Search

Your search keyword '"Massa, O"' showing total 95 results
Start Over Author "Massa, O"
95 results on '"Massa, O"'

5. Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED). No sign of proliferative retinopathy in 15 patients with permanent neonatal diabetes with a median diabetes duration of 24 years

Author

IAFUSCO, Dario, Salardi S, Chiari G, Toni S, Rabbone I, Pesavento R, Pasquino B, de Benedictis A, Maltoni G, Colombo C, Russo L, Massa O, Sudano M, Cadario F, Porta M, Barbetti F., Iafusco, Dario, Salardi, S, Chiari, G, Toni, S, Rabbone, I, Pesavento, R, Pasquino, B, de Benedictis, A, Maltoni, G, Colombo, C, Russo, L, Massa, O, Sudano, M, Cadario, F, Porta, M, and Barbetti, F.

Published
2014

6. A heterozygous mutation of the glucokinase gene associated to permanent neonatal diabetes mellitus (PNDM)

Author

Massa, O., Vanelli, M., Cerutti, F., Carbone, I., Njolstad, P., Bonfanti, R., German, M., Santer, R., Prisco, F., Lorini, R., Matschinsky, F., Iafusco, D., Fabrizio Barbetti, Massa, O, Vanelli, M, Cerutti, F, Carbone, I, Njolstad, P, Bonfanti, R, German, M, Santer, R, Prisco, F, Lorini, R, Matschinsky, F, Iafusco, D, Barbetti, F, Massa O, Vanelli M, Cerutti F, Carbone I, Njolstad P, Bonfanti R, German M, Santer R, Prisco F, Lorini R, Matshinsky F, Iafusco D, Barbetti F., Matshinsky, F, Barbetti, F., Iafusco, Dario, and 224 PO, Barbetti F. Congresso Annuale 2003 dell’American Diabetes A. s. s. o. c. i. a. t. i. o. n. Diabetes June 2003 Abstr n.

Published
2003

7. Minimal Incidence of neonatal /infancy onset diabetes in Italy is 1:90000 live births

Author

Iafusco D, Massa O, Pasquino B, Colombo C, Iughetti L, Bizzarri C, Mammi C, Lo Presti D, Suprani T, Schiaffini R, Nichols CG, Russo L, Grasso V, Meschi F, Bonfanti R, Brescianini S, Barbetti F., Iafusco, D, Massa, O, Pasquino, B, Colombo, C, Iughetti, L, Bizzarri, C, Mammi, C, Lo Presti, D, Suprani, T, Schiaffini, R, Nichols, Cg, Russo, L, Grasso, V, Meschi, F, Bonfanti, R, Brescianini, S, and Barbetti, F.

Published
2011

8. Mutational Analysis of KATP Channel in Patients with Transient Neonatal Diabetes and Assessment of Minimal Incidence of Neonatal Diabetes in Italy

Author

RUSSO L, PASQUINO B, IAFUSCO, Dario, IUGHETTI L, CERUTTI F, MESCHI F, SCHIAFFINI R, MASSA O, CALCATERRA V, COLIN G. NICHOLS, STAZI MA, BRESCIANINI S, CADARIO F, GRASSO V, BARBETTI F., American Diabetes Association, Russo, L, Pasquino, B, Iafusco, Dario, Iughetti, L, Cerutti, F, Meschi, F, Schiaffini, R, Massa, O, Calcaterra, V, COLIN G., Nichol, Stazi, Ma, Brescianini, S, Cadario, F, Grasso, V, and Barbetti, F.

Abstract

Results: Neonatal/Infancy onset diabetes mellitus (NDM) is a genetic form of diabetes with onset within 6 months from birth. Two distinct types of NDM are recognized: permanent (PNDM) and transient (TNDM). In TNDM remission of hyperglycemia usually occurs within 6 months from diagnosis. TNDM is frequently caused by paternal isodisomy of chromosome 6 and PNDM by mutations of insulin gene, but both condition can be associated with gain-of-function mutations in genes encoding the subunits of the KATP channel, KCNJ11 and ABCC8. Incidence of PNDM in Italy is 1:210.000. ABCC8 and KCNJ11 genes were screened in 14 patients with TNDM. Minimal incidence of NDM was calculated counting patients with PNDM and TNDM born in Italy between 2005 and 2009 and referred to our laboratory for genetic screening by members of the Italian study group on diabetes of ISPED. We identified mutations in 10 patients with TNDM: three heterozygous mutations of KCNJ11 (R50Q [x2], E229K, E179K) in 4 subjects and 7 heterozygous mutations of ABCC8 (H105Y, S459R, T540I, R826W, R1380C, R1380H, V1523M) in 6 patients (1 compound het. for H105 and T540I). In these 10 patients, duration of insulin therapy ranged between 17 day and 8 months. No difference in mode of presentation of diabetes was found between patients with TNDM or PNDM (29 subjects) due to mutations of KATP channel identified in our laboratory. Mild hyperglycemia (

Published
2011

9. Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families

Author

Lorini, R., Klersy, C., D'Annunzio, G., Massa, O., Minuto, N., Iafusco, D., Bellanne Chantelot, C., Frongia, A. P., Toni, S., Meschi, F., Cerutti, F., Barbetti, F., Pediatric Endocrinology Italian Society, O. F., Diabetology Study Group, Sulli, Nicoletta, Lorini, R, Klersy, C, D'Annunzio, G, Massa, O, Minuto, N, Iafusco, D, Bellannè Chantelot, C, Franzese, Adriana, Frongia, Ap, Toni, S, Meschi, F, Cerutti, F, Barbetti, F, Italian Society of Pediatric, Endocrinology, and Diabetology Study, G. r. o. u. p.

Published
2009

11. Permanent Neonatal/Infancy-Onset Diabetes Mellitus Caused by Seven Novel Mutations of the Insulin Gene

Author

Colombo, C., Porzio, O., Ming, L., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., Hansen, T., Pesavento, R., Cadario, F., Federici, G., Ghirri, P., Arvan, P., Iafusco, D., Fabrizio Barbetti, Colombo, C, Porzio, O, Ming, L, Massa, O, Vasta, M, Salardi, S, Beccaria, L, Monciotti, C, Toni, S, Pedersen, O, Hansen, T, Pesavento, R, Cadario, F, Federici, G, Ghirri, P, Arvan, P, Iafusco, Dario, and Barbetti, F.

Abstract

Results: Permanent Neonatal/Infancy-Onset Diabetes Mellitus is a rare disease, which occurs in about 1 in 140.000 live births in Italy. In a group of 37 patients with this condition we found 19 heterozygous activating mutations of Kir6.2 (KCNJ11) gene and 1 homozygous mutation of the glucokinase. In one of the remaining patients we observed a surprisingly high C-peptide level (8.5 ng/ml) at diabetes onset, a finding similar to that reported in patients with familial hyper(pro)insulinemia caused by mutations in the insulin (INS) gene. We thus screened the entire coding region of the insulin gene in KCNJ11-negative subjects. We detected 7 different heterozygous mutations in 9 Italian probands: the mutation R65C (at the dibasic doublet between the C-peptide and the A-chain) in 3 probands (2 familial cases), and the mutations LB6P, LB6V, LB11P, LB15YB16delinsH, CA6Y, and YA19X. In addition, we found the CA6Y mutation in a proband from Denmark. Diabetes onset spanned from 1 to 6 months from birth, but the affected parents of the 2 familial cases showed diabetes onset at 1 and 4 years of age, respectively. In patients carrying an INS gene mutation diabetes onset occurred later than individuals with KCNJ11 gene mutation by a median of 5 weeks. By transfecting HEK293 cells with wild type, neonatal diabetes (ND) mutations and the R65L familial hyper(pro)insulinemia (control) mutation (pro)insulin cDNAs, we found that wt (pro)insulin and the R65L mutation but not ND mutations are secreted by 293 cells. XBP1 splicing, a marker of endoplasmic reticulum stress, was induced in 293 cells transfected with ND mutations, but not by wt or R65L (pro)insulin expression. Annexin V (early apoptosis) and propidium iodide (late apoptosis) analyzed by FACS were found increased in 203 cells transfectd with the LB15YB16delinsH and CA6Y mutations. Accordingly, after transfection of INS-1E cells with wild type, the R65L or ND mutations only cells expressing wild type or R65L (pro)insulin were viable after 96 hours. We conclude that INS gene mutations can cause permanent neonatal/infancy onset diabetes by ER stress-induced apoptosis of the beta cells. Category: Genetics - Type 2 Diabetes

Published
2008

14. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes

Author

MASSA O., D'AMATO E., GLOYN A., HATTERSLEY A., PASQUINO B., TONINI G., DAMMACCO F., ZANNETTE G., MESCHI F., PORZIO O., BOTTAZZO G., CRINO A., LORINI R., CERRUTTI F., VANELLI M., BARBETTI F., IAFUSCO, Dario, Massa, O., Iafusco, Dario, D'Amato, E., Gloyn, A., Hattersley, A., Pasquino, B., Tonini, G., Dammacco, F., Zannette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerrutti, F., Vanelli, M., and Barbetti, F.

Subjects
Kir6.2, gene kcnj11, Male, Potassium Channels, Developmental delay, adenosine triphosphate, DNA Mutational Analysis, KATP channel, KCNJ11, Neonatal diabetes, PNDM, amino acid, adolescent, article, autoimmune disease, child, clinical article, controlled study, developmental disorder, diabetes mellitus, female, gene, gene mutation, heterozygote, human, infant, insulin dependent diabetes mellitus, male, motor dysfunction, newborn disease, nucleotide sequence, permanent neonatal diabetes mellitus, priority journal, Diabetes Mellitus, Diabetes Mellitus, Type 1, Female, Humans, Infant, Infant, Newborn, Italy, Mutation, Potassium Channels, Inwardly Rectifying, Settore MED/13 - Endocrinologia, Settore BIO/12, Newborn, Inwardly Rectifying, neonatal diabete, Type 1
Abstract

Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes.

Published
2005

18. Phosphorylation of seminal vesicle protein IV on Ser58 enhances its peroxidase-stimulating activity

Author

METAFORA V, FRANCO P, MASSA O, MORELLI F, FERRANTI P, MAMONE G, MALORNI A, STOPPELLI MP, METAFORA S., STIUSO, Paola, Metafora, Mv, Franco, P, Massa, O, Morelli, F, Stiuso, P, Ferranti, Pasquale, Mamone, G, Malorni, A, Stoppelli, P, Metafora, S., Metafora, V, Stiuso, Paola, Ferranti, P, and Stoppelli, Mp

Subjects
Male, Glutathione Peroxidase, Spectrometry, Mass, Electrospray Ionization, Molecular Sequence Data, Seminal Plasma Proteins, Proteins, Seminal Vesicles, Cyclic AMP-Dependent Protein Kinases, Peptide Fragments, Rats, Inbred F344, Rats, Kinetics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Serine, Animals, Tetradecanoylphorbol Acetate, Amino Acid Sequence, Phosphorylation, Rats, Wistar, Chromatography, High Pressure Liquid, Horseradish Peroxidase, Protein Kinase C
Abstract

In this study we show that SV-IV, a major immunomodulatory, anti-inflammatory, and sperm immunoprotective protein secreted from the rat seminal vesicle epithelium, acts in vitro as a substrate of protein kinase C (PKC) competing efficiently with H1 histone, a very well known PKC substrate. Electrospray mass spectrometry (ES-MS) analysis demonstrated that approximately 10% of the native SV-IV molecules were phosphorylated by PKC and that such a modification involved only a single serine residue (Ser58) out of the 22 occurring in the protein. Interestingly, this modification produced a substantial enhancement (approximately 50%) of the native SV-IV's ability to stimulate the activity of both horseradish peroxidase (POD) and selenium-dependent glutathione peroxidase (GPX), an enzyme that is known to protect the mammalian spermatozoa from oxidative stress and loss of motility in the female genital tract following ejaculation. In contrast, the phosphorylation of SV-IV on Ser58 did not produce any effect on the anti-inflammatory properties of SV-IV, as measured by its ability to inhibit the phospholipase A2.

Published
2001

20. Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families

Author

Lorini, R, Klersy, C, D'Annunzio, G, Massa, O, Minuto, N, Iafusco, D, Bellanne-Chantelot, C, Frongia, A, Toni, S, Meschi, F, Cerutti, F, Barbetti, F, Manca Bitti, M, and Italian Society of Pediatric Endocrinology and Diabetology (ISPED) Study Group

Subjects
Male, Settore MED/38 - Pediatria Generale e Specialistica, Adolescent, Infant, Settore MED/13 - Endocrinologia, Humans, Glucokinase, Child, Italy, Child, Preschool, Hyperglycemia, Diabetes Mellitus, Type 2, Hepatocyte Nuclear Factor 1-alpha, Mutation, Female, Diabetes Mellitus, Preschool, Type 2
Published
2009

23. Missense mutations in the TGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes. Mutation in brief no. 982. Online

Author

Porzio, O., Massa, O., Cunsolo, V., Colombo, C., Malaponti, M., Bertuzzi, F., Hansen, T., Johansen, A., Pedersen, O., Meschi, F., Alessandro Terrinoni, Melino, G., Federici, M., Decarlo, N., Menicagli, M., Campani, D., Marchetti, P., Ferdaoussi, M., Froguel, P., Federici, G., Vaxillaire, M., and Barbetti, F.

Subjects
Adult, Heterozygote, Transglutaminases, Settore MED/09 - Medicina Interna, Settore M-EDF/01 - Metodi e Didattiche delle Attivita' Motorie, Adolescent, Animals, Age of Onset, COS Cells, Humans, GTP-Binding Proteins, Mutation, Missense, Cercopithecus aethiops, Diabetes Mellitus, Type 2, Immunohistochemistry, Settore BIO/12, Settore MED/13 - Endocrinologia, Chlorocebus aethiops, Mutation, Diabetes Mellitus, Protein Glutamine gamma Glutamyltransferase 2, Missense, Type 2
Abstract

Transglutaminase 2 (TG2 or TGM2) is a multi-functional enzyme which catalyzes transamidation reactions or acts as a G-protein in intracellular signalling. Tgm2-/- Mice lacking TG2 activity are glucose intolerant and show impairment of insulin secretion, suggesting an important physiological role for TG2 in the pancreatic beta cell. We have previously described a TGM2 heterozygous missense mutation ((c.998AG, p.N333S) in a 14 year-old patient with insulin-treated diabetes and in his diabetic father. The aim of this study was to further investigate the role of TG2 in early-onset type 2 diabetes. We analysed the TGM2 gene in 205 patients with clinically defined Maturity Onset Diabetes of the Young (MODY) or early-onset type 2 diabetes. We found two novel heterozygous mutations (c.989TG, p.M330R; c.992TA, p.I331N), which were not detected in 300 normoglycemic controls. All mutations were in residues which are located close to the catalytic site and impaired transamidating activity in vitro. Gene expression of TGM family genes and localization of TG2 in normal human pancreas indicated that TG2 is the only transglutaminase significantly expressed in human pancreatic islet cells. We conclude that reduced TG2 activity can contribute to disorders of glucose metabolism possibly via an impairment of insulin secretion.

Published
2007

24. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes

Author

Massa, O, Iafusco, D, D'Amato, E, Gloyn, Al, Hattersley, At, Pasquino, B, Tonini, G, Dammacco, F, Zanette, G, Meschi, F, Porzio, O, Bottazzo, G, Crino, A, Lorini, RENATA GIUSEPPINA, Cerutti, F, Vanelli, M, Barbetti, F, and EARLY ONSET DIABETES STUDY GROUP OF THE ITALIAN SOCIETY OF PEDIATRIC ENDOCRINOLOGY AND DIABETOLOGY

Published
2005

26. In vitro receptor imaging for characterization of human solid tumors

Author

DEL VECCHIO, SILVANA, SALVATORE, MARCO, Stoppelli MP, Carriero MV, Fonti R, Massa O, Li PY, Botti G, Cerra M, D'Aiuto G, Esposito G, DEL VECCHIO, Silvana, Stoppelli, Mp, Carriero, Mv, Fonti, R, Massa, O, Li, Py, Botti, G, Cerra, M, D'Aiuto, G, Esposito, G, and Salvatore, Marco

Published
1994

28. The second activating glucokinase mutation (A456V): Implications for glucose homeostasis and diabetes therapy

Author

Henrik Thybo Christesen, Jacobsen, B. B., Odili, S., Buettger, C., Cuesta-Munoz, A., Hansen, T., Brusgaard, K., Massa, O., Magnuson, M. A., Shiota, C., Matschinsky, F. M., and Barbetti, F.

Subjects
Male, Adolescent, Diazoxide, Infant, Newborn, Mutation, Missense, Settore MED/13 - Endocrinologia, Enzyme Activation, Kinetics, Glucose, Allosteric Regulation, Glucokinase, Infant, Small for Gestational Age, Insulin Secretion, Diabetes Mellitus, Homeostasis, Humans, Insulin, Phosphorylation, Glutathione Transferase
Abstract

In this study, a second case of hyperinsulinemic hypoglycemia due to activation of glucokinase is reported. The 14-year-old proband had a history of neonatal hypoglycemia, treated with diazoxide. He was admitted with coma and convulsions due to nonketotic hypoglycemia. His BMI was 34 kg/m(2), and his fasting blood glucose ranged from 2.1 to 2.7 mmol/l, associated with inappropriately high serum levels of insulin, C-peptide, and proinsulin. An oral glucose tolerance test (OGTT) showed exaggerated responses of these peptides followed by profound hypoglycemia. Treatment with diazoxide and chlorothiazide was effective. His mother never had clinical hypoglycemic symptoms, even though her fasting blood glucose ranged from 2.9 to 3.5 mmol/l. Increases in serum insulin, C-peptide, and proinsulin in response to an OGTT suggested a lower threshold for glucose-stimulated insulin release (GSIR). Screening for mutations in candidate genes revealed a heterozygous glucokinase mutation in exon 10, substituting valine for alanine at codon 456 (A456V) in the proband and his mother. The purified recombinant glutathionyl S-transferase fusion protein of the A456V glucokinase revealed a decreased glucose S(0.5) (the concentration of glucose needed to achieve the half-maximal rate of phosphorylation) from 8.04 (wild-type) to 2.53 mmol/l. The mutant's Hill coefficient was decreased, and its maximal specific activity k(cat) was increased. Mathematical modeling predicted a markedly lowered GSIR threshold of 1.5 mmol/l. The theoretical and practical implications are manifold and significant.

