Browsing by Subject "Insulin"

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  • Pakkanen, Soile Anja Eliisa; de Vries, Annemarie; Raekallio, Marja Riitta; Mykkänen, Anna Kristina; Palviainen, Mari Johanna; Sankari, Satu Marja; Vainio, Outi Maritta (2018)
    Background: Romifidine, an alpha-2 adrenoceptor agonist, is a widely-used sedative in equine medicine. Besides the desired sedative and analgesic actions, alpha-2 adrenoceptor agonists have side effects like alterations of plasma concentrations of glucose and certain stress-related hormones and metabolites in various species. Vatinoxan (previously known as MK-467), in turn, is an antagonist of alpha-2 adrenoceptors. Because vatinoxan does not cross the blood brain barrier in significant amounts, it has only minor effect on sedation induced by alpha-2 adrenoceptor agonists. Previously, vatinoxan is shown to prevent the hyperglycaemia, increase of plasma lactate concentration and the decrease of insulin and non-esterified free fatty acids (FFAs) caused by alpha-2 adrenoceptor agonists in different species. The aim of our study was to investigate the effects of intravenous romifidine and vatinoxan, alone and combined, on plasma concentrations of glucose and some stress-related hormones and metabolites in horses. Results: Plasma glucose concentration differed between all intravenous treatments: romifidine (80 mu g/kg; ROM), vatinoxan (200 mu g/kg; V) and the combination of these (ROM+V). Glucose concentration was the highest after ROM and the lowest after V. Serum FFA concentration was higher after V than after ROM or ROM+V. The baseline serum concentration of insulin varied widely between the individual horses. No differences were detected in serum insulin, cortisol or plasma adrenocorticotropic hormone (ACTH) concentrations between the treatments. Plasma lactate, serum triglyceride or blood sodium and chloride concentrations did not differ from baseline or between the treatments. Compared with baseline, plasma glucose concentration increased after ROM and ROM+V, serum cortisol, FFA and base excess increased after all treatments and plasma ACTH concentration increased after V. Serum insulin concentration decreased after V and blood potassium decreased after all treatments. Conclusions: Romifidine induced hyperglycaemia, which vatinoxan partially prevented despite of the variations in baseline levels of serum insulin. The effects of romifidine and vatinoxan on the insulin concentration in horses need further investigation.
  • Pakkanen, Soile A E; de Vries, Annemarie; Raekallio, Marja R; Mykkänen, Anna K; Palviainen, Mari J; Sankari, Satu M; Vainio, Outi M (BioMed Central, 2018)
    Abstract Background Romifidine, an α-2 adrenoceptor agonist, is a widely-used sedative in equine medicine. Besides the desired sedative and analgesic actions, α-2 adrenoceptor agonists have side effects like alterations of plasma concentrations of glucose and certain stress-related hormones and metabolites in various species. Vatinoxan (previously known as MK-467), in turn, is an antagonist of α-2 adrenoceptors. Because vatinoxan does not cross the blood brain barrier in significant amounts, it has only minor effect on sedation induced by α-2 adrenoceptor agonists. Previously, vatinoxan is shown to prevent the hyperglycaemia, increase of plasma lactate concentration and the decrease of insulin and non-esterified free fatty acids (FFAs) caused by α-2 adrenoceptor agonists in different species. The aim of our study was to investigate the effects of intravenous romifidine and vatinoxan, alone and combined, on plasma concentrations of glucose and some stress-related hormones and metabolites in horses. Results Plasma glucose concentration differed between all intravenous treatments: romifidine (80 μg/kg; ROM), vatinoxan (200 μg/kg; V) and the combination of these (ROM + V). Glucose concentration was the highest after ROM and the lowest after V. Serum FFA concentration was higher after V than after ROM or ROM + V. The baseline serum concentration of insulin varied widely between the individual horses. No differences were detected in serum insulin, cortisol or plasma adrenocorticotropic hormone (ACTH) concentrations between the treatments. Plasma lactate, serum triglyceride or blood sodium and chloride concentrations did not differ from baseline or between the treatments. Compared with baseline, plasma glucose concentration increased after ROM and ROM + V, serum cortisol, FFA and base excess increased after all treatments and plasma ACTH concentration increased after V. Serum insulin concentration decreased after V and blood potassium decreased after all treatments. Conclusions Romifidine induced hyperglycaemia, which vatinoxan partially prevented despite of the variations in baseline levels of serum insulin. The effects of romifidine and vatinoxan on the insulin concentration in horses need further investigation.
