medication. In contrast, in the PreDM and T2D groups, these associa-tions were lost. Conclusions: our data suggest that in subjects with abnormal glucose metabolism and statin therapy, the significant PCSK9-mediated effects on the lipid metabolites are lost com-pared to NGT subjects, but statins reduced the LDL-C and VLDL-C levels.

Background: We have previously suggested that some of the mutations defining mitochondrial DNA (mtDNA) haplogroups J and K produce an uncoupling effect on oxidative phosphorylation and thus are detrimental for elite endurance performance. Here, the association between haplogroups J and K and physical performance was determined in a population-based cohort of 1036 Finnish military conscripts. Results: Following a standard-dose training period, excellence in endurance performance was less frequent among subjects with haplogroups J or K than among subjects with non-JK haplogroups (p = 0.041), and this finding was more apparent among the best-performing subjects (p < 0.001). Conclusions: These results suggest that mtDNA haplogroups are one of the genetic determinants explaining individual variability in the adaptive response to endurance training, and mtDNA haplogroups J and K are markers of low-responders in exercise training.