31 results on '"Gomis, R"'
Search Results
2. Genetic models rule out a major role of beta cell glycogen in the control of glucose homeostasis.
- Author
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Mir-Coll J, Duran J, Slebe F, García-Rocha M, Gomis R, Gasa R, and Guinovart JJ
- Subjects
- Animals, Female, Glycogen physiology, Glycogen Synthase genetics, Glycogen Synthase metabolism, Homeostasis, Insulin genetics, Insulin metabolism, Insulin-Secreting Cells physiology, Male, Mice, Mice, Knockout, Glucose metabolism, Glycogen metabolism, Insulin-Secreting Cells metabolism
- Abstract
Aims/hypothesis: Glycogen accumulation occurs in beta cells of diabetic patients and has been proposed to partly mediate glucotoxicity-induced beta cell dysfunction. However, the role of glycogen metabolism in beta cell function and its contribution to diabetes pathophysiology remain poorly understood. We investigated the function of beta cell glycogen by studying glucose homeostasis in mice with (1) defective glycogen synthesis in the pancreas; and (2) excessive glycogen accumulation in beta cells., Methods: Conditional deletion of the Gys1 gene and overexpression of protein targeting to glycogen (PTG) was accomplished by Cre-lox recombination using pancreas-specific Cre lines. Glucose homeostasis was assessed by determining fasting glycaemia, insulinaemia and glucose tolerance. Beta cell mass was determined by morphometry. Glycogen was detected histologically by periodic acid-Schiff's reagent staining. Isolated islets were used for the determination of glycogen and insulin content, insulin secretion, immunoblots and gene expression assays., Results: Gys1 knockout (Gys1 (KO)) mice did not exhibit differences in glucose tolerance or basal glycaemia and insulinaemia relative to controls. Insulin secretion and gene expression in isolated islets was also indistinguishable between Gys1 (KO) and controls. Conversely, despite effective glycogen overaccumulation in islets, mice with PTG overexpression (PTG(OE)) presented similar glucose tolerance to controls. However, under fasting conditions they exhibited lower glycaemia and higher insulinaemia. Importantly, neither young nor aged PTG(OE) mice showed differences in beta cell mass relative to age-matched controls. Finally, a high-fat diet did not reveal a beta cell-autonomous phenotype in either model., Conclusions/interpretation: Glycogen metabolism is not required for the maintenance of beta cell function. Glycogen accumulation in beta cells alone is not sufficient to trigger the dysfunction or loss of these cells, or progression to diabetes.
- Published
- 2016
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3. Modifications of the homeostasis model assessment of insulin resistance index with age.
- Author
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Soriguer F, Colomo N, Valdés S, Goday A, Rubio-Martín E, Esteva I, Castaño L, Ruiz de Adana MS, Morcillo S, Calle A, García-Fuentes E, Catalá M, Gutiérrez-Repiso C, Delgado E, Gomis R, Ortega E, and Rojo-Martínez G
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cross-Sectional Studies, Diabetes Mellitus, Type 2 epidemiology, Female, Humans, Male, Middle Aged, Obesity epidemiology, Prevalence, Spain epidemiology, Young Adult, Aging metabolism, Health Status Indicators, Homeostasis, Insulin Resistance physiology, Models, Theoretical
- Abstract
The aim of the study was to analyze the association between aging and insulin resistance estimated by the homeostasis model assessment of insulin resistance (HOMA-IR). This work involved two studies: (1) the Di@bet.es study is a cross-sectional study including 4,948 subjects, comprising a representative sample of the adult Spanish population; (2) the Pizarra study is a population-based cohort study undertaken in Pizarra (Spain), in which 1,051 subjects were evaluated at baseline and 714 completed the 6-year follow-up study. Study variables included a clinical and demographic structured survey, a lifestyle survey, a physical examination, and an oral glucose tolerance test in subjects without diabetes. In the Di@bet.es study overall, an increase occurred in blood glucose until the age of 50, after which it remained stable (data adjusted for gender, body mass index, abnormal glucose regulation [AGR]). The HOMA-IR increased significantly with age (p = 0.01), due to a higher prevalence of obesity (p < 0.0001) and AGR (p < 0.001). In non-obese subjects without AGR, HOMA-IR values were not modified with age (p = 0.30), but they were with body mass index (p < 0.001). In the Pizarra study, the HOMA-IR was significantly lower after 6-year follow-up in the whole study population. Subjects with a HOMA-IR level higher than the 75th percentile at baseline were more likely to develop diabetes (OR 2.2, 95 % CI 1.2-3.9; p = 0.007) than subjects with a lower HOMA-IR. We concluded that age per se did not increase HOMA-IR levels, changes that might be related to higher rates of obesity and AGR in older subjects. The HOMA-IR was associated with an increased risk of developing type 2 diabetes 6 years later.
- Published
- 2014
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4. Integrative analysis reveals novel pathways mediating the interaction between adipose tissue and pancreatic islets in obesity in rats.
- Author
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Malpique R, Figueiredo H, Esteban Y, Rebuffat SA, Hanzu FA, Vinaixa M, Yanes O, Correig X, Barceló-Batllori S, Gasa R, Kalko SG, and Gomis R
- Subjects
- Animals, Male, Proteomics, Rats, Rats, Wistar, Triglycerides metabolism, Adipose Tissue metabolism, Islets of Langerhans metabolism, Obesity metabolism
- Abstract
Aims/hypothesis: Comprehensive characterisation of the interrelation between the peripancreatic adipose tissue and the pancreatic islets promises novel insights into the mechanisms that regulate beta cell adaptation to obesity. Here, we sought to determine the main pathways and key molecules mediating the crosstalk between these two tissues during adaptation to obesity by the way of an integrated inter-tissue, multi-platform analysis., Methods: Wistar rats were fed a standard or cafeteria diet for 30 days. Transcriptomic variations by diet in islets and peripancreatic adipose tissue were examined through microarray analysis. The secretome from peripancreatic adipose tissue was subjected to a non-targeted metabolomic and proteomic analysis. Gene expression variations in islets were integrated with changes in peripancreatic adipose tissue gene expression and protein and metabolite secretion using an integrated inter-tissue pathway and network analysis., Results: The highest level of data integration, linking genes differentially expressed in both tissues with secretome variations, allowed the identification of significantly enriched canonical pathways, such as the activation of liver/retinoid X receptors, triacylglycerol degradation, and regulation of inflammatory and immune responses, and underscored interaction network hubs, such as cholesterol and the fatty acid binding protein 4, which were unpredicted through single-tissue analysis and have not been previously implicated in the peripancreatic adipose tissue crosstalk with beta cells., Conclusions/interpretation: The integrated analysis reported here allowed the identification of novel mechanisms and key molecules involved in peripancreatic adipose tissue interrelation with beta cells during the development of obesity; this might help the development of novel strategies to prevent type 2 diabetes.
- Published
- 2014
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5. Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat.