  • Vus, Kateryna; Girych, Mykhailo; Trusova, Valeriya; Gorbenko, Galyna; Kurutos, Atanas; Vasilev, Aleksey; Gadjev, Nikolai; Deligeorgiev, Todor (2019)
    The potential of novel cyanine dyes to inhibit the insulin amyloid formation was evaluated using thioflavin T fluorescence assay, quantum-chemical calculations, molecular docking and molecular dynamics simulations. According to the ability to suppress the insulin fibrillization under physiological conditions the examined compounds were found to follow the order: trimethines > pentamethines > monomethines > heptamethines. Of these, the trimethines 3-3 and 3-5, and pentamethines 5-3 and 5-9 almost completely prevented the protein aggregation by retarding both nucleation (except 3-3) and elongation processes. The quantum-chemical calculations revealed a complex relationship between the dye structure and its inhibitory effects. The molecular docking studies showed that most cyanines bind specifically to the L17 ladder of the B chain, located at the dry steric zipper of the insulin fibril protofilament, and form the stable complexes with the helices of the insulin monomer. The molecular dynamics simulations provided evidence for the increase of insulin helicity in the presence of cyanines. Collectively, the presented findings highlight two possible mechanisms by which cyanines can inhibit the insulin fibrillization: i) stabilization of the native protein structure followed by the retardation of the protein nucleation (all dyes); and ii) blocking the lateral extension of beta-sheets via the dye-protein stacking interactions (3-3, 3-5, 5-3, 5-9). Overall, the obtained results may prove of importance for the design of small molecules capable of preventing amyloid fibril formation by insulin and other proteins. (C) 2018 Elsevier B.V. All rights reserved.
  • Yki-Jarvinen, Hannele (2016)
    Non-alcoholic fatty liver disease (NAFLD) increases risk of mortality from liver and cardiovascular disease (CVD) and is the major cause of hepatocellular carcinoma (HCC), which may develop without cirrhosis. NAFLD predicts type 2 diabetes, even independently of obesity. Globally, the prevalence of NAFLD averages 25% and is as common as the metabolic syndrome. The majority of patients with type 2 diabetes have NAFLD. The challenge for the diabetologist is to identify patients at risk of advanced liver disease and HCC. At a minimum, liver function tests (LFTs), despite being neither specific nor sensitive, should be performed in all patients with the metabolic syndrome or type 2 diabetes. Increases in LFTs, for which the updated reference values are lower (serum ALT approximate to 30 U/l in men and approximate to 20 U/l in women) than those hitherto used in many laboratories, should prompt assessment of fibrosis biomarkers and referral of individuals at risk to a NAFLD/hepatology clinic. Preferably, evaluation of NAFLD should be based on measurement of steatosis biomarkers or ultrasound if easily available. A large number of individuals carry the patatin-like phospholipase domain containing 3 (PNPLA3) I148M variant (30-50%) or the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant (11-15%). These variants increase the risk of advanced liver disease and HCC but not of diabetes or CVD. Genotyping of selected patients for these variants is recommended. Many patients have 'double trouble', i.e. carry both a genetic risk factor and have the metabolic syndrome. Excess use of alcohol could be a cause of 'triple trouble', but such patients would be classified as having alcoholic fatty liver disease. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Kenneth Cusi, DOI: 10.1007/s00125-016-3952-1, and by John Jones, DOI: 10.1007/s00125-016-3940-5) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x).