Published
2002

29. High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insuline response, insuline sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP)

Author

Massa, O, Meschi, F, CUESTA MUNOZ, A, Caumo, A, Cerutti, F, Toni, S, Cherubini, V, Guazzarotti, L, Sulli, N, Matschinsky, Fm, Lorini, RENATA GIUSEPPINA, Iafusco, D, Barbetti, F, and ITALIAN SOCIETY OF PAEDIATRIC ENDOCRINOLOGY AND DIABETES SIEDP

Published
2001

32. Missense mutations in theTGM2 gene encoding transglutaminase 2 are found in patients with early-onset type 2 diabetes

Author

Porzio, O., primary, Massa, O., additional, Cunsolo, V., additional, Colombo, C., additional, Malaponti, M., additional, Bertuzzi, F., additional, Hansen, T., additional, Johansen, A., additional, Pedersen, O., additional, Meschi, F., additional, Terrinoni, A., additional, Melino, G., additional, Federici, M., additional, Decarlo, N., additional, Menicagli, M., additional, Campani, D., additional, Marchetti, P., additional, Ferdaoussi, M., additional, Froguel, P., additional, Federici, G., additional, Vaxillaire, M., additional, and Barbetti, F., additional

Published
2007
Full Text
View/download PDF

34. High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI

Author

Cuesta-Munoz, A., primary, Caumo, A., additional, Cerutti, F., additional, Toni, S., additional, Sulli, N., additional, Matschinsky, F. M, additional, Barbetti, F., additional, Cherubini, V., additional, Guazzarotti, L., additional, Massa, O., additional, Meschi, F., additional, Lorini, R., additional, and Iafusco, D., additional

Published
2001
Full Text
View/download PDF

35. In search of new type 1 diabetes autoantigens

Author

Russo, L., Massimo, A., Nardo, G., Massignan, T., Bonetto, V., Bertuzzi, F., Bonfanti, R., Iafusco, D., Fabrizio Barbetti, Massa, O., Russo, L, Massimo, A, Nardo, G, Massignan, T, Bonetto, V, Bertuzzi, F, Bonfanti, R, Iafusco, D, Barbetti, F, Massa, O, Iafusco, Dario, and Massa, O.

36. Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families.

Author

Lorini R, Klersy C, d'Annunzio G, Massa O, Minuto N, Iafusco D, Bellannè-Chantelot C, Frongia AP, Toni S, Meschi F, Cerutti F, Barbetti F, Italian Society of Pediatric Endocrinology and Diabetology (ISPED) Study Group, Lorini, Renata, Klersy, Catherine, d'Annunzio, Giuseppe, Massa, Ornella, Minuto, Nicola, Iafusco, Dario, and Bellannè-Chantelot, Christine

Abstract

Objective: To investigate the prevalence of maturity-onset diabetes of the young (MODY) in Italian children with incidental hyperglycemia.Research Design and Methods: Among 748 subjects age 1-18 years with incidental hyperglycemia, minimal diagnostic criteria for MODY were met by 172 families. Mutational analyses of the glucokinase (GCK) and hepatocyte nuclear factor 1alpha (HNF1A) genes were performed.Results: We identified 85 GCK gene mutations in 109 probands and 10 HNF1A mutations in 12 probands. In GCK patients, the median neonatal weight and age at the first evaluation were lower than those found in patients with HNF1A mutations. Median fasting plasma glucose and impaired fasting glucose/impaired glucose tolerance frequency after oral glucose tolerance testing were higher in GCK patients, who also showed a lower frequency of diabetes than HNF1A patients.Conclusions: GCK mutations are the prevailing cause of MODY (63.4%) when the index case is recruited in Italian children with incidental hyperglycemia. [ABSTRACT FROM AUTHOR]

Published
2009
Full Text
View/download PDF

37. Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families

Author

Barone, V., Massa, O., Sorrentino, V., Intravaia, E., Bracco, A., Martino, A. Di, Cozzolino, S., and Tegazzin, V.

Abstract

Point mutations in the ryanodine receptor (RYR1) gene are associated with malignant hyperthermia, an autosomal dominant disorder triggered in susceptible people (MHS) by volatile anaesthetics and depolarising skeletal muscle relaxants. To date, 17 missense point mutations have been identified in the human RYR1 gene by screening of the cDNA obtained from muscle biopsies. Here we report single strand conformation polymorphism (SSCP) screening for nine of the most frequent RYR1 mutations using genomic DNA isolated from MHS patients. In addition, the Arg163Cys mutation was analysed by restriction enzyme digestion. We analysed 57 unrelated patients and detected seven of the known RYR1 point mutations. Furthermore, we found a new mutation, Arg2454His, segregating with the MHS phenotype in a large pedigree and a novel amino acid substitution at position 2436 in another patient, indicating a 15.8% frequency of these mutations in Italian patients. A new polymorphic site in intron 16 that causes the substitution of a G at position -7 with a C residue was identified.

Published
1999

38. Protein kinase C-dependent in vivo phosphorylation of prourokinase leads to the formation of a receptor competitive antagonist.

Author

Franco, P, Massa, O, Garcia-Rocha, M, Chiaradonna, F, Iaccarino, C, Correas, I, Mendez, E, Avila, J, Blasi, F, and Stoppelli, M P

Abstract

We recently reported that in vivo phosphorylation of urokinase-type plasminogen activator on Ser138/303 prevents its catalytic-independent ability to promote myelomonocytic cell adherence and motility. We now show that Ca2+ activated, phospholipid-dependent protein kinase C from rat brain phosphorylates in vitro a peptide corresponding to prourokinase residues 133-143 (DGKKPSSPPEE) and the full-length molecule on Ser138/139. The in vivo involvement of the protein kinase C isoenzyme family is supported by the finding that inhibition of kinase C activity prevents prourokinase phosphorylation on Ser138/303 in A431 human carcinoma cells. Conversely, a short treatment of A431 cells with phorbol myristate acetate increases the extent of phosphorylated prourokinase and, concomitantly, affects its function; under these conditions, the capability of prourokinase to up-regulate U937 monocyte-like cell adherence is severely impaired, although receptor binding is unaltered. By the aid of a "phosphorylation-like" variant (Ser138 to Glu) we show that modification of Ser138 is sufficient to confer to prourokinase the antagonistic properties observed following in vivo stimulation of protein kinase C activity. These observations provide the first evidence that protein kinase C directs the formation of a receptor competitive antagonist by regulating the in vivo phosphorylation state of prourokinase.

Published
1998

39. Insulin gene mutations are found in children with diabetes and negative to T1D autoantibodies

Author

Bonfanti, R., Colombo, C., Nocerino, V., Geng, X., Drain, P., Massa, O., Viscard, M., Iafusco, D., Chiumello, G., Meschi, F., Fabrizio Barbetti, Bonfanti, R, Colombo, C, Nocerino, V, Geng, X, Drain, P, Massa, O, Viscardi, M, Iafusco, Dario, Chiumello, G, Meschi, F, and Barbetti, F.

Abstract

Results: Heterozygous mutations of insulin (INS) gene are found in patients with neonatal/infancy-onset diabetes. We have evidence that INS gene mutations cause permanent diabetes by endoplasmic reticulum stress-induced apoptosis of the beta cells. Probands of the Italian series who carry insulin mutations show diabetes in isolation with onset between 1 to 6 months from birth. However, 2 affected parents of familial cases bearing the R65C (or R89C) mutation presented with diabetes at 1 and 4 years of age, respectively. We screened the INS gene in 4 patients with diabetes onset above 1 year of age, who were negative to the search of ICA, GAD, IA-A2, IAA and zinc transporter 8 (ZnT8) autoantibodies. We detected 2 INS gene mutations: the already described GB8S (or G32S) and the novel ASignal23S. The GB8S mutant had diabetes onset at 2 years, 10 months of age with detectable C peptide at outset (0.49 ng/ml), and after 2 years (0.34 ng/ml); presently, his insulin dose is 0.5 U Kg-1 d-1. The individual with the ASignal23S mutation presented with typical symptoms of diabetes (polyuria, polydipsia) when he was 6 years 8 months old (HBA1c= 11%). Insulin was started and continued for 6 months; during the following 2 years the patient went off/on insulin several times. Currently, he is on insulin at the dose of 0.2 U Kg-1 d-1. C-peptide measured 11 and 24 months after onset of hyperglycemia was 1.32 and 0.7 ng/ml, respectively. We conclude that: 1) INS gene mutations can be found in children previuosly classified as T1D; 2) the clinical presentation of diabetes in these patients, who do not show any associated feature, is indistinguishable from common T1D diabetes.

43. Mutation screening of the RYR1 gene and identification of two novel mutations in Italian malignant hyperthermia families

Author

Barone, V., Massa, O., Intravaia, E., Bracco, A., Di Martino, A., Tegazzin, V., Cozzolino, S., and Vincenzo Sorrentino

Subjects
Male, Polymorphism, Genetic, Nemaline, Muscles, Single-Stranded Conformational, Ryanodine Receptor Calcium Release Channel, Original Articles, Myopathies, Nemaline, Pedigree, Italy, Genetic, Caffeine, Humans, Point Mutation, Female, genetics, Myopathies, Polymorphism, metabolism, DNA Primers, Female, Halothane, metabolism, Humans, Italy, Male, Malignant Hyperthermia, genetics, Muscles, metabolism, Myopathies, genetics, Pedigree, Point Mutation, Polymorphism, Genetic, Polymorphism, Single-Stranded Conformational, Ryanodine Receptor Calcium Release Channel, Halothane, Malignant Hyperthermia, metabolism, Polymorphism, Single-Stranded Conformational, DNA Primers
Abstract

Point mutations in the ryanodine receptor (RYR1) gene are associated with malignant hyperthermia, an autosomal dominant disorder triggered in susceptible people (MHS) by volatile anaesthetics and depolarising skeletal muscle relaxants. To date, 17 missense point mutations have been identified in the human RYR1 gene by screening of the cDNA obtained from muscle biopsies. Here we report single strand conformation polymorphism (SSCP) screening for nine of the most frequent RYR1 mutations using genomic DNA isolated from MHS patients. In addition, the Arg163Cys mutation was analysed by restriction enzyme digestion. We analysed 57 unrelated patients and detected seven of the known RYR1 point mutations. Furthermore, we found a new mutation, Arg2454His, segregating with the MHS phenotype in a large pedigree and a novel amino acid substitution at position 2436 in another patient, indicating a 15.8% frequency of these mutations in Italian patients. A new polymorphic site in intron 16 that causes the substitution of a G at position -7 with a C residue was identified. Keywords: malignant hyperthermia; central core disease; ryanodine receptor; in vitro contracture test

44. 40 EASD Annual Meeting of the European Association for the Study of Diabetes : Munich, Germany, 5-9 September 2004