- Author
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Rebuffat SA, Oliveira JM, Altirriba J, Palau N, Garcia A, Esteban Y, Nadal B, and Gomis R
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- Animals, Cell Proliferation, Male, Membrane Proteins genetics, Obesity genetics, Rats, Rats, Wistar, Insulin-Secreting Cells cytology, Insulin-Secreting Cells metabolism, Membrane Proteins metabolism, Obesity metabolism
- Abstract
Aims/hypothesis: During obesity, the increment in beta cell mass in response to the rising demand for insulin is essential to maintain normal glucose homeostasis. However, the precise cellular and molecular mechanisms involved in beta cell mass plasticity remain poorly understood. The Wnt signalling pathway has been suggested as one possible modulator of beta cell proliferation, which represents the principal process involved in beta cell mass expansion. Here, we sought to determine the mechanisms involved in beta cell mass proliferation using diet-induced obese rats., Methods: Wistar rats aged 8 weeks old were fed a standard or cafeteria diet. Global transcriptomic analysis of pancreatic rat islets was performed using microarray analysis. Genetic loss-of-function approaches were performed in dispersed primary rat islets and the beta cell line INS1E. Gene expression was measured by real-time PCR, protein levels by immunoblot analysis, proliferation rates by ELISA and apoptosis by flow cytometry., Results: Sfrp5, coding for secreted frizzled-related protein 5, is downregulated in the pancreatic islets of cafeteria-diet-fed rats as well as in the pancreatic islets of human obese patients. We demonstrate that silencing Sfrp5 increases beta cell proliferation, which correlates with activation of Wnt signalling and enhanced levels of proliferation markers. In addition, we show that expression of Sfrp5 in beta cells is modulated by IGF binding protein 3 (IGFBP3) secreted from visceral adipose tissue., Conclusions/interpretation: Together, these findings reveal an important role for SFRP5 and Wnt signalling in the regulation of beta cell proliferation in obesity.
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- 2013
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6. Prevalence of the metabolic syndrome in Spain using regional cutoff points for waist circumference: the di@bet.es study.
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Marcuello C, Calle-Pascual AL, Fuentes M, Runkle I, Rubio MA, Montañez C, Rojo-Martinez G, Soriguer F, Bordiu E, Goday A, Bosch-Comas A, Carmena R, Casamitjana R, Castaño L, Castell C, Catalá M, Delgado E, Franch J, Gaztambide S, Girbés J, Gomis R, Urrutia I, López-Alba A, Martínez-Larrad MT, Menéndez E, Mora-Peces I, Ortega E, Pascual-Manich G, Serrano-Rios M, Valdés S, Vázquez JA, and Vendrell J
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- Adult, Aged, Aged, 80 and over, Blood Glucose, Female, Humans, Male, Metabolic Syndrome epidemiology, Middle Aged, Obesity, Abdominal epidemiology, Spain epidemiology, Metabolic Syndrome diagnosis, Obesity, Abdominal diagnosis, Waist Circumference
- Abstract
The aim of the study is to assess the prevalence of metabolic syndrome (MetS) in Spain using specific cutoff points for waist circumference (WC) (>94.5 cm for men and >89.5 cm for women) and evaluating the influence of several socio-demographic and economic factors. Data on MetS were obtained from a national study of 4,727 subjects from 18 to 90 years of age, conducted in Spain between 2009 and 2010 (The di@bet.es study). MetS was defined applying the new Harmonized definition (evaluating the use of abdominal obesity (AO) as a obligatory criterion for MetS or not) as well as with other widely used criteria. Results were then compared with data from previous studies. Multiple logistic regression models were used to evaluate the influence of different social factors. The age-standardized MetS prevalence was 38.37 % (CI 35.74-40.99) in men and 29.62 % (CI 27.56-31.69) in women, when AO was required as a diagnostic criterion; 42.13 % (CI 39.37-44.89) and 32.31 % (CI 30.15-34.47) in men and women, respectively, if AO was not considered mandatory. Prevalence of MetS increased with age (p < 0.001 for trend). Women with a lower educational level were more likely to have MetS (OR 4.4; 95 % CI: 2.84-6.7) as compared with those with a higher educational level. Subjects with MetS had a worse physical quality of life. The combination of AO, hypertension and carbohydrate alterations was the most common MetS' pattern. A high prevalence of MetS was detected in the Spanish population especially in men, the elderly and women with a low educational level.
- Published
- 2013
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7. The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice.
- Author
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Pardo FN, Altirriba J, Pradas-Juni M, García A, Ahlgren U, Barberà A, Slebe JC, Yáñez AJ, Gomis R, and Gasa R
- Subjects
- Animals, Blotting, Western, Cell Proliferation drug effects, Diabetes Mellitus, Experimental drug therapy, Fluorescent Antibody Technique, Homeostasis, Male, Mice, Mice, Knockout, Phenotype, Phosphatidylethanolamine Binding Protein pharmacology, Phosphorylation, Diabetes Mellitus, Experimental pathology, Insulin-Secreting Cells metabolism, Insulin-Secreting Cells pathology, NF-kappa B metabolism, Phosphatidylethanolamine Binding Protein metabolism
- Abstract
Aims/hypothesis: Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function., Methods: Rkip1 (also known as Pebp1) knockout (Rkip1 (-/-)) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 (-/-) mice after streptozotocin treatment., Results: Rkip1 (-/-) mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 (-/-) mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice., Conclusions/interpretation: These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.
- Published
- 2012
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8. Prevalence of diabetes mellitus and impaired glucose regulation in Spain: the Di@bet.es Study.
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Soriguer F, Goday A, Bosch-Comas A, Bordiú E, Calle-Pascual A, Carmena R, Casamitjana R, Castaño L, Castell C, Catalá M, Delgado E, Franch J, Gaztambide S, Girbés J, Gomis R, Gutiérrez G, López-Alba A, Martínez-Larrad MT, Menéndez E, Mora-Peces I, Ortega E, Pascual-Manich G, Rojo-Martínez G, Serrano-Rios M, Valdés S, Vázquez JA, and Vendrell J
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Cross-Sectional Studies, Diabetes Mellitus ethnology, Female, Glucose Intolerance ethnology, Glucose Metabolism Disorders epidemiology, Glucose Metabolism Disorders ethnology, Health Surveys, Humans, Male, Middle Aged, Prevalence, Risk Factors, Sex Distribution, Spain epidemiology, Young Adult, Diabetes Mellitus epidemiology, Glucose Intolerance epidemiology
- Abstract
Aims/hypothesis: The Di@bet.es Study is the first national study in Spain to examine the prevalence of diabetes and impaired glucose regulation., Methods: A population-based, cross-sectional, cluster sampling study was carried out, with target population being the entire Spanish population. Five thousand and seventy-two participants in 100 clusters (health centres or the equivalent in each region) were randomly selected with a probability proportional to population size. Participation rate was 55.8%. Study variables were a clinical and demographic structured survey, lifestyle survey, physical examination (weight, height, BMI, waist and hip circumference, blood pressure) and OGTT (75 g)., Results: Almost 30% of the study population had some carbohydrate disturbance. The overall prevalence of diabetes mellitus adjusted for age and sex was 13.8% (95% CI 12.8, 14.7%), of which about half had unknown diabetes: 6.0% (95% CI 5.4, 6.7%). The age- and sex-adjusted prevalence rates of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined IFG-IGT were 3.4% (95% CI 2.9, 4.0%), 9.2% (95% CI 8.2, 10.2%) and 2.2% (95% CI 1.7, 2.7%), respectively. The prevalence of diabetes and impaired glucose regulation increased significantly with age (p < 0.0001), and was higher in men than in women (p < 0.001)., Conclusions/interpretation: The Di@bet.es Study shows, for the first time, the prevalence rates of diabetes and impaired glucose regulation in a representative sample of the Spanish population.
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- 2012
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9. Increased neuronal nitric oxide synthase dimerisation is involved in rat and human pancreatic beta cell hyperactivity in obesity.