  • Mokkala, Kati; Juhila, Juuso; Houttu, Noora; Sorsa, Timo; Laitinen, Kirsi (2020)
    Lower level of insulin-like growth factor-binding protein (IGFBP-1) has been observed in insulin resistance, while higher level of matrix metalloproteinase-8 (MMP-8) has been linked to obesity. The aim here was to study in overweight and obese women, typically manifesting with insulin resistance, whether IGFBP-1 and MMP-8 are related to and reflect systemic low-grade inflammation, metabolism and diet. Fasting serum from overweight and obese pregnant women (n = 100) in early pregnancy were analysed for IGFBP-1, phosphorylated IGFBP-1 (phIGFBP-1) and MMP-8. High-sensitivity CRP and GlycA were used as markers for low grade inflammation. GlycA and lipids were quantified using NMR. IGFBP-1 associated negatively with GlycA, evidenced by higher concentrations in the lowest quartile (median 1.53 (IQR 1.45-1.72)) compared to the highest (1.46 (1.39-1.55)) (P = 0.03). Several lipid metabolites, particularly HDL-cholesterol, correlated inversely with phIGFBP-1 (FDR
  • Bian, Hua; Hakkarainen, Antti; Zhou, You; Lundbom, Nina; Yki-Järvinen, Hannele (2018)
    Aims: To examine the distribution of liver fat (LFAT) in non-diabetic subjects and test whether the fat in the right as compared to the left lobe correlates better with components of the metabolic syndrome or not. Methods: In this cross sectional study, we determined LFAT by H-1-MRS in the right lobe (LFAT%(MRS)), and by MRI (LFAT%(MRI)) in four regions of interest (ROIs 1-4, two in the right and two in the left lobe) in 97 non-diabetic subjects (age range 22-74 years, BMI 18-41 kg/m(2)) and compared the accuracy of LFAT(MRI) in the different ROIs in diagnosing non-alcoholic fatty liver disease (NAFLD) using areas under the receiver operator characteristic (AUROC) curves. Results: 38% of the subjects had NAFLD (LFAT%(MRS)). LFAT%(MRI) was significantly higher in the right (5.7 +/- 0.5%) than the left (5.1 +/- 0.4%) lobe (p <0.02). The AUROC for LFAT%(MRI) in the right lobe for diagnosing NAFLD was significantly better than that in the left lobe. The relationships between several metabolic parameters and LFAT%(MRI) in the left lobe were significantly worse than those for LFAT%(MRS) while there was no difference between LFAT%(MRS) and right lobe ROIs. Conclusions: Liver right lobe contains more fat and correlates better with components of the metabolic syndrome than the left in non-diabetic subjects. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
  • Khunti, Kamlesh; Alsifri, Saud; Aronson, Ronnie; Berkovic, Maja Cigrovski; Enters-Weijnen, Catherine; Forsen, Tom; Galstyan, Gagik; Geelhoed-Duijvestijn, Petronella; Goldfracht, Margalit; Gydesen, Helge; Kapur, Rahul; Lalic, Nebojsa; Ludvik, Bernhard; Moberg, Erik; Pedersen-Bjergaard, Ulrik; Ramachandran, Ambady; HAT Investigator Grp (2017)
    Aims: Data on the impact of hypoglycaemia on patients' daily lives and diabetes self-management, particularly in developing countries, are lacking. The aim of this study was to assess fear of, and responses to, hypoglycaemia experienced by patients globally. Materials and methods: This non-interventional, multicentre, 4-week prospective study using self-assessment questionnaires and patient diaries consisted of 27,585 patients, >= 18 years, with type 1 diabetes (n = 8022) or type 2 diabetes (n = 19,563) treated with insulin for > 12 months, at 2004 sites in 24 countries worldwide. Results: Increased blood glucose monitoring (69.7%) and seeking medical assistance (62.0%) were the most common responses in the 4 weeks following hypoglycaemic events for patients with type 1 diabetes and type 2 diabetes, respectively. Approximately 44% of patients with type 1 diabetes or type 2 diabetes increased calorie intake in response to a hypoglycaemic episode. Following hypoglycaemia, 3.9% (type 1 diabetes) and 6.2% (type 2 diabetes) of patients took leave from work or study. Regional differences in fear of, and responses to, hypoglycaemia were evident - in particular, a lower level of hypoglycaemic fear and utilisation of healthcare resources in Northern Europe and Canada. Conclusions: Hypoglycaemia has a major impact on patients and their behaviour. These global data for the first time reveal regional variations in response to hypoglycaemia and highlight the importance of patient education and management strategies. (C) 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the
  • Araújo, Francisca; Shrestha, Neha; João Gomes, Maria; Herranz Blanco, Bárbara; Liu, Dongfei; Hirvonen, Jouni Tapio; L. Granja, Pedro; Almeida Santos, Helder; Sarmento, Bruno (2016)
    Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.
