Browsing by Subject "insulin"

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  • Hlushchuk, Irena; Barut, Justyna; Airavaara, Mikko; Luk, Kelvin; Domanskyi, Andrii; Chmielarz, Piotr (2022)
    There are several links between insulin resistance and neurodegenerative disorders such as Parkinson's disease. However, the direct influence of insulin signaling on abnormal alpha-synuclein accumulation-a hallmark of Parkinson's disease-remains poorly explored. To our best knowledge, this work is the first attempt to investigate the direct effects of insulin signaling on pathological alpha-synuclein accumulation induced by the addition of oc-synuclein preformed fibrils in primary dopaminergic neurons. We found that modifying insulin signaling through (1) insulin receptor inhibitor GSK1904529A, (2) SHIP2 inhibitor AS1949490 or (3) PTEN inhibitor VO-OHpic failed to significantly affect alpha-synuclein aggregation in dopaminergic neurons, in contrast to the aggregation-reducing effects observed after the addition of glial cell line-derived neurotrophic factor. Subsequently, we tested different media formulations, with and without insulin. Again, removal of insulin from cell culturing media showed no effect on alpha-synuclein accumulation. We observed, however, a reduced alpha-synuclein aggregation in neurons cultured in neurobasal medium with a B27 supplement, regardless of the presence of insulin, in contrast to DMEM/F12 medium with an N2 supplement. The effects of culture conditions were present only in dopaminergic but not in primary cortical or hippocampal cells, indicating the unique sensitivity of the former. Altogether, our data contravene the direct involvement of insulin signaling in the modulation of alpha-synuclein aggregation in dopamine neurons. Moreover, we show that the choice of culturing media can significantly affect preformed fibril-induced oc-synuclein phosphorylation in a primary dopaminergic cell culture.
  • Kokkonen, Tuomo Juhani; Salin, Siru; Jaakkola, Seija Liisa; Taponen, Juhani Olavi; Elo, Kari Tapani; Vanhatalo, Aila Orvokki (2018)
    The aim was to study if overconsumption of grass silage during the far-off dry period (FODP) and decreasing feed allowance in close-up dry period (CUDP) affect body condition score (BCS) and body weight (BW) changes, as well as lactation performance and body tissue mobilization after calving in dairy cows. Control diet (CON) was fed to meet the metabolizable energy (ME) requirements, the test diet (HEI) averaged 144% and 119% of ME requirements in the FODP and CUDP, respectively. All cows were fed concentrates in the CUDP (30% of ME d(-1)). Plasma non-esterified fatty acids (NEFA) were lower and insulin tended to be higher in HEI vs. CON prepartum. No dietary effects in accretion or mobilization of body reserves were observed, and accordingly no differences in silage DMI, ME balance and plasma parameters postpartum were detected. Concentrate DMI and milk yield tended to be lower in HEI vs. CON during early lactation.
  • Gao, Jianguo (Helsingfors universitet, 2017)
    Obesity and insulin resistance (IR) are key factors lead to equine metabolic syndrome and laminitis. Diet may play an important role in eliciting obesity by affecting insulin dynamics. Insulin-pathway signaling and mTORC1 genes may contribute to incred IR. The first objective of this study was to find and validate internal control genes for quantitative PCR method for adipose tissues in Finnhorse mares. The second aim was to quantitate the expression of mTORC1 and insulin-pathway associated genes after pasture season in two different treatment groups of Finnhorse mares and compare gene expression differences between treatment groups. In addition, gene expression differences were compared between two different adipose tissues. Twenty-two mares were equally divided into eleven equal pairs, the two mares of each group were randomly grazed either on cultivated high-yielding pasture (CG) or on semi-natural grassland (NG) from the end of May to the beginning of September. Eight pairs of Finnhorse