Browsing by Subject "INSULIN"

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  • Bauer, Witold; Veijola, Riitta; Lempainen, Johanna; Kiviniemi, Minna; Härkönen, Taina; Toppari, Jorma; Knip, Mikael; Gyenesei, Attila; Ilonen, Jorma (2019)
    Context: Children with initial autoantibodies to either insulin (IAA) or glutamic acid decarboxylase (GADA) differ in peak age of seroconversion and have different type 1 diabetes (T1D) risk gene associations, suggesting heterogeneity in the disease process. Objective: To compare the associations of age at seroconversion, HLA risk, and specificity of secondary autoantibodies with the progression of islet autoimmunity between children with either IAA or GADA as their first autoantibody. Design and methods: A cohort of 15,253 children with HLA-associated increased risk of T1D participated in a follow-up program in which islet autoantibodies were regularly measured. The median follow-up time was 6.7 years. Spearman correlation, Kaplan-Meier survival plots, and Cox proportional-hazard models were used for statistical analyses. Results: Persistent positivity for at least one of the tested autoantibodies was detected in 998 children; 388 of children progressed to clinical T1D. Young age at initial seroconversion was associated with a high probability of expansion of IAA-initiated autoimmunity and progression to clinical diabetes, whereas expansion of GADA-initiated autoimmunity and progression to diabetes were not dependent on initial seroconversion age. The strength of HLA risk affected the progression of both IAA- and GADA-initiated autoimmunity. The simultaneous appearance of two other autoantibodies increased the rate of progression to diabetes compared with that of a single secondary autoantibody among subjects with GADA-initiated autoimmunity but not among those with IAA as the first autoantibody. Conclusions: Findings emphasize the differences in the course of islet autoimmunity initiated by either IAA or GADA supporting heterogeneity in the pathogenic process.
  • Hosio, Mayu; Urpilainen, Elina; Hautakoski, Ari; Marttila, Mikko; Arffman, Martti; Sund, Reijo; Ahtikoski, Anne; Puistola, Ulla; Läärä, Esa; Karihtala, Peeter; Jukkola, Arja (2021)
    We investigated the survival of female patients with pre-existing type 2 diabetes (T2D) diagnosed with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of breast, in relation to the use of metformin, other antidiabetic medication (ADM) and statins. The study cohort consisted of 3,165 women (2,604 with IDC and 561 with ILC). The cumulative mortality from breast cancer (BC) and from other causes was calculated using the Aalen-Johansen estimator. The cause-specific mortality rates were analysed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of different medications. No evidence of an association of metformin use with BC mortality was observed in either IDC (HR 0.92, 95% confidence interval [CI] 0.64-1.31) or ILC (HR 0.68, 95% CI 0.32-1.46) patients, when compared to other oral ADMs. The mortality from other causes was found to be lower amongst the IDC patients using metformin (HR 0.64, 95% CI 0.45-0.89), but amongst ILC patients the evidence was inconclusive (HR 1.22, 95% CI 0.64-2.32). Statin use was consistently associated with reduced mortality from BC in IDC patients (HR 0.77, 95% CI 0.62-0.96) and ILC patients (HR 0.59, 95% CI 0.37-0.96), and also mortality from other causes in IDC patients (HR 0.81, 95% CI 0.67-0.96) and in ILC patients (HR 0.66, 95% CI 0.43-1.01). We found no sufficient evidence for the possible effects of metformin and statins on the prognosis of BC being different in the two histological subtypes.