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Mezghenna K, Pomiès P, Chalançon A, Castex F, Leroy J, Niclauss N, Nadal B, Cambier L, Cazevieille C, Petit P, Gomis R, Berney T, Gross R, and Lajoix AD
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- Animals, Cells, Cultured, Female, Gene Expression Regulation, Enzymologic, Humans, Insulin Resistance, Insulin Secretion, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells ultrastructure, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Islets of Langerhans ultrastructure, Male, Middle Aged, Mitochondria drug effects, Mitochondria metabolism, Mitochondria ultrastructure, Nitric Oxide Synthase Type I antagonists & inhibitors, Nitric Oxide Synthase Type I genetics, Protein Transport, RNA, Messenger metabolism, Rats, Rats, Mutant Strains, Rats, Zucker, Tissue Culture Techniques, Dimerization, Insulin metabolism, Insulin-Secreting Cells metabolism, Nitric Oxide Synthase Type I metabolism, Obesity metabolism
- Abstract
Aims/hypothesis: Pancreatic beta cell hyperactivity is known to occur in obesity, particularly in insulin-resistant states. Our aim was to investigate whether changes in neuronal nitric oxide synthase (nNOS) function affect beta cell compensation in two relevant models: the Zucker fa/fa rats and pancreatic islets from obese humans., Methods: Glucose-induced insulin response was evaluated in the isolated perfused rat pancreas and in human pancreatic islets from obese individuals. Expression of nNOS (also known as NOS1) and subcellular localisation of nNOS were studied by quantitative RT-PCR, immunoblotting, immunofluorescence and electron microscopy., Results: Pancreatic beta cells from Zucker fa/fa rats and obese individuals were found to be hyper-responsive to glucose. Pharmacological blockade of nNOS was unable to modify beta cell response to glucose in fa/fa rats and in islets from obese individuals, suggesting an abnormal control of insulin secretion by the enzyme. In both cases, nNOS activity in islet cell extracts remained unchanged, despite a drastic increase in nNOS protein and an enhancement in the dimer/monomer ratio, pointing to the presence of high amounts of catalytically inactive enzyme. This relative decrease in activity could be mainly related to increases in islet asymmetric dimethyl-arginine content, an endogenous inhibitor of nNOS activity. In addition, mitochondrial nNOS level was decreased, which contrasts with a strongly increased association with insulin granules., Conclusions/interpretation: Increased nNOS production and dimerisation, together with a relative decrease in catalytic activity and relocalisation, are involved in beta cell hyperactivity in insulin-resistant rats but also in human islets isolated from obese individuals.
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- 2011
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10. The role of transmembrane protein 27 (TMEM27) in islet physiology and its potential use as a beta cell mass biomarker.
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Altirriba J, Gasa R, Casas S, Ramírez-Bajo MJ, Ros S, Gutierrez-Dalmau A, Ruiz de Villa MC, Barbera A, and Gomis R
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- Animals, Blotting, Western, Cell Proliferation, Cells, Cultured, Fluorescent Antibody Technique, Humans, In Vitro Techniques, Male, Membrane Glycoproteins genetics, Polymerase Chain Reaction, Rats, Rats, Wistar, Insulin-Secreting Cells metabolism, Islets of Langerhans metabolism, Membrane Glycoproteins metabolism
- Abstract
Aims/hypothesis: Transmembrane protein 27 (TMEM27) is a membrane protein cleaved and shed by pancreatic beta cells that has been proposed as a beta cell mass biomarker. Despite reports of its possible role in insulin exocytosis and cell proliferation, its function in beta cells remains controversial. We aimed to characterise the function of TMEM27 in islets and its potential use as a beta cell mass biomarker., Methods: To determine TMEM27 function, we studied TMEM27 gene expression and localisation in human healthy and diabetic islets, the correlation of its expression with cell cycle and insulin secretion genes in human islets, its expression in tungstate-treated rats, and the effects of its overproduction on insulin secretion and proliferation in a beta cell line and islets. To elucidate its utility as a beta cell mass biomarker, we studied TMEM27 cleavage in a beta cell line, islets and primary proximal tubular cells., Results: TMEM27 mRNA levels in islets are lower in diabetic donors than in controls. Its gene expression correlates with that of insulin and SNAPIN in human islets. TMEM27 expression is downregulated in islets of tungstate-treated rats, which exhibit decreased insulin secretion and increased proliferation. TMEM27 overproduction in a beta cell line and islets significantly enhanced glucose-induced insulin secretion, with modest or no effects on proliferation. Finally, TMEM27 is cleaved and shed by renal proximal tubular cells and pancreatic islets., Conclusions/interpretation: Our data support a role for TMEM27 in glucose-induced insulin secretion but not in cell proliferation. The finding that its cleavage is not specific to beta cells challenges the current support for its use as a potential beta cell mass biomarker.
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- 2010
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11. Regeneration of insulin production by autologous bone marrow blood autotransplantation in patients with type 1 diabetes.
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Esmatjes E, Montaña X, Real MI, Blanco J, Conget I, Casamitjana R, Rovira M, Gomis R, and Marin P
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- Adult, Age of Onset, Antigens, CD34 blood, Body Mass Index, Bone Marrow Transplantation methods, Diabetes Mellitus, Type 1 physiopathology, Diabetic Angiopathies surgery, Humans, Infusions, Intravenous, Insulin Secretion, Male, Middle Aged, Pilot Projects, Regeneration, Transplantation, Autologous, Bone Marrow Transplantation physiology, Diabetes Mellitus, Type 1 blood, Insulin biosynthesis, Insulin metabolism
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- 2010
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12. Calcium elevation in mouse pancreatic beta cells evoked by extracellular human islet amyloid polypeptide involves activation of the mechanosensitive ion channel TRPV4.
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Casas S, Novials A, Reimann F, Gomis R, and Gribble FM
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- Amyloid ultrastructure, Animals, Cell Line, Cell Survival drug effects, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Humans, Insulin-Secreting Cells cytology, Islet Amyloid Polypeptide, Mice, Microscopy, Electron, Transmission, Substrate Specificity, TRPV Cation Channels genetics, Amyloid pharmacology, Calcium metabolism, Insulin-Secreting Cells drug effects, Insulin-Secreting Cells metabolism, TRPV Cation Channels metabolism
- Abstract
Aims/hypothesis: To investigate the mechanism by which human islet amyloid polypeptide (hIAPP) fibril formation results in calcium influx across the plasma membrane of pancreatic beta cells, and its association with apoptosis., Methods: Cytoplasmic intracellular calcium concentrations ([Ca(2+)](i)) were monitored for 2 h as the 340/380 nm fluorescence ratio in fura-2 loaded cells of the MIN6 mouse pancreatic beta cell line. Cell morphology was evaluated by transmission electron microscopy, and viability by FACS., Results: hIAPP (10 micromol/l) increased [Ca(2+)](i) in 21% of MIN6 cells in standard buffer, and in 8% of cells in Na(+)-free buffer. Transient receptor potential (TRP) channel inhibitors (gadolinium and ruthenium red) prevented the [Ca(2+)](i) rise under both conditions, whilst nifedipine was only effective in the presence of Na(+). hIAPP increased apoptosis in both insulinoma cells and islets in primary culture, and cell viability was partially rescued by ruthenium red (p < 0.001). By RT-PCR, we detected expression of the mechanosensitive TRP cation channel subfamily V member 4 (Trpv4) in MIN6 cells and mouse pancreas. Small interference RNA against Trpv4 prevented hIAPP-induced [Ca(2+)](i) rises, decreased hIAPP-triggered expression of the endoplasmic reticulum (ER) stress response, and reduced hIAPP-triggered cell death by 50% (p < 0.05)., Conclusions/interpretation: Alterations in [Ca(2+)](i) play a key role in hIAPP-induced beta cell cytotoxicity. By electron microscopy, we detected extracellular hIAPP aggregates adjacent to irregular invaginated regions of the plasma membrane. We propose that TRPV4 channels may sense physical changes in the plasma membrane induced by hIAPP aggregation, enabling Ca(2+) entry, membrane depolarisation and activation of L-type Ca(2+) channels. Decreasing the activity of TRPV4 prevented hIAPP-induced [Ca(2+)](i) changes, reduced hIAPP-triggered ER stress and improved cell viability.
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- 2008
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13. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol.
