COST Action B17

INSULIN RESISTANCE, OBESITY AND DIABETES MELLITUS IN THE ELDERLY

PROGRESS REPORT

Period: from (12-99) to (12-02)

This Report is prepared by the Management Committee of the Action and presented to the relevant Technical Committee or directly to the Committee of Senior Officials.
The report is a "cumulative" report, i.e. it is updated annually and covers the period beginning from the start date of the Action.

CONTENTS

1. Overview: action identification data

2. Objectives

3. TECHNICAL DESCRIPTION AND IMPLEMENTATION

3.1 Mode of Operation

3.2 Working Groups of COST B17

3.3 Secretarial Services

4. PARTICIPATION AND COORDINATION

4.1 Management Committee

4.2 Participating Institutions

4.3 Meetings of the Management Committee

4.4 Meetings of the Working Groups

4.5 Short-term Scientific Missions and their Results

5. RESULTS

5.1 Key Scientific Outcomes

5.2 Outstanding Scientific Publications

5.3 Joint Publications and Reports

5.4 Participation and Awards of Young Scientists

6. DISSEMINATION OF RESULTS

6.1 Scientific Publications

6.2 Conferences and Workshops

6.3 Web-site

6.4 Scientific and Technical Cooperation

6.5 Transfer of results

6.6 Information of the Public and Influence on Politics

7. ECONOMIC DIMENSION

7.1 Total Manpower per Year

7.2 Funds received from the Commission

7.3 Costs of the Action

8. SELF EVALUATION (will be added only to the last annual progress report)

1. Overview: Action Identification Data

COST Action B17 Title INSULIN RESISTANCE, OBESITY AND DIABETES MELLITUS IN THE ELDERLY

TC Recommendation: ) 12/2/99	First MC meeting: (day/month/year) 10/03/00
CSO Approval: 27/5/99	Last MC meeting: (day/month/year) N.A.
Start date: (day/month/year) ^(1) 16/12/99	Final Report: (day/month/year) ^(2) N.A.
Duration: months: 60	Evaluation Report: (day/month/year) ^(2) N.A.
Extension: months --	TC Evaluation: (day/month/year) N.A.
End date: (day/month/year) 15/12/04

Number of signatories: (number) 22

Signatories and date of signature: (day/month/year)

Austria 5/4/2000	Greece 12/1/200	Poland
Belgium 9/2/2000	Hungary 7/1/2000	Portugal
Bulgaria	Iceland	Romania 25/2/2000
Croatia	Ireland 26/1/2000	Slovakia 12/1/2000
Cyprus	Italy 5/1/2000	Slovenia 3/2/2000
Czech Rep. 2/2/2000	Latvia	Spain 16/12/99
Denmark 16/12/99	Lithuania 15/5/2000	Sweden 16/12/99
Estonia	Luxembourg 7/2/2001	Switzerland 15/12/99
Finland	Malta	Turkey
France 16/12/99	Netherlands 16/12/99	United Kingdom 16/12/99
Germany 16/12/99	Norway 20/12/99	Israel 19/12/2000

Institutes of non-COST countries: (list) None

Area: N.A.

Action Web site: http://www.webio.hu/workshops/cost/

Chairperson:

Title, name Prof. Peter Csermely Tel.: +36-1-266-2755 extn.: 4102

Affiliation Semmelweis Univ., Dept. Med. Chem. Fax:+36-1-266-7480

Postal Address P.O.Box 260, H-1444 Budapest 8, Hungary E-Mail:csermely@puskin.sote.hu

TC Rapporteur:

Title, name Prof. Kerstin Nyberg Tel.: +44-207-636-5422

Affiliation Medical Research Council Fax:+44-207-670-5124

Postal Address 20 Park CrescentUK-W1N 4AL London E-Mail:kerstin.nyberg@headoffice.mrc.ac.uk

External Evaluator: Title, name, affiliation, country N.A.

External Evaluator: Title, name, affiliation, country N.A.

⁽¹⁾ When 5 Signatures have been collected

⁽²⁾ When the report is received by TC Secretariat
2. Objectives

General objectives Diabetes mellitus of aged people is a considerable health burden of western societies. At present no widely established screening method is available to detect the persons who are predisposed in the population and due to our incomplete knowledge on the molecular mechanisms leading to NIDDM we have very few means to influence the onset and development of this diverse disease. The ongoing research of candidate genes as well as various differential screening methods will be coordinated with the new Action.

Various steps of insulin action will be studied starting from the insulin receptor and following insulin action till it reaches the cell nucleus with special emphasis on the investigation of pathological changes of the molecular mechanism of insulin action in insulin resistance, obesity and NIDDM of the aged people. This research acitivity is thought to lead to the development new drug-candidates for the curing-easing of the consequences of this diverse disease.