  • Junttila, Ilkka S.; Vuorio, Alpo; Budowle, Bruce; Laukkala, Tanja; Sajantila, Antti (2018)
    Diabetes mellitus (DM) could cause pilot incapacitation and result in aviation fatalities. The mechanisms could be directly as a consequence of acute hypoglycemia/subacute diabetic ketoacidosis (DKA) or indirectly as an acute cardiovascular event by contributing to the development of atherosclerosis in coronary or carotid and cerebral arteries. In this study, DM-related fatal flight accidents in the US National Transport Bureau's database between years 2011-2016 were analyzed with special emphasis on postmortem (PM) glucose levels and correlation of toxicological reports with anamnestic information on DM. Additionally, autopsy results on coronary arteries were reviewed. In 43 out of 1491 (similar to 3%) fatal accidents pilots had DM. Postmortem glucose or glycated hemoglobin percentage (Hb1Ac) was measured in 12 of the 43 cases; while antidiabetic medication was found in 14 of the cases (only two of the cases had both glucose measurements and medication). With the increasing prevalence of DM, a possibility of pilot incapacitation due to DM or complications of DM should be actively studied, even if no anamnestic information of DM was available. While PM hypoglycemia is difficult to assess, we propose a systematic investigation based on measurement of glucose, Hb1Ac%, and ketone bodies, and documentation of atherosclerotic lesions in major arteries to identify or rule out DM as a cause of pilot incapacitation.
  • Finnish Pediat Diabet Register; Turtinen, Maaret; Härkönen, Taina; Parkkola, Anna; Ilonen, Jorma; Knip, Mikael (2019)
    Aims/hypothesis In previous studies, the risk of developing familial type 1 diabetes has been reported to be more than two times higher in the offspring of affected fathers than in those of affected mothers. We tested the hypothesis that index children with an affected father may have a more aggressive disease process at diagnosis than those with other affected first-degree relatives. Methods A cross-sectional, observational study was performed using the Finnish Pediatric Diabetes Register. Clinical and metabolic characteristics, beta cell autoantibodies and HLA class II genetics were analysed from index children in Finland diagnosed before the age of 15 years between January 2003 and December 2016. Information on the presence of type 1 diabetes in first-degree relatives was collected at diagnosis using a structured questionnaire. Results Out of 4993 newly diagnosed index children, 519 (10.4%) had familial type 1 diabetes. More than 5% (n = 253, 5.1%) had an affected father, 2.8% (n = 141) had an affected mother, 1.9% (n = 95) had an affected sibling and 0.6% (n = 30) had two or more affected family members. All clinical and metabolic variables were markedly poorer in children with sporadic vs familial diabetes. The index children with an affected father or mother were younger than those with an affected sibling (median age 7.59 vs 6.74 vs 10.73 years, respectively; p <0.001). After age- and sex-adjusted analyses, index children with an affected father presented more often with ketoacidosis (9.7% vs 3.6%; p = 0.033) and had greater weight loss before diagnosis (3.2% vs 0%; p = 0.006) than those with an affected mother. Children with familial disease tested negative for all autoantibodies more often (3.5% vs 2.1%; p = 0.041) and had insulin autoantibodies more frequently (49.8% vs 42.2%; p = 0.004) than those with sporadic disease. Both major HLA risk haplotypes (DR3-DQ2 and DR4-DQ8) were more often lacking among children with sporadic vs familial disease (15.9% vs 11.2%; p = 0.006). The DR4-DQ8 haplotype was more frequent in the familial vs the sporadic group (75.7% vs 68.5%; p = 0.001) and especially among children with an affected father when compared with children with sporadic disease (77.5% vs 68.5%; p <0.05). When comparing index children with affected parents diagnosed before or after the birth of the index child, a clear male preponderance was seen among the affected parents diagnosed before the birth of the index child (fathers 66.2% vs mothers 33.8%; p = 0.006), whereas the proportion of fathers and mothers was similar if type 1 diabetes was diagnosed after the birth of the index child. Conclusions/interpretation The more severe metabolic derangement at diagnosis in children with sporadic type 1 diabetes compared with those with familial type 1 diabetes was confirmed. The higher frequency of diabetic ketoacidosis and increased weight loss at diagnosis in index children with an affected father compared with an affected mother support the hypothesis that paternal type 1 diabetes is associated with more severe disease in the offspring than maternal diabetes. The sex difference seen between affected parents diagnosed before and after the birth of the index child supports the hypothesis that maternal insulin treatment protects against type 1 diabetes.