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Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Dargie H, Komajda M, Gubb J, Biswas N, and Jones NP
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- Diabetes Mellitus, Type 2 blood, Drug Therapy, Combination, Female, Humans, Male, Metformin therapeutic use, Rosiglitazone, Safety, Sulfonylurea Compounds therapeutic use, Blood Glucose metabolism, Diabetes Mellitus, Type 2 drug therapy, Hypoglycemic Agents therapeutic use, Thiazolidinediones therapeutic use
- Abstract
Aims/hypothesis: Studies suggest that in addition to blood glucose concentrations, thiazolidinediones such as rosiglitazone improve some cardiovascular (CV) risk factors and surrogate markers, that are abnormal in type 2 diabetes. However, fluid retention might lead to cardiac failure in a minority of people. The aim of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study is to evaluate the long-term impact of these effects on CV outcomes, as well as on long-term glycaemic control, in people with type 2 diabetes., Materials and Methods: RECORD is a 6-year, randomised, open-label study in type 2 diabetic patients with inadequate blood glucose control (HbA1c 7.1-9.0%) on metformin or sulphonylurea alone. The study is being performed in 327 centres in Europe and Australasia. After a 4-week run-in, participants were randomised by current treatment stratum to add-on rosiglitazone, metformin or sulphonylurea, with dose titration to a target HbA1c of < or = 7.0%. If confirmed HbA1c rises to > or = 8.5%, either a third glucose-lowering drug is added (rosiglitazone-treated group) or insulin is started (non-rosiglitazone group). The same criterion for failure of triple oral drug therapy in the rosiglitazone-treated group is used for starting insulin in this group. The primary endpoint is the time to first CV hospitalisation or death, blindly adjudicated by a central endpoints committee. The study aim is to evaluate non-inferiority of the rosiglitazone group vs the non-rosiglitazone group with respect to CV outcomes. Safety, tolerability and study conduct are monitored by an independent board. All CV endpoint and safety data are held and analysed by a clinical trials organisation, and are not available to the study investigators while data collection is open., Results: Over a 2-year period a total of 7,428 people were screened in 25 countries. Of these, 4,458 were randomised; 2,228 on background metformin, 2,230 on background sulphonylurea. Approximately half of the participants are male (52%) and almost all are Caucasian (99%)., Conclusions/interpretation: The RECORD study should provide robust data on the extent to which rosiglitazone, in combination with metformin or sulphonylurea therapy, affects CV outcomes and progression of diabetes in the long term.
- Published
- 2005
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14. Lack of effect of intermittently administered sodium fusidate in patients with newly diagnosed type 1 diabetes mellitus: the FUSIDM trial.
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Conget I, Aguilera E, Pellitero S, Näf S, Bendtzen K, Casamitjana R, Gomis R, and Nicoletti F
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- Adult, C-Peptide blood, Diabetes Mellitus, Type 1 physiopathology, Double-Blind Method, Female, Follow-Up Studies, Glycated Hemoglobin analysis, Glycated Hemoglobin metabolism, Humans, Hypoglycemic Agents therapeutic use, Insulin therapeutic use, Islets of Langerhans drug effects, Islets of Langerhans physiopathology, Male, Anti-Bacterial Agents therapeutic use, Diabetes Mellitus, Type 1 drug therapy, Fusidic Acid therapeutic use, Immunologic Factors therapeutic use
- Abstract
Aims/hypothesis: We evaluated in a double-blind study the effect of early treatment with the immunomodulatory drug fusidin in patients with newly diagnosed type 1 diabetes mellitus., Methods: Twenty-eight adults with newly diagnosed type 1 diabetes were included in the study. The patients were randomly assigned (computer-generated random number sequence) to two experimental groups. Patients allocated to the fusidin (FUS) group (n=15) received sodium fusidate (fusidin; 500 mg orally three times daily for 4 weeks). Subsequently the drug was given at the same dose and scheduled for two consecutive weeks a month followed by 2 weeks a month without the drug for 20 weeks. Subjects allocated to the placebo (PCB) group (n=13) received placebo according to the same schedule and conditions described for sodium fusidate in the FUS group. All patients received a diet adjusted to their age and BMI, and intensive insulin therapy., Results: There were no statistically significant differences between the FUS and PCB groups in beta cell function, evaluated by basal and glucagon-stimulated C-peptide values during the follow-up (24 and 48 weeks). There was also no difference between the two groups in insulin requirement after 48 weeks (0.4+/-0.2 and 0.4+/-0.2 U/kg body weight for the FUS and PCB groups, respectively). Antibody titres, including insulin autoantibodies, were similar in the two groups during the follow-up., Conclusions/interpretation: Early treatment of newly diagnosed type 1 diabetes patients with intermittently administered fusidin failed to influence the natural course of the disease.
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- 2005
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15. Mutation at position -132 in the islet amyloid polypeptide ( IAPP) gene promoter enhances basal transcriptional activity through a new CRE-like binding site.
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Novials A, Mato E, Lucas M, Franco C, Rivas M, Santisteban P, and Gomis R
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- Amino Acid Substitution, Animals, Binding Sites, DNA-Binding Proteins metabolism, Insulin genetics, Islet Amyloid Polypeptide, Mice, Mice, Transgenic, Rats, Replication Origin, Amyloid genetics, Cyclic AMP Response Element-Binding Protein metabolism, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic, Transcription, Genetic genetics
- Abstract
Aims/hypothesis: Mutations in the islet amyloid polypeptide ( IAPP) gene may play a potential role in the abnormal regulation or expression of the peptide. The aim of this study was to determine the functional role of the -132 G/A mutation reported in the promoter region of the IAPP gene in a population of Spanish Type 2 diabetic patients., Methods: We investigated the transcriptional activity using MIN6 cells and luciferase reporter plasmids in several culture conditions. Key regulatory elements of the IAPP promoter region were also analysed by electrophoretic mobility shift assays (EMSA)., Results: The mutant construct doubled IAPP transcriptional activity ( p<0.001). Both constructs showed severely reduced promoter activity (four-fold decrease) in the presence of verapamil and diazoxide. In contrast, IAPP promoter activity was doubled after incubation with forskolin or dexamethasone, regardless of the glucose concentrations in the culture media. EMSA revealed that the -132 G/A mutation increased the binding affinity through two DNA-protein complexes. In addition, a cAMP-responsive element binding protein (CREB) was identified by super-shift EMSA., Conclusions/interpretation: Our studies show that the wild-type and the mutant constructs are regulated in a similar pattern under all conditions, strongly indicating that the -132 G/A mutation increases basal but not inducible transcription. These results may be explained by new binding to the mutant region through CREB and other transcription factors not yet identified.
- Published
- 2004
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16. Acarbose for the prevention of Type 2 diabetes, hypertension and cardiovascular disease in subjects with impaired glucose tolerance: facts and interpretations concerning the critical analysis of the STOP-NIDDM Trial data.