mares were selected for gene expression profiling. Subcutaneous adipose tissue (SAT) samples were collected from two groups of Finnhorse mares after pasture season. Gene expression of neck and tailhead SAT were determined with quantitative Real-Time PCR method (qPCR). The selected internal control genes were actin beta (ACTB), glucuronidase beta (GUSB) and mitochondrial ribosomal protein L39 (MRPL39). Candidate genes were mechanistic target of rapamycin (MTOR), sterol regulatory element binding transcription factor 1 (SREBF1), sterol regulatory element binding transcription factor 2 (SREBF2), TBC1 domain family member 7 (TBC1D7), leptin (LEP), glucose transporter type 4 (GLUT4), monocyte chemoattractant protein-1 (MCP-1), retinol binding protein 4 (RBP4), tuberous sclerosis 1 (TSC1), tuberous sclerosis 2 (TSC2). There were no distinct gene expression differences between NG and CG groups in both neck and tailhead SAT. However, RBP4 had significantly (P=0.035) higher and GLUT4 had a trend (P=0.064) to higher mRNA expression in CG group in neck SAT. TSC1 had a trend (P=0.071) of higher expression in CG group in tailhead SAT. Gene expression differences were observed between tailhead and neck SAT. SREBF1 and GLUT4 had significantly (P=0.007 and P=0.026, respectively) higher expression levels in tailhead SAT compared to neck SAT. RBP4 had a trend (P=0.066) to higher expression in neck SAT compared to tailhead SAT. Minor differences in gene expression between NG and CG groups indicate that pasture-associated fat depositionmaynotconsiderably affect expressionof insulin-pathway and mTORC1 genes associated to obesity and IR in studied subcutaneous adipose tissues. These results also provide additional evidence to our hypothesis that fattening resulting on unrestricted grazing on cultivated high-yielding pasture does not increase the risk of metabolic diseases in Finnhorse mares when they have normal body condition at the beginning of the grazing season.
  • Miettinen, Helena E.; Rönö, Kristiina; Koivusalo, Saila; Stach-Lempinen, Beata; Pöyhönen-Alho, Maritta; Eriksson, Johan G.; Hiltunen, Timo P.; Gylling, Helena (2014)
  • Harloff-Helleberg, Stine; Fliervoet, Lies A. L.; Fano, Mathias; Schmitt, Mechthild; Antopolski, Maxim; Urtti, Arto; Nielsen, Hanne Morck (2019)
    Oral drug delivery is an attractive noninvasive alternative to injectables. However, oral delivery of biopharmaceuticals is highly challenging due to low stability during transit in the gastrointestinal tract (GIT), resulting in low systemic bioavailability. Thus, novel formulation strategies are essential to overcome this challenge. An interesting approach is increasing retention in the GIT by utilizing mucoadhesive biomaterials as excipients. Here, we explored the potential of the GRAS excipient sucrose acetate isobutyrate (SAIB) to obtain mucoadhesion in vivo. Mucoadhesive properties of a 90% SAIB/10% EtOH (w/w) drug delivery system (DDS) were assessed using a biosimilar mucus model and evaluation of rheological behavior after immersion in biosimilar intestinal fluid. To ease readability of this manuscript, we will refer to this as SAIB DDS. The effect of SAIB DDS on cell viability and epithelial membrane integrity was tested in vitro prior to in vivo studies that were conducted using SPECT/CT imaging in rats. When combining SAIB DDS with biosimilar mucus, increased viscosity was observed due to secondary interactions between biosimilar mucus and sucrose ester predicting considerable mucoadhesion. Mucoadhesion was confirmed in vivo, as radiolabeled insulin entrapped in SAIB DDS, remained in the small intestine for up to 22 h after administration. Moreover, the integrity of the system was investigated using the dynamic gastric model under conditions simulating the chemical composition of stomach fluid and physical shear stress in the antrum under fasted conditions. In conclusion, SAIB is an interesting and safe biomaterial to promote high mucoadhesion in the GIT after oral administration.
  • 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.