  • Holm, Matilda; Saraswat, Mayank; Joenväärä, Sakari; Ristimäki, Ari; Haglund, Caj; Renkonen, Risto (2018)
    Over 1.4 million people are diagnosed with colorectal cancer (CRC) each year, making it the third most common cancer in the world. Increased screening and therapeutic modalities including improved combination treatments have reduced CRC mortality, although incidence and mortality rates are still increasing in some areas. Serum-based biomarkers are mainly used for follow-up of cancer, and are ideal due to the ease and minimally invasive nature of sample collection. Unfortunately, CEA and other serum markers have too low sensitivity for screening and preoperative diagnostic purposes. Increasing interest is focused on the possible use of biomarkers for predicting treatment response and prognosis in cancer. In this study, we have performed mass spectrometry analysis (UPLC-UDMSE) of serum samples from 19 CRC patients. Increased levels of C-reactive protein (CRP), which occur during local inflammation and the presence of a systemic inflammatory response, have been linked to poor prognosis in CRC patients. We chose to analyze samples according to CRP values by dividing them into the categories CRP 30, and, separately, according to short and long 5-year survival. The aim was to discover differentially expressed proteins associated with poor prognosis and shorter survival. We quantified 256 proteins and performed detailed statistical analyses and pathway analysis. We discovered multiple proteins that are up- or downregulated in patients with CRP >30 as compared to CRP
  • McManus, Bettina; Korpela, Riitta; O'Connor, Paula; Schellekens, Harriet; Cryan, John F.; Cotter, Paul D.; Nilaweera, Kanishka N. (2015)
    Background: Several studies in both humans and rodents have examined the use of lactoferrin as a dietary solution to weight gain and visceral fat accretion and have shown promising results in the short term (up to 7 weeks). This study examined the effects of giving lactoferrin over a longer period of time. Methods: For 13 weeks, male C57/BL6J mice were given a diet containing 10 % kJ fat and 20 % kJ casein (LFD) or a diet with 45 % kJ fat and either 20 % kJ casein (HFD) or 20 % kJ lactoferrin (HFD + Lac). Physiological, metabolic, and biochemical parameters were investigated. Gene expression was investigated by Real-Time PCR and microarray. All data was assessed using t-test, ANOVA or ANCOVA. Gene Set Enrichment Analysis was used to interpret microarray data and assess the impact on gene sets with common biological roles. Results: By the end of the trial, HFD + Lac fed mice did not alter energy balance, body composition, bodyweight, or weight gain when compared to the HFD group. Notably, there were no changes in subcutaneous or epididymal adipose leptin mRNA levels between high fat diet groups, however plasma leptin was significantly reduced in the HFD + Lac compared to HFD group (P <0.05) suggesting reduced leptin secretion. Global microarray analysis of the hypothalamus indicate an overall reduction in gene sets associated with feeding behaviour (P <0.01) and an upregulation of gene sets associated with retinol metabolism in the HFD + Lac group compared to the HFD group (P <0.01). Genes in the latter catergory have been shown to impact on the hypothalamic-pituitary-adrenal axis. Notably, plasma corticosterone levels in the HFD + Lac group were reduced compared to the HFD fed mice (P <0.05). Conclusions: The data suggests that prolonged feeding of full-length dietary lactoferrin, as part of a high fat diet, does not have a beneficial impact on weight gain when compared to casein. However, its impact on leptin secretion and accompanying changes in hypothalamic gene expression may underlie how this dietary protein alters plasma corticosterone. The lactoferrin fed mouse model could be used to identify leptin and corticosterone regulated genes in the hypothalamus without the confounding effects of body weight change.