Secondary objectives

The following steps of insulin action will be studied to gain a better understanding of the etiology of insulin resistance, obesity and NIDDM of the aged people, in hope to develop drug-candidates and a reliable screening method to detect the individuals with inherited risk for the disease.

1. Identification of diabetogenes

1.1. examination of candidate genes

1.2. utilization of various differential screening methods

1.3. possible links of diabetes-related genes to insulin signalling

1.4. search for diabetes-related obesity genes

1.5. age-dependent analysis of critical genes

2. Studies on the intracellular mechanism of insulin action in normal and pathological states

2.1. mechanism of the interactions between insulin receptor and its substrates, analysis of tissue-specificity of insulin signalling pathways

2.2. molecular characterization of glucose transport in normal and insulin-resistant states

2.3. molecular analysis of insulin signalling and action during the whole lifespan

2.4. interrelationships of insulin resistance and leptin action

2.5. development of insulin- and leptin-related signalling molecules as potential drug candidates

The list of secondary objectives is open for amendments incorporating the specific aims of new goups willing to participate in the concerted action. To join to the proposed research action an expertise in insulin (leptin, insulin-like growth factor) dependent signal transduction, insulin resistance/obesity-related physiological changes and/or in structural studies of insulin resistance/obesity-related genes is required.

3. Technical description and implementation

3.1. MODE OF OPERATION

The Action is focused on promoting collaboration and joint actions between scientists of participating countries in the field. This is performed by organizing collaborative meetings, where free discussions bring the participating laboratories, and invited guests together, by establishing working groups and by promoting a series of short term scientific missions. These areas of collaboration-promotion are extended by the web/site of the Action as well as by regular, informal exchanges of research materials as well as scientific expertise and ideas by letters, FAX-es and mostly: by email. It is a primary goal of the Action to encourage joint publications of collaborative research in top-level international scientific journals.

3.2. WORKING GROUPS OF COST B17

Keeping in mind the major areas of diabetes and aging mechanism and research, the MC decided to set up 5 WGs. Only one Co-ordinator per WG was nominated :

WG 1: Genetic aspects of NIDDM, obesity, insulin resistance and ageing

Co-ordinator: Ton Maassen

Objectives:

· identification of population studies in Europe that can be used for genetic association studies.

· what kind of clinical data are minimally required for proper genetic association studies.

· what techniques need improvement (high throughput SNP analysis on large populations, what microarray systems are most suited for human and mouse system?)

2002 status:

Currently, a number of cohorts are available within the network of WG-1 for studies related to the development of insulin resistance and beta cell dysfunction in an ageing population. These cohorts are the Prague Cohort (B.Bendlova), the Hoorn cohort (Maassen-Heine) for genetic analysis related to insulin resistance. These cohorts will be evaluated for SNP association related to newly discovered biochemical steps that modulate insulin sensitivity (Van Obberghen, Nice-France). Also the results emerging from the other Working Groups will be translated into assays that allows genetic association analysis. Part of the Hoorn cohort (Heine-‘t Hart) , the Utrecht cohort (van Haeften) and the collaboration with the Stumvoll-Fritsche-Häring consortium in Tübingen-Germany also allows a detailed analysis of changes in glucose-induced insulin secretion in relation to the development of glucose intolerance. These cohorts are used to test the contribution of candidate genes that emerge from the biochemical studies within the Working Groups 2-5 to changes in diabetes-related clinical parameters.

WG 2: Glucose and other transport processes and ageing

Co-ordinator: Antonio Zorzano

Objectives:

· identification of the molecular basis of glucose transport regulation in cells and tissues,

· identification of processes related to glucose transport in cells or tissues which are defective in ageing,

· determination of whether any of the regulatory proteins on glucose transport is amenable of pharmacological manipulation to prevent or treat diseases associated to ageing,

· identification of the role played by small GTP-binding proteins on glucose transport and specific mechanisms involved,

· covalent modification of glucose transporters and regulation of glucose transport in cells,

· mechanisms that mediate glucose transporter internalization,

· expression of glucose transporters in cells,

· mechanisms by which phosphatidylinositol 3-kinases and protein kinases regulate glucose transport,

· regulation of glucose transport in response to cellular stress,

· glucose transporter trafficking in adipose and muscle cells,

2002 status:

Ongoing intensive collaboration in several research areas, where participating groups utilize the combination of their widely different expertise:

· GLUT4 trafficking in muscle cells: J. Eckel (D), P. Shepherd (UK), F. Giorgino (I), C. Reynet (DK), J. Jensen (N), S. Sasson (IL), A. Handberg (DK), A. Zorzano (E) and J.R. Zierath (S)

· expression of glucose transporters and of regulatory proteins of GLUT4 trafficking: J. Eckel (D), F. Giorgino (I), C. Reynet (DK), J. Jensen (N), A. Handberg (DK), A. Zorzano (E) and J.R. Zierath (S)

· collaboration with WG4 (Drugs and New Preventive Therapeutic Approaches to Improve Glucose Metabolism and Insulin Resistance)

· collaboration with WG3 (Muscle and Ageing)

WG 3: Muscle and ageing

Co-ordinator: Aase Handberg

Objectives:

· Study the impact of age, primary and secondary insulin resistance, exercise, adrenaline, and fatty acids on the expression and function of transporting and signalling proteins important for substrate uptake and processing in skeletal muscle

· biological factors behind muscle differentiation

· combined cellular and physiological approach using different muscle-specific transgenic mouse models (AMPK, etc.).