  • Yki-Järvinen, Hannele (2017)
  • Vehkavaara, Satu; Tuomaala, Anna-Kaisa (2020)
    Säännöllisen liikunnan on osoitettu parantavan insuliiniherkkyyttä ja vaikuttavan edullisesti sydän- ja verisuonitautiriskiin. Siksi insuliininpuutosdiabetesta sairastaville suositellaan liikunnan harrastamista. Hypoglykemia on tavallisin liikuntaan liittyvä haittavaikutus, ja etenkin sen pelko voi estää liikunnan harrastamista. Insuliininpuutosdiabeteksen hyvä omahoito mahdollistaa hyvän hoitotasapainon vaihtuvissa arkipäivän tilanteissa, kuten liikunnan yhteydessä. Tämä kuitenkin edellyttää, että insuliininpuutosdiabetesta sairastava ymmärtää eri liikuntamuotojen sekä liikunnan intensiivisyyden ja keston vaikutukset oman elimistönsä reaktioihin ja ennen kaikkea verenglukoosiarvoihinsa. Jatkuva glukoosisensorointi yhdessä kehittyvän insuliinipumpputeknologian ja entistä fysiologisempien insuliinien myötä auttaa insuliininpuutosdiabetesta sairastavan omahoitoa myös liikunnan aikana merkittävästi.
  • Ojala, Johanna; Bäcklund, Tom; Matikainen, Niina (2018)
  • Tuomaala, Anna-Kaisa; Sandini, Lorenzo; Haro, Sulka (2018)
    • Yhdysvalloissa on markkinoilla ensimmäinen kaupallinen ns. hybridikeinohaima. Se annostelee insuliinia automaattisesti kudosglukoosipitoisuuden mukaan. • Avoimeen koodiin perustuva, käyttäjien ohjelmoima OpenAPS-järjestelmä on myös lähellä sitä, ettei käyttäjän tarvitse annostella ateriainsuliinia. • Tekniikan kehitys muuttaa diabeteshoitajien ja -lääkärien työtä.
  • Matikainen, Niina; Gordin, Daniel; Laine, Merja K. (2018)
  • Pulkkinen, Mari-Anne; Kataja, Janne; Saarikoski, Liisa; Tuomaala, Anna-Kaisa (2019)
  • Knip, Mikael (2017)
    About 20 years ago an American study suggested that daily subcutaneous injections of a metabolically inactive insulin analogue with a single amino acid substitution (aspartic acid instead of phenylalanine) at position 25 of the B chain was as effective as intact insulin in preventing autoimmune diabetes in NOD mice. In this issue of Diabetologia Grnholm et al (DOI: 10.1007/s00125-017-4276-5) report that parenteral administration of the same insulin analogue has no preventive effect whatsoever on the development of diabetes in NOD mice; in fact, high doses of the metabolically inactive insulin accelerated disease development. The authors were also unable to show any tolerogenic effect of an insulin peptide mimetope given via a subcutaneous osmotic pump. These data do not support the use of metabolically inactive insulin for the prevention of autoimmune diabetes and question whether insulin alone, intact or inactivated has any role in preventing progression to symptomatic diabetes. Future and ongoing intervention trials in humans with preclinical type 1 diabetes should indicate whether the administration of oral insulin has any protective, neutral or even predisposing effects on the development of symptomatic diabetes.