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Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, and Laakso M
- Subjects
- Blood Glucose chemistry, Body Weight drug effects, Canada, Cardiovascular Diseases complications, Cardiovascular Diseases drug therapy, Clinical Protocols, Data Collection ethics, Data Collection methods, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Double-Blind Method, Eating physiology, Ethics, Clinical, Fasting blood, Female, Follow-Up Studies, Glucose Intolerance complications, Glucose Intolerance drug therapy, Humans, Hypertension complications, Hypertension drug therapy, Male, Middle Aged, Patient Selection, Randomized Controlled Trials as Topic, Research Design, Risk Reduction Behavior, Stroke classification, Stroke etiology, Stroke prevention & control, Time Factors, Treatment Outcome, Withholding Treatment ethics, Acarbose therapeutic use, Cardiovascular Diseases prevention & control, Diabetes Mellitus, Type 2 prevention & control, Glucose Intolerance prevention & control, Hypertension prevention & control, Reproducibility of Results
- Abstract
The STOP-NIDDM Trial has shown that acarbose treatment in subjects with impaired glucose tolerance is associated with a significant risk reduction in the development of diabetes, hypertension and cardiovascular complications. Kaiser and Sawicki have accused the investigators of the STOP-NIDDM Trial of major biases in the conduct of the study, of manipulating the data and of conflict of interest. The aim of this paper is to present data and explanations refuting these allegations. In the STOP-NIDDM Trial, 61 subjects were excluded from the efficacy analysis before unblinding for legitimate reasons: failure to satisfy major entry criteria (n=17) and lack of post-randomisation data (n=44). Blinding and randomisation were carried out by an independent biostatistician. Titration of placebo/acarbose is well described in the protocol and in the study design paper. Of the study population, 9.3% had a fasting plasma glucose of > or =7.0 mmol/l at screening and could have been diabetic according to the new diagnostic criteria. However, even if these subjects are excluded, patients having acarbose treatment still saw a significant risk reduction in the development of diabetes (p=0.0027). The changes in weight are consistent in different publications and are related to different times of follow-up and assessment. Weight change does have an effect on the development of diabetes, but acarbose treatment is still effective even after adjusting for this (p=0.0063). The cardiovascular endpoints were a clearly designated assessment in the original protocol, and only those defined in the protocol and ascertained by the independent Cardiovascular Event Adjudication Committee were used in the analysis. Hypertension was defined according to the most recent diagnostic criteria. The STOP-NIDDM Trial results are scientifically sound and credible. The investigators stand strongly behind these results demonstrating that acarbose treatment is associated with a delay in the development of diabetes, hypertension and cardiovascular complications in a high-risk population with IGT.
- Published
- 2004
- Full Text
- View/download PDF
17. Pancreatic islets from cyclin-dependent kinase 4/R24C (Cdk4) knockin mice have significantly increased beta cell mass and are physiologically functional, indicating that Cdk4 is a potential target for pancreatic beta cell mass regeneration in Type 1 diabetes.
- Author
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Marzo N, Mora C, Fabregat ME, Martín J, Usac EF, Franco C, Barbacid M, and Gomis R
- Subjects
- Animals, Cell Division drug effects, Cell Division physiology, Cyclin-Dependent Kinase 4, Enzyme Activation physiology, Genetic Therapy, Genetic Vectors, Glucose metabolism, Glucose pharmacology, Glucose Tolerance Test, Humans, Insulin genetics, Insulin metabolism, Islets of Langerhans metabolism, Lentivirus genetics, Mice, Mice, Transgenic, Organ Size, Oxidation-Reduction, Proinsulin biosynthesis, Proinsulin genetics, Regeneration genetics, Cyclin-Dependent Kinases genetics, Diabetes Mellitus, Type 1 therapy, Islets of Langerhans cytology, Islets of Langerhans physiology, Proto-Oncogene Proteins genetics
- Abstract
Aims/hypothesis: Cyclin-dependent kinase 4 (Cdk4) is crucial for beta cell development. A mutation in the gene encoding for Cdk4, Cdk4R24C, causes this kinase to be insensitive to INK4 cell cycle inhibitors and induces beta cell hyperplasia in Cdk4R24C knockin mice. We aimed to determine whether this Cdk4R24C mutation also affects proper islet function, and whether it promotes proliferation in human islets lentivirally transduced with Cdk4R24C cDNA., Methods: Our study was conducted on wild-type and Cdk4R24C knockin mice. Pancreases were morphometrically analysed. Intraperitoneal glucose tolerance tests and intravenous insulin tolerance tests were performed on wild-type and Cdk4R24C mice. We also did in vitro islet perifusion studies and islet metabolic labelling analysis. Human islets were transduced with Cdk4R24C cDNA., Results: Pancreatic islets from Cdk4R24C knockin mice exhibit a larger insulin-producing beta cell area and a higher insulin content than islets from wild-type littermates. Insulin secretion in response to glucose is faster and reaches a higher peak in Cdk4R24C mice without leading to hypoglycaemia. Conversion of pro-insulin into insulin and its intermediates is similar in Cdk4R24C and wild-type mice. Glucose utilisation and oxidation measured per islet were similar in both experimental groups. Insulin secretion was faster and enhanced in Cdk4R24C islets perifused with 16.7 mmol/l glucose, with slower decay kinetics when glucose returned to 2.8 mmol/l. Moreover, human islets expressing Cdk4R24C cDNA exhibited higher beta cell proliferation., Conclusions/interpretation: Despite their hyperplastic growth, Cdk4R24C insulin-producing islet cells behave like differentiated beta cells with regard to insulin production, insulin secretion in response to glucose, and islet glucose metabolism. Therefore Cdk4 could possibly be used to engineer a source of beta cell mass for islet transplantation.
- Published
- 2004
- Full Text
- View/download PDF
18. Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate.
- Author
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Fernández-Alvarez J, Barberà A, Nadal B, Barceló-Batllori S, Piquer S, Claret M, Guinovart JJ, and Gomis R
- Subjects
- Animals, Cell Division drug effects, Islets of Langerhans drug effects, Islets of Langerhans pathology, Organ Size drug effects, Pancreas anatomy & histology, Pancreas drug effects, Rats, Rats, Wistar, Regeneration drug effects, Diabetes Mellitus, Experimental pathology, Islets of Langerhans physiology, Regeneration physiology, Tungsten Compounds pharmacology
- Abstract
Aims/hypothesis: Sodium tungstate has recently emerged as an effective oral treatment for diabetes. We examined the effects of tungstate administration in the beta-cell mass of the pancreas as well as its therapeutic potential., Methods: Sodium tungstate was administered via drinking water to healthy and neonatal streptozotocin (nSTZ)-diabetic rats for one month. The pancreas from each rat was removed and morphometric and immunocytochemical studies were carried out. The molecular mechanism of tungstate's action was also studied., Results: In nSTZ rats administration of this compound normalised glycaemia, and increased insulinaemia and islet insulin content. Blood glucose concentrations were normalised as early as on day 4 of treatment, and tungstate treatment produced a partial recovery of beta-cell mass. The rats remained normoglycaemic after tungstate withdrawal. Morphometric studies showed that the increase in beta-cell mass was not due to beta-cell hypertrophy but to hyperplasia, with an increase in islet density in treated diabetic rats. Tungstate treatment increased extra-islet beta-cell replication without modifying intra-islet beta-cell replication rates. Moreover, the treatment induced increases in insulin-positive cells located close to ducts; and in PDX-1 positive cells scattered in the exocrine tissue, suggesting active neogenesis. In islets from treated diabetic rats, tungstate is able to increase the phosphorylation state of PDX-1 through the activation of p38., Conclusion/interpretation: These observations indicate that tungstate treatment is able to regenerate a stable, functional pancreatic beta-cell population which leads to and maintains normoglycaemia.
- Published
- 2004
- Full Text
- View/download PDF
19. -To: Poa NR, Cooper GJS, Edgar PF: Amylin gene promoter mutations predispose to Type 2 diabetes in New Zealand Maori. Diabetologia 46: 574-578.
- Author
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Novials A, Kistauri A, Chico A, and Gomis R
- Subjects
- Exons genetics, Genetic Predisposition to Disease genetics, Humans, Islet Amyloid Polypeptide, Mutation, Prevalence, Promoter Regions, Genetic genetics, Sequence Deletion, Amyloid genetics, Diabetes Mellitus, Type 2 genetics
- Published
- 2003
- Full Text
- View/download PDF
20. A high carbohydrate diet does not induce hyperglycaemia in a mitochondrial glycerol-3-phosphate dehydrogenase-deficient mouse.