  • Ambrosio, Elena; Podmore, Adrian; dos Santos, Ana L. Gomes; Magarkar, Aniket; Bunker, Alex; Caliceti, Paolo; Mastrotto, Francesca; van der Walle, Christopher F.; Salmaso, Stefano (2018)
    Peptide therapeutics have the potential to self-associate, leading to aggregation and fibrillation. Noncovalent PEGylation offers a strategy to improve their physical stability; an understanding of the behavior of the resulting polymer/ peptide complexes is, however, required. In this study, we have performed a set of experiments with additional mechanistic insight provided by in silico simulations to characterize the molecular organization of these complexes. We used palmitoylated vasoactive intestinal peptide (VIP-palm) stabilized by methoxy-poly(ethylene glycol)(skDa)-cholane (PEG-cholane) as our model system. Homogeneous supramolecular assemblies were found only when complexes of PEG-cholane/VIP-palm exceeded a molar ratio of 2:1; at and above this ratio, the simulations showed minimal exposure of VIP-palm to the solvent. Supramolecular assemblies formed, composed of, on average, 9-11 PEG-cholane/VIP-palm complexes with 2:1 stoichiometry. Our in silico results showed the structural content of the helical conformation in VIP-palm increases when it is complexed with the PEG-cholane molecule; this behavior becomes yet more pronounced when these complexes assemble into larger supramolecular assemblies. Our experimental results support this: the extent to which VIP-palm loses helical structure as a result of thermal denaturation was inversely related to the PEG-cholane:VIP-palm molar ratio. The addition of divalent buffer species and increasing the ionic strength of the solution both accelerate the formation of VIP-palm fibrils, which was partially and fully suppressed by 2 and >4 mol equivalents of PEG-cholane, respectively. We conclude that the relative freedom of the VIP-palm backbone to adopt nonhelical conformations is a key step in the aggregation pathway.
  • Bronsveld, Heleen K.; Jensen, Vibeke; Vahl, Pernille; De Bruin, Marie L.; Cornelissen, Sten; Sanders, Joyce; Auvinen, Anssi; Haukka, Jari; Andersee, Morten; Vestergaard, Peter; Schmidt, Marjanka K. (2017)
    Background Women with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes. Methods and Findings This cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000-2010. Stratified by age at breast cancer diagnosis (50 years), women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories) to women without diabetes, to select similar to 300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR), HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211) and women without diabetes (n = 101), irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR-negative (OR = 2.44(95%C1:1.07-5.55)), HER2-negative (OR = 2.84(95%C1:1.11-7.22)), and basal-like (OR = 3.14(95%C1:1.03-9.60) tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95`)/X1:0.95-6.45)) and triple negative (OR = 2.60(95%CI:0.88-7.67) tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general. Conclusions We found no compelling evidence that women with diabetes, treated with or without insulin, develop different breast cancer subtypes than women without diabetes. However, premenopausal women with diabetes tended to develop breast tumors that do not express hormonal receptors, which are typically associated with poor prognosis.
  • Salkinoja-Salonen, Mirja Sinikka (Helsingin yliopisto, Elintarvike- ja ympäristötieteiden laitos, 2016)
    Mikrobiologian julkaisuja
    The text describes several novel methods and tools for sampling and analysis of specimens from damaged indoor spaces, as well as results obtained with these methods. The report is divided in sections dealing with specific topics, the novel results combined with relevant background literature. Contents: Sisällys: 1. History of indoor epidemics in Finland; 2. Adverse health effects, microbes and toxicity; 3. Adverse health effects connected to indoor microorganisms; 4. Mycotoxins and their producer microbes connected to damaged indoor environment; 5. Bacteria with adverse and beneficial effects on indoor environment; 6. Adverse chemical emissions from building materials; 7. Exposure to deleterious substances from indoor air 8. Sickness connected to exposures in indoor air
  • Bahijri, Suhad; Al-Raddadi, Rajaa; Ajabnoor, Ghada; Jambi, Hanan; Al Ahmadi, Jawaher; Borai, Anwar; Barengo, Noël C; Tuomilehto, Jaakko (2020)
    Abstract Aims/Introduction To develop a non-invasive risk score to identify Saudis having prediabetes or undiagnosed type 2 diabetes. Methods Adult Saudis without diabetes were recruited randomly using a stratified two-stage cluster sampling method. Demographic, dietary, lifestyle variables, personal and family medical history were collected using a questionnaire. Blood pressure and anthropometric measurements were taken. Body mass index was calculated. The 1-h oral glucose tolerance test was carried out. Glycated hemoglobin, fasting and 1-h plasma glucose were measured, and obtained values were used to define prediabetes and type 2 diabetes (dysglycemia). Logistic regression models were used for assessing the association between various factors and dysglycemia, and Hosmer?Lemeshow summary statistics were used to assess the goodness-of-fit. Results A total of 791 men and 612 women were included, of whom 69 were found to have diabetes, and 259 had prediabetes. The prevalence of dysglycemia was 23%, increasing with age, reaching 71% in adults aged ≥65 years. In univariate analysis age, body mass index, waist circumference, use of antihypertensive medication, history of hyperglycemia, low physical activity, short sleep and family history of diabetes were statistically significant. The final model for the Saudi Diabetes Risk Score constituted sex, age, waist circumference, history of hyperglycemia and family history of diabetes, with the score ranging from 0 to 15. Its fit based on assessment using the receiver operating characteristic curve was good, with an area under the curve of 0.76 (95% confidence interval 0.73?0.79). The proposed cut-point for dysglycemia is 5 or 6, with sensitivity and specificity being approximately 0.7. Conclusion The Saudi Diabetes Risk Score is a simple tool that can effectively distinguish Saudis at high risk of dysglycemia.