· co-culture of human adipocytes and human skeletal muscle cells for studies on the pathogenesis of insulin resistance

2002 status:

· signaling through insulin and IGF1 receptors: K. Siddle (UK), C. Reynet (Denmark), A. Handberg (Denmark), J.A. Maassen (Netherlands), A.C. Rustan (Norway)

· molecular, cellular and metabolic perspectives of insulin resistance using human skeletal muscle cells in culture: A. Handberg (Denmark), C. Reynet (Denmark), A. C. Rustan (Norway), J. Jensen (Norway), J.R. Zierath (Sweden), P. Shepherd (UK), A. Zorzano (Spain), J.Eckel (Germany)

· critical role of AMPK: J.R. Zierath (Sweden), L. Hue (Belgium), M.H. Rider (Belgium), A.C. Rustan (Norway)

· collaboration with WG2 (“Glucose Transport and Ageing”) and WG4 (“Drugs and New Preventive Therapeutic Approaches to improve Glucose metabolism and Clinical Insulin Resistance”); planned joint action with WG5

· plans to develop joint actions on interactions between muscle and fat

WG 4: Drugs and new preventive therapeutic approaches to improve glucose metabolism and clinical insulin resistance

Co-ordinator: Francesco Giorgino

Objectives:

· Study of insulin action and insulin resistance at molecular and clinical levels; identification of critical signaling intermediates for glucose utilization; investigation of molecules that act as stimulators of glucose utilization or targets for drugs known to regulate this process; clarification of the mechanism of action of insulin-sensitizing drugs; gene therapy of insulin resistance.

· Investigation of indexes of insulin resistance in ageing people; validation of surrogate markers for in vivo insulin sensitivity; creation of transgenic animals mimicking human models of insulin resistance.

2002 status:

To accomplish the above goals this WG works in cooperation with all other WG of the action (genetics, glucose transport, muscle, cardiovascular) and act to develop the therapeutic implications of the activities of each WG and provide contacts with pharmacological and biotechnology industries to pursue therapeutic outcomes. Specific programmes:

· mechanism of action of insulin sensitizers

· tissue determinants of in vivo insulin resistance

· pharmaceutical control of glucose metabolism through regulation of gene expression

WG 5: Cardio-vascular diseases and ageing

Co-ordinator: Maya Simionescu

Objectives:

· effects of high glucose on the signaling pathways of the cells of the vascular wall;

· effects of hypercaloric diet on hamster, as an experimental model for mild diabetes

· the possible roles of leptin in cardiovascular function

· insulin glycation

2002 status:

· a highly successful WG meeting was held in Bucharest in the fall of 2002 where several bi- and multilateral collaborations were established, like

· a collaboration between the Institute of Cellular Biology and Pathology "N.Simionescu" (Bucharest, Romania) and the University College of London, Department of Biochemistry (UK) on studies on the effects of lipids, glucose and leptin on the cardiovascular system

· a collaboration of the laboratory "Posttranslational modifications of proteins" from the Institute of Biochemistry, Bucharest, Romania with the University of Rhode Island, Kingston, USA, Dept. of Chemistry, on the inhibitory effects of various compounds on early or advanced glycation products formation.

· the WG plans to develop intensive interactions with WG3 and WG4

3.3. SECRETARIAL SERVICES

The Secretarial Services are kindly provided by the European Commission. The financial administration of short term scientific missions as well as the maintenance of the web-site is provided by Prof. Csermely’s institute.

4. Participation and coordination

4.1. MANAGEMENT COMMITTEE

4.1.1. Chairperson

Prof. Peter CSERMELY

Semmelweis University,

Dept. Med. Chem.