Author

Veitenhansl, M., Stegner, K., Hierl, F-X, Dieterle, C., Feldmeier, H., Gutt, B., Landgraf, R., Garrow, A. P., Vileikyte, L., Findlow, A., Waterman, C., Boulton, A. J. M., Shankhdhar, K., Shankhdhar, L., Shankhdhar, U., Petrova, N. L., Foster, A. V. M., Edmonds, M. E., Ferraresi, R., Caravaggi, C., Giglio, R., Cavaiani, P., Pogliaghi, I., Sommariva, E., Katz, I. A., Harlan, A., Miranda-Palma, B., Prieto-Sanchez, L., Armstrong, D. G., Bowker, J. H., Mizel, M. S., Cernea, S., Wohlgelernter, J., Kidron, M., Modi, P., Raz, I., Arbit, E., Nosek, L., Kapitza, C., Beckett, P., Gelfand, R., Goldberg, M., Heise, T., Testa, M. A., Turner, R. R., Hayes, J. F., Scranton, R. E., Simonson, D. C., Yang, Y-W, Hsu, Y-J, Naujok, O., Francini, F., Jorns, A., Tiedge, M., Lenzen, S., Abdel-Wahab, Y. H. A., Marenah, L., Orr, D. F., Shaw, C., Flatt, P. R., Chokkalingam, K., Mansell, P. I., Clausen, P., Ekbom, P., Damm, P., Feldt-Rasmussen, U., Nielsen, B., Mathiesen, E. R., Feldt-Rasmussen, B., Dewan, S., Da Silva, N., Ternan, P. Mc, Leong, K. S., Wilding, J. P. H., Asatiani, N., Kurashvili, R., Dundua, M., Shelestova, E., Pagava, K., Ramazashvili, M., Hod, M., Smirnov, S., Petersen, J. L. A., Justesen, T. I., Ringholm Nielsen, L., Muller, C., Hojlund, K., Wensaas, A., Kase, E. T., Aas, V., Rustan, A. C., Thoresen, G. H., Levin, K., Beck-Nielsen, H., Gaster, M., Im, S-S, Kang, S-Y, Kim, S-Y, Ahn, Y-H, Lihn, A. S., Schmoll, D., Werner, T., Kienitz, A., Meyer, M., Barthel, A., Ailett, F., Sutherland, C., Walther, R., Grempler, R., Sasson, S., Reich, R., Tenenbaum, T., Alpert, E., Anfossi, G., Russo, I., Traversa, M., Massucco, P., Mattiello, L., Doronzo, G., Trovati, M., Lally, S., Tan, C. Y., Owens, D., Tomkin, G. H., Porchay, I., Pean, F., Bellili, N., Betoulle, D., Balkau, B., Tichet, J., Marre, M., Fumeron, F., Group D.E.S.I.R., Chatellier, G., Alhenc-Gelas, F., Diabhycar, Study Group, Nichols, G. A., Brown, J. B., Hayes, R. P., Bowman, L., Drexel, H., Saely, C. H., Marte, T., Benzer, W., Langer, P., Hoefle, G., Moll, W., Aczel, S., Karagiannis, E., Lubben, G., Urquhart, R., Edwards, G., Bruce, S., Howlett, H. S. C., Cugnardey, N., Turner, K. C., Park, J-S, Fiedorek, F. T., Avogaro, A., Gallo, A., Pinton, P., Rizzuto, R., Murphy, E., Ceolotto, G., Caterson, I., Guy-Grand, B., Hill, J., Barone, M., Aiello, A., Allochis, G., Borzi, V., Cannata, F., Caronna, S., D Avanzo, A., Elli, R., Formoso, G., Paroli, A., Scardapane, R., Sorichetti, P., Tatti, P., Viviani, G., Santeusanio, F., Italian Repaglinide Study Group, Manzella, D., Grella, R., Abbatecola, A. M., Paolisso, G., Sondergaard, L. G., Monster, T. B. M., Johnsen, S. P., Olsen, M. L., Mclaughlin, J. K., Sorensen, H. T., Lervang, H. H., Rungby, J., Lyssenko, V., Fredriksson, J., Almgren, P., Anevski, D., Orho-Melander, M., Sjogren, M., Tuomi, T., Groop, L., Jaziri, R., Aubert, R., Tuomilehto, J., Hu, G., Jousilahti, P., Peltonen, M., Lindstrom, J., Laina, A., Alevizaki, M., Philippou, G., Souvatzoglou, A., Anastasiou, E., Alba, S., Metcalf, B. S., Voss, L. D., Jeffery, A. N., Wilkin, T. J., Gluimer, C., Colagiuri, S., Vistisen, D., Borch-Johnsen, K., Haynes, A., Bower, C., Bulsara, M. K., Jones, T. W., Davis, E. A., Mortensen, H. B., Hougaard, P., Holl, R., Swift, P., Pociot, F., Knip, M., Hansen, L., Szadkowska, A., Pietrzak, I., Zmyslowska, A., Wyka, K., Bodalski, J., Holl, R. W., Swift, R., Hougaard, R., Gerstl, E-M, Engelsberger, I., Rabl, W., Rosenbauer, J., Grobe, H., Hofer, S. E., Krause, U., DPV-Wiss-Study Group, Dabelea, D., Morgan, T., Pettitt, D. J., Dolan, L., Mayer-Davis, E. J., Pihoker, C., Hillier, T. A., Imperatore, G., Ruggiero, A., Hamman, R. E., Stylianou, A., Tentolouris, N., Perrea, D., Tselepis, A. D., Lourida, E., Kitsou, E., Katsilambros, N., Vedovato, M., Dodesini, A. R., Lepore, G., Tiengo, A., Trevisan, R., Penno, G., Miccoli, R., Pucci, L., Lucchesi, D., Bandinelli, S., Fotino, C., Triscornia, S., Baldassari, E., Del Prato, S., Reboldi, P., Santeusanio, E., Fuller, J., Langham, R. G., Gow, R. M., Zhang, Y., Kelly, D. J., Christensen, P. K., Parving, H-H, Gilbert, R. E., Chibalin, A. V., Zhong, Z., Kotova, O., Davidescu, A., Ehren, I., Ekberg, K., Wahren, J., Wassef, L., Buckley, A. J., Rooney, K. B., Briody, J., Thompson, M., Ozanne, S. E., Thompson, C. H., Chamson-Reig, A., Summers, K., Arany, E. J. R., Hill, D. J., Solerte, S. B., Gazzaruso, C., Locatelli, E., Precerutti, S., Schifino, N., Ferrari, E., Fioravanti, M., Phenekos, C. V., Ginis, A., Fragaki, I., Chalkiadaki, M., Tzioras, C., Powell, L. A., Mcguire, G. M., Jewhurst, V., Trimble, E. R., Rasmussen, B. M., Vessby, B., Uusitupa, M., Berglund, L., Pedersen, E., Riccardi, G., Rivellese, A. A., Tapsell, L., Hermansen, K., Kanwu, Study Group, Da Silva Xavier, G., Rutter, J., Rutter, G. A., Briaud, I. M., Lingohr, M. K., Dickson, L. M., Mccuaig, J. R., Lawrence, J. C., Rhodes, C. J., Wikstrom, J. D., Katzman, S. M., Shirihai, O. S., Yang, J., Deng, S., Wang, X., Hessner, M. J., Wu, J., Wong, R. K., Sukumvanich, S., Markman, J. F., Naji, A., Wolf, B. A., Gao, Z., Rubi, B., Del Arco, A., Satrustegui, J., Maechler, P., Del Guerra, S., Lupi, R., Bugliani, M., Sbrana, S., Torri, S., Boggi, U., Vistoli, F., Mosca, F., Marchetti, P., Rennings, A. J. M., Smits, P., Stewart, M. W., Tack, C. J. J., Li, L., Nystrom, T., Gutniak, M., Ahren, B., Holst, J., Sjoholm, A., Gomes, M. B., Cailleaux, S., Tibirica, E., Albertini, J-P, Chen, H., Mather, R., Valensi, P. E., Chisalita, S. I., Arnqvist, H. J., Kraenkel, N., Adams, V., Linke, A., Gielen, S., Schuler, G., Humbrecht, R., Cipollone, F., Iezzi, A., Fazia, M., Pini, B., Cucurullo, C., Cesare, D., Schmidt, A. M., Mazurek, T., Zang, L. F., Mannion, J., Diehl, J., Martin, J., Martella, A., Zalewski, A., Shi, Y., Otter, W., Winter, M., Doering, W., Standi, E., Schnell, O., Kragelund, C., Kober, L., Faber, J., Hildebrandt, P., Steffensen, R., Pankowska, E., Szypowska, A., Lipka, M., Herwig, J., Scholl-Schilling, G., Bohles, H., Robertson, K. J., Schonle, E., Gucev, Z., Mordhorst, L., Tamer, S. C., Gall, M-A, Ludvigsson, J., Hoogma, R. P. L., Hammond, P. J., Gomis, R., Kerr, D., Bruttomesso, D., Bouter, P., Wiefels, K. J., La Calle, H., Schweitzer, D. H., Pfohl, M., Torlone, E., Krinelke, L. G., 205-Nations Study Group, Conget, I., Storms, F., Rodriguez, J., Leperlier, C., Davies, M., At Lantus, Study Group, Peter, R., Luzio, S. D., Dunseath, G., Miles, A., Hare, B., Backx, K., Pauvaday, V., Owens, D. R., Caselli, A., Marfia, G. A., Battista, C., Veves, A., Spallone, V., Uccioli, L., Gonzalez, J. S., Peyrot, M. F., Rubin, R. R., Leventhal, H., Scheffler, N., Ulbrecht, J. S., Cavanagh, P. R., Boulton, A. J., Perrin, N. A., Oglesby, A., Bastyr, E. J., Ziegler, D., Siekierka-Kleiser, E., Meyer, B., Schweers, M., Selvarajah, D., Wilkinson, I. D., Emery, C. J., Shaw, P. J., Griffiths, P. D., Tesfaye, S., Obrosova, I. G., Arezzo, J., Phillips, K., Fidarestat Study Group, Gribble, F. M., Williams, L., Reimann, F., Iakoubov, R., Whiteside, C., Brubaker, P. L., Acitores, A., Gonzalez, N., Sancho, V., Valverde, I., Villanueva-Penacarrillo, M. L., Martin-Duce, A., Trigo, M. V., Arnes, L., Burkart, V., Ichino, N., Ohashi, A., Klein, B. S., Paxian, S., Schmid, R., Karlsen, A. E., Heding, P. E., Frobose, H., Ronn, S. G., Kruhoffer, M., Orntoft, T. F., Nerup, J., Mandrup-Poulsen, T., Billestrup, N., Cardozo, A. K., Ortis, F., Feng, Y-M, Rasschaert, J., Eylen, F., Storling, J., Herchuelz, A., Eizirik, D. L., Wang, H., Kouri, G., Wollheim, C. B., Ribaux, P., Hammar, E., Parnaud, G., Rouiller, D., Bosco, D., Halban, P., Midthjell, K., Carlsson, S., Grill, V., Lau, C., Farch, K., Glumer, C., Tetens, I., Jorgensen, T., Tillin, T., Forouhi, N., Mckeigue, P., Chaturvedi, N., Zethelius, B., Hales, C. N., Berne, C., Coleman, R. L., Stevens, R. J., Holman, R. R., Christensen, J. O., Sandbak, A., Lauritzen, T., Irwin, N., Gault, V. A., Green, B. D., Harriott, P., O Harte, F. P. M., Bouman, S. D., Urso, B., Brand, C. L., Rolin, B., Ribel, U., Schaffer, L., Maggs, D. G., Ceriello, A., Frias, J. P., Wang, Y., Ruggles, J. A., Kolterman, O. G., Piconi, L., Weyer, C., Want, L. L., Ratner, R. E., Uwaifo, G. I., Thornberry, N. A., Eiermann, G., Kim, D., Lankas, G., Leiting, B., Li, Z., Lyons, K., Petrov, A., Sinha Roy, R., Woods, A., Woods, J., Zhang, B. B., Fisher, M., Moller, D. E., Weber, A. E., Dreyer, M., Bellin, C., Schmitz, V., Roesen, R., Nescheret, A. P., Bose, A. K., Mocanu, M. M., Carr, R. D., Yellon, D. M., Manolopoulos, K., Born, S., Wagner, A., Jeziorska, M., Ben Drief, A., Bashir, M., Tomlinson, D., Malik, R. A., Zeymer, U., Schwarzmaier-D Assie, A., Petzinna, D., Chiasson, J-L, Stratton, I. M., Af Bjorkesten, C-G, Fagerudd, J., Rosengard-Barlund, M., Forsblom, C., Pettersson-Fernholm, K., Waden, J., Saraheimo, M., Ronnback, M., Thorn, L., Groop, P-H, Mollsten, A., Svensson, M., Kockum, I., Rudberg, S., Brismar, K., Dahlquist, G., Hovind, P., Hansen, T. K., Tarnow, L., Thiel, S., Jensen, B. R., Flyvbjerg, A., Kankova, K., Hertlova, M., Krusova, D., Schwenke, S., Ott, J., Thom, S. A. M., Mistry, P., Sjolie, A., Larsen, B., Witt, N., Hughes, A. D., Samira, H. H., Lahiry, S., Howlader, S. R., Parveen, S., Azad Khan, A. K., Clarke, P. M., Gray, A., Stevens, R., Holman, R., Phillips, L., Phillips, P. J., Chittleborough, C., Baldock, K., Taylor, A., North West Adelaide Health Study Team, Davis, W. A., Davis, T. M. E., Knuiman, M. W., Hendrie, D., Worthley, D., Nicolucci, A., Pellegrini, F., Berardis, G., Franciosi, M., Belfiglio, M., Rossi, M. C. E., Sacco, M., Valentini, M., Richardson, C. C., Jones, P., Persaud, S., Hussain, K., Clark, A., Christie, M. R., Gniuli, D., Hribal, M. L., Accili, D., Khan, M., Zervou, S., Cheung, L., Abouna, S., Ifandi, V., Pelengaris, S., Luco, R. F., Ferrer, J., Ma, D., Shield, J. P. H., Dean, W., Leclerc, I., Knauf, C., Burcelin, R., Kelsey, G., Powers, A. C., Shostak, A., Ferrara, N., Poffenberger, G., Jerome, W. G., Brissova, M., Geloneze, S. R., Tambascia, M. A., Pareja, J. C., Chaim, E., Silveira, H. V., Geloneze, B., Ravikumar, B., Carey, P. E., Snaar, J. E., Dheelchand, D., Cook, D. B., Neely, D., Taylor, G., Morris, P. G., Taylor, R., Stears, A. J., Masding, M. G., Wootton, S. A., Sandeman, D. D., Klimes, I., Wein, S., Gasperikova, D., Ukropec, J., Wiernsperger, N., Sebokova, E., Manco, M., Mingrone, G., Granato, L., Greco, A. V., Nanni, G., Castagneto, M., Vidal, H., Calvani, M., Ferrannini, E., Alvarsson, M., Sundkvist, G., Lager, I., Henricsson, M., Berntorp, K., Fernqvist-Forbes, E., Steen, L., Orn, T., Shutler, S., Bianchi-Biscay, M., Rosenstock, J., Sugimoto, D., Strange, P., Stewart, J., Soltes Rak, E., Dailey, G., Kloos, C., Muller, U., Samann, A., Femerling, M., Risse, A., Jecht, M., Haak, T., Garg, R., Lawrence, I. G., Akinsola, M. O., Davies, M. J., Mcnally, P. G., Garber, A. J., Kim, H., Draeger, E., Aydin, L., Sengul, A., Kurklu, A., Ucak, S., Basat, O., Seber, S., Altuntas, Y., Jin, J., Yu, Y., Yu, H., Zhang, X., Mattoo, V., Eckland, D., Widel, M., Duran, S., Fajardo, C., Strand, J., Knight, D., Oakley, D., Tan, M., Sato, A., Nagao, M., Aki, N., Nakagami, T., Iwamoto, Y., Zhou, Z., Li, X., Huang, G., Yan, X., Yang, L., Peng, J., Wang, J., Tan, S., Tang, W., Furnsinn, C., Brunmair, B., Wagner, L., Gras, F., Artwohl, M., Zierhut, B., Waldhausl, W., Shine, B. L., Hopkins, D., Anand, V., Lim, E., Raval, U., Sharp, P., Corder, R., Lipkin, D., Lahiri, A., Bartnik, M., Ryden, L., Ferrari, R., Malmberg, K., Pyorala, K., Simoons, M. L., Standl, E., Soler-Soler, J., Ohrvik, J., Euro Heart Survey Investigators, Bruce, D. G., Starkstein, S. E., Schauer, U. J. W., Astrup, A. S., Pietraszek, L., Nielsen, F. S., Rossing, P., Ali, S., Smidt, U. M., Yokoyama, H., Pavkov, M. E., Knowler, W. C., Bennett, P. H., Nelson, R. G., Lopez-Alba, A., Morcillo, L., Caballero, A., Montoya, L., Jimenez, A., Maceira, B., Lewis, J. B., Ravid, M., Wajman, A., Tadgell, C., Remuzzi, G., Hunsicker, L. G., Wessman, M., Taskinen, M-R, FinnDiane Study Group, Pugliese, G., Amadio, L., Menini, S., Oddi, G., Ricci, C., Iacobini, C., Pricci, F., Sorcini, M., Pesce, C., Migliaccio, E., Giorgio, M., Pelicci, P., Di Mario, U., Lassila, M., Jandeleit-Dahm, K., Seah, K. K., Calkin, A. C., Allen, T. J., Cooper, M. E., Lopes Faria, J. M., Cavakcanti, T. C., Silva, K. C., Ferrari, A. L., Lopes Faria, J. B., Cellek, S., Foxwell, N. A., Cotter, M. A., Cameron, N. E., Tennagels, N., Jordan, H., Stahl, P., Voss, M. D., Welte, S., Werner, U., Lehmann, R., Moeschel, K., Baumgartner, F., Oeckinghaus, A., Beck, A., Weigert, C., Hennige, A., Schleicher, E. D., Haring, H. U., Mussig, K., Staiger, H., Haring, H-U, Natalicchio, A., Laviola, L., Tullio, C., Renna, L., Giorgino, R., Giorgino, F., Falasca, M., Maffucci, T., Park, D., Kang, S., Song, J., Lee, D., Lee, Y., Hariharan, N., Kunselman, L., Gu, L., Sasseville, V., Harrity, T., Cheng, P. T. W., Pratley, R. E., Schweizer, A., Mills, D., Kim, T-H, Song, X-L, Poelje, P. D., Potter, S. C., Dang, Q., Fujitaki, J. M., Linemeyer, D. L., Landau, B. R., Erion, M. D., Pankop, M., Golay, A., Despres, J., Sjostrom, L., Lawlor, D. L., Legg, K. T., Ur, E., Houweling, S. T., Kleefstra, N., Meyboom-De Jong, B., Bilo, H. J. G., Schlomer, G. J., Meyer, G., Kasper, J., Muhlhauser, I., Young, B., Taylor, J., Friede, T., Hollis, S., Mason, J., Long, A., Gambling, T., Pauline, L., Burns, E., New, J., Gibson, M., Betteridge, D. J., Leiter, L. A., Audit, Investigators, Whitty, P. M., Eccles, M. P., Hawthorne, G., Grimshaw, J., Steen, I. N., Vanoli, A., Wood, L., Speed, C., Mcdowell, D., Rewers, M., Maahs, D., Wadwa, R., Eckel, R., Tracy, R., Pfutzner, A., Strotmann, H-J, Schulze, J., Hohberg, C., Pahler, S., Forst, T., Ambery, P. D., Sydall, H., Cooper, C., Dennison, E., Sayer, A. Aihie, Barker, D., Phillips, D., Lalic, N. M., Ostojic, M., Lalic, K., Zamaklar, M., Jotic, A., Ilic, M., Rajkovic, N., Lukic, L., Milicic, T., Verges, B., Zeller, M., Steg, P. G., Beer, J. C., Brisard, C., Brindisi, M. C., Dentan, G., Laurent, Y., Janin-Manificat, L., Makki, H., Ravisy, J., Cottin, Y., Ajjan, R. A., Grant, P. J., Futers, T. S., Brown, J. M., Carter, A. M., Rasmussen, M. S., Bruun, J. M., Pedersen, S. B., Richelsen, B., Dietze-Schroeder, D., Sell, H., Koenen, M., Eckel, J., Delporte, M-L L., Bauche, I. B., Brichard, S. M., Ait El Mkadem, S., Rezsohazy, R., Tsiotra, P. C., Tsigos, C., Gatsiou, C., Raptis, S. A., Walker, C. G., Bryson, J. M., Hancock, D. P., Caterson, I. D., Takahashi, N., Hatakeyama, H., Kasai, H., Gauthier, B. R., Iezzi, M., Fukuda, M., Duhamel, D. L., Ravier, M. A., Dufer, M., Neye, Y., Krippeit-Drews, P., Hennige, A. M., Sausbier, U., Arntz, C., Sausbier, M., Neuhuber, W., Ruth, P., Drews, G., Beauvois, M. C., Rolland, J-F, Jonas, J-C, Merezak, C., Henquin, J-C, Gilon, P., Jabin