  • Ajao, Charmaine; Andersson, Maria; Teplova, Vera V; Nagy, Szabolcs; Gahmberg, Carl G.; Andersson, Leif C.; Hautaniemi, Maria; Kakasi, Balazs; Roivainen, Merja; Salkinoja-Salonen, Mirja Sinikka (2015)
    Effects of triclosan (5-chloro-2’-(2,4-dichlorophenoxy)phenol) on mammalian cells were investigated using human peripheral blood mono nuclear cells (PBMC), keratinocytes (HaCaT), porcine spermatozoa and kidney tubular epithelial cells (PK-15), murine pancreatic islets (MIN-6) and neuroblastoma cells (MNA) as targets. We show that triclosan (1 – 10 μg ml-1) depolarised the mitochondria, upshifted the rate of glucose consumption in PMBC, HaCaT, PK-15 and MNA, and subsequently induced metabolic acidosis. Triclosan induced a regression of insulin producing pancreatic islets into tiny pycnotic cells and necrotic death. Short exposure to low concentrations of triclosan (30 min, ≤ 1 μg / ml) paralysed the high amplitude tail beating and progressive motility of spermatozoa, within 30 min exposure, depolarized the spermatozoan mitochondria and hyperpolarised the acrosome region of the sperm head and the flagellar fibrous sheath (distal part of the flagellum). Experiments with isolated rat liver mitochondria showed that triclosan impaired oxidative phosphorylation, downshifted ATP synthesis, uncoupled respiration and provoked excessive oxygen uptake. These exposure concentrations are 100 - 1000 fold lower that those permitted in consumer goods. The mitochondriotoxic mechanism of triclosan differs from that of valinomycin, cereulide and the enniatins by not involving potassium ionophoric activity.
  • Koivisto, Veikko; Ranki-Pesonen, Marjut; Kontula, Kimmo (2016)
  • Paajanen, Hanna; Tuomi, Tiinamaija (2019)
  • Patterson-Kane, J.C.; Karikoski, N.P.; McGowan, C.M. (2018)
    Laminitis, one of the most debilitating conditions of all equids, is now known to be the result of several systemic disease entities. This finding, together with other recent developments in the field of laminitis research, have provoked a rethink of our clinical and research strategies for this condition. First, laminitis is now considered to be a clinical syndrome associated with systemic disease (endocrine disease, sepsis or systemic inflammatory response syndrome, SIRS) or altered weight bearing rather than being a discrete disease entity. Next, laminitis associated with endocrine disease (endocrinopathic laminitis) is now believed to be the predominant form in animals presenting (primarily) for lameness. Third, the designation of laminitis as a primary and severe basement membrane pathology now requires revision. Instead, current data now proposes a variable subclinical phase associated with gross changes in the hoof capsule, with stretching and elongation of the lamellar cells an early and key event in the pathophysiology. These findings have fuelled new mechanistic hypotheses and research directions that will be discussed, together with their implications for future clinical management. (C) 2017 The Authors. Published by Elsevier Ltd.
  • Cai, Mengyin; Bompada, Pradeep; Salehi, Albert; Acosta, Juan R.; Prasad, Rashmi B.; Atac, David; Laakso, Markku; Groop, Leif; De Marinis, Yang (2018)
    Osteopontin (OPN) is involved in various physiological processes and also implicated in multiple pathological states. It has been suggested that OPN may have a role in type 2 diabetes (T2D) by protecting pancreatic islets and interaction with incretins. However, the regulation and function of OPN in islets, especially in humans, remains largely unexplored. In this study, we performed our investigations on both diabetic mouse model SUR1-E1506K+/+ and islets from human donors. We demonstrated that OPN protein, secretion and gene expression was elevated in the diabetic SUR1-E1506K+/+ islets. We also showed that high glucose and incretins simultaneously stimulated islet OPN secretion. In islets from human cadaver donors, OPN gene expression was elevated in diabetic islets, and externally added OPN significantly increased glucose-stimulated insulin secretion (GSIS) from diabetic but not normal glycemic donors. The increase in GSIS by OPN in diabetic human islets was Ca2+ dependent, which was abolished by Ca2+-channel inhibitor isradipine. Furthermore, we also confirmed that OPN promoted cell metabolic activity when challenged by high glucose. These observations provided evidence on the protective role of OPN in pancreatic islets under diabetic condition, and may point to novel therapeutic targets for islet protection in T2D. (C) 2017 Elsevier Inc. All rights reserved.