  • Klemetti, Miira M.; Teramo, Kari; Kautiainen, Hannu; Wasenius, Niko; Eriksson, Johan G.; Laine, Merja K. (2021)
    Objective To investigate associations between exposure to fetal hypoxia and indicators of metabolic health in young adult offspring of women with type 1 diabetes (OT1D). Methods 156 OT1D born between 7/1995 and 12/2000 at Helsinki University Hospital, Finland, were invited for follow-up between 3/2019 and 11/2019. A control group of 442 adults born from non-diabetic pregnancies, matched for date and place of birth, was obtained from the Finnish Medical Birth Register. In total, 58 OT1D and 86 controls agreed to participate. All OT1D had amniotic fluid (AF) sampled for erythropoietin (EPO) measurement within two days before delivery in order to diagnose fetal hypoxia. In total, 29 OTID had an AF EPO concentration = 14.0 mU/ml, defined as fetal hypoxia, and were categorized into the high EPO (H-EPO) group. At the age of 18-23 years, participants underwent a 2-h 75g oral glucose tolerance test (OGTT) in addition to height, weight, waist circumference, body composition, blood pressure, HbA(1c), cholesterol, triglyceride, high-sensitivity CRP and leisure-time physical activity measurements. Results Two OT1D were diagnosed with diabetes and excluded from further analyses. At young adult age, OT1D in the H-EPO group had a higher BMI than those in the L-EPO group. In addition, among female participants, waist circumference and body fat percentage were highest in the H-EPO group. In the OGTTs, the mean (SD) 2-h post-load plasma glucose (mmol/L) was higher in the H-EPO [6.50 (2.11)] than in the L-EPO [5.21 (1.10)] or control [5.67 (1.48)] offspring (p=0.009). AF EPO concentrations correlated positively with 2-h post-load plasma glucose [r=0.35 (95% CI: 0.07 to 0.62)] and serum insulin [r=0.44 (95% CI: 0.14 to 0.69)] concentrations, even after adjusting for maternal BMI, birth weight z-score, gestational age at birth and adult BMI. Control, L-EPO and H-EPO groups did not differ with regards to other assessed parameters. Conclusions High AF EPO concentrations in late pregnancy, indicating fetal hypoxia, are associated with increased adiposity and elevated post-load glucose and insulin concentrations in young adult OT1D.
  • Peltola, Elina; Hannula, Päivi; Huhtala, Heini; Sintonen, Harri; Metso, Saara; Sand, Juhani; Laukkarinen, Johanna; Tiikkainen, Mirja; Schalin-Jäntti, Camilla; Siren, Jukka; Soinio, Minna; Nuutila, Pirjo; Moilanen, Leena; Ebeling, Tapani; Jaatinen, Pia (2021)
    Objective Insulinomas are rare pancreatic neoplasms, which can usually be cured by surgery. As the diagnostic delay is often long and the prolonged hyperinsulinemia may have long-term effects on health and the quality of life, we studied the long-term health-related quality of life (HRQoL) in insulinoma patients. Design, patients and measurements The HRQoL of adults diagnosed with an insulinoma in Finland in 1980-2010 was studied with the 15D instrument, and the results were compared to those of an age- and gender-matched sample of the general population. The minimum clinically important difference in the total 15D score has been defined as +/- 0.015. The clinical characteristics, details of insulinoma diagnosis and treatment, and the current health status of the subjects were examined to specify the possible determinants of long-term HRQoL. Results Thirty-eight insulinoma patients participated in the HRQoL survey (response rate 75%). All had undergone surgery with a curative aim, a median of 13 (min 7, max 34) years before the survey. The insulinoma patients had a clinically importantly and statistically significantly better mean 15D score compared with the controls (0.930 +/- 0.072 vs 0.903 +/- 0.039, P = .046) and were significantly better off regarding mobility, usual activities and eating. Among the insulinoma patients, younger age at the time of survey, higher level of education and smaller number of chronic diseases were associated with better overall HRQoL. Conclusions In the long term, the overall HRQoL of insulinoma patients is slightly better than that of the general population.