Gustafsson, A., Dzabic, M., Islam, M. S., Vaxillaire, M., Cheyssac, C., Dina, C., Vasseur-Delannoy, V., Lepretre, F., Siddiq, A., Froguel, P., Neve, B., Fernandez-Zapico, M. E., Ashkenazi-Katalan, V., Urrutia, R., Melloul, D., Froguel, R., Poulsen, P., Wojtaszewski, J., Richter, E., Vaag, A., Granhall, C., Renstrom, E., Luthman, H., Isomaa, B., Gloyn, A. L., Edghill, E. L., Pearson, E. R., Mackay, D. J. G., Temple, I. K., Noyes, K., Freedenberg, D., Gillespie, K. M., Lambert, A. P., Gale, E. A., Ellard, S., Hattersley, A. T., Fanelli, C. G., Porcellati, F., Rossetti, P., Busciantella, N. R., Billi, C., Burrin, D. G., Bolli, G. B., Bingham, E. M., Dunn, J., Sutcliffe-Goulden, J., Marsden, P., Amiel, S., Davis, R. E., Kennedy-Martin, T., Peters, J. R., Wittrup-Jensen, K. U., Mcewan, P., Morrissey, M., Currie, C. J., Akram, K., Pedersen-Bjergaard, U., Thorsteinsson, B., Pibernik-Okanovic, M., Peros, K., Begic, D., Szabo, S., Metelko, Z., Vlaiculescu, M. V., Calota, I., Busila, T., Bruckner, I., Giannakopoulou, D. F., Lindner, H. D., Hrachovinova, T., Fejfarova, V., Csemy, L., Malcomson, J., Campbell, M., Pandolfi, A., Giardinelli, A., Di Tomo, P., Di Silvestre, S., Di Fulvio, P., Capani, F., Consoli, A., Roesen, P., Patruno, A., Grilli, A., Capani, R., Felaco, M., Boner, G., Mccarroll, K., Brenner, B. M., Zeeuw, D., Kowey, P., Shahinfar, S., Crow, R. S., Iso, K., Kuboki, K., Tada, H., Yoshino, G., Schjoedt, K. J., Andersen, S., Distiller, L. A., Degenhardt, T. P., Szabo, J. R., Khalifah, R. G., Schotzinger, R. J., Achenbach, P., Knopff, A., Naserke, H., Ziegler, A. G., Bonifacio, E., Valera, L., Jardin, B., Roche, S., Lampasona, V., Pugniere, M., Roquet, F., Granier, C., Laune, D., Afifiyan, F., Cheung, R., Yantha, J., Jackowski, G., Dosch, H-M, Nakanishi, K., Kogawa, N., Komatsu, Y., Fontes, G., Imamura, T., Ilic, C., Puech, C., Ktorza, A., Bataille, D., Dalle, S., Sorensen, H., Fosgerau, K., Gelling, R. W., Nishimura, E., Andersen, B., Madsen, P., Lau, J., Streicher, R., Wagner, K., Vettermann, R., Potterat, O., Renard, E., Panteleon, A. E., Kolopp, M., Rebrin, K., Steil, G., Steil, G. M., Hariri, F., Darwin, C., Saad, M. F., Buckingham, B., Kunselman, B., Wong, L., Istoc, E., Leach, J., Purvis, R., Monfre, S. L., Fischer, J. S., Garg, S., Ahmann, A. J., Ruchti, T. L., Gandhi, G. Y., Nuttall, G. A., Mullany, C. J., Schaff, H. V., Williams, B. A., Rizza, R. A., Mcmahon, M. M., Gates, G., Mentel, J., Smith, R., Crook, J., Hosszufalusi, N., Vatay, A., Palik, E., Fust, G., Karadi, I., Romics, L., Panczel, P., Aurich, K., Voelker, U., Braun, A., Muller, U. A., Nguyen, L. L., Kriketos, A. D., Hancock, D., Denver, G. S., Uceyler, N., Schutt, M., Lesch, K-P, Mossner, R., Sommer, C., Seda, O., Liska, F., Kazdova, L., Sedova, L., Krenova, D., Zima, T., Tremblay, J., Kren, V., Hamet, P., Kloting, N., Follak, N., Kloting, I., Dessapt, C., Dei Cas, A., Baradez, M-O, Hayward, A., Thomas, S., Viberti, G., Gnudi, L., Gale, C. P., Jandeleit-Dahm, K. A. M., Thallas, V., Thomas, M. C., Candido, R., Burns, W. C., Forbes, J. M., Shymanskyy, I., Kuchmerovska, T., Klimenko, A., Jaeckel, E., Manns, M. P., Boehmer, H., Hedrich, H. J., Tellez, N., Montolio, M., Estimes, E., Rodriguez-Mulero, S., Soler, J., Montanya, E., Liu, Y., Chen, J., Rowlands, D., Chan, H., Simeonov, I. S., Anthony, K., Bingham, E., Marsden, P. K., Amiel, S. A., Malik, R. J. A., Zelaya, F., Williams, S., Brammer, M., Mountjoy, P. D., Bailey, S. J., Shaw, J. E., Sicree, R., Dunstan, D., Cameron, A., Zimmet, P. Z., Hewitt, S., Graff-Iversen, S., Assah, F. K., Fezeu, L., Kengne, A., Awah, P. K., Mbanya, J. N., Shu, J. A., Kamadjeu, R. K. K., Kiawi, E. C., Mbanya, J., Assah, F., Kerenyi, Z., Peterfalvi, A., Bosnyak, Z., Madarasz, E., Tabak, A. G., Szantho, J., Rakoczi, I., Tamas, G., Di Bartolo, P., Valpiani, G., Di Martino, M., Scaramuzza, A., Saragoni, S., Degli Esposti, E., Gudbjornsdottir, S., Cederholm, J., Nilsson, P., Eliasson, B., Miettinen, M. E., Miettinen, J., Nan, H. R., Dong, Y., Gao, W., Sun, B., Wang, N., Fu, F., Shi, H., Ding, M., Lorenzo, C., Serrano-Rios, M., Martinez-Larrad, M. T., Gonzalez-Sanchez, J. L., Seclen, S., Villena, A., Gonzalez-Villalpando, C., Williams, K., Stern, M. P., Haffner, S. M., Sakurai, M., Miura, K., Kita, Y., Takamura, T., Ota, T., Ishizaki, M., Morikawa, Y., Nakagawa, H., Szybinski, Z., Szurkowska, M., Mardarowicz, G., Lopatynski, J., Gilis-Januszewska, A., Szafraniec, K., Nicer, T., Kwon, H-S, Lee, J-H, Lee, H-J, Park, Y-M, Choi, Y-H, Kim, S-R, Jang, S-A, Song, B-R, Yoon, K-H, Kim, H-S, Lee, W-C, Cha, B-Y, Lee, K-W, Son, H-Y, Kang, S-K, Jorgensen, M. E., Moustgaard, H., Bjerregaard, P., Ebara, F., Dunstan, D. W., Salmon, J., Owen, N., Cameron, A. J., Welborn, T. A., Armstrong, T., Jolley, D., Galtier, F., Deschamps, V., Borys, J-M, Lasfargues, G., Andre, P., Born, C., Royer, B., Wilpart, E., Cailleau, M., Eschwege, E., Timar, R. Z., Serban, V., Vlad, A. R., Diaconu, L. F., Rosu, M., Olari, O., Sima, A. C., Qiao, Q., Chappuis, B., Diem, P., Christ, E. R., Iafusco, D., Prisco, F., Gemma, C., Mattera, S., Sanges, M., Menneila, C., Sommese, L., Jarosz-Chobot, P., Polanska, J., Feltbower, R. G., Mckinney, P. A., Stephenson, C. R., Bodansky, H. J., Icks, A., Du Prel, J-B, Grabert, M., Giani, G., Kyvik, K. O., Skytthe, A., Ioacara, S., Farcasiu, E., Bradescu, O., Guja, C., Scutaru, G., Savu, O., Ionescu-Tirgoviste, C., Ola, T. O., Hawa, M. I., Buzzetti, R., Scherbaum, W., Kolb, H., Thivolet, C., Hunter, S., Hadden, D., Guntram, S., Leiva, A., Mauricio, D., Pozzilli, P., Leslie, R. D. G., Benediktsson, R., Jonsdottir, A. M., Einarsdottir, A. S., Reynisdottir, I., Aspelund, T., Grant, S. F. A., Thorleifsson, G., Sigurdsson, G., Stefansson, K., Gudnason, V., Wollitzer, A. O., Jovanovic, L., Lobo, P. E., Marti, M. L., Preiti, M. C., Urdaneta, R. F., Juarez, S. S., Schober, E., Thon, A., Rami, B., Hofer, S., Tringham, J. R., Buyukbese, M. A., Sakamoto, Y., Inoue, Y., Matsumoto, H., Oono, K., Tokumasa, Y., Gorter, K. J., Janssen, P. G. H., Stolk, R. P., Hessen, P. A. W., Rutten, G. E. H., Niedermayer, D., Murro, A., Geloneze, S., Coghi, C., Federici, M. Orsini, Benedetti, M. Massi, Koehler, C., Henkel, E., Temelkova-Kurktschiev, T., Stier, U., Ott, P., Siegert, G., Bergmann, S., Hanefeld, M., Leonhardt, W., Sayeed, M. A., Mahtab, H., Khanam, P. A., Banu, A., Rashid, M. A., Mulnier, H., Seaman, H., Lovell, D., Soedamah-Mathu, S., Colhoun, H., Lawrenson, R., Diehm, C., Lange, S., Darius, H., Pittrow, D., Haberl, R., Stritzky, B., Tepohl, G., Allenberg, J. R., Trampisch, H-J, Soinio, M., Marniemi, J., Laakso, M., Lehto, S., Ronnemaa, T., Ito, C., Sasaki, H., Ishida, S., Maeda, R., Barengo, N. C., Lakka, T. A., Kohler, C., Benke, I., Raccah, D., Bailleau, C., Vexiau, P., Vaur, L., Aydin, N., Topsever, P., Filiz, T. M., Dayan, A., Bulgurlu, S., Gebeloglu, N., Demirtunc, R., Dagar, A., Skliros, E., Sotiropoulos, A., Vassibosis, A., Xipnitos, C., Liva, E., Chronopoulos, I., Merkouris, P., Skourtis, S., Pappas, S., Charbonnel, B., Baigts, F., Dumenil, V., Paillasson, S., Baleydier, A., Hanaire, H., Sert, C., Chabrier, G., Rodier, M., Fontaine, P., Kim, J-I, Miyake, Y., Sakai, T., Takamatsu, K., Tomioka, Y., Sugano, H., Murao, S., Shimizu, I., Unwin, N. C., Nag, S., Roglic, G., Connolly, V., Roper, N., Goodwin, J., Kelly, W., Lervang, H-H, Thomsen, R. W., Hundborg, H. H., Schonheyder, H. C., Khalangot, M. D., Gang, H., Tajima, N., Bianchi, C., Giovannitti, M. G., Pellegrini, G., Caricato, F., Bertolotto, A., Corfini, M., Guzder, R., Gatling, W., Byrne, C., Varillas, V. F., Boronat, M., Carrillo, A., La Roche, F., Ojeda, A., Lopez, Y., Marrero, D., Novoa, J., Shahidul Alam Khan, A. K. M., Thaware, P. K., Gangat, I., Howlett, T. A., Jenum, A. K., Holme, I., Birkeland, K. I., Sourij, H., Stoschitzky, K., Klein, W., Roth, M., Dittrich, P., Wascher, T. C., Hilding, A., Eriksson, A-K, Agardh, E. E., Efendic, S., Ostenson, C-G, Levitt, N. S., Bradshaw, D., Salzsieder, E., Freyse, E-J, Rutscher, A., Heinke, P., Augstein, P., Makino, H., Kainou, Y., Konoue, E., Ohno, K., Ebisui, O., Fujii, Y., Kondo, S., Fujiyama, M., Tanaka, K., Takemoto, K., Kida, K., Onuma, Y., Osawa, H., Tuomilehto-Wolf, E., Kinnunen, L., Laine, A-P, Kokko, T., Kakko, T., Hermann, R., Veijola, R., Simell, O., Ilonen, J., Guglielmi, C., Galgani, A., Beretta Anguissola, G., D Avola, D., Bakhtadze, E., Weiss, H., Hedrich, H-J, Wedekind, D., Bilbao, J. R., San Pedro, J. I., Vitoria, J. C., Martul, P., Castano, L., Badenhoop, K., Ramos Lopez, E., Usadel, K. H., Wagner, A. M., Cloos, P. A. C., Stahlhut, M., Bergholdt, R., Ramos, E., Taxvig, C., Vella, A., Smyth, D., Cooper, J. D., Undlien, D. E., Ronningen, K. S., Savage, D. A., Dunger, D. B., Strachan, D. P., Ring, S. M., Todd, J. A., Mironczuk, K., Kretowski, A., Kinalska, I., Nutland, S., Guja, L., Nielsen, L. B., Gammeltoft, S., Schwarz, P. E. H., Towers, W. G., Fischer, S., Mcrae, J. F., Willis, J. A., Scott, R. S., Potter, H. C., Merriman, T. R., Frampton, C. M., George, P. M., Spranger, J., Mohlig, M., Hoffmann, K., Muller, S., Osterhoff, M., Ristow, M., Boeing, H., Pfeiffer, A. F. H., Li, Y., Fisher, E., Burwinkel, B., Schrezenmeir, J., Mager, U., Pulkkinen, L., Lindi, V., Xiu, L. L., Sui, Y., Weng, J. P., Kalis, M., Cilio, C. M., Olde, B., Owman, C., Groop, L. C., Leveen, P., Da Ros, R., Assaloni, R., Maier, A., Quagliaro, L., Zuodar, G., Zakja, E., Gu, H. F., Nordman, S., Brookes, A. J., Prince, J. A., Helwig, U., Rubin, D., Hampe, J., Schreiber, S., Folsch, U. R., Doring, F., Porzio, O., Massa, O., Cunsolo, V., Hansen, T., Njolstad, P. R., Terrinoni, A., Melino, G., Federici, M., Colombo, C., Federici, G., Barbetti, F., Herder, C., Bongardt, F., Schopfer, A., Rathmann, W., Martin, S., Holle, R., Thorand, B., Wichmann, H. E., Koenig, W., Illig, T., Kora, Group, Blasiak, J., Arabski, M., Krupa, R., Wozniak, K., Dabrowski, J., Kasznicki, J., Zurawska, M., Drzewoski, J. S., Kose, H., Matsumoto, K., Wilke, B., Kerr-Bayles, L. J., Walder, K., Civitarese, A., Jowett, J., Curran, J., Elliott, K., Trevaskis, J., Bishara, N., Wanyonyi, S., Sanigorski, A. M., Zimmet, P., Blangero, J., Kissebah, A., Collier, G. R., Carlsson, E., Arner, P., Ridderstrale, M., Nitz, I., Lindner, I., Suzuki, S., Hinokio, Y., Hirai, M., Yamada, T., Yoshizumi, S., Tanizawa, Y., Matsutani, A., Ishihara, H., Takahashi, K., Katagiri, H., Oka, Y., Nam, M., Hong, S. B., Kim, H. J., Ahn, C. W., Kim, Y. S., Lee, H. C., Zeggini, E., Parkinson, J., Groves, C. J., Frayling, T. M., Hitman, G. A., Walker, M., Sampson, M., Levy, J. C., Weedon, M. N., Wiltshire, S., Owen, K. R., Halford, S., Mccarthy, M. I., Shehadeh, N., Bakri, D., Gershoni-Baruch, R., Yasuda, K., Okada, T., Sunaga, Y., Kajimoto, Y., Shibasaki, T., Kaburagi, Y., Kadowaki, T., Estalella, I., Rica, I., Vazquez, J. A., Mody, Spanish Group Of, Andrade, P., Den Ouweland, J. M. W., Maassen, J. A., Huoponen, K., Savontaus, M-L, Dimitrijevic Sreckovic, V. S., Djordjevic, P. B., Popovic, S. S., Gostiljac, D., Canovic, F., Sreckovic, B. M., Colak, E., Obrenovic, R., Milic, G., Glisic, B., Etemadi, A., Saadat, N., Azizi, F., Tsur, A., Cohen, Y., Yerushalmi, Y., Wainstein, J., Israel Diabetes Research Group (IDRG), Norberg, M., Eriksson, J. W., Lindahl, B., Andersson, C., Rolandsson, O., Stenlund, H., Weinehall, L., Lecomte, P. J., Vol, S., Caces, E., Chabrolle, C., Halimi, J-M, Nijpels, G., Dekker, J. M., Bouter, L. M., Heine, R. J., Lobner, K., Mollenhauer, U., Baumgarten, A., Com, E., Sargin, M., Karadeniz, S., Suleymanoglu, Y., Pekcanli, N., Yilmaz, T., Cicero, A. F. G., Dormi, A., Miconi, A., D Addato, S., Laghi, L., Brillante, R., Bernardi, R., Grandi, E., Gaddi, A. V., Jones, M., Lacey, L., Bergenheim, K., Yamagata, F., Yamakoshi, M., Takahashi, M., Kawazu, S., Festa, A., Hanley, A. J. G., Otvos, J. D., Goff, D. C., Wajngot, A., Cerasi, E., Baumert, J., Schneider, A., Lowel, H., Roussel, R., Muller-Brandes, C., Ballmann, M., Nahrlich, L., Thalhammer, G., Nastoll, M., Schwarz, J., Johne, U., Erfurth, M., Luddeke, H-J, Liebl, A., Kotowa, W., Maclaine, G., Evers, T., Pontiroli, A. E., Pizzocri, P., Paganelli, M., Folli, F., Lee, K., Jung, D-S, Park, M-K, Henriksen, J. E., Durck, T. T., Rasmussen, M., Weghuber, D., Roden, M., Tura, A., Pacini, G., Bischof, M., Widhalm, K., Sharp, G. W. G., Shanmugam, G., Straub, S. G., Michael, D., Chow, R., Regazzi, R., Gerona, R., Martin, T. F. J., Waselle, L., Tomas, A., Min, L., Pessin, J. E., Halban, P. A., Bjorklund, A., Ma, Z., Portwood, N., Parton, L. E., Smith, E. R., Diraison, F., Tsuboi, T., Lehtihet, M., Webb, D-L, Honkanen, R. E., Knoch, K-P, Meisterfeld, R., Bergert, H., Kolpe, M., Altkruger, A., Saeger, H-D, Solimena, M., Haspel, D., Aguilar-Bryan, L., Bryan, J., Ullrich, S., Berchtold, S., Ranta, F., Seebohm, G., Alexander, D., Wulff, P., Kuhl, D., Lang, F., Speier, S., Yang, S-B, Rose, T., Rupnik, M., Varadi, A., Mitchell, K. J., Schwappach, B., Bleck, C., Wienbergen, A., Rustenbeck, I., Vieira, E., Gylfe, E., Seissler, J., Wohlrab, U., Schmiegelt, D., Ruetter, R., Herten, M., Lechner, A., Nolan, A. L., Blacken, R. A., Habener, J. F., Gao, R., Ustinov, J., Korsgren, O., Mikkola, M., Lundin, K., Otonkoski, T., Jahr, H., Bieback, K., Kern, S., Brendel, C., Brendel, M. D., Bretzel, R. G., Taniguchi, S., Ohgawara, H., Tsuchiya, K., Tsuchiya, M., Okochi, H., Kelter, A-R, Dohrmann, C., Austen, M., Aicher, B., Maedler, K., Schumann, D. M., Iwakura, Y., Donath, M. Y., Peter, A., Opel, A., Seufert, J., Fernandez, E., Serradas, P., Martin, M. A., Plachot, C., Bailbe, D., Gangnerau, M. N., Gavete, M. L., Fajardo, S., Escriva, F., Portha, B., Alvarez, C., Lipsett, M., Jamal, A-M, Hanley, S., Castellarin, M., Rosenberg, L., Bhushan, A., Georgia, S., Calderari, S., Gangnerau, M-N, Meile, M-J, Miettinen, P. J., Palgi, J., Virkamaki, A., Ferris, W. F., Campbell, S. C., Armstrong, L., Hole, N., Lako, M., Macfarlane, W. M., Barbera, A., Altirriba, J., Nadal, B., Larsen, M. O., Gotfredsen, C. F., Holst, J. J., Reusens, B., Sparre, T., Kalbe, L., Leunda, A., Orntoft, T., Remade, C., Dasilva