P.O.Box 260

H-1444 Budapest

Tel: + 36-1-266 2755/4102

Fax: +36-1-266 7480

E-mail : csermely@puskin.sote.hu

4.1.2. Vice Chairperson

Prof. Jürgen ECKEL

Deutsches Diabetes-Forschungsinstitut

Aufm Hennekamp 65

D-40225 Düsseldorf

Tel./Fax : +49 211 3382 561

Mobile : +49 172 2045 992

E-mail : eckel@uni-duesseldorf.de

4.1.3. Secretary

Prof. Mihail PASCU

DG Research / B5 - COST Secretaria

Rue de la Loi 200

Office: B 7 - 3/27

B-1049 Brussels

Tel: +32-2-299 15 56

Fax: +32-2-296 42 89

E-mail : mihail.pascu@cec.eu.int

4.1.4. Members

AUSTRIA

Prof. Josef PATSCH

Univ. Klinik f. Innere Medizin

Universität Innsbruck

Prof. K. H. TRAGL

Ludwig Boltzmann-Institut für Altersforschung

I. Med. Abt./Donauspital, SMZO

BELGIUM

Prof. Louis HUE

Université Catholique de Louvain

ICP Département de Biochimie et de Biologie cellulaire

CZECH REPUBLIC

Dr. Bela Bendlova

Institute of Endocrinology

Dr. Jaroslav VESELY

Institute of Pathophysilogy - Medical faculty

Palacky University

DENMARK

Dr. Aase HANDBERG

Diabetes Research Center

Odense Universitets Hospital

Dr. Christine REYNET

Diabetes Biology

Health Care Discovery Novo Nordisk

FRANCE

Dr. Emmanuel VAN OBBERGHEN

INSERM U 145

Dr. Eric CLAUSER

INSERM U36

GERMANY

Prof. Jürgen ECKEL

Deutsches Diabetes-Forschungsinstitut

GRAND DUCHE DE LUXEMBOURG

GREECE

Prof. George DIMITRIADIS

Athens

Dr. Effie TSILIBARI

NRCPS “Demokritos”

Institute of Biology

HUNGARY

Prof. Peter CSERMELY

Semmelweis University,

Dept. Med. Chem.

Dr. György JERMENDY

Bajcsy-Zsilinszky Hospital, 3^rd Medical Department

IRELAND

Dr. John J. NOLAN

Metabolic Research Unit

Department of Endocrinology

St James Hospital

ISRAEL

Prof. Shlomo SASSON

Department of Pharmacology

Hebrew University of Jerusalem

Prof. Nava BASHAN

Dept. Clin. Biochem.

Ben Gurion Univ. Negev

ITALY

Prof. Francesco GIORGINO

Universita di Bari

LITHUANIA

Dr. Vaidotas URBANAVICIUS

Vilnius University Hospital

Clinics of Internal Medicine - Dept of Endocrinology

Dr. Valentinas MATULEVICIUS

Institute of Endocrinology - Kaunas Medical University

NETHERLAND

Dr. J.A. MAASSEN

Leiden University Medical Center

Department of Molecular Cell Biology

NORWAY

Dr. Jorgen JENSEN

National Institute of Occupational Health

Dept of Physiology

Prof. Arild Chr. RUSTAN

University of Oslo

Dept. of Pharmacology

ROMANIA

Prof. Maya SIMIONESCU

Institute of Cellular Biology and Pathology “Nicolae Simionescu”

Prof. Dan CHETA

Institute of Diabetes Nutrition and Metabolic Diseases

SLOVAKIA

Dr. Elena SEBOKOVA

Institute of Experimental Endocrinology

Slovak Academy of Sciences

Dr. Iwar KLIMES

Institute of Experimental Endocrinology

Slovak Academy of Sciences

SLOVENIA

Prof. Marjan KORDAS

University of Ljubljana

Institute of Pathophysiology

Prof. Robert ZOREC

Institute of Pathophysiology

University of Ljubljana

SPAIN

Prof. Antonio ZORZANO

Universidad de Barcelona

Dpto. Bioquimica y Biologia Molecular

Dr. Isabel VARELA-NIETO

Universidad Autonomica - CSIC

Instituto Investigaciones Biomedicas “Alberto Sols”

Prof. Margarita LORENZO

Departamento de Bioquimica Biol. Mol. II

Facultad de Farmacia, Universitad Complutense

SWEDEN

Dr. Juleen R. ZIERATH

Karolinska Institutet

Inst. för kirugisk vetenskap

Assoc. Prof. Jan ERIKSSON

Department of Medicine

Umea University Hospital

SWITZERLAND

Dr. Markus NIESSEN

Universitätsspital Zürich

Prof. Jean-Louis CARPENTIER

Faculty of Medicine - Dept. of Morphology

University of Geneva

UNITED KINGDOM

Dr. Peter SHEPHERD

Department of Biochemistry

University College London

Prof. Kenneth SIDDLE

University of Cambridge

Department of Clinical Biochemistry

Addenbrooke’s Hospital

4.2 Participating Institutions

N.A.