- Author
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Barberà A, Gudayol M, Eto K, Corominola H, Maechler P, Miró O, Cardellach F, and Gomis R
- Subjects
- Animals, Blood Glucose analysis, Cell Respiration drug effects, Dose-Response Relationship, Drug, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Lipids blood, Mice, Mice, Knockout, Mitochondria physiology, Time Factors, Diabetes Mellitus, Type 2 etiology, Dietary Carbohydrates administration & dosage, Glycerolphosphate Dehydrogenase deficiency, Hyperglycemia etiology, Mitochondria enzymology
- Abstract
Aims/hypothesis: The electrons of the glycolysis-derived reduced form of NADH are transferred to mitochondria through the NADH shuttle system. There are two NADH shuttles: the glycerol phosphate and malate-aspartate shuttle. Mice with a targeted disruption of mitochondrial glycerol-3-phosphate dehydrogenase, a rate-limiting enzyme of the glycerol phosphate shuttle, are not diabetic and have normal islet glucose-induced secretion. In this study, we analyzed if environmental factors, such as a high carbohydrate diet could contribute to the development of Type 2 diabetes mellitus in mice with a specific defective genetic background., Methods: The mice were fed with a high carbohydrate diet for 1 and 6 months, and several biochemical parameters were analysed. The mitochondrial respiratory activity was assayed by polarography; and the islet function was studied by islet perifusion and pancreas perfusion., Results: The high carbohydrate diet induced hyperglycaemia, hyperinsulinaemia, and islet hyperplasia in the wild-type and heterozygote mice. Activity of the respiratory chain complex I also increased in these mice. In contrast, these effects were not observed in the null mice fed with the diet; in addition, these null mice had an increased insulin sensitivity compared to wild-type mice., Conclusion/interpretation: The phenotype of the mice with an impairment of NADH shuttles does not worsen when fed a high carbohydrate diet; moreover, the diet does not compromise islet function.
- Published
- 2003
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- View/download PDF
21. Serum concentrations of the interferon-gamma-inducible chemokine IP-10/CXCL10 are augmented in both newly diagnosed Type I diabetes mellitus patients and subjects at risk of developing the disease.
- Author
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Nicoletti F, Conget I, Di Mauro M, Di Marco R, Mazzarino MC, Bendtzen K, Messina A, and Gomis R
- Subjects
- Adult, Antibodies analysis, Autoantibodies analysis, Chemokine CXCL10, Diabetes Mellitus, Type 1 physiopathology, Female, Glutamate Decarboxylase immunology, Humans, Interferon-gamma blood, Male, Middle Aged, Osmolar Concentration, Reference Values, Risk Factors, Chemokines, CXC blood, Diabetes Mellitus, Type 1 blood, Diabetes Mellitus, Type 1 etiology
- Abstract
Aims/hypothesis: Chemokines are chemotactic cytokines controlling the recruitment of leukocytes from the blood by regulating integrin adhesiveness. It has been shown that the migration of CD4+Th1 and CD4+Th2 cells is governed by specific chemokines. Increasing evidence suggests that the CD4+Th1 cheomoattractant chemokine CXCL10, also termed Interferon (IFN)-gamma -inducible protein (IP)-10 is pathogenetically involved in several immunoinflammatory and autoimmune diseases., Methods: IFN-gamma and IP-10 were quantified by solid-phase ELISA in sera of patients with either newly diagnosed or long-term Type I (insulin-dependent) diabetes mellitus, and in sera of their healthy first degree relatives. The latter were subdivided into "low" and "high" risk prediabetic subjects depending on whether they were negative or positive for the anti-beta-cell autoantibodies ICA and GAD., Results: Compared with healthy control subjects (18%, 9/50), those with a low risk of disease (21%, 5/24) and the group of patients with long-term Type I diabetes (24%, 12/50), IP-10 was found more frequently and at increased concentrations in both newly diagnosed Type I diabetic patients (84%, 42/50) and in those with a high risk of disease (73%, 16/22); in the latter, the IP-10 concentrations correlated with those of IFN-gamma., Conclusion/interpretation: Circulating IP-10 concentrations is increased in patients with Type I diabetes, but only during the early and subclinical stage of the disease.
- Published
- 2002
- Full Text
- View/download PDF
22. A novel mutation in islet amyloid polypeptide (IAPP) gene promoter is associated with Type II diabetes mellitus.
- Author
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Novials A, Rojas I, Casamitjana R, Usac EF, and Gomis R
- Subjects
- Aged, Female, Humans, Islet Amyloid Polypeptide, Male, Middle Aged, Amyloid genetics, Diabetes Mellitus, Type 2 genetics, Mutation, Promoter Regions, Genetic
- Published
- 2001
- Full Text
- View/download PDF
23. MFP14, a multifunctional emerging protein with immunomodulatory properties, prevents spontaneous and recurrent autoimmune diabetes in NOD mice.
- Author
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Panerai AE, Nicoletti F, Sacedote P, Arvidsson L, Conget I, Gomis R, Bartorelli A, and Sandler S
- Subjects
- Animals, Blood Glucose metabolism, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Heat-Shock Proteins metabolism, Humans, Interferon-gamma blood, Interleukin-10 blood, Interleukin-12 blood, Interleukin-4 blood, Islets of Langerhans Transplantation physiology, Lipopolysaccharides pharmacology, Mice, Mice, Inbred NOD, Recombinant Proteins pharmacology, Time Factors, Tumor Necrosis Factor-alpha metabolism, Diabetes Mellitus, Type 1 prevention & control, Heat-Shock Proteins pharmacology, Protein Synthesis Inhibitors pharmacology, Proteins, Ribonucleases
- Abstract
Aims/hypothesis: To test the effects of multifunctional protein 14 (MFP14), which shares structural homology with heat shock proteins (HSPs), on the development of Type I (insulin-dependent) diabetes mellitus in NOD mice., Methods: MFP14 was given to euglycaemic female NOD mice from either the 4th to the 25th or from the 12th until the 35th week, or commencing one day before islet transplantation and until the reappearance of hyperglycaemia. Pancreata from NOD mice treated with multifunctional protein 14 for 14 consecutive weeks until 18 weeks of age were examined histologically for insulitis. Anti-CD3 and/or lipopolysaccharide (LPS)-induced blood levels of interferon (IFN)-gamma, interleukin (IL)-4, IL-10, IL-12 and tumour necrosis factor (TNF)-alpha were measured by ELISA in 10 week-old female NOD mice treated for 6 consecutive weeks with either MFP14 or PBS. Unless otherwise stated, multifunctional protein 14 was administered daily 5 times a week at a dose of 25 microg. Control mice received PBS or, in selected experiments, heat-inactivated MFP14., Results: MFP 14 treated mice had a significantly lower incidence of spontaneous diabetes compared to control mice. The MFP14 was equally effective both upon early and late prophylaxis and the protection persisted until week 50 in mice treated from weeks 4 to 25. Insulitis was significantly reduced by the MFP14. The MFP14 also delayed recurrence of hyperglycaemia in syngeneic islet-transplanted NOD mice. Although MFP14 reduced anti-CD3 and/or LPS-induced blood levels of IFN-gamma, TNF-alpha and IL-12 it increased IL-4 and IL-10., Conclusion/interpretation: The MFP14 could be a possible candidate for the prevention or early treatment of human Type I (insulin-dependent) diabetes mellitus.