Xavier, G., Motakis, E., Nason, G. P., Leibiger, B., Berggren, P-O, Leibiger, I. B., Uhles, S., Moede, T., Welters, H. J., Senkel, S., Erdmann, S., Thomas, H., Morgan, N. G., Irminger, J-C, Rickenbach, K., Donath, M., Rouiller, D. G., Taylor, J. P., Jackson, D. A., Chan, S. L. F., Dezaki, K., Watanabe, M., Hosoda, H., Kangawa, K., Yada, T., Kuhnen, P., Laubner, K., Hernandez, R., Silvestre, R. A., Egido, E. M., Chatenet, D., Leprince, J., Chartrel, N., Vaudry, H., Marco, J., Zhang, F., Zhang, Q., Tengholm, A., Thore, S., Costes, S., Longuet, C., Broca, C., Baltrusch, S., Dyachok, O., Thams, P., Anwar, M. R., Capito, K., Radu, R. G., Fujimoto, S., Mukai, E., Shimono, D., Nabe, K., Shimodahira, M., Kominato, R., Aramaki, Y., Yamada, Y., Seino, Y., Giroix, M. H., Agascioglu, E., Courtois, P., Malaisse, W. J., Sener, A., Piquer, S., Barcelo-Batllori, S., Julia, M., Li, J., Li, X. J., Lou, M., Zhang, J., Zhou, Q., Zhao, G. Z., Webb, G. C., Dalal, S., Garcia, C., Saxena, P., Houk, M., Nenquin, M., Abdel-Ghany, M., Miele, C., Romano, C., Corbo, V., Maitan, M. A., Andreozzi, F., Ungaro, P., Oriente, F., Raciti, G. A., Formisano, P., Beguinot, F., Mcclenaghan, N. H., Mccluskey, J. T., Patterson, S., Efanov, A., Sewing, S., Bokvist, K., Gromada, J., Frederiksen, A. L., Juhl, C. B., Schwarts, M., Schmitz, O., Andersen, P. H., Valeri, C., Castelli, M. D., Bonfante, R., Beyan, H., Elouil, H., Khaldi, M. Z., Evangelista, S., Zeender, E., Berney, T., Schumann, D., Franklin, I., Sergeev, P., Chervonsky, A. V., Wollheim, C., Nyblom, H., Ahmed, M., Bergsten, P., Sol, E-R, Kharroubi, I., Ladriere, L., Cnop, M., Moffitt, J. H., Fielding, B., Currie, J., Staiger, K., Brandhorst, D., Winter, D., Kellerer, M., Oprescu, A. I., Naassan, A., Klimentova, T., Constantin, S. A., Tang, C., Uchino, H., Lam, L., Wheeler, M. B., Fantus, G. I., Giacca, A., Ortsater, H., Sundsten, T., Youshikawa, H., Winzell, M. S., Montrone, C., Martemucci, S., Perrini, S., Caccioppoli, C., Grassetti, D., Scipioni, A., Dotta, F., Yamamoto, N., Tsunekawa, S., Ito, Y., Oiso, Y., Miura, Y., Niki, I., Scrocchi, L. A., Ha, K. B. N., Wang, F., Chen, Y., Wu, L., Fraser, P. E., Yermen, B., Lilla, V., Kaminski, A., Mathe, Z., Dupraz, P., Zbinden, M., Filo, A., Bucher, P., Rinsch, C., Thorens, B., Pepper, M. S., Estilles, E., Sigrist, S., Rieger, L., Mandes, K., Bohbot, A., Pinget, M., Kessler, L., Parab, P. B., Katdare, M. R., Galande, S., Saha, B., Yoshida, A., Satoh, J., Homo-Dekarche, F., Coulaud, J., Durant, S., Drexhage, H. A., Mabley, J. G., Deb, A., Wallace, R., Pacher, P., Elder, R. H., Szabo, C., Schlosser, M., Mentel, R., Moya-Suri, V., Wassmuth, R., Gurtler, L., Ankelo, M., Westerlund, A., Blomberg, K., Hinkkanen, A. E., Popova, V. V., Gruzov, M. A., Afanasyeva, V. V., Kulikovskaya, A. V., Melnichenko, S. V., Mankovsky, B. N., Zak, K. P., Koczwara, K., Warncke, K., Kawasaki, E., Imagawa, A., Uchigata, Y., Kobayashi, M., Abiru, N., Yamasaki, H., Eguchi, K., Chrul, S., Polakowska, E., Heinrich, A., Walter, M., Pitocco, D., Visalli, N., Crino, A., Costantino, F., Manfrini, S., Spera, S., Suraci, C., Patera, P., Matteoli, M. C., Schiaffini, R., Ghirlanda, G., Leotta, S., Imdiab, Group, Hatziagelaki, E., Tsiavou, A., Degiannis, D., Chaidaroglou, A., Manginas, A., Koniavitou, K., Desai, M., Williams, A. J. K., Horton, V. A., Bingley, P. J., Cull, C. A., Citarrella, R., Richiusa, P., Mattina, A., Criscimanna, A., Mantione, L., Bronte, V., Pizzolanti, G., Galluzzo, A., Giordano, C., Giulietti, A., Stoffels, K., Overbergh, L., Mathieu, C., Bilgic, S., Aktas, E., Salman, F., Yillar, G., Yilmaz, M., Deniz, G., Valorani, G. M., Imdiab, G., Pozzilli, R., Weets, I., Truyen, I., Verschraegen, I., Auwera, B., Schepper, J., Dorchy, H., Lebrethon, M-C, Gaal, L., Rooy, P., Pipeleers, D. G., Gorus, F. K., Belgian Diabetes Registry (Brussels, Belgium), Shtandel, S. A., Atramentova, L. A., Karachentsev, Y. I., Kravchun, N. A., Koval, S. N., Poltorak, V. V., Levchenko, T. P., Snegurakaya, I. A., Miloslavskiy, D. K., Bojko, V. V., Resnik, L. A., Chico, A., Rojas, I., Novials, A., Bendlova, B., Vcelak, J., Vankova, M., Sramkova, D., Samalikova, P., Kvasnickova, H., Vondra, K., Petrone, A., Vania, A., Zavarella, S., Alemanno, I., Di Cola, S., Ribaudo, M. C., Leonetti, F., Angel, B., Carrasco, E., Santos, J., Albala, C., Oyarzun, A., Perez-Bravo, F., Petry, C. J., Ong, K. K., Michelmore, K., Artigas, S., Wingate, D. L., Zegher, F., Ibanez, L., Prestle, J., Adomeit, A., Hammer, E., Zieher, T., Missler, B., Appl, T., Schindler, M., Brodbeck, K., Machicao, F., Haring, H., Just, M., Fargeman, N., Knudsen, J., Quint, M., Tschank, G., Korn, M., Henriksen, E. J., Dokken, B. B., Sloniger, J. A., Dorig, J., Quarre, L., Piatkiewicz, P., Taton, J., Czech, A., Gorski, A., Jebens, E., Brennesvik, E. O., Ktori, C., Ruzzin, J., Shepherd, P. R., Jensen, J., Lakka, H-M, Rankinen, T., Leon, A. S., Skinner, J. S., Wilmore, J. H., Rao, D. C., Bouchard, C., Vendrell, J. J., Chacon, M. R., Garcia-Espana, A., Fernandez-Real, J., Gutierrez, C., Richart, C., Takeshita, Y., Shimizu, A., Hamaguchi, E., Kaneko, S., Hrebicek, J., Orel, M., Lichnovska, R., Gwozdziewiczova, S., Chlup, R., Faturos, I., Tournis, S., Fotinakis, P., Thomakos, P., Manousaki, M., Leontsini, D., Taxildaris, K., Mitrakou, A., Kim, S., Hur, K., Shim, W., Ahn, C., Cho, Y., Lim, S., Kim, K., Lee, H., Cha, B., Beregszaszi, M., Chevenne, D., Sebag, G., Kerdanet, M., Huet, F., Polak, M., Lacombe, D., Paoli, A., Levy-Marchal, C., Mokhort, T., Shishko, E., Shepelkevich, A., Benito, M., Arribas, M., Valverde, A. M., Menghini, R., Marchetti, V., Cardellini, M., Sbraccia, P., Lauro, D., Lauro, R., Ali, A. T., Penny, C., Merwe, M-T, Paiker, J. E., Psaras, G., Ekram, F., Crowther, N. J., Musri, M. M., Corominola, H., Casamitjana, R., Parrizas, M., Renstrom, F., Buren, J., Park, C., Park, Y., Lee, G., Kang, E., Kim, K-S, Sanchez-Margalet, V., Gonzalez-Yanes, C., Diaz-Troya, S., Rodriguez Fonseca, F., Mcnamara, M. R. J., Boschetti, N., Schmid, D., Spinas, G. A., Trub, T., Niessen, M., Kuhlmann, J., Neumann-Haefelin, C., Belz, U., Juretschke, H-P, Kramer, W., Herling, A. W., Markova, I., Oliyarnyk, O., Cahova, M., Manders, R. J. F., Koopman, R., Zorenc, A. H. G., Keizer, H. A., Loon, L. J. C., Straczkowski, M., Kowalska, I., Dzienis-Straczkowska, S., Nikolajuk, A., Gorska, M., Zabielski, P., Baranowski, M., Gorski, J., Tack, C. J., Haan, J., Klomp, D., Heerschap, A., Corpeleijn, E., Budzinski, R. M., Stengele, I., Schuler, M., Selzle, N., Lehmann-Lintz, T., Heckel, A., Vavrinkova, H., Meskhishvili, E., Furier, S. M., Parkes, H. A., Cooney, G. J., Alemzadeh, R., Tushaus, K. M., Nencioni, S., Giovannitti, G., Longo, V., Vries, R., Kerstens, M. N., Tol, A., Dullaart, R. P. F., Mcbride, R., Denke, M. A., Pearson, T., Battisti, W. P., Brady, W. E., Palmisano, J., Tuzova, O. V., Wahl, H. G., Hong, Q., Luz, K., Xu, G., Schmulling, R. M., Liebich, H. M., Oomen, P. H. N., Hattori, H., Smit, A. J., Scheek, L. M., Thomaseth, K., Lajoix, A-D, Gauthey, A., Dietz, S., Jahannault, C., Manteghetti, M., Petit, P., Gross, R., Quynh, N. T. T., Floren, A., Langel, U., Gedulin, B. R., Smith, P., Prickett, K. S., Tryon, M., Barnhill, S., Yeoh, T., Young, A. A., Hiles, R., Carpenter, T., Serota, D., Schafer, K., Ross, P., Nelson, D., Rebelatto, M., Ikeda, H., Nagashima, K., Tsukiyama, K., Todo, T., Trombetta, M., Boselli, L., Cali, A., Cretti, A., Monauni, T., Bifari, F., Bonora, E., Muggeo, M., Bonadonna, R. C., Gredal, C., Rosenfalck, A., Dejgaard, A., Hilsted, J., Rudovich, N. N., Rochlitz, H. J., Ritzel, R. A., Butler, A. E., Butler, P. C., Murphy, M. J., Korner, A., Csillag, J., Pinter, A., Cameron, N., Toman, M., Gray, I. P., Vielwerth, S. E., Rinnov, A., Jensen, R. B. B., Juul, A., Uitterlinden, P., Bruining, G. J., Lamberts, S. W., Rasmussen, E., Malis, C., Ekstrom, C., Arne, A., James, J. L., Thomas, P., Cavan, D. C., Owona, A. M., Ozaki, R., So, W., Tong, P., Chan, M., Wong, G., Cockram, C., Chan, J., Redemann, N. H., Gotz, B., Lahm, P., Mader, G., Tadayyon, M., Oh, Y., Schippmann, V., Kluge, R., Bornstein, S. R., Scherbaum, W. A., Joost, H-G, Bae, H. Y., Kim, S. Y., Lee, B. R., Vertigan, H., Carroll, D., Griffiths, L., Coghlan, M. P., Freeman, S., Toffolo, G., Dalla Man, C., Basu, R., Rizza, R., Cobelli, C., Bertoldo, A., Price, J., Mathis, C. A., Mason, N. S., Holt, D., Kelley, C., Mckolanis, T. M., Kelley, D. E., Whyte, M., Jackson, N., Beale, R., Treacher, D., Carroll, P., Jones, R. H., Umpleby, M., Jaquet, D., Boiko, J., Rigal, O., Czernichow, P., Qvisth, V., Hagstrom-Toft, E., Moberg, E., Bolinder, J., Sjostrand, M., Strindberg, L., Lonnroth, P., Mick, D. D., Sumarac-Dumanovic, M., Cvijovic, G. M., Kendereski, A., Pejkovic, D., Zoric, S., Casanueva, F. F., Dieguez, C. C., Singh, R. J., Basu, A., Chittilapilly, E. G., Johnson, M. C., Abdallah, B. M., Shubeska Stratrova, S., Svendsen, O. L., Dhatariya, K. K., Bigelow, M. L., Nair, K. S., Lundgren, M., Ruge, T., Myrnas, T., Gimeno, R. E., Suri, V., Li, D., Huard, C., Martine PUGNIERE, Vettore, M., Sironi, A. M., Gastaldelli, A., Mari, A., Ciociaro, D., Buzzigoli, E., Pettiti, M., Positano, V., Lombardi, M., Radziuk, J., Pye, S., Brehm, A. R., Krssak, M., Bernroider, E., Anderwald, C., Nowotny, P., Cline, G., Shulman, G. I., Kotsa, K., Papazisi, A., Spanopoulos, I., Giovos, I., Suzuki, A., Sobajima, H., Naruse, S., Kitagawa, M., Ishiguro, H., Futakuchi, S., Goto, H., Hines, G., Kennedy, I., Matthews, D., Levy, J., Radikova, Z., Koska, J., Ksinantova, L., Imrich, R., Huckova, M., Vigas, M., Wallace, T. M., Matthews, D. R., Rajala, U., Hiltunen, L., Keinanen-Kiukaanniemi, S., Noh, J-H, Kim, D-J, Choi, N-H, Lee, B-W, Chung, J-H, Min, Y-K, Lee, M-S, Kim, K-W, Lee, M-K, Byrne, C. D., Holt, H. B., Phillips, D. I. W., Wood, P. J., Darekar, A. A., Astrup, A., Gross, S., Matthies, K., Weck, M., Malinska, H., Beifort, R. S., Berria, R., Defronzo, R., Cusi, K., Gorshunska, M. Y., Karachenzev, Y. I., Lopez-Bermejo, A., Pratt, K. L., Hwa, V., Recasens, M., Broch, M., Vendrell, J., Rosenfeld, R. G., Fernandez-Real, J. M., Ricart, W., Grunnet, L., Pedersen, B. K., Franke, B., Fleming, S., Lemke, N., Laue, C., Pfeuffer, M., Lecube, A., Hernandez, C., Genesca, J., Garcia, L., Francisco, G., Simo, R., Kraml, P. J., Syrovatka, P., Brunerova, L., Smejkalova, V., Potockova, J., Andel, M., Leshchenko, Z., Poltorack, V., Krasova, N., Gladkih, A., Yang, K., Chamson, A., Thyssen, S. M., Rojo Llobet, A. M., Christoffersen, B. O., Raun, K., Fledelius, C., Svendsen, O., Vinterby, A., Golozoubova, V., Afonso, R. A., Ribeiro, R. T., Macedo, M. P., Guarino, M. P., Yang, G., Kurita, S., Misu, H., Akahori, H., Cerf, M. E., Nkomo, X. I., Muller, C. J., Du Toit, D. F., Louw, J., Wolfe-Coote, S. A., Nikishin, P., Zagayko, A., Taylor, K. D., Guo, X., Langefeld, C. D., Cur, J., Jinagouda, S., Bowden, D., Hokanson, J., Rotter, J. I., Liew, C. F., Wise, S. D., Yeo, K. P., Teng, C. H., Lee, K. O., Fisher, F. M., Trujillo, M. E., Hanif, W., Mcternan, P. G., Barnett, A. H., Scherer, P. E., Kumar, S., Kaltenbach, S., Stumvoll, M., Mlynarski, W., Andrzejewski, W., Shojaee-Moradie, F., Das, S., Stolinski, M., Jefferson, W., Cramb, R., Shahmanesh, M., Lyngso, D., Simonsen, L., Bulow, J., Meinardi, J. R., Sluiter, W. J., Wolffenbuttel, B. H. R., Bonnet, F., Guebre-Egziabher, F., Rabasa, R., Laville, M., Gosby, A. K., Maloney, C. A., Haering, H-U, Patarrao, R. S., Lautt, W. W., Correia, N. C., Santos, A. I., Leite, V., Boavida, J. M., Nanwei, T. N. W., Bobbioni-Harsch, E., Lehmann, T., Sztajzel, J., Morel, P., Huber, O., Chassot, G., Assimacopoulos-Jeannet, F., Gedulin, G., Baron, A., Hendrickx, H., Lane, J., Coverly, J., Simcox, J., Stocks, J., Brown, L., Beha, A., Juretschke, P., Gerl, M., Klebach, M., Biemer-Daub, G., Perez-Del-Pulgar, S., Zorzano, A., Heinsbroek, A. C. M., D Alessio, D., Dijk, G., Tornero, M. P., Bailey, C. J., Mack, C. M., Wilson, J. K., Parkes, D. G., Kusunoki, M., Sakakibara, F., Kato, K., Okabayashi, N., Nakamura, T., Miyata, T., Habu, S., Nakamura, R., Nakasone, Y., Yasaka, T., Ishihara, R., Morikawa, R., Otake, K., Nakaya, Y., Ruzickova, J., Rossmeisl, M., Flachs, P., Sponarova, J., Prazak, T., Matejkova, O., Kopecky, J., Gram, D. X., Liu, W., Bodvarsdottir, T., Hansen, J. B., Sturis, J., Kern, W., Hallschmid, M., Benedict, C., Schultes, B., Born, J., Fehm, H. L., Westerbacka, J., Lammi, K., Hakkinen, A-M, Rissanen, A., Yki-Jarvinen, H., Mayr, P., Mertl-Roetzer, M., Lauster, F., Pohl, M., Lerch, M., Haslbeck, M., Eriksen, J., Rahlfs, V. W., Serhiyenko, V. A., Serhiyenko, A. A., Serhiyenko, L. M., Radulian, G., Vladica, M., Panaite, C., Balas, B., Derosa, G., Dumas, A., Fiorito, A., Prieto, P. G., Cancelas, J., Loba, J., Czupryniak, L., Bialasiewicz, P., Pawlowski, M., Nowak, D., Dupuy, O., Le Berre, J. P., Bordier, L., Rousseau, C., Mayaudon, H., Bauduceau, B., Bossi, A. C., Meregalli, G., Balini, A., Berzi, D., Cremonesi, B., Cerrato, D., Rezzani, C., Tumiati, M., Han, K., Min, K., Kim, E., Ahn, K., Ahn, H., Arguelles, I., Forga, L., Izquierdo, M., Gorostiaga, E., Fuentes, C., Ibanez, J., Rivero, A., Baynes, K., Pentecost, C., Bell, J. D., Thomas, E. L., Jackson, N. C., Umpleby, A. M., Kuhl, J., Ruderman, N. B., Musi, N., Goodyear, L. J., Patti, M. E., Thorell, A., Nygren, J., Ljungkvist, O., Degerblad, M., Stahle, A., Brismar, T. B., Saha, A. K., Bavenholm, P. N., Aydemir, D., Kiran, B., Unal, M., Okumus, N., Kayserilioglu, A., Perkins, J., Salman, S., Ozer, E., Kayserilioǧlu, A., Dinccaǧ, N., Tikkanen, H., Lakka, T., Macdonald, A. L., Harrison, M., Dickinson, H., Bone, A. J., Watt, P. W., Ostergard, T., Short, K., Saltin, B., Nair, K., Di Mauro, M., Papalia, G., Battiato, R., Giuffrida, D., Boemi, G., Castellino, P., Akter, S., Akhter, A., Pervin, T., Ahmed, S., Ahmed, K. R., Saleh, F., Chaudhury, H. S., Tankova, T., Dakovska, G., Lazarova, M., Dakovska, L., Kirilov, G., Koev, D., Torgerson, J. S., Hauptman, J., Boldrin, M., Shi, Y-F, Pan, C-Y, Gao, Y., Lindgarde, F., Broom, I., Takeda, H., Oana, F., Matsuzawa, A., Hashizume, H., Akahane, S., Howlett, H. C. S., Cornes, M., Lund, S. S., Poulsen, G., Frandsen, M., Pedersen, O., Pankiv, V. I., Yngen, M., Hjemdahl, P., Wallen, N. H., Florow, D., Leyck Dieken, M. G., Kitahara, Y., Mine, T., Konya, H., Hamaguchi, T., Satani, K., Umehara, A., Ishikawa, T., Kohri, K., Hasegawa, Y., Suehiro, A., Kakishita, E., Namba, M., Wang, F. N., Liao, Z. H., Yao, B., Li, Y. B., Hu, G. L., Belcher, G., Mariz, S., Tan, M. H., Moules, I., Pfutzner, A. H., Butzer, R., Langenfeld, M., Koder, C., Cooper, M., Majali, K. Al, Adiseshiah, M., Betteridge, J., Pratipanawatr, T., Chotmongkol, R., Kanhasura, S., Pratipanawatr, W., Miyazaki, Y., Matsuda, M., Defronzo, R. A., Nagasawa, T., Kuroda, J., Dey, D., Chovatia, M., Nag, A., Pandey, B., Nag, B., Thomas, L., Krauth, M., Allgauer, S., Besenfelder, U., Dennenmoser, J., Moon, C-K, Chae, S-H, Kim, M-H, Jo, Y-Y, Shin, J-S, Ahn, S-K, Lee, H-W, Lee, S-J, Panadero Moya, A., Rodriguez, E., Gonzalo, A., Sanchez-Vilar, O., Lara, J. I., Rovira, A., Otto, C., Otto, B., Goke, B., Parhofer, K. G., Juurinen, L., Tiikkainen, M., Graner, M., Bajaj, M., Suraamornkul, S., Argon, D., Canbek, E., Schofl, C., Franzen, C., Gregg, R. E., Swaminathan, A., Frost, C., Nepal, S., Raymond, R., Mosqueda-Garcia, R., Johns, D., Gilmore, K., Perriello, G., Pampanelli, S., Di Pietro, C., Rinaldi, T., Brunetti, P., Oshinyemi, K., Garcia, S., Curtis, P., Zambanini, A., Home, P. D., Pocock, S., Dargie, H., Komajda, M., Jones, N. P., Record, Study Group, Munscher, C., Potthoff, F., Golbach, U., Weidenhammer, J., Kusterer, K., Lundershausen, R., O