  • Eskian, Mahsa; Alavi, Abass; Khorasanizadeh, MirHojjat; Viglianti, Benjamin L.; Jacobsson, Hans; Barwick, Tara D.; Meysamie, Alipasha; Yi, Sun K.; Iwano, Shingo; Bybel, Bohdan; Caobelli, Federico; Lococo, Filippo; Gea, Joaquim; Sancho-Munoz, Antonio; Schildt, Jukka; Tatci, Ebru; Lapa, Constantin; Keramida, Georgia; Peters, Michael; Boktor, Raef R.; John, Joemon; Pitman, Alexander G.; Mazurek, Tomasz; Rezaei, Nima (2019)
    Objectives To evaluate the effect of pre-scan blood glucose levels (BGL) on standardized uptake value (SUV) in F-18-FDG-PET scan. Methods A literature review was performed in the MEDLINE, Embase, and Cochrane library databases. Multivariate regression analysis was performed on individual datum to investigate the correlation of BGL with SUVmax and SUVmean adjusting for sex, age, body mass index (BMI), diabetes mellitus diagnosis, F-18-FDG injected dose, and time interval. The ANOVA test was done to evaluate differences in SUVmax or SUVmean among five different BGL groups (200 mg/dl). Results Individual data for a total of 20,807 SUVmax and SUVmean measurements from 29 studies with 8380 patients was included in the analysis. Increased BGL is significantly correlated with decreased SUVmax and SUVmean in brain (p <0.001, p <0.001,) and muscle (p <0.001, p <0.001) and increased SUVmax and SUVmean in liver (p = 0.001, p = 0004) and blood pool (p=0.008, p200 mg/dl had significantly lower SUVmax. Conclusion If BGL is lower than 200mg/dl no interventions are needed for lowering BGL, unless the liver is the organ of interest. Future studies are needed to evaluate sensitivity and specificity of FDG-PET scan in diagnosis of malignant lesions in hyperglycemia.
  • Neonatal Diabet Int Collaborative; Bowman, Pamela; Tuomi, Tiinamaija (2018)
    Background KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients. Methods In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA(1c) and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. Findings 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5.5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10.2 years (IQR 9.3-10.8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA(1c) and sulfonylurea at all time points (ie, pre-transfer [for HbA(1c)], year 1, and most recent followup; n=64)-median HbA(1c) was 8.1% (IQR 7.2-9.2; 65.0 mmol/mol [55.2-77.1]) before transfer to sulfonylureas, 5.9% (5.4-6.5; 41.0 mmol/mol [35.5-47.5]; p Interpretation High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years. Copyright (C) 2018 The Author(s). This is an Open Access article under the CC BY 4.0 license.