- Published
- 2001
- Full Text
- View/download PDF
24. Tungstate is an effective antidiabetic agent in streptozotocin-induced diabetic rats: a long-term study.
- Author
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Barberà A, Gomis RR, Prats N, Rodríguez-Gil JE, Domingo M, Gomis R, and Guinovart JJ
- Subjects
- Aging, Alanine Transaminase blood, Animals, Aspartate Aminotransferases blood, Blood Glucose metabolism, Cornea pathology, Diabetes Mellitus, Experimental metabolism, Diabetes Mellitus, Experimental pathology, Fructosediphosphates analysis, Glucokinase analysis, Glucose metabolism, Glucose-6-Phosphate analysis, Kidney pathology, Liver chemistry, Liver metabolism, Liver pathology, Male, Pyruvate Kinase analysis, Rats, Rats, Wistar, Tungsten Compounds administration & dosage, Tungsten Compounds adverse effects, Diabetes Mellitus, Experimental drug therapy, Tungsten Compounds therapeutic use
- Abstract
Aims/hypothesis: Recent studies have shown the anti diabetic effects of oral sodium tungstate treatment in several animal models of diabetes based on short-term experiments. In this study, we examined the effectiveness of long-term tungstate treatment of streptozotocin-induced-diabetic rats., Methods: Tungstate was administered to the drinking water of rats for eight months., Results: The treatment resulted in a reduction in serum glucose concentrations in diabetic rats, but no change in glycaemia was detected in healthy rats. Alterations in the hepatic glucose metabolism due to diabetes were almost completely counteracted by tungstate treatment. The partial recovery of glucokinase activity, not found in diabetic animals, normalised glycogen and glucose 6-phosphate concentrations. Tungstate treatment also restored pyruvate kinase activity and fructose 2,6-bisphosphate concentrations. In healthy rats, tungstate treatment did not modify the majority of the hepatic parameters studied. Moreover, tungstate treatment prevented diabetes-induced morphological changes in the kidney and ocular lens and also reduced mortality. Furthermore, no hypoglycaemic episodes or undesirable side effects were observed in treated diabetic or healthy rats. In addition, there is no evidence of intolerance developing after prolonged use., Conclusion/interpretation: Tungstate could play a helpful part in the long-term treatment of diabetes.
- Published
- 2001
- Full Text
- View/download PDF
25. Serum levels of the interferon-gamma-inducing cytokine interleukin-18 are increased in individuals at high risk of developing type I diabetes.
- Author
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Nicoletti F, Conget I, Di Marco R, Speciale AM, Morìnigo R, Bendtzen K, and Gomis R
- Subjects
- Adolescent, Adult, Autoantibodies blood, Biomarkers blood, Diabetes Mellitus, Type 1 blood, Family, Female, Glutamate Decarboxylase immunology, Humans, Male, Prediabetic State blood, Prediabetic State genetics, Reference Values, Risk Assessment, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, Interleukin-18 blood, Prediabetic State immunology
- Abstract
Aims/hypothesis: Interleukin (IL)-18 is a cytokine primarily produced by macrophages and capable of inducing T lymphocyte synthesis of interferon (IFN)-gamma. An up-regulated synthesis of IFN-gamma with consequential Type I cytokine dominance has been repeatedly shown in Type I (insulin-dependent) diabetes mellitus and thought to be involved in its pathogenesis. Because increased production of IFN-gamma could be secondary to a dysregulated synthesis of IL-18, we compared the circulating levels of IL-18 in patients with newly diagnosed Type I diabetes with those of non-diabetic first-degree relatives and healthy control subjects., Methods: Serum samples were obtained from healthy control subjects, patients with newly diagnosed Type I diabetes, and their healthy first-degree relatives. The latter were subdivided into "low" and "high" risk prediabetics depending on whether they were negative or positive for two or more of the anti-pancreatic autoantibodies ICA, GAD, IA-2 and IAA. Serum levels of IL-18 were measured by solid-phase ELISA., Results: Interleukin (IL)-18 was above the detection limit of 25 pg/ml in 7 of 40 (17%) healthy control subjects, in 5 of 35 (14%) patients and in 3 of 30 (10%) first-degree relatives at low risk of developing Type I diabetes. In contrast, IL-18 could be detected in 19 of 28 (68%; p < 0.0001) relatives at high risk. The mean serum level of IL-18 was higher in these individuals when compared with the low-risk relatives, patients and control subjects., Conclusions/interpretation: IL-18 serum levels are increased selectively during the early, subclinical stage of Type I diabetes.
- Published
- 2001
- Full Text
- View/download PDF
26. Effects of tungstate in neonatally streptozotocin-induced diabetic rats: mechanism leading to normalization of glycaemia.
- Author
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Barberà A, Fernàndez-Alvarez J, Truc A, Gomis R, and Guinovart JJ
- Subjects
- Animals, Animals, Newborn, Diabetes Mellitus, Experimental chemically induced, Diabetes Mellitus, Type 2 chemically induced, Male, Rats, Rats, Wistar, Streptozocin, Blood Glucose metabolism, Diabetes Mellitus, Experimental physiopathology, Diabetes Mellitus, Type 2 physiopathology, Insulin metabolism, Liver Glycogen metabolism, Tungsten Compounds administration & dosage
- Abstract
The effects of oral administration of tungstate to an animal model of non-insulin-dependent diabetes mellitus (NIDDM), the neonatally streptozotocin-induced diabetic rat was studied. Islet insulin content and beta-cell mass were lowered in these animals. Furthermore, the islets lost their ability to release insulin in response to an increase in glucose concentration. However, the hepatic glucose metabolism in these diabetic animals before the treatment was not significantly altered with regard to glycogen content, or glucokinase or glycogen phosphorylase activities compared with healthy animals. On the other hand, the activation state of glycogen synthase was higher although the total activity was unchanged. Moreover, a 20% increase in the concentrations of liver glucose 6-phosphate compared to their healthy siblings was observed. Oral administration of tungstate for 15 days normalized glycaemia in these diabetic animals (4.6 vs 7.8 mmol/l). Tungstate administration was also able to normalize beta-cell insulin secretion in response to 16.7 mmol/l glucose stimulus, reaching values similar to those observed in healthy animals. Concomitantly, a partial recovery in the insulin content and in preproinsulin mRNA levels was found in the islets of treated animals, which was associated with an increase in the number of beta-cells in the pancreas (1.73 vs 0.86%). The treatment did not change the liver parameters studied, except that it restored glucose 6-phosphate concentrations to healthy values. These data suggest that tungstate administration causes a normalization of glycaemia through the restoration of islet function.
- Published
- 1997
- Full Text
- View/download PDF
27. Anti-islet cell and anti-insulin antibody production by CD5+ and CD5- B lymphocytes in IDDM.
- Author
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Muñoz A, Gallart T, Usac EF, Fernández-Alvarez J, Viñas O, Somoza N, Barceló J, and Gomis R
- Subjects
- Adolescent, Adult, Antibodies, Monoclonal, CD5 Antigens, Cell Separation, Cell Transformation, Viral, Child, Female, Fluorescent Antibody Technique, Humans, Immunoglobulin M analysis, Islets of Langerhans cytology, Male, Antigens, CD immunology, Autoantibodies biosynthesis, B-Lymphocyte Subsets immunology, Diabetes Mellitus, Type 1 immunology, Insulin immunology, Islets of Langerhans immunology
- Abstract
Although CD5 + B lymphocytes are mostly committed to the production of polyreactive natural autoantibodies, CD5 + B lymphocytes committed to the production of somatically mutated and monoreactive high-affinity IgM autoantibodies have been also shown. Increased proportions of CD5 + B lymphocytes in some autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM), have been noticed. The present study was undertaken to analyse the differences between CD5 + and CD5- B lymphocyte subsets for production of IDDM-related autoantibodies, i.e. anti-human insulin antibodies (IA) and anti-human islet cell antibodies (ICA). For this purpose, Epstein-Barr Virus (EBV)-transformation of FACS cell-sorted CD5 + and CD5- B lymphocytes and unfractionated enriched B lymphocytes from nine IDDM patients treated exclusively with recombinant human insulin, and from four healthy control subjects was performed; a mean of 102-216 microcultures with a mean of 1,000-2,333 cells/microculture for each B-lymphocyte fraction and individual was established. Data show that both CD5 + and CD5- B-lymphocyte subsets from either normal subjects or from IDDM patients receiving recombinant human insulin, contain B lymphocytes committed to the production of IA-IgM as a common element of their repertoire. In contrast, cells committed to the production of IA-IgG were only detected among the CD5- B lymphocyte subset from some IDDM patients. Only one microculture, out of a total of 6,211 screened (from control subjects and patients), in the CD5- B-cell subset from a recently-diagnosed IDDM patient, was found to produce ICA-IgM lambda. This might suggest that the frequency of circulating B lymphocytes committed to the production of ICA is very low even in IDDM patients bearing serum ICA. EBV-transformed B cells producing the ICA-IgM lambda were stabilized and cloned by somatic hybridization technique. This ICA-IgM lambda human monoclonal antibody, designated HY1-MB91, is not polyreactive, but shows a restricted reactivity with human pancreatic islets, failing to react with other human tissues including cerebellar cortex, and lacking rheumatoid factor and anti-DNA antibody activities. It also lacks reactivity with pancreatic islets from other mammalian species (rat, mouse and monkey) as well as with other rat tissues, including cerebellar cortex. The antigen recognized by HY1-MB91 antibody in human islet cells is a cytoplasmic component mostly found in beta cells.