Neill, M. C., Goldstein, B. J., Wooddell, M. J., Strow, L. J., Waterhouse, B. R., Cobitz, A. R., Wyne, K. L., Porter, L. E., Weston, W. M., Chen, T., James, R. E., Kravitz, B. G., Pinkowski, D., Ruxer, J., Mozdzan, M., Siejka, A., Kaiser, M., Hauser, C., Jacober, S. J., Zagar, A. J., Althouse, S. K., Pinaire, J. A., Becker, R. H. A., Frick, A. D., Rave, K., Moses, R., Ways, K., Krones, R., Basir, S., Klein, C., Sawicki, P. T., Rotella, C. M., Pala, L., Dicembrini, I., Mannucci, E., Annuzzi, G., Natale, C., Bozzetto, L., Patti, L., Cipriano, P., Campaigne, B., Malone, J. K., Bai, S., Reviriego, J., Augendre-Ferrante, B., Schreiber, S. A., Schneider, K., Schweitzer, M-A, Fach, E-M, Busch, K., Karimi Anderesi, Z., Hoe, Study Group, Dunseath, G. J., Sengul, A. M., Haupt, A., Eckert, H., Schweitzer, M. A., Peiker, J., Fritsche, A., Janka, H. U., Plewe, G., Kliebe-Frisch, C., Maxeiner, S., Teng, L., Chan, C., Ernest, C. S., Skrivanek, Z., Brodows, R. G., Soon, D., Pan, C. Y., Chung, K-D, Russmann, A., Ryysy, L., Hanninen, J., Hulme, S., Kauppinen-Makelin, R., Lahdenpera, S., Lehtonen, R., Levanen, H., Nikkia, K., Tulokas, T., Virtamo, H., Vahatalo, M., Fulcher, G. R., Lavalle-Gonzalez, F., Soon, D. K. W., La Pena, A., Lim, M., Scholtz, H. E., Derezinski, T., Gerber, R. A., Hauber, A. B., Bolinder, B., Johnson, F. R., Boehm, B. O., Keiding, J., Home, P., Raastam, J., Moller, M. K., Parkner, T., Chen, J-W, Jorgensen, C., Smedegaard, J., Christiansen, J. S., Mcdougall, A., Fitch, M., Nelson, G., Mueller, U. A., Saemann, A., Ishii, H., Iburi, T., Furuya, M., Yamagami, K., Sekine, O., Yamashiro, S., Ishibashi, R., Tsujii, S., Sauriol, L., Lescrauwaet, B., Heckmann, B., Helbig, C., Franke, I., Schiel, R., Oguzhan, B., Gursoy, N., Turkish Diabetes Centers Study Group, Gutierrez, E., Garcia, P., Rokeya, B., Hossain, M. E., Ali, L., Ivanova, O. V., Gorbenko, N. I., Gladkich, A. I., Leshchenko, Z. A., Gorbenko, N., Ivanova, O., Gorbenko, K., Blase, E., Taylor, K., Nguyen, T., Su, G., Gao, H-Y, Carr, E., Wintle, M., Fineman, M., Calara, F., Han, J., Aisporna, M., Zabala, E., Fehse, F., Trautmann, M. E., Halseth, A. E., Nauck, M. A., Kendall, D. M., Riddle, M. C., Zhuang, D., Kim, D. D., Fineman, M. S., Baron, A. D., Buse, J., Henry, R., Ratner, R., Linnebjerg, H., Kothare, P., Ernest, C. Nd, Atkins, M., Trautmann, M., Bjerre Knudsen, L., Voss, P. V., Nauck, M., Hompesch, M., Filipczak, R., Le, T. T. D., Nielsen, L., Zdravkovic, M., Gumprecht, J., Deacon, C. F., Plamboeck, A., Guivarch, P-H, Dreyfus, J-F, Mathi, S., Castaigne, J-P, Drucker, D. J., Kruger, D., Burrell, T., Gloster, M., Crean, J., Herrmann, K., Maggs, D., Kolterman, O., Kovatchev, B., Cox, D. J., Mccall, A., Whitehouse, F., Kovatchev, B. P., Chapman, I., Parker, B., Doran, S., Feinle-Bisset, C., Wishart, J., Lush, C., Mcintyre, S., Deckhut, D., Horowitz, M., El-Ouaghlidi, A., Rehring, E., Holmes, D., Sallas, W. M., He, Y. L., Watson, C., Ligueros-Saylan, M., Foley, J. E., Narayanan, S., Thomas, A., Shah, D., Gopalan, B., Vakkalanka, S., Arch, J., Ryskjar, J., Krarup, T., Madsbad, S., Vilsboll, T., Ciani, S., Bardini, G., Pezzatini, A., Cappadona, A., Bodvarsdottir, T. B., Joergensen, M. S., Jensen-Holm, H. B., Kristensen, L., Kanstrup, A. B., Mckillop, A. M., Duffy, N., Lindsay, J. R., Bell, P. M., Hansen, B. S., Gronemann, S., Wilken, M., Herman, G. A., Zhao, P-L, Dietrich, B., Golor, G., Schrodter, A., Keymeulen, B., Lasseter, K. C., Kipnes, M. S., Hilliard, D., Tanen, M., Smet, M., Dyck, K., Tanaka, W., Gottesdiener, K. M., Wagner, J. A., Hoffmann, T., V Horsten, S., Demuth, H-U, Paule, S. G., Myers, M. A., Nikolovski, B., Fujiwara, H., Hosokawa, M., Fukuda, K., Nishi, Y., Fujita, Y., Yamada, K., Ueda, N., Jones-Leone, A. R., Yu, T., Barilla, D., He, Y-L, Ho, Y., Foley, J., Makrilakis, K., Panagiotakos, D. B., Dimosthenopoulos, C., Ioannidis, I., Chrysohoou, C., Pitsavos, C., Kuo, S-W, Levendal, R-A, Frost, C. L., Poonsatha, S., Jones, G., Fahey, R., Collier, G., Hoa, N. K., Norberg, A., Liepinsh, E., Phan, D. V., Thuan, N. D., Jornvall, H., Sillard, R., Ostenson, C. G., Tessari, P., Kiwanuka, E., Cristini, M., Zaramella, M., Enslen, M., Garcia-Rodenas, C., Yazawa, M., Imai, Y., Ohmura, E., Tsuchida, A., Matsuda, A., Hosaka, D., Horie, H., Ichita, M., Hisano, Y., Woodhead, S., Xu, W., Chen, X. H., Cavalot, F. L., Bonomo, K., Perna, P., Bacillo, E., Salacone, P., Gallo, M., Gaia, E., Vinik, A. I., Yu, D., Heise, M. A., Freed, M. I., Aguilera, E., Pellitero, S., Naf, S., Bendtzen, K., Nicoletti, F., Hahn, J-U, Bochnig, S., Koenig, H., Sporleder, B., Maisonneuve, P., Lowenfels, A. B., Kerner, W., Lankisch, P. G., Thai, A. C., Mohan, V., Khalid, B. A. K., Yeo, J. P., Asdiab, Study Group, Gasiorowska, A., Talar-Wojnarowska, R., Malecka-Panas, E., Schindler, K., Rieger, A., Gmeinhart, B., Schlembacher, K., Merz, P., Ludvik, B., Muller, N., Rodriguez, F. U., Aas, A-M, Seljeflot, I., Huang, C., Biswas, N., Hashimoto, N., Kamatani, Y., Suzuki, Y., Yagui, K., Saito, Y., Iwai, R., Takahashi, H., Yoshida, S., Skowronski, M., Zozulinska, D., Juszczyk, J., Wierusz-Wysocka, B., Bohles, H. J., Peterkova, V. A., Kuraeva, T. L., Scherbacheva, L. N., Andrianova, E. A., Maximova, V. P., Titovich, E. V., Danne, T., Bittner, C., Hanaire-Broutin, H., Schumicki, D-M, Souhami, E., Morrison, G., Purewal, T. S., Weston, P. J., Smahelova, A., Rusavy, Z., Koznarova, R., Loykova, V., Belobradkova, J., Devries, J. H., Retnakaran, R., Hochman, J., Melki, V., Zinman, B., Corbi, S., Costanza, F., Fioriti, E., Cappa, M., Jaron, M., Martinek, V., Piechatzek, R., Klaff, L., Prager, R., Robinson, A., Penfornis, A., Garg, S. K., Thomas, R., Selam, J. L., Sola-Gazagnes, A., Vitacolonna, E., Canonico, V., Fabietti, P., Iorio, M., Orsini Federici, M., Timi, A., Massi Benedetti, M., Sarti, E., Ashwell, S. G., Gebbie, J., Siebenhofer, A., Plank, J., Berghold, A., Horvath, K., Mrak, P., Jeitler, K. J., Pieber, T. R., Heller, S., Gottlieb, P., Paul, J., Chase, P., Menditto, L., Antuna, R., Grimaldi, A., Brun, J-M, Vialettes, B., Halimi, S., Dubroca, I., Blayo, A., Gomez-Peralta, F., Santos-Mazo, E., Payeras-Mas, F., Abreu-Padin, C., Santos-Palacios, S., Salvador-Rodriguez, J., Burge, M. R., Schroeder, E., Witthaus, E., Johnston, P., Bradley, C., Kudva, Y. C., Jenkins, G., Pons, G., Quandt, L., Gebel, J., Vogelsang, D., Smith, S., Isley, W., Russell-Jones, D., Maier, C., Mustapic, D., Schuster, E., Luger, A., Eher, R., Rubesova, I., Pelikanova, T., Skibova, J., Sanz, F. J., Ampudia-Blasco, F. J., Gabaldon, J., Catala, M., Carmena, R., Heinemann, L., Kronshage, B., Ward, K., Sass, D., Essenpreis, M., Voelkel, D., Lodwig, V., Nguyen, M., Mondok, A., Friedrich, C., Caduff, A., Totonelli, A., Longhitano, S., Agro, F., Edelman, S. V., Morrison, Z., Velazquez, F., Howard, S., Banks, R., Berger, B., Burian, P., Nilsson, K. A., Karlen, M., Rylander, E., Blonde, L., Freemantle, N., Ross, S. A., Duhot, D., Eggertsen, R., Hobbs, F. D. R., Martinez, L., Stridde, E., Skyler, J. S., Tusek, C., Stephan, J-A, Krasner, A., Landschulz, W. H., Sha, S., Bott, S., Bergenstal, R. M., Damge, C., Ubrich, N., Kaltenbacher, M-C, Maincent, P., Wutte, A., Bock, G., Balent, B., Midtgaard, A., Ronn, B. B., Pieber, T., Edgerton, D. S., Cherrington, A. D., Neal, D. W., Scott, M., Glass, D., Bowen, L. E., Wilson, W., Hobbs, C. H., Leach, C., Sivakumaran, S., Strack, T. R., Meyts, P., Aladdin, H., Palsgaard, J., Theede, A-M, Sajid, W., Hinrichsen, J., Klaproth, B., Lademann, J., Ostergaard, J., Andersen, A. S., Boss, A. H., Cheatham, W. W., Pfuetzner, A., Larbig, M., Forst, S., Abdollahnia, R., Grenningloh, M., Leatherdale, B., Bartley, E., Schwartz, S. L., Buchea, O., Shin, J., Hoss, U., Shah, R., Endo, T., Hata, S., Yamazaki, H., Hernandez Campos, S., Busciantella Ricci, N., Kaufman, F., Halvorson, M., Carpenter, S., Cooper, K., Mueller, J., Wasen, H., Brumberg, J., Rduch, K., Mertens, S., Reess, F., Renz, H., Maran, A., Sparacino, G., Pavanini, A., Corazza, S., Crepaldi, M., Poscia, A., Acosta, D., Salcedo, D., Delgado, E., Hawkins, F., Parramon, M., Mesa, J., Parhimovich, R. M., Darko, D. A., Odusanya, P. O. T., Pullen, F., Hopkins, D. F., Mukherjee, S., Child, D. F., Redkin, Y. A., Dreval, A. A., Bogomolov, V. V., Dreval, A. V., Ostgren, C. J., Grodzinsky, E., Lindstrom, K., Borgquist, L., Fegan, G., Hamliton, P., Mccrimmon, R. J., Evans, M. L., Fan, X., Ding, Y., Sherwin, R., Boomsma, F., Pramming, S., Fischer, B. M., Soydan, N., Eckhard, M., Saar, P., Kreuder, J., Linn, T., Holstein, A., Plaschke, A., Ptak, M., Egberts, E-H, El-Din, J., Kirchheiner, J., Hoashi, S., Khamis, A., Kilbane, M. T., Cannon, D. E., Gribben, A. P., Firth, R. G. R., Kinsley, B. T., Cranston, I. C., Galan, B. E., Mol, P., Wennekes, L., Due-Andersen, R., Lundkvist, J., Jonsson, L., Mukhopadhyay, B., Deans, K. A., Kesson, C. M., Jendrike, N., Buck, H., Abicht, A., Haug, C., Freckmann, G., Warren, R. E., Sommerfield, A. J., Allen, K. V., Deary, I. J., Frier, B. M., Hoi-Hansen, T., Wu, A., Holtman, V., Plaschke, A. J., Tenberken, O., Maurer, H. H., Al-Zakwani, I., Bullano, M. F., Baron, J. J., Willey, V. J., Nattrass, M., Kurtzhals, P., Colding-Jorgensen, M., Riddle, M., Massi-Benedetti, M., Murray, F., Lin, Z., Kolendorf, K., Prasek, M., Philotheou, A., Javashvili, L., Virsaladze, D., Kajaia, N., Raposo, J. F., Pratas, S., Fernandes, C., Valadas, C., Duarte, R., Gardete-Correia, L., Boavida, J., Locatelli, M., Patera, I. P., Bottazzo, G. F., Hadjidakis, D., Mylonakis, A., Raptis, A., Papaefstathiou, A., Hedman, C. A., Frystyk, J., Fridell, K., Jonsson, A., Lindstrom, T., Saito, M., Eto, M., Kaku, K., Stotzka, M., Stein, G., Prince, M. J., Kulzer, B., Scholze, A., Hermanns, N., Kubiak, T., Starostina, E. G., Shavrikova, E. P., Furuhashi, N., Hirose, T., Kuroda, M., Kimura, M., Ishizawa, M., Sarui, H., Takeda, N., Furuta, T., Drewelow, S., Lindloh, C., Paddison, C. A. M., Faimalie, M., Flett, R. A., Micheletti, S., Perelli Cippo, P., Mantovani, L. G., Su, M., Trento, M., Bajardi, M., Passera, P., Miselli, V., Tomalino, M., Borgo, E., Cavallo, F., Porta, M., Miclea, S., Bogatean, M., Hancu, N. D., Leppert, K., Rittmeier, H., Hancu, N., Mchorney, C., Myers, J., Reinecker, H., Meier, J. J., Gallwitz, B., Askenas, M., Vollmer, K., Schmidt, W. E., Kyrou, I., Souvatzoglou, E., Cseh, K., Baranyi, E., Kaszas, E., Szocs, A., Melczer, Z., Sikter, M., Szenthe, P., Hajos, P., Pogatsa, G., Winkler, G., Pardo, I. C. G., Barros-Filho, A. A., Jahan, S., Huq, F., Biswas, K. B., Chowdhury, T. A., Khan, A. R., Ritterath, C., Talai Rad, N., Siegmund, T., Heinze, T., Henrich, W., Siebert, G., Dudenhausen, J., Buhling, K., Kautzky-Willer, A., Mustafa, S., Winzer, C., Vukovich, T., Shaat, N., Ekelund, M., Lernmark, A., Ivarsson, S., Zmudzinska, M., Bronisz, A., Pufal, M., Junik, R., Beran, D. H., Toledano, Y., Giveon, S., Kahan, E., Aycheh, S., Guttman, N., Jaffe, A., Alberti, H., Boudriga, N., Nabli, M., Jaiveer, S., Jaiveer, P. K., Lee, J. D., Shaikh, S., Gopinath, A., Morrissey, J. R., Patel, V., Lenz, M., Dvoynishnikova, O. M., Mayorov, A. Y., Galstyan, G. R., Antsiferov, M. B., Dedov, I. I., Rybarczyk, M., Scalone, L., Palmer, A. J., Morgutti, M., Valentine, W. J., Renaudin, C., Roze, S., Morsanutto, A., Berto, P., Lopatriello, S., Voinovich, D., Gelisio, R., Brandie, M., Russ, W., Greiner, R. A., Rubio Terres, C., Pablos, P., Smith, I. C., Wittrup-Jensen, K., Morgan, C. L., Tsutskiridze, L., Haag, B., Delbuono, B., Silva, C., Fox, A., Padilla, V., Naraine, K., Cypryk, K., Szymczak, W., Szosland, K., Sobczak, M., Zawodniak-Szalapska, M., Lewinski, A., Schvarcz, E., Lindqvist, A., Stenninger, E., Ostlund, I., Aman, J., Lapolla, A., Dalfra, M., Di Benedetto, A., Dolci, M., Franzetti, I., Masotti, M., Napoli, A., Salietti, G., Santini, C., Tortul, C., Di Cianni, G., Popow, C., Waldhor, T., Horn, W., Biermann, E., Rihl, J., Riedl, M., Kastner, P., Kollmann, A., Pusch, W., Schreier, G., Hearnshaw, H. M., Lowe, P., Griffiths, F. E., Stapperfend, M. C., Baehring, T. U., Cosson, E., Benchimol, M., Carbillon, L., Paries, J., Lormeau, B., Valensi, P., Pharisien, I., Tourel, E., Uzan, M., Attali, J-R, Zabarovskaya, Z. V., Mulyarchik, O. V., Shepelkevich, A. P., Barsukov, A. N., Guseva, T. K., Begum, K., Haque, L., Bokor, A., Rigo, J., Garamvolgyi, Z., Pusztai, P., Somogyi, A., Hanson, U., Nystrom, L., Blohmo, G., Ekbom-Schnell, A., Ostman, J., Persson, B., Parretti, E., Cioni, R., Marzari, C., Masin, M., Scarselli, G., Mello, G., Seghieri, G., Bellis, A., Anichini, R., Alviggi, L., Franconi, F., Breschi, C. M., Dworacka, M., Wender-Ozegowska, E., Winiarska, H., Macugowska, M., Zawiejska, A., Bobkiewicz-Kozlowska, T., Pietryga, M., Brazert, J., Bousboulas, S., Politakis, P., Papadimitriou, P., Lyu, R., Yin, D. D., Green, A., Kristensen, J. K., Rodriguez-Saldana, J., Clark, C. M. Jr, Morales Teresa, M., Escorza-Dominguez, A. B., Ortiz-Gress, A. A., Monroy-Mayorga, A., Mejia-Pedraza, B. J., Seeliger, S., Kaiser, J., Muller, E., Maxion-Bergemann, S., Bergemann, R., Goertz, A., Shearer, A., Bagust, A., Schoeffski, O., Mayorov, A., Shestakova, M., Antsiferov, M., Balabolkin, M., Chugunova, L., Shamkhalova, M., Zaytseva, N., Naumenkova, I., Brevnova, N., Dedov, I., Tsibina, L., Rosak, C., Petzoldt, R., Stammer, H., Dehmel, B., Seidel, D. K., Roth, W., Fennenkotter, U., Gottschall, V., Kanatsuka, A., Lauenborg, J., Mathiesen, E., Hornnes, P., Wagner, O. F., Zajdenverg, L., Halfoun, V. L. C., Oliveira, J. E. P., Lencioni, C., Volpe, L., Chatzianagnostou, K., Cuccuru, I., Ghio, A., Pardini, E., Salvadorini, M., Saltiki, A., Korakovouni, A., Stavrianos, H., Zapanti, E., Antsaklis, A., Pithova, P., Sporna, M., Bustani, R., Todd, D. M., Lawrence, I., Guerrero, R., Vazquez, M., Amaya, M., Dios, E., Quijada, D., Garcia-Hernandez, N., Astorga, R., Gandhi, R. A., Jayawarna, C., Fernando, D. J. S., Hill, R. P., Lloyd-Mostyn, R. H., Thomson, G. A., Rewers, A., Bothner, J., Klingensmith, G., Sysoyeva, O., Karlovich, N., Rankins, D., Wellard, M., Werther, G., Northam, E., Kordonouri, O., Haberland, H., Hauschild, M., Kapellen, T., Kraft, V., Wiemann, D., Lange, K., Witte, D. R., Fuller, J. H., Eurodiab Pcs, Group, Laude, D., Dabire, H., Hadj Brahim, F., Papanas, N., Papatheodorou, K., Christakidis, D., Papazoglou, D., Giassakis, G., Piperidou, H., Monastiriotis, H., Maltezos, E., Barrett, C., Serghides, H., Tindali, H., Kelly, F., Chiheb, S., Chen, Q., Brahimi, M., Cynober, L., Delaporte, C., Scionti, L., Conti, M., Vermigli, C., Galimberti, G., Cazzetta, G., Bosi, E., Sugimoto, K., Shoji, M., Yasujima, M., Suda, T., Yagihashi, S., Mabley, J., Zsengeller, Z., Charniauskaya, T., Abatan, O. I., Kimura, I., Tsuneki, H., Hara, S., Sasaki, K., Nangle, M. R., Gibson, T. M., Yorek, M. A., Hirooka, H., Stevens, M. J., Tarhzaoui, K., Cohen-Boulakia, F., Smith, G., Lestrade, R., Behar, A., Komori, H., Oi, K., Takahashi, D., Kunitou, T., Moroi, M., Philips, J-C, Marchand, M., Geronooz, I., Scheen, A. J., Gambardella, S., Ciampittiello, G., Bracaglia, D., Cicconetti, E., Gigli, F., Verri, C., Baroni, A., Frontoni, S., Szabo, M., German, M., Farkas, L., Szentendrei, D., Maiello, M. R., Mandica, S., Morganti, R., Menzinger, G., Bernardi, L., Aso, Y., Wakabayashi, S., Takebayashi, K., Takemura, Y., Inukai, T., Kalter-Leibovici, O., Lifshitz, A., Yerushalmy, Y., Stern, E., Ogawa, K., Nanjo, K., Kawamori, R., Katayama, S., Shirai, M., Fonseca, V., Seftel, A., Denne, J., Fredlund, P., Buvat, J., Schmitt, H., Ahlen, H., Varanese, L., Lips, J., Hoekstra, J. B. L., Banga, J-D, Legros, J-J, Lufuma, M., Bouter, K. P., Fan, L. F., Lu, J. M., Zheng, Y. G., Zhang, X. Q., Spruce, M. C., Jones, C., Coppini, D. V., Lavery, L. A., Holtz-Neiderer, K., Mohler, M. J., Wendel, C. S., Nixon, B. P., Jurado, J., Bataller, F., Dorca, A., Garcia, F., Brossa, N., Barnera, T., Pou