  • Teirlinck, Eline; Barras, Alexandre; Liu, Jing; Fraire, Juan C.; Lajunen, Tatu; Xiong, Ranhua; Forier, Katrien; Li, Chengnan; Urtti, Arto; Boukherroub, Rabah; Szunerits, Sabine; De Smedt, Stefaan C.; Coenye, Tom; Braeckmans, Kevin (2019)
    Impaired penetration of antibiotics through bacterial biofilms is one of the reasons for failure of antimicrobial therapy. Hindered drug diffusion is caused on the one hand by interactions with the sticky biofilm matrix and on the other hand by the fact that bacterial cells are organized in densely packed clusters of cells. Binding interactions with the biofilm matrix can be avoided by encapsulating the antibiotics into nanocarriers, while interfering with the integrity of the dense cell clusters can enhance drug transport deep into the biofilm. Vapor nanobubbles (VNB), generated from laser irradiated nanoparticles, are a recently reported effective way to loosen up the biofilm structure in order to enhance drug transport and efficacy. In the present study, we explored if the disruptive force of VNB can be used simultaneously to interfere with the biofilm structure and trigger antibiotic release from light-responsive nanocarriers. The antibiotic tobramycin was incorporated in two types of light-responsive nanocarriersliposomes functionalized with gold nanoparticles (Lip-AuNP) and graphene quantum dots (GQD)and their efficacy was evaluated on Pseudomonas aeruginosa biofilms. Even though the anti-biofilm efficacy of tobramycin was improved by liposomal encapsulation, electrostatic functionalization with 70 nm AuNP unfortunately resulted in premature leakage of tobramycin in a matter of hours. Laser-irradiation consequently did not further improve P. aeruginosa biofilm eradication. Adsorption of tobramycin to GQD, on the other hand, did result in a stable formulation with high encapsulation efficiency, without burst release of tobramycin from the nanocarriers. However, even though laser-induced VNB formation from GQD resulted in biofilm disruption, an enhanced anti-biofilm effect was not achieved due to tobramycin not being efficiently released from GQD. Even though this study was unsuccessful in designing suitable nanocarriers for simultaneous biofilm disruption and light-triggered release of tobramycin, it provides insights into the difficulties and challenges that need to be considered for future developments in this regard.
  • DCCT EDIC Res Grp; Finndiane Study Grp; Syreeni, Anna; Sandholm, Niina; Cao, Jingjing; Toppila, Iiro; Maahs, David M.; Rewers, Marian J.; Snell-Bergeon, Janet K.; Costacou, Tina; Orchard, Trevor J.; Caramori, M. Luiza; Mauer, Michael; Klein, Barbara E. K.; Klein, Ronald; Valo, Erkka; Parkkonen, Maija; Forsblom, Carol; Harjutsalo, Valma; Paterson, Andrew D.; Groop, Per-Henrik (2019)
    Glycated hemoglobin (HbA(1c)) is an important measure of glycemia in diabetes. HbA(1c) is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA(1c) in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA(1c) in FinnDiane at genome-wide significance (P <5 x 10(-8)). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA(1c) also in the meta-analysis with RASS (P <5 x 10(-8)), where these variants had minor allele frequencies 1%. Furthermore, these SNPs were associated with HbA(1c) in an East Asian population without diabetes (P 0.013). A weighted genetic risk score created from 55 HbA(1c)-associated variants from the literature was associated with HbA(1c) in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA(1c) may lead to better prevention of diabetes complications.
  • Rounge, Trine B.; Page, Christian M.; Lepistö, Maija; Ellonen, Pekka; Andreassen, Bettina K.; Weiderpass, Elisabete (2016)
    Aim: We performed an epigenome-wide association study within the Finnish Health in Teens cohort to identify differential DNA methylation and its association with BMI in adolescents. Materials & methods: Differential DNA methylation analyses of 3.1 million CpG sites were performed in saliva samples from 50 lean and 50 heavy adolescent girls by genome-wide targeted bisulfite-sequencing. Results: We identified 100 CpG sites with p-values <0.000524, seven regions by 'bumphunting' and five CpG islands that differed significantly between the two groups. The ten CpG sites and regions most strongly associated with BMI substantially overlapped with obesity-and insulin-related genes, including MC2R, IGFBPL1, IP6K1 and IGF2BP1. Conclusion: Our findings suggest an association between the saliva methylome and BMI in adolescence.