- Published
- 1995
- Full Text
- View/download PDF
28. Enzymatic, metabolic and secretory patterns in human islets of type 2 (non-insulin-dependent) diabetic patients.
- Author
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Fernandez-Alvarez J, Conget I, Rasschaert J, Sener A, Gomis R, and Malaisse WJ
- Subjects
- Adolescent, Adult, Aged, Alanine Transaminase metabolism, Aspartate Aminotransferases metabolism, Diabetes Mellitus, Type 2 enzymology, Diabetes Mellitus, Type 2 metabolism, Female, Glucokinase metabolism, Glucose pharmacology, Glutamate Decarboxylase metabolism, Glutamate Dehydrogenase metabolism, Glycerolphosphate Dehydrogenase metabolism, Glycolysis, Hexokinase metabolism, Humans, Insulin Secretion, Islets of Langerhans enzymology, Male, Middle Aged, Reference Values, Diabetes Mellitus, Type 2 physiopathology, Glucose metabolism, Insulin metabolism, Islets of Langerhans metabolism
- Abstract
Islets were isolated by automatic digestion from non-diabetic cadaveric organ donors and from Type 2 (non-insulin-dependent) diabetic subjects. The activity of FAD-glycerophosphate dehydrogenase, but not that of either glutamate dehydrogenase, glutamate-oxalacetate transaminase or glutamate-pyruvate transaminase, was lower in Type 2 diabetic patients than control subjects. Hexokinase, glucokinase and glutamate decarboxylase activities were also measured in islets from control subjects. The utilization of D-[5-3H]glucose, oxidation of D-[6-14C]glucose and release of insulin evoked by D-glucose were all lower in Type 2 diabetic patients than control subjects. The secretory response to the combination of L-leucine and L-glutamine appeared less severely affected. Islets from Type 2 diabetic patients may thus display enzymatic, metabolic and secretory anomalies similar to those often observed in animal models of Type 2 diabetes, including a deficiency of beta-cell FAD-linked glycerophosphate dehydrogenase, the key enzyme of the glycerol phosphate shuttle.
- Published
- 1994
- Full Text
- View/download PDF
29. Human pancreatic islet function at the onset of type 1 (insulin-dependent) diabetes mellitus.
- Author
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Conget I, Fernández-Alvarez J, Ferrer J, Sarri Y, Novials A, Somoza N, Pujol-Borrell R, Casamitjana R, and Gomis R
- Subjects
- Adolescent, Colforsin pharmacology, Female, Glucose pharmacology, Humans, Insulin Secretion, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Proinsulin genetics, Protein Precursors genetics, RNA, Messenger metabolism, Diabetes Mellitus, Type 1 physiopathology, Diabetic Ketoacidosis physiopathology, Insulin metabolism, Islets of Langerhans physiopathology
- Abstract
Viable human pancreatic islets isolated from a recent-onset Type 1 (insulin-dependent) diabetic patient were used to perform in vitro studies. Pre-proinsulin mRNA and insulin content, as well as insulin response were analysed. Insulin response to glucose and forskolin was completely absent in diabetic islets, as compared to control islets. Insulin content was reduced to only one-third of control values (395.0 +/- 3.5 vs 989.0 +/- 46.3 microU/islet) and 20.7 +/- 3.9% of islets from the diabetic pancreas contained insulin-positive cells in immunofluorescence studies. Northern blot analysis revealed a severe reduction in the content of pre-proinsulin mRNA in diabetic pancreatic tissue. Our results indicate that although markedly decreased, beta cells in human pancreatic islets at the onset of Type 1 diabetes are still present. Nevertheless, pancreatic islet function is disproportionately impaired with a complete absence of an insulin response.
- Published
- 1993
- Full Text
- View/download PDF
30. Prevalence of islet cell antibodies, insulin antibodies and hyperglycaemia in 2291 schoolchildren.
- Author
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Bergua M, Solé J, Marion G, Perez MC, Recasens A, Fernàndez J, Casamitjana R, and Gomis R
- Subjects
- Adolescent, Blood Glucose metabolism, Female, Humans, Immunoglobulin G analysis, Male, Autoantibodies analysis, Diabetes Mellitus, Type 1 immunology, Hyperglycemia immunology, Insulin Antibodies analysis, Islets of Langerhans immunology
- Abstract
Islet cell antibodies, insulin antibodies and hyperglycaemia were investigated in 2291 healthy schoolchildren. Eight of the subjects had islet cell antibodies and eight had insulin antibodies. However, no schoolchild who was positive for islet cell antibodies also had insulin antibodies present. Hyperglycaemia was observed in five children but neither islet cell antibodies nor insulin antibodies could be detected in the sera from these particular subjects.
- Published
- 1987
- Full Text
- View/download PDF
31. Effect of nicotinamide therapy upon B-cell function in newly diagnosed type 1 (insulin-dependent) diabetic patients.
- Author
-
Mendola G, Casamitjana R, and Gomis R
- Subjects
- Adolescent, Autoantibodies analysis, C-Peptide metabolism, Clinical Trials as Topic, Diabetes Mellitus, Type 1 drug therapy, Female, Humans, Islets of Langerhans drug effects, Islets of Langerhans immunology, Male, C-Peptide blood, Diabetes Mellitus, Type 1 physiopathology, Islets of Langerhans metabolism, Niacinamide therapeutic use
- Abstract
This study describes the effects of nicotinamide therapy on B-cell function in Type 1 (insulin-dependent) diabetes. C-peptide secretion was studied in 20 patients newly diagnosed with Type 1 diabetes at basal state and also after an i.v. glucagon stimulus. Patients were randomly allocated according to a single-blind schedule, to one of the following treatments over a 45-day period: Group 1: 10 patients, nicotinamide 1 g/day; Group 2: 10 patients, placebo. The C-peptide secretion tests were performed before treatment and on days 15, 45, 180, 365 of the follow-up. The clinical and metabolic data were similar in the two groups of patients. Basal and stimulated C-peptide levels increased by 45 days in both groups, but the increase in stimulated C-peptide response was greater in the nicotinamide group (p less than 0.01). However, the B-cell function decreased after the period of nicotinamide administration. No difference in the number of clinical remissions or insulin requirement and HbA1 between the groups was observed. These data suggest that treatment of Type 1 diabetes with nicotinamide at diagnosis is associated with a moderate increase of C-peptide secretion recovery.
- Published
- 1989
- Full Text
- View/download PDF
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