Torello, J. M., Bregovski, V. B., Karpova, I. A., Hedetoft, C., Rasmussen, A., Fabrin, J., Driver, V. R., Thoms, T. L., Jeffcoate, W. J., Monaghan, J., Game, F. L., Dalla Noce, S., Cimmino, M., Caruso, S., Manes, C., Mikoudi, K., Sossidou, E., Pigas, G., Karagianni, D., Skoutas, D., Fotiadis, S., Pruna, S., Eroshkin, I. A., Vasiljev, Y. G., Udovichenko, O. V., Udovichenko, A. E., Bondarenko, O. N., Dang, C. N., Prasad, Y. D. M., Anwar, R., Thomas, G., Malik, R., Lobmann, R., Motzkau, M., Pittasch, D., Lehnert, H., Piaggesi, A., Marsocci, A., Fanara, M. G., Rizzo, L., Palumbo, F., Campi, F., Tedeschi, A., Scatena, A., Goretti, C., Baicchi, U., Chipchase, S., Treece, K., Pound, N., Hill, N. R., Cyganek, K., Mirkiewicz-Sieradzka, B., Malecki, M., Wolkow, P., Skupien, J., Naskalska, A., Sieradzki, J., Tapp, R. J., Tonkin, A. M., Harper, A., Mccarty, D. J., Soderberg, S., Taylor, H. R., Chitson, P., Alberti, G. K. M., Sheetz, M. J., Aiello, L. P., Davis, M. D., Milton, R. C., Arora, V., Hu, K., Girach, A., Vignati, L., Tyrberg, M., Melander, A., Lindblad, U., Giannarelli, R., Coppelli, A., Sartini, M., Aragona, M., Fletcher, E. L., Ninkovic, S., Foster, L. E., Jones, D., Gooyer, T., Stitt, A., Vingrys, A. J., Wilkinson-Berka, J. L., Lewandowska, A. B., Randeva, H. S., Komorowski, J., Lewandowski, K. C., Jurowski, P., Sankar, S., Gos, R., Kowluru, R. A., Odenbach, S., Shinn, S., Oh, Y-S, Kim, J., Agardh, C-D, Hultberg, B., Agardh, E., Segura, R. M., Fonollosa, A., Berrone, E., Beltramo, E., Solimine, C., Ubertalli, A., Islam, N., Esteve, E., Fernandez, M., Recas, I., Mauri, S., Biarnes, F., Junca, E., Fernadez-Real, J., Rossner, S., Stenlof, K., Levy, B., Perry, B., Fitchet, M., Chrysos, G., Kamaratos, A., Lepeniotis, G., Kokkoris, S., Varytimiadis, K., Stasini, F., Mikros, S., Gianneli, D., Tryfinopoulou, K., Melidonis, A., Nikolopoulou, C., Harley, K., Ryder, R., De, P, Vannieuwenhoven, F. A., Rossing, K., Oliver, N., Goldschmeding, R., Jacobsen, P. K., Tan, F., Liew, S., Mukherjee, J. J., Lim, P., Frojdo, S., Sjolind, L., Parkkonen, M., Makinen, V., Tikellis, C., Nieuwenhoven, F. A. V., Macisaac, R. J., Tsalamandris, C., Mcneil, K. J., Panaiotopoulos, S., Smith, T. J., Ho, M., Matthews, P. G., Jerums, G., Hut, H., Den Meiracker, A. H., Nakhjavani, M., Behjati, J., Esteghamati, A., Esfahanian, F., Aghamohamadzadeh, N., Abbasi, M., Kohnert, K-D, Zander, E., Krabbe, S., Stehouwer, C. D., Schalkwijk, C. G., Saraheimo, M. T., Krarup Hansen, T., Teppo, A-M, Ebeling, P., Hansen, B. V., Abdella, N. A., Mojiminiyi, O. A., Al Dahi, W. A., Al Mohammedi, H., Al Jebely, S., Neugebauer-Baba, S., Baba, T., Ohashi, H., Nakajima, S., Hesselmann, C., Watanabe, T., Nargis, M., Zaid, R. B., Voronko, O. E., Shestakova, M. V., Shamkhalova, M. S., Tchugunova, L. A., Vikulova, O. K., Nosikov, V. V., Liu, L., Zheng, T., Li, M., Zhang, R., Xiang, K., Hadjadj, S., Jeunemaitre, X., Vervoort, G., Veldman, B., Berden, J., Wetzels, J., Singh, B. M., Holland, M. R., Baskar, V., Oh, J., Seo, J., Choi, K., Baik, S., Choi, D., Kim, N., Matsumoto, S., Suetsugu, M., Matsutomo, R., Pisarczyk-Wiza, D., Banaszak, A., Wysocki, H., Usui, H., Shikata, K., Okada, S., Ogawa, D., Yozai, K., Kido, Y., Nagase, R., Ohga, S., Tone, A., Sasaki, M., Wada, J., Unno, Y., Horiuchi, S., Mclennan, S. V., Kamarinos, M., Kelly, D., Waltham, M., Dy, V., Yue, D., Langham, R., Gilbert, R., Zdychova, J., Komers, R., Cresci, B., Giannini, S., Manuelli, C., Giunti, S., Pinach, S., Ianni Palarchio, A., Arnaldi, L., Vittone, F., Camussi, G., Cavallo Perin, P., Gruden, G., Marshall, S. M., Jones, S. E., White, K. E., Brizzi, M., Dentelli, P., Rosso, A., Calvi, C., Gambino, R., Cassader, M., Salvidio, G., Deferrari, G., Pegoraro, L., Pagano, G., Cavallo-Perin, P., Oates, R., Ellery, C., Beebe, D., Coutcher, J., Qian, Y-Z, Lowe, V., Appleton, T., Raunig, D., O Neil, S., Mylari, B., Amazonas, R. B., Fujita, A., Doi, A., Matsuno, S., Okamoto, K., Matsumoto, E., Furuta, H., Nishi, M., Tsuno, T., Taniguchi, H., Bessho, H., Wasen, E., Isoaho, R., Mattila, K., Vahlberg, T., Kivela, S-L, Irjala, K., Rigalleau, V., Lasseur, C., Perlemoine, C., Barthes, N., Raffaitin, C., Chauveau, P., Combe, C., Baillet-Blanco, L., Beauvieux, M-C, Gin, H., Heinrich, S., Steiner, T., Ott, U., Holdass, H., Fellstrom, B., Jardine, A., Staffler, B., Logan, J. O., Gimpelewicz, C., Stanciu, C. C., Pena, C. M., Serafinceanu, C. C., Gonzalez-Posada, J. M., Hernandez, D., Perez-Tamajo, L., Lo, A. J., Herna Alarco, M., Meneses, M., Barsotti, M., Rizzo, G., Schmauss, S., Havrdova, T., Saudek, F., Boucek, P., Adamec, M., Invitti, C., Gilardini, L., Parati, G., Mazzilli, G., Pontiggia, B., Sartorio, A., Lutgers, H. L., Groenier, K. H., Zasadzinska, G., Saryusz-Wolska, M., Temelkova-Kurktschiev, T. S., Kurktschiev, D. P., Majdrakova, I., Varbanova, T., Todorova, B., Bajo-Martinez, A., Bernal, E., Sanchez, O., Ugalde-Canitrot, A., Sanchez-Largo, E., Coca-Robinot, D., Fabregate, R., Calbacho, M., Marquez, J., Saban-Ruiz, J., Penesova, A., Cizmarova, E., Blazicek, P., Jongh, R. T., Serne, E. H., Ijzerman, R. G., Vries, G., Stehouwer, C. D. A., Poulsen, P. L., Andersen, N. H., Knudsen, S. T., Helleberg, K., Mogensen, C. E., Walus, M., Idzior-Walus, B., Sztefko, K., Cieslik, G., Fedak, D., Wozniakiewicz, E., Lin, S. D., Guo, M. Y., Lin, C. J., Liu, X. C., Francisco, M-M J., Rodriguez-Rosas, H., Peiro-Martinez, I., Macias-Batista, A., Harte, A. L., Rodriguez-Cuenca, S., Valsamakis, G., Chetty, R., Anderson, L. A., Roca, P., Matyka, K., Lasalle, J., Hershon, K., Berman, L., Gibson, E., Gillen, D., Maroni, J., Simmons, D., Hiukka, A., Forder, P., Leinonen, E., Hilden, H., Fruchart, J., Fruchart, J-C, Keech, A., Farnier, M., Freeman, M., Macdonell, G., Perevozskaya, I., Mitchel, Y., Gumbiner, B., Didangelos, T. P., Athyros, V. G., Mikhailidis, D. P., Papageorgiou, A. A., Bouloukos, V. I., Pehlivanidis, A. N., Symeonidis, A. N., Elisaf, M., Mckenney, J., Insull, W. Jr, Lewin, A., Maccubbin, D., Lee, M., Kush, D., Schuster, H., Barter, P. J., Stender, S., Cheung, R. C., Bonnet, J., Morrell, J. M., Watkins, C., Kallend, D., Stalenhoef, A. F. H., Ballantyne, C. M., Murin, J., Tonstad, S., Rose, H., Wilpshaar, W., Jenkins, A., Karschimkus, C., Dragicevic, G., Rowley, K., Wolthers, T., Best, J. D., Voet, B., Murdoch, S. J., Marcovina, S. M., Chen, H. C., Brunzell, J. D., Caparevic, Z. V., Kostic, N. D., Ilic, S. M., Sartore, G., Piarulli, F., Cantaro, S., Reitano, R., Fiore, C., Marin, R., Bassan, S., Manzato, E., Fedele, D., Solini, A., Santini, E., Thornalley, P. J., Babaei-Jadidi, R., Karachalias, N., Kupich, C., Ahmed, N., Fowler, A. E., Baker, A. R., Starczynski, J., O Hare, P., Szepietowska, B., Szelachowska, M., Puch, U., Glebocka, A., Quinn, D. W., Da Silva, N. F., Mcternan, C. L., Bonser, R. S., Mcternan, P., Dimitriou, K., Apostolou, O., Kontela, E., Devangelio, E., Gould, E. M., Serri, O., Roussin, A., Buithieu, J., Mamputu, J-C, Renier, G., Giordanetti, S., Amici, E., Poggi, G., Turpini, C., Fratino, P., Garzaniti, A., Yin, D., Banu, I., Roman, G., Negrean, M., Bala, C. G., Nita, C., Kistorp, C., Gustafsson, F., Chong, A., Lip, G., Galatius, S., Shearer, A. T., Ari, N., Sahilli, M., Ceylan-Isik, A., Ozansoy, G., Karasu-Yilmaz, C., Matteucci, E., Rosada, J., Pallini, M., Evangelista, I., Cassetti, G., Giusti, C., Giampietro, O., Capaldo, B., Galderisi, M., Cicala, S., Turco, A., Imbroinise, A., Nosso, G., D Errico, A., Divitiis, O., Klimontov, V. V., Korolyova, E. A., Jeltova, L. I., Bondar, I. A., Tarkun, I., Arslan, B., Canturk, Z., Tarkun, P., Agacdiken, A., Komsuoglu, B., Meneveau, N., Pierre-Justin, E., Alsayed, M., Sabbah, R., Paulin, S., Marcu, S., Tauveron, I., Zimmermann, C., Schiele, F., Seronde, M-E, Vautrin, P., Lusson, J-R, Thieblot, P., Bernard, Y., Mistry, A., Pye, M. P., Peovska, I., Maksimovic Pavlovic, J., Vavlukis, M., Pop Gorceva, D., Bosevski, M., Scognamiglio, R., Negut, C., Kreutzenberg, S., Madonna, R., Caterina, R., Willerson, J. T., Geng, Y-J, Vahsen, S., Ledwig, D., Ramrath, S., Frantz, S., Schmidt, I., Calvillo, L., Dienesch, C., Elbing, I., Bischoff, H., Ertl, G., Bauersachs, J., Davydov, A. L., Mkrtum Yan, A. M., Baranova, L. Y., Ikeda, Y., Suehiro, T., Osaki, F., Ota, K., Arii, K., Kumon, Y., Hashimoto, K., Doney, A. S. F., Fischer, B., Morris, A. D., Palmer, C. N. A., Ahn, Y-M, Lee, B-C, Kim, S-I, Byun, S-H, Ahn, S-Y, Doo, H-K, Pagnin, E., Calo, L. A., Fadini, G., Kubaszek, A., Chai, S., Chai, Q., Rasmussen, L., Ledet, T., Wogensen, L., Lengyel, C., Varro, A., Virag, L., Magyar, J., Biro, T., Jost, N., Skoumal, R., Nanasi, P., Toth, M., Horkay, F., Papp, J. G., Zacharopoulou, O., Athanaselis, S., Tsokos, N., Doupis, J., Psallas, M., Cokkinos, D., Pavlatos, S., Liatis, S., Akhobadze, T., Dzneladze, L., Samarguliani, I., Taskiran, M., Rasmussen, V., Rasmussen, B., Jensen, G. B., Fisher, A. A., Petrovsky, N., Davis, M. W., Srikusalanukul, W., Budge, M. M., Trifunovic-Zamaklar, D. D., Zivkovic, M., Jelic, V., Vukomanovic, G., Ristic, A. D., Seferovic, P. M., Costa, J. V., Duarte, S., Manley, S. E., Sailesh, S., Venkataraman, A., Haider, Y., Groza, I., Oprean, M., Ardelean, A., Morosanu, A., Darkow, T., Vanderplas, A., Mamas, M. A., Mcelduff, P., Burns, J., Edwards, R., Fitchet, A., Young, R. J., Gibson, J. M., New, J. P., Lichiardopol, R., Niculescu, N., Totora, A., Pencea, C., Tomescu, I., Cinteza, M., Manicardi, V., Coscelli, C., Navazio, A., Catellani, E., Michelini, M., Dall Asta, D., Guberti, A., Piazza, A., Gasparini, E., Pantaleoni, M., Guiducci, U., Manari, A., Sejil, S., Janand-Delenne, B., Avierinos, J-F, Habib, G., Labastie, N., Vague, P., Lassmann-Vague, V., Luzniak, P., Wojciechowska Luzniak, A., Zairis, M., Lyras, A., Patsourakos, N., Tsirimbis, V., Foussas, S., Lupon, J., Urrutia, A., Herreros, J., Gonzalez, B., Coll, R., Altimir, S., Prats, M., Valle, V., Abreu-Padi, C., Rabago, G., Ivanova, L. A., Brasacchio, D., Calkin, A., Jandeleit-Dahm, K. A., Harno, E., Keenan, A. K., Li, H. L., Yu, Y. R., Lu, Z. M., Zhang, X. E., Ke, L., Liu, H., Zhang, X. X., Jeong, I-K, Chae, M-K, Choi, M-H, Yoo, H-J, Kim, C. D., Yun, M. R., Na, M. A., Kang, Y. H., Kong, O. N., Son, S. M., Kim, I. J., Kim, Y. K., Tanaka, N., Hosoi, M., Matsuyama, Y., Fukumoto, M., Yamakita, T., Yoshioka, K., Ishii, T., Sato, T., Fujii, S., Aoki, T., Shibata, T., Mizutani, N., Suzuki, J-Y, Fowelin, J. H. R., Samuelsson, P., Brandrup-Wogsen, G., Okumura, K., Tokmakova, A. Y., Staroverova, D. N., Antcieferov, M. B., Shutichina, I. V., Kuntchevich, G. I., Vriesendorp, T. M., Morelis, Q. J., Legemate, D. A., Schaper, F., Mainas, E. I., Gkioulmpasanis, I., Panagiotou, I., Vassilikos, G., Skorda, L., Sidira, M., Christoforidou, M., Alaveras, A., Artikis, V., Evdemon, E., Lechleitner, M., Koch, T., Ebenbichler, C., Sturm, W., Moretti, L., Moruzzo, D., Boldrini, E., Pandolfo, C., Kameyama, M., Iwasa, R., Cho, M-H, Nam, J-Y, Kim, C-S, Kim, D-M, Ahn, C-W, Cha, B-S, Lim, S-K, Kim, K-R, Lee, H-C, Huh, K-B, Kaplar, M., Paragh, G., Erdei, A., Csongradi, E., Garai, I., Varga, J., Galuska, L., Udvardy, M., Higa, M., Kaneko, Y., Hiroi, N., Koziarska, D., Nowacki, P., Majkowska, L., Wojciechowska-Luzniak, A., Tushuizen, M. E., Nieuwland, R., Snoeck, D. P., Sturk, A., Diamant, M., Aguiar, L. G. K., Bahia, L., Villela, N., Laflor, C., Conde, C., Bottino, D., Dorigo, D., Bouskela, E., Pu, S., Yu, H. L., Luo, Z. T., Lam, K. S. L., Dan, Q., Xu, A., Shen, J., Cheng, K., Xu, J. Y. U., Thamer, C., Stefan, N., Haap, M., Heller, E., Tschritter, O., Prado, A., Ortiz, A., Ybarra, J., Gich, I., Pou, J. M., Ehren, M., Meyer, M. F., Roggenland, D., Reinsen, B., Klein, H. H., Rittig, K., Stock, J., Kocher, B., Balletshofer, B., Lee, J., Shon, H. S., Chung, D. S., Nakatani, Y., Matsuhisa, M., Kaneto, H., Hatazaki, M., Yoshiuchi, K., Katakami, N., Kawamori, D., Ohtoshi, K., Sakamoto, K., Matsuoka, T-A, Ozawa, K., Ogawa, S., Hori, M., Yamasaki, Y., Zitouni, K., Harry, D., Nourooz-Zadeh, J., Betteridge, J. D., Earle, K. A., Rasmussen, L. M., Olesen, P., Franco, L., Corvaja, C., Semplicini, A., Rosen, P., Lee, I-K, Kim, M-J, Park, K-G, Jung, E-D, Shin, D-W, Jo, S-R, Obuobie, K., Prakash, P. K., Hanna, F. W., Evans, M., Lazarus, J., Varadhan, L., Gurushankar, J., James, D., Sheikh, S., Gaede, P., Li, H., Zou, D., Lee, S. J., Choi, M. G., Kim, D. S., Kim, T. W., Vilarrasa, N., Perez-Maraver, M., Mena, E., Perez, D., Setti, G., Buckingham, R., Urbancic, V., Stefanovska, A., Bernjak, A., Azman-Juvan, K., Kocijancic, A., Glowania, A., Filters, T. S., Fosmark, D. S., Torjesen, P. A., Kilhovd, B., Berg, T. J., Sandvik, L., Hanssen, K. F., Mentink, C. J. A., Kilhovd, B. K., Kuchmerovska, T. M., Shymanskyy, I. O., Donchenko, G. V., Stepanenko, S. P., Klimenko, A. P., Park, J., Maingrette, F., Deng, H. C., Lindenmair, A., Waldhausl, W. K., Freudenthaler, A., Baumgartner-Parzer, S. M., Nizheradze, K., Khoruzhenko, A., Tronko, N., Sheu, W. H. H., Ou, H-C, Shen, H-M, Lin, T-M, Wu, H-S, Yang, C-H, Mogylnytska, L., Mankovsky, B., Schmoelzer, I., Davies, J. I., Band, M., Morris, A., Struthers, A. D., Prazny, M., Skrha, J., Kasalova, Z., Neelotpol, S., Jahan, P., Kauschke, S. G., Harrop, C. A., Schafer, A., Widder, J., Eigenthaler, M., Walter, U., Uchimura, I., Ikebukuro, M., Kaibara, M., Hirata, M., Helal, R., Pervin, F., Khan, A. K. A., Yang, X., Jansson, P-A, Nagaev, I., Jack, M. M., Carvalho, E., Sunnerhagen, K. Stibrant, Cam, M. C., Cushman, S. W., Smith, U., Creely, S. J., Farmer, J., Creely, S., Gustafson, B., Kusminski, C. M., Krusinova, E., Wohl, P., Klementova, M., Lanska, V., Mcdougall, C., Thomas, S. J., Kelly, I., Abbas, Z. G., Lutale, J. K., Archibald, L. K., Karunajeewa, H., Stingemore, N., Stuccio, G., Mcgechie, D., Muller, L. M. A., Hak, E., Goudzwaard, W. L., Montorsi, F., Homering, M., Sprenger, K., Goldstein, I., Asnaghi, V., Ferrari, G., Rastaldi, M., Gabellini, D., Antonio, G., Maestroni, A., Ruggieri, D., Luzi, L., Piemonti, L., Zerbini, G., Anafaroglu, I., Tutuncu, N. B., Sultana, M., Siddiqua, N., Iwasaki, T., Nakajima, A., Yoneda, M., Mukasa, K., Tanaka, S., and Sekihara, H.