4.3 Meetings of the Management Committee

1^st MC meeting: 10/03/00, Brussels, Belgium

2^nd MC meeting: 9-10/10/00, Oslo, Norway

3^rd MC meeting: 23/05/01, Kerkrade, The Netherlands

4^th MC meeting: 10/09/01, Glasgow, Scotland, UK

5^th MC meeting: 16/02/02, Praha, Czech Republic

6^th MC meeting: 17/11/02, Bari, Italy

4.4 Meetings of the Working Groups

2000

· WG 5 « Cardiovascular » : Bucarest – Romania – 28 November 2000, organisers : P. Shepherd, M. Simionescu (approx. 50 participants)

· WG 2 « Glucose transport » : Barcelona – Spain – 21 December 2000 (participants : J. Eckel, A. Zorzano, A. Guma).

2001

· WG 2 « Glucose and other transport processes and ageing » Kerkrade – The Netherlands – 22-23 May 2001 (organisers: J. Eckel, H. Joost, approx. 100 participants).

2002

· WG 1 « Genetics of diabetes, obesity and ageing » Prague – Czech Republic – 16 February 2002 (organisers: B. Bendlova, T. Maassen, approx. 50 participants).

· WG 5 « Cardiovascular dysfunction » Bucharest – Romania – 10-13 October 2002 (organiser: M. Simionescu, approx. 150 participants).

· WG 2+4 « Clinical and experimental insulin resistance/glucose transporter trafficking » Bari – Italy – 15-16 November 2002 (organiser: F. Giorgino, approx. 80 participants).

4.5 Short-term scientific missions and their results

(List: dates, hosts and nationality of scientists and topics)

First round

Name of Applicant	Country	Host Institute	Date	Topics
Jorgen Jensen	Norway	Univ. Coll. London	28/6-6/7/01	PI-3-kinase measurements
Shlomo Sasson	Israel	Diab. Forschungsinst. Düsseldorf, Germany	19-25/01/01	PPAR-related competitive PCR measurements
Andrej Janez	Slovenia	Diab. Forschungsinst. Düsseldorf, Germany	Cancelled	N.A.
Valentinas Matulevicius	Latvian	Univ. Barcelona	5/02-4/03/01	preparation of future collaboration involving clinical subjects
Elisabet Suarez	Spain	Karolinkska Inst.	10-31/05/01	to study heregulin-stimulated glucose trp.
Doina Popov	Romania	Univ. Coll. London	16-30/7/01	MAPK/STAT measurements in vascular smooth muscle cells
Michael Gaster	Denmark	Univ. Oslo	30/7-12/8/01	Fatty acid metabolism of satellite cells
Erlend Olav Brennesvik	Norway	Univ. Coll. London	1-15/9/01	learning of PI-3-kinase techniques
Doina Popov	Romania	Univ. Coll. London	28/11-5/12/01	Leptin signaling of human aortic endothelial cells

Second round

Name of Applicant	Country	Host Institute	Date	Topics
Tetzlaff Stephan	Germany	Leiden Univ.	26-31/8/02	analysis of the 3243 mutation in mitochondrial DNA
Daniela Sramkova	Czech Republic	Univ. Cambridge, Dept. Med. Clin. Biochem.	2/10-29/11/02	site-directed mutagenesis, linkage studies, fat biopsies, RT-PCR

STSM results:

· the STSM-s of Jorgen Jensen and Shlomo Sasson resulted in a long-term collaboration and several joint publications of the participating labs

· the STSM-s of Michael Gaster, Erlend Brennesvick and Doina Popov resulted in joint publications, which are in preparation

5. Results

5.1. KEY SCIENTIFIC OUTCOMES

(names and years in parentheses refer to the respective publications of section 6.1.)

At the initial phase the Action identified five different areas where an extra effort is needed to fulfill the aims of the MoU. The following major results have been achieved and published so far in the Action in these areas:

WG 1: Genetic aspects of NIDDM, obesity, insulin resistance and ageing

· Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13 (Magre et al., a Nature Medicine paper)

· ApoB genetic variations (Mazura et al, 2000)

· Genetic background of the PPAR-related polycystic ovary syndrome has been studied in detail (Bendlova et al, 2001; Vybrikova et al., 2000, 2001)

WG2: Glucose and other transport processes and ageing

· Glucose transporters of human skeletal muscle (Gaster et al, 2000a,b; Kawano et al, 1999; Krook et al, 2000)

· GLUT4 is reduced in slow fibers of diabetic muscle (Gaster et al, 2001)

· GLUT4 translocation mechanism in adypocytes (Enrique-Tarancon et al, 2000)

· Molecular mechanisms of glucose transport (Dimitriadis and Newsholme, 2000; Newsholme and Dimitriadis, 2001; Till et al., 2000)

· PI-3-kinase and GLUT4 transport (Kessler et al, 2001)

· Rab11 and GLUT4 transport (Kessler et al, 2000)

· Semicarbazide sensitive amine oxidase substrates and glucose transport (Morin et al, 2001)

· Surface GLUT4 (Ryder et al., 2000)

· Ubc9 plays an essential role in insulin-stimulated glucose transport in adipocytes but not in undifferentiated fibroblasts (Giorgino, 2002)