  • Galante, Laura; Pundir, Shikha; Lagström, Hanna; Rautava, Samuli; Reynolds, Clare Marie; Milan, Amber Marie; Cameron-Smith, David; Vickers, Mark Hedley (2020)
    Background:Human milk bioactives may play a role in infant health and development. Although the variability in their concentrations in milk is well-established, the impact of differential milk profiles on infant growth outcomes remains unclear. Thus, the aim of the present study was to investigate whether different concentrations of metabolic hormones are associated with different weight and BMI in infants beyond the first year of life. Methods:Milk samples at 2.6 (+/- 0.4) months after birth and anthropometric measures at 13 months, 2, 3, and 5 years were collected as part of the Finnish STEPS cohort study from 501 mothers and the respective 507 infants. Leptin, adiponectin, insulin-like growth factor (IGF)-1 and cyclic glycine-proline (cGP) in milk were analyzed. Multiple regression models and a repeated measures mixed model were used to examine associations between milk hormone concentrations and weight and BMI z-scores across time, at each time-point, and weight gain from birth to each follow-up visit. All models were corrected for birth weight, infant sex, duration of exclusive and total breastfeeding, time of introduction of solid foods and maternal pre-pregnancy BMI. Results:Higher milk IGF-1 was associated with higher weight at 13 months (p= 0.004) but lower weight at 3 (p= 0.011) and 5 years of age (p= 0.049). Higher cGP was associated with lower weight across the 5 years (p= 0.019) but with higher BMI at 5 years (p= 0.021). Leptin and adiponectin did not display associations with infant growth at this time. Sex interactions were also absent. Conclusions:Our results suggest that the interplay between human milk-borne IGF-1 and cGP is similar to that reported in other mammals and may have an important role in defining infant growth trajectories beyond the first year of life. Further research should explore the determinants and origins of these milk-borne compounds and evaluate their effect on infant growth and metabolism.
  • Huvinen, Emilia; Eriksson, Johan G.; Stach-Lempinen, Beata; Tiitinen, Aila; Koivusalo, Saila B. (2018)
    AimsGestational diabetes (GDM) affects a growing number of women and identification of individuals at risk, e.g., with risk prediction models, would be important. However, the performance of GDM risk scores has not been optimal. Here, we assess the impact of GDM heterogeneity on the performance of two top-rated GDM risk scores.MethodsThis is a substudy of the RADIEL triala lifestyle intervention study including women at high GDM risk. We assessed the GDM risk score by Teede and that developed by Van Leeuwen in our high-risk cohort of 510 women. To investigate the heterogeneity of GDM, we further divided the women according to GDM history, BMI, and parity. With the goal of identifying novel predictors of GDM, we further analyzed 319 women with normal glucose tolerance in the first trimester.ResultsBoth risk scores underestimated GDM incidence in our high-risk cohort. Among women with a BMI30kg/m(2) and/or previous GDM, 49.4% developed GDM and 37.4% received the diagnosis already in the first trimester. Van Leeuwen score estimated a 19% probability of GDM and Teede succeeded in risk identification in 61%. The lowest performance of the risk scores was seen among the non-obese women. Fasting plasma glucose, HbA(1c), and family history of diabetes were predictors of GDM in the total study population. Analysis of subgroups did not provide any further information.ConclusionsOur findings suggest that the marked heterogeneity of GDM challenges the development of risk scores for detection of GDM.