47. Serological Proteome Analysis (SERPA) as a tool for the identification of new candidate autoantigens in type 1 diabetes

Author

Tarcisio Not, Lucia Russo, Giovanni Nardo, Patrizia Ippolita Patera, Riccardo Bonfanti, Federico Bertuzzi, Valentina Bonetto, Massimo Alessio, Claudio Tiberti, Ornella Massa, Giorgio Federici, Fabrizio Barbetti, Alessandra Paladini, Dario Iafusco, Massa, O, Alessio, M, Russo, L, Nardo, G, Bonetto, V, Bertuzzi, F, Paladini, A, Iafusco, Dario, Patera, P, Federici, G, Not, T, Tiberti, C, Bonfanti, R, Barbetti, F., Iafusco, D, Not, Tarcisio, and Barbetti, F

Subjects
Male, Serum, endocrine system, Type 1 diabete, endocrine system diseases, Adolescent, Proteome, auto-antigens, Biophysics, Autoimmunity, medicine.disease_cause, Type 1 diabetes, Biochemistry, Autoantigens, Immunoproteomics, Serology, Autoantigen, Serological Proteome Analysi, Insulin-Secreting Cells, medicine, Electrophoresis, Two-Dimensional Gel, Humans, Child, Cells, Cultured, Autoimmune disease, business.industry, Settore BIO/12, Pancreatic islets, Autoantibody, Immunoproteomic, nutritional and metabolic diseases, Infant, medicine.disease, Type I diabete, medicine.anatomical_structure, Diabetes Mellitus, Type 1, Insulin-Secreting Cell, Child, Preschool, Immunology, Female, Radiobinding assay, business, Human
Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by the presence of circulating autoantibodies directed against proteins of islet beta-cell. Autoantibody testing is used for diagnostic purposes; however, up to 2-5% of patients who are clinically diagnosed with T1D are found negative for known antibodies, suggesting that the T1D autoantigen panel is incomplete. With the aim of identifying new T1D autoantigen(s), we used sera from subjects clinically diagnosed with T1D, but who tested negative for the four T1D autoantibodies currently used in clinical practice and for genes responsible for sporadic cases of diabetes.Sera from these patients were challenged by Western blot against the proteome from human pancreatic beta-cells resolved by 2DE. Eleven proteins were identified by MS. A radiobinding assay (RBA) was developed to test the reactivity to Rab GDP dissociation inhibitor beta (GDI beta) of T1D sera using an independent method. Depending on the construct used (open reading frame or COOH-terminus) 22% to 32% of fifty T1D sera showed increased binding to GDI beta by RBA. In addition, 15% of patients with celiac disease had raised binding to the COOH-terminus GDI beta. These results indicate that immunoproteomics is a feasible strategy for the identification of candidate T1D autoantigens.Biological significanceSeveral approaches have been previously used to look for new type 1 diabetes autoantigens. With the present work we show that carefully selected sera from rare patients with diabetes both negative for the 5 autoantibodies currently used in clinical practice and for genes responsible for sporadic cases of diabetes, may be exploited in experiments utilizing human pancreatic islets extracts as a target for SERPA to identify novel candidate T1D autoantigens. (C) 2013 Elsevier B.V. All rights reserved.

Published
2013

48. Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?

Author

Franco Cerutti, Franco Meschi, C. Monciotti, Ivana Rabbone, Valeria Favalli, Alfonso Galderisi, C. Colombo, Riccardo Bonfanti, Ornella Massa, Dario Iafusco, Fabrizio Barbetti, Enzo Bonora, Sara Gombos, Valeria Grasso, Grasso, V, Colombo, C, Favalli, V, Galderisi, A, Rabbone, I, Gombos, S, Bonora, E, Massa, O, Meschi, F, Cerutti, F, Iafusco, Dario, Bonfanti, R, Monciotti, C, and Barbetti, F.

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Gene mutation, Bartter syndrome, Extreme insulin resistance, Severity of Illness Index, Endocrinology, Internal medicine, Bartter's syndrome, Insulin receptor, Mutation, Acanthosis Nigricans, Bartter Syndrome, Child, Preschool, Donohue Syndrome, Female, Humans, Infant, Infant, Newborn, Insulin Resistance, Nephrocalcinosis, Receptor, Insulin, Internal Medicine, medicine, Insulin, Child, Preschool, Acanthosis nigricans, business.industry, General Medicine, medicine.disease, Newborn, Hyperaldosteronism, Diabetes and Metabolism, Bartter’s syndrome, Donohue syndrome, business, Hyperinsulinism, Receptor
Abstract

Biallelic insulin receptor (INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter's syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR.

Published
2013

49. Opposite clinical phenotypes of glucokinase disease: Description of a novel activating mutation and contiguous inactivating mutations in human glucokinase (GCK) gene

Author

Pablo Rodriguez-Bada, Maria Adelaida Garcia-Gimeno, Lorenzo Lenzi, Elena Baixeras, Paolo Ciampalini, Pascual Sanz, Carlo Dionisi-Vici, Nadia Cobo-Vuilleumier, Patrizia Banin, Ornella Massa, Fernando Rodríguez de Fonseca, Juan Carlos Aledo, Carlo Colombo, Fabrizio Barbetti, Francisco Javier Bermúdez-Silva, Sonia Toni, A. Cuesta-MuNoz, [Barbetti,F, Dionisi-Vici,C, Ciampalini,P, Massa,O, Colombo,C] Bambino Gesú Pediatric Hospital Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy. [Barbetti,F] Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. Laboratory of Molecular Endocrinology and Metabolism, S Raffaele Biomedical Park Foundation, Rome, Italy. [Cobo-Vuilleumier,N, Rodriguez-Bada,P, Bermudez-Silva,FJ, Rodriguez de Fonseca,F, Aledo,JC, Baixeras,E, Cuesta-Muñoz,AL] Center for the Study of Pancreatic-Cell Diseases. Instituto Mediterráneo para el Avance de la Biotecnología y la Investigación Sanitaria Foundation and Carlos Haya Hospital, Málaga, Spain. [Toni,S, Lenzi,L] Regional Center for Juvenile Diabetes, Meyer Pediatric Hospital, Florence, Italy. [Garcia-Gimeno,MA, Sanz,P] Institute of Biomedicine of Valencia (CSIC). CIBERER-ISCIII, Valencia, Spain. [Banin,P] Pediatric and Adolescent Unit, S. Anna Hospital, Ferrara, Italy. [Aledo,JC] Molecular Biology and Biochemistry Department University of Málaga, Spain., This work was supported by grants (to A.L.C.-M. and N.C.-V.) from Ministerio de Ciencia e Innovación, Dirección General de Investigación Científica y Técnica (SAF2005-08014, SAF2006-12863) and Junta de Andalucía (SAS/PI-024/2007, and SAS/PI-0236/2009).

Subjects
Male, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Phenomena and Processes::Physical Phenomena::Mechanical Phenomena::Kinetics [Medical Subject Headings], medicine.medical_treatment, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Pedigree [Medical Subject Headings], Mutagénesis Sitio-Dirigida, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hypoglycemia [Medical Subject Headings], medicine.disease_cause, Settore MED/13 - Endocrinologia, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical [Medical Subject Headings], Endocrinology, Glucokinase structural analysis, Recién Nacido, Monogenic Diabetes, Glucokinase, Masculino, Original Research, Genetics, Glucokinase mutations, Mutation, Femenino, Modelos Teóricos, General Medicine, Phenotype, Phenomena and Processes::Genetic Phenomena::Genotype::Genetic Predisposition to Disease [Medical Subject Headings], Pedigree, Humanos, Monogenic Hyperinsulinism, Glucokinase Disease, Female, Hipoglucemia, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Engineering::Protein Engineering::Mutagenesis, Site-Directed [Medical Subject Headings], Fenotipo, medicine.medical_specialty, Familiar Hyperinsulinism, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], Predisposición Genética a la Enfermedad, Check Tags::Male [Medical Subject Headings], Biology, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Glucokinase [Medical Subject Headings], Named Groups::Persons::Age Groups::Infant::Infant, Newborn [Medical Subject Headings], Cinética, Internal medicine, Diabetes mellitus, Linaje, medicine, Humans, Genetic Predisposition to Disease, Molecular Biology, Mutación, Insulin, Neonatal hypoglycemia, Infant, Newborn, Models, Theoretical, medicine.disease, Glucoquinasa, Hypoglycemia, Kinetics, Check Tags::Female [Medical Subject Headings], Congenital hyperinsulinism, Mutagenesis, Site-Directed
Abstract

7 páginas, 3 figuras, 2 tablas., Glucokinase is essential for glucose-stimulated insulin release from the pancreatic beta-cell, serving as glucose sensor in humans. Inactivating or activating mutations of glucokinase lead to different forms of glucokinase disease, i.e. GCK-monogenic diabetes of youth, permanent neonatal diabetes (inactivating mutations), and congenital hyperinsulinism, respectively. Here we present a novel glucokinase gene (GCK)-activating mutation (p.E442K) found in an infant with neonatal hypoglycemia (1.5 mmol/liter) and in two other family members suffering from recurrent hypoglycemic episodes in their childhood and adult life. In contrast to the severe clinical presentation in the index case, functional studies showed only a slight activation of the protein (relative activity index of 3.3). We also report on functional studies of two inactivating mutations of the GCK (p.E440G and p.S441W), contiguous to the activating one, that lead to monogenic diabetes of youth. Interestingly, adult family members carrying the GCK pE440G mutation show an unusually heterogeneous and progressive diabetic phenotype, a feature not typical of GCK-monogenic diabetes of youth. In summary, we identified a novel activating GCK mutation that although being associated with severe neonatal hypoglycemia is characterized by the mildest activation of the glucokinase enzyme of all previously reported, This work was supported by grants (to A.L.C.-M. and N.C.-V.) from Ministerio de Ciencia e Innovación, Dirección General de Investigación Científica y Técnica (SAF2005-08014; SAF2006-12863) and Junta de Andalucía (SAS/PI-024/2007; SAS/PI-0236/2009)

Published
2009

50. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus

Author

Peter Arvan, Mario Vasta, Giorgio Federici, C. Monciotti, Oluf Pedersen, Ming Liu, Luca Federici, Roberta Pesavento, Francesco Cadario, Carlo Colombo, Sonia Toni, Torben Hansen, Dario Iafusco, Ottavia Porzio, Luciano Beccaria, Fabrizio Barbetti, Ornella Massa, Silvana Salardi, Paolo Ghirri, Colombo, C., Porzio, O., Liu, M., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., Hansen, T., Federici, L., Pesavento, R., Cadario, F., Federici, G., Ghirri, P., Arvan, P., Iafusco, D, and Barbetti, F.

Subjects
Male, X-Box Binding Protein 1, medicine.medical_specialty, endocrine system, Heterozygote, diabetes of infancy, endocrine system diseases, medicine.medical_treatment, Mutant, DNA Mutational Analysis, Molecular Sequence Data, Regulatory Factor X Transcription Factors, Biology, medicine.disease_cause, MDI, Settore MED/13 - Endocrinologia, Diabetes mellitus genetics, Internal medicine, Diabetes mellitus, medicine, Diabetes Mellitus, Humans, Insulin, Amino Acid Sequence, Insulinoma, Endoplasmic Reticulum Chaperone BiP, Heat-Shock Proteins, Proinsulin, permanent neonatal diabete, Mutation, PNDM, Infant, Nuclear Proteins, General Medicine, Permanent neonatal diabetes mellitus, medicine.disease, Pedigree, DNA-Binding Proteins, Settore BIO/18 - Genetica, Endocrinology, monogenic diabetes of infancy, Female, hormones, hormone substitutes, and hormone antagonists, Research Article, Molecular Chaperones, Transcription Factors
Abstract

Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.

Published
2008

Catalog

Books, media, physical & digital resources
See catalog results