  • Seppälä, Laura K.; Vettenranta, Kim; Pitkäniemi, Janne; Hirvonen, Elli; Leinonen, Maarit K.; Madanat-Harjuoja, Laura-Maria (2020)
    An association between maternal diabetes, its medication and childhood cancer has not been previously explored in a registry-based setting. With a case-control design, we aimed to explore whether maternal diabetes is associated with an increased risk of childhood cancer in the offspring. Combining data from population-based registries, we analyzed a total of 2,029 cases, i.e. persons with childhood cancer diagnosed under the age of 20?years between years 1996-2014 and a total of 10,103 matched population controls. The mothers of the cases/controls and their diagnoses of diabetes (DM) before/during pregnancy as well as their insulin/metformin prescriptions during pregnancy were identified. Conditional logistic regression modelling was used to analyze the risk of childhood cancer. The OR for childhood cancer among those exposed to any maternal diabetes was 1.32 (95% CI 1.14-1.54) compared to the offspring of the non-diabetic mothers. The effect of maternal diabetes on the risk of childhood cancer remained elevated even after adjusting for maternal age, parity and smoking. Our data suggest that maternal diabetes medication may reduce the risk for childhood cancer (adjusted OR 0.83, 95% CI 0.36-1.94), especially in gestational diabetes (adjusted OR 0.26, 95% CI 0.05-1.25), compared to the diabetic mothers without medication. The risk of childhood leukemia was significantly higher among children exposed to any maternal diabetes (OR 1.36, CI 1.04-1.77) compared to the unexposed. Maternal diabetes appears to be associated with an increased risk of childhood cancer in the offspring. The possible risk-reducing effect of an exposure to diabetes medication on offspring cancer risk warrants further investigation. This article is protected by copyright. All rights reserved.
  • Lallukka, S.; Yki-Jarvinen, H. (2016)
    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is commonly associated with features of the metabolic/insulin resistance syndrome ('Metabolic/Obese NAFLD') and may therefore predict type 2 diabetes (T2DM). For this review, we searched for prospective studies examining whether NAFLD predicts T2DM, and if so, whether this occurs independently of factors such as age and obesity. These studies included NAFLD diagnosed by ultrasonography (n = 6) or liver enzymes (n = 14). All ultrasonography studies found NAFLD to predict the risk of T2DM independently of age, and in 4 out of 6 studies NAFLD was also a predictor independently of BMI. NAFLD was a predictor of T2DM in all 14 studies where NAFLD was diagnosed by liver enzymes. In 12 of these studies, ALT or AST or GGT were significant predictors of T2DM risk, independently of age and BMI. NAFLD, however, is heterogeneous and may also be caused by common genetic variants. The I148M variant in PNPLA3 and the E167K variant in TM6SF2 are both associated with increased liver fat content, but not features of the metabolic/insulin resistance syndrome. These genetic forms of NAFLD predict NASH and cirrhosis but not T2DM. Taken together these data imply that 'Metabolic/Obese NAFLD' predicts T2DM independently of age and obesity and support the role of hepatic insulin resistance in the pathogenesis of this disease. (C) 2016 Elsevier Ltd. All rights reserved.
  • Lallukka, Susanna; Luukkonen, Panu K.; Zhou, You; Isokuortti, Elina; Leivonen , Marja; Juuti, Anne; Hakkarainen, Antti; Orho-Melander, Marju; Lundbom, Nina; Olkkonen, Vesa M.; Lassila, Riitta; Yki-Järvinen, Hannele (2017)
    Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant ('IR') versus insulin-sensitive ('IS')] and PNPLA3 genotype (PNPLA3(148MM/MI) vs PNPLA3(148II)). Liver fat content (H-1-MRS) was similarly increased in 'IR' (13 +/- 1%) and PNPLA3(148MM/MI) (12 +/- 2%) as compared to 'IS' (6 +/- 1%, p
  • Khunti, K.; Alsifri, S.; Aronson, R.; Berkovic, M. Cigrovski; Enters-Weijnen, C.; Forsen, T.; Galstyan, G.; Geelhoed-Duijvestijn, P.; Goldfracht, M.; Gydesen, H.; Kapur, R.; Lalic, N.; Ludvik, B.; Moberg, E.; Pedersen-Bjergaard, U.; Ramachandran, A.; HAT Investigator Grp (2016)
    Aims: To determine the global extent of hypoglycaemia experienced by patients with diabetes using insulin, as there is a lack of data on the prevalence of hypoglycaemia in developed and developing countries. Methods: This non-interventional, multicentre, 6-month retrospective and 4-week prospective study using self-assessment questionnaire and patient diaries included 27 585 patients, aged >= 18 years, with type 1 diabetes (T1D; n = 8022) or type 2 diabetes (T2D; n = 19 563) treated with insulin for > 12 months, at 2004 sites in 24 countries worldwide. The primary endpoint was the proportion of patients experiencing at least one hypoglycaemic event during the observational period. Results: During the prospective period, 83.0% of patients with T1D and 46.5% of patients with T2D reported hypoglycaemia. Rates of any, nocturnal and severe hypoglycaemia were 73.3 [95% confidence interval (CI) 72.6-74.0], 11.3 (95% CI 11.0-11.6) and 4.9 (95% CI 4.7-5.1) events/patient-year for T1D and 19.3 (95% CI 19.1-19.6), 3.7 (95% CI 3.6-3.8) and 2.5 events/patient-year (95% CI 2.4-2.5) for T2D, respectively. The highest rates of any hypoglycaemia were observed in Latin America for T1D and Russia for T2D. Glycated haemoglobin level was not a significant predictor of hypoglycaemia. Conclusions: We report hypoglycaemia rates in a global population, including those in countries without previous data. Overall hypoglycaemia rates were high, with large variations between geographical regions. Further investigation into these differences may help to optimize therapy and reduce the risk of hypoglycaemia.