  • Strawbridge, Rona J.; Silveira, Angela; den Hoed, Marcel; Gustafsson, Stefan; Luan, Jian'an; Rybin, Denis; Dupuis, Josee; Li-Gao, Ruifang; Kavousi, Maryam; Dehghan, Abbas; Haljas, Kadri; Lahti, Jari; Gadin, Jesper R.; Backlund, Alexandra; de Faire, Ulf; Gertow, Karl; Giral, Phillipe; Goel, Anuj; Humphries, Steve E.; Kurl, Sudhir; Langenberg, Claudia; Lannfelt, Lars L.; Lind, Lars; Lindgren, Cecilia C. M.; Mannarino, Elmo; Mook-Kanamori, Dennis O.; Morris, Andrew P.; de Mutsert, Renee; Rauramaa, Rainer; Saliba-Gustafsson, Peter; Sennblad, Bengt; Smit, Andries J.; Syvanen, Ann-Christine; Tremoli, Elena; Veglia, Fabrizio; Zethelius, Bjorn; Bjorck, Hanna M.; Eriksson, Johan G.; Hofman, Albert; Franco, Oscar H.; Watkins, Hugh; Jukema, J. Wouter; Florez, Jose C.; Wareham, Nicholas J.; Meigs, James B.; Ingelsson, Erik; Baldassarre, Damiano; Hamsten, Anders; IMPROVE Study Grp (2017)
    Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.
  • Huang, Yisong; Ollikainen, Miina; Muniandy, Maheswary; Zhang, Tao; van Dongen, Jenny; Hao, Guang; van Der Most, Peter J.; Pan, Yue; Pervjakova, Natalia; Sun, Yan; Hui, Qin; Lahti, Jari; Fraszczyk, Eliza; Lu, Xueling; Sun, Dianjianyi; Richard, Melissa A.; Willemsen, Gonneke; Heikkila, Kauko; Leach, Irene Mateo; Mononen, Nina; Kähönen, Mika; Hurme, Mikko A.; Raitakari, Olli T.; Drake, Amanda J.; Perola, Markus; Nuotio, Marja-Liisa; Huang, Yunfeng; Khulan, Batbayar; Räikkönen, Katri; Wolffenbuttel, Bruce H. R.; Zhernakova, Alexandra; Fu, Jingyuan; Zhu, Haidong; Dong, Yanbin; van Vliet-Ostaptchouk, Jana V.; Franke, Lude; Eriksson, Johan G.; Fornage, Myriam; Milani, Lili; Lehtimäki, Terho; Vaccarino, Viola; Boomsma, Dorret; van Der Harst, Pim; de Geus, Eco J. C.; Salomaa, Veikko; Li, Shengxu; Chen, Wei; Su, Shaoyong; Wilson, James; Snieder, Harold; Kaprio, Jaakko; Wang, Xiaoling (2020)
    We conducted an epigenome-wide association study meta-analysis on blood pressure (BP) in 4820 individuals of European and African ancestry aged 14 to 69. Genome-wide DNA methylation data from peripheral leukocytes were obtained using the Infinium Human Methylation 450k BeadChip. The epigenome-wide association study meta-analysis identified 39 BP-related CpG sites withP
  • Galli, Emilia; Harkonen, Taina; Sainio, Markus; Ustav, Mart; Toots, Urve; Urtti, Arto; Yliperttula, Marjo; Lindahl, Maria; Knip, Mikael; Saarma, Mart; Lindholm, Paivi (2016)
    Mesencephalic astrocyte-derived neurotrophic factor (MANF) was recently shown to be essential for the survival and proliferation of pancreatic beta-cells in mice, where deletion of MANF resulted in diabetes. The current study aimed at determining whether the concentration of circulating MANF is associated with the clinical manifestation of human type 1 diabetes (T1D). MANF expression in T1D or MANF levels in serum have not been previously studied. We developed an enzyme-linked immunosorbent assay (ELISA) for MANF and measured serum MANF concentrations from 186 newly diagnosed children and adolescents and 20 adults with longer-term T1D alongside with age-matched controls. In healthy controls the mean serum MANF concentration was 7.0 ng/ml. High MANF concentrations were found in children 1-9 years of age close to the diagnosis of T1D. The increased MANF concentrations were not associated with diabetes-predictive autoantibodies and autoantibodies against MANF were extremely rare. Patients with conspicuously high MANF serum concentrations had lower C-peptide levels compared to patients with moderate MANF concentrations. Our data indicate that increased MANF concentrations in serum are associated with the clinical manifestation of T1D in children, but the exact mechanism behind the increase remains elusive.