  • Liu, Ying; Mattila, Jaakko; Hietakangas, Ville (2020)
    Insulin/insulin-like growth factor signaling (IIS) is a conserved mechanism to regulate animal physiology in response to nutrition. IIS activity controls gene expression, but only a subset of transcriptional regulators (TRs) targeted by the IIS pathway is currently known. Here we report the results of an unbiased screen forDrosophilaTRs phosphorylated in an IIS-dependent manner. To conduct the screen, we built a library of 857 V5/Strep-tagged TRs under the control of Copper-inducible metallothionein promoter (pMt). The insulin-induced phosphorylation changes were detected by using Phos-tag SDS-PAGE and Western blotting. Eight proteins were found to display increased phosphorylation after acute insulin treatment. In each case, the insulin-induced phosphorylation was abrogated by mTORC1 inhibitor rapamycin. The hits included two components of the NURF complex (NURF38 and NURF55), bHLHZip transcription factor Max, as well as theDrosophilaortholog of human proliferation-associated 2G4 (dPA2G4). Subsequent experiments revealed that the expression of thedPA2G4gene was promoted by the mTOR pathway, likely through transcription factor Myc. Furthermore, NURF38 was found to be necessary for growth in larvae, consistent with the role of IIS/mTOR pathway in growth control.
  • Brännback, Emilia (Helsingin yliopisto, 2020)
    Considering that dogs originate from wolves, who are carnivores, one may speculate whether high amounts of carbohydrates are beneficial to dogs’ health. The aim of this master’s thesis was to compare two different type of diets regarding glucose markers in dogs. Fasting blood samples were taken before and after a diet intervention for the analysis of blood glycosylated hemoglobin (HbA1c), glucose, insulin and glucagon concentrations to compare the differences between dogs fed a high-carbohydrate diet (dry food diet) and a diet containing no dietary carbohydrates (raw food diet). Also bodyweight was evaluated before and after the trial. This master’s thesis was part of a larger study that investigated associations between diet and atopic dermatitis in Staffordshire bull terrier dogs at the University of Helsinki. The dietary intervention lasted for 50-188 days (median 136 days). The high-carbohydrate diet contained: 42% carbohydrates, 23% proteins and 34% fats of total metabolic energy dry matter. Two different low-carbohydrate diets were used. One was a pork-chicken-lamb diet, which contained: 0%: carbohydrates, 25% proteins and 75% fats of total metabolic energy dry matter, and the other was a beef-turkey-salmon, which contained: 0% carbohydrates, 30% proteins and 70% fats of total metabolic energy dry matter. Water was allowed ad libitum. The results showed that feeding a carbohydrate-rich dry food to pet dogs for 4,5 months increased the percentage of HbA1c. In contrast, a raw food diet with low carbohydrate content did not affect the percentage of HbA1c. Both blood glucose and glucagon concentrations decreased within the raw food diet group; while they were not affected in the dry food diet group. No statistical changes in insulin concentrations were found. Based on the results of this study it can be concluded that a high-carbohydrate diet, and a low-carbohydrate, respectively, have different effects on glucose metabolism in dogs. More research is needed to understand how this affects the dog’s health.