WG 3: Muscle and ageing

· Unbalanced expression of the different subunits of elongation factor 1 in diabetic skeletal muscle (Reynet and Kahn, a PNAS paper)

· Contraction inhibits insulin-stimulated insulin receptor substrate-1/2 associated PI 3-kinase activity, but not PKB activation or glucose uptake in rat muscle (Whitehead et al, 2000)

· fiber type dependent expression of GLUT11 in human skeletal muscle (Handberg, 2002)

· development of a relevant human skeletal muscle cell model to test and stydy mechanism of action of selected hit compounds that regulate glucose metabolism (Reynet, 2002)

WG4: Drugs and new preventive therapeutic approaches to improve glucose metabolism and clinical insulin resistance

· Benzylamine and vanadate in STZ-diabetes (Marti et al, 2001)

· Insulin secretagogues (Raptis and Dimitriadis, 2001)

· Receptor binding of insulin analogues (Kurtzhas et al, 2000)

· Role of molecular chaperones in diabetes and ageing (Csermely 2001a,b; Nardai et al, 2001, Soti and Csermely, 2000)

· Small insulin mimetic (Zhang et al, 1999 a Science paper)

WG5: Cardio-vascular diseases and ageing

· AGE-formation (Georgescu and Popov, 2000)

· Characterization of endothelial dysfunction (Costache et al, 2000a,b; Dobrian et al, 2000; Jinga et al., 2000; Popov et al, 2001; Raicu et al, 2000; Simionescu, 2000, 2001; Simionescu et al, 2001)

Additional results have also been achieved in accordance with points of the MoU:

5.1.1. Identification of diabetogenes (see WG1)

5.1.2. Studies on the intracellular mechanism of insulin action in normal and pathological states

5.1.2.1. mechanism of the interactions between insulin receptor and its substrates, analysis of tissue-specificity of insulin signalling pathways

· The lipid phosphatase SHIP2 controls insulin sensitivity (Clement et al., 2001 a Nature paper)

· Exercise-induced changes in IRS-signaling (Chibalin et al, 2000, a PNAS paper; Yu et al., 2001)

· Insulin action in spinal injury (Mohr et al, 2001)

· Muscle fibre type specificity (Song et al., 1999)

· mTOR and PKB (Nave et al, 1999)

· Insulin receptor signaling occurs at least in part from the cell surface and does not require internalization of the receptor. This is true for the signaling resulting in the metabolic actions (including glucose transport) of the insulin receptor. This signaling is occuring from microvilli and apparentls also from caveolae.

5.1.2.2. molecular characterization of glucose transport in normal and insulin-resistant states (see WG2)

5.1.2.3. molecular analysis of insulin signalling and action during the whole lifespan

· Inositol lipids in insulin signalling (Jones and Varela-Nieto, 1999

· PI-3-kinase (Sebokova et al, 1999)

5.1.2.4. interrelationships of insulin resistance and leptin action

· Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signalling pathways (O’Rourke and Shepherd, 2002; O’Rourke et al., 2001; 2002)

· Analysis of paradoxical observations on the association between leptin and insulin resistance. (Ceddia et al, 2002)

· Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients - potential role of steroid hormones and leptin in the development of insulin resistance. (Janson et al, 2002)

5.1.2.5. development of insulin- and leptin-related signalling molecules as potential drug candidates (see WG4)

Other papers on insulin, diabetes and ageing

· Chaperone-overload is a possible contributor to “civilization diseases”: atherosclerosis, cancer, diabetes (Csermely, 2001, a Trends in Genetics hypothesis)

· Acetylcholinesterase and diabetes (Kiss et al., 2001)

· Amine oxidase subtrates and adypocytes differentiation (Fontana et al., 2001)

· Diffusible transcription factor in ear development (Frago et al., 2000)

· Membrane changes in diabetes (Somogyi et al., 2001)

· Thiazolidindiones (Jermendy and Csermely, 2001)

· Thyroid hormones and glucose intolerance (Dimitriadis and Raptis, 2001)

· a glomerular epithelial cell receptor (podocalyxin) is anti-adhesive and antagonizes the adhesive effect of integrins (Tsilibari et al, 2002)

· IGF-I deficit is associated with a progressive age-dependent lost of auditory neurons by apoptosis (Varela-Nieto et al., 2002)

5.2. OUTSTANDING SCIENTIFIC PUBLICATIONS (published in journals with an impact factor higher than 10)

1. Magre J, Delepine M, Khallouf E, Gedde-Dahl T, Jr., Van Maldergem L, Sobel E, Papp J, Meier M, Megarbane A, Bachy A, Verloes A, d'Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J 2001 Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365-370 IF: 30,9

2. Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature. 2001 Jan 4;409(6816):92-7. IF: 25.8

3. Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Diez MT, Pelaez F, Ruby C, Kendall RL, Mao X, Griffin P, Calaycay J, Zierath JR, Heck JV, Smith RG, Moller DE. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science. 1999 284:974-977. IF: 23.9

4. Ouwens DM, de Ruiter ND, van der Zon GC, Carter AP, Schouten J, van der BC, Kooistra K, Bos JL, Maassen JA, van Dam H 2002 Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38. EMBO J 21:3782-3793, 2002, IF: 14,0

5. Reig N, Chillaron J, Bartoccioni P, Fernandez E, Bendahan A, Zorzano A, Kanner B, Palacin M, Bertran J. The light subunit of system b(o,+) is fully functional in the absence of the heavy subunit. EMBO J. 21, 4906-4914, 2002, IF: 14,0

6. Csermely, P. Chaperone-overload as a possible contributor to “civilization diseases”: atherosclerosis, cancer, diabetes. Trends in Genetics, 17, 701-704, 2001, IF: 12.9

7. Almind, K., Delahaye, L., Hansen, T., VanObberghen, E., Pedersen, O., and Kahn, C.R.: Characterization of the Met3261Ie variant of phosphatidylinositol 3-kinase p85 alpha. Proc Natl. Acad. Sci. USA 99, 2124-2128, 2002. IF: 10.8

8. Chibalin AV, Yu M, Ryder JW, Song XM, Galuska D, Krook A, Wallberg-Henriksson H, Zierath JR. Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: differential effects on insulin-receptor substrates 1 and 2. Proc Natl Acad Sci U S A. 2000 97:38-43. IF: 10.8

9. Reynet C and Kahn CR. Unbalanced expression of the different subunits of elongation factor 1 in diabetic skeletal muscle. PNAS, 2001, 98: 3422-3427, IF: 10.8

10. Rupnik, M. M. Kreft, I., S. K. Sikdar, S. Grilc., R. Romih, G. Zupančič, T. F. J. Martin, and R. Zorec (2000) Rapid Regulated Dense-Core Vesicle Exocytosis Requires the CAPS Protein PNAS 97:5627-5632. IF: 10.8

5.3. JOINT PUBLICATIONS AND REPORTS

(the collaborating scientists from different countries have been set in boldface)

1999

1. Dransfeld, O., Uphues, I., Sasson, S., Schurmann, A., Joost, H.G. and Eckel, J.: Regulation of subcellular distribution of GLUT4 in cardiomyocytes: Rab4A reduces basal glucose transport and augments insulin responsiveness. Exp. Clin. Endocrinol. Diabetes 107, 26-36, 1999.

2. Franch, J., Aslesen, R. & Jensen, J. Regulation of glycogen synthesis after contractile activity in rat skeletal muscle. Effect of adrenaline on glycogen synthesis and activation of glycogen synthase and glycogen phosphorylase. Biochem. J. 344:231-235, 1999.

3. Nave, B.T., Ouwens, M., Withers, D.J., Alessi, D.R. and Shepherd, P.R.: Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427-431, 1999.

4. Sebokova, E., Gasperikova, D., Ouwens, M., Dorrestijn, J., Eckel, J., Maasen, A. and Klimes, I.: Defect in long-term activation of phosphatidylinositol 3-kinase by insulin in vivo: studies in insulin-resistant hHTg rats. Endocr. Regul. 33, 49-54, 1999.

2000

1. Kessler, A. E. Tomàs, D. Immler, H.E. Meyer, A. Zorzano, J. Eckel. Rab 11 is associated with GLUT4-containing vesicles and redistributes in response to insulin. Diabetologia. 43, 1518-1527, 2000.

2. Kurtzhals, P., Schaffer, L., Sorensen, A., Kristensen, C., Jonassen, I., Schmid, C., and Trub, T.: Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49, 999-1005, 2000.

3. Till, M., Ouwens, D.M., Kessler, A. and Eckel, J.: Molecular mechanisms of contraction-regulated cardiac glucose transport. Biochem. J. 346, 841-847, 2000.

4. Whitehead J. P., Soos, M. A., Aslesen, R., O’Rahilly, S., & Jensen, J. Contraction inhibits insulin-stimulated insulin receptor substrate-1/2 associated PI 3-kinase activity, but not PKB activation or glucose uptake in rat muscle. Biochem. J. 349:775-781, 2000.

5. Whitehead J.P., Soos, M.A., Aslesen, R., O Rahilly, S., and Jensen, J.: Contraction inhibits insulin-stimulated insulin receptor substrate-1/2 associated PI 3-kinase activity, but not PKB activation or glucose uptake in rat muscle. Biochem. J. 349, 775-781, 2000.

2001

1. Aslesen, R., Engebretsen, E.M.L., Franch, J. & Jensen, J. Glucose uptake and metabolic stress in rat muscles stimulated electrically with different protocols. J. Appl. Physiol. 91:1237-1244, 2001.

2. Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature. 2001 Jan 4;409(6816):92-7.

3. Dransfeld O, Rakatzi I, Sasson S, Gruzman A, Schmitt M, Haussinger D, Eckel J. Eicosanoids participate in the regulation of cardiac glucose transport by contribution to a rearrangement of actin cytoskeletal elements. Biochem. J. 359, 47-54, 2001.

4. Červenková K., Belejová M., Veselý J., Chmela Z., Rypka M., Ulrichová J., Modrianský M., Maurel P.: Cell suspensions, cell cultures, and tissue slices – important metabolic in vitro systems. Biomed. Papers, 145, 57-60, 2001.

5. Kessler, A., Uphues, I., Ouwens, D.M., Till, M. and Eckel, J.: Diversification of cardiac insulin signaling involves the p85alpha/beta subunits of phosphatidylinositol 3-kinase. Am. J. Physiol. 280, E65-E74, 2001.

6. Soos, M. A., Jensen, J., Brown, R.A., O’Rahilly, S., Shepherd, P.R., & Whitehead, J.P. Class II phosphoinositide 3-kinase is activated by insulin but not by contraction in skeletal muscle. Arch Biochem. Biophys. 396:244-248, 2001.

2002

1. Aas, V., Torblĺ, S., Andersen, M.H., Jensen, J. and Rustan, A.C.: Electrical stimulation improves insulin responses in a human skeletal muscle cell model of insulin resistance. Ann. N.Y. Acad. Sci. 967, 506-515, 2002.

2. Búren, J., Liu, H.-X., Jensen, J. and Eriksson, J.W. Dexamethasone impairs insulin signalling and glucose transport by depletion of IRS-1, PI3-kinase and Protein kinase B in primary cultured rat adipocytes. Eur.J.Endocrinol. 146 (3):419-429, 2002

3. Dransfeld, O., Rakatzi, I., Sasson, S. and Eckel, J.: Eicosanoids and the regulation of cardiac glucose transport. Ann. N.Y. Acad. Sci. 967, 1-9, 2002.

4. Foukas, L.C., Daniele, N., Ktori, C., Anderson, K.E., Jensen, J., and Shepherd, P.R. Direct effects of caffeine and theophylline on the p110d and other phosphoinositiode 3-kinases; Differential effects on lipid kinase and protein kinase activities. J. Biol. Chem. 277, 37124-37130, 2002.

5. Franch, J., Andersen, J.L., Jensen, J., Pedersen, P.K., & Knudsen, J. Acyl-CoenzymeA binding protein is expressed fibre type specific in rat skeletal muscles but not affected by moderate endurance training. Pflügers Arch. 443:387-393, 2002.

6. Franch, J., Knudsen, J., Ellis, B.A., Pedersen, P.K., Cooney, G.J. & Jensen, J. Acyl-CoA binding protein expression is fiber type- specific and elevated in muscles from the obese insulin-resistant Zucker rat. Diabetes. 51(2):449-454, 2002.

7. Madsen, L., Guerre-Millo, M., Flindt, E.N., Berge, K., Tronstad, K.J., Bergene E., Sebokova, E., Rustan, A.C., Jensen, J., Mandrup, S., Kristiansen, K., Klimes, I., Staels, B. and Berge, R.K.: Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance. J. Lipid Res. 43, 742-750, 2002.

8. Magre J, Delepine M, Khallouf E, Gedde-Dahl T, Jr., Van Maldergem L, Sobel E, Papp J, Meier M, Megarbane A, Bachy A, Verloes A, d'Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J 2001 Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365-370

5.4. PARTICIPATION AND AWARDS OF YOUNG SCIENTISTS

The Action makes always a special effort tomobilize extra funds to help the participation of young scientists in the WG meetings and workshops of the Action. There is an increasing ratio of young scientists in Short Term Scientific Missions. Young scientists are regular first- and co-authors of the joint publications listed in points 5.3. and 6.1.

The following international awards have been received by young scientists belonging to participating labs:

· Best Poster Award of the EMBO course on molecular chaperones in Warsaw, Poland (Judit Hargitai in Peter Csermely’s lab, October 2002)

· Prize of European Life Scientist Organization June 2002, Nice, France (A. Burlacu and M. Voinea in Maya Simionescu’s institute)

6. Dissemination of results

6.1. SCIENTIFIC PUBLICATIONS

Total number of COST B17-related publications

1999: 8

2000: 34

2001: 65

2002: >125

2003: >35

2004: N.A.

1999

1. Brown R. A., Domin, J., Arcaro, A., Waterfield M.D., and Shepherd P.R. (1999) Insulin activates the alpha isoform of class-II phosphoinositide 3-kinase Journal of Biological Chemistry  274: 14529-14532

2. Franch, J., Aslesen, R. & Jensen, J. Regulation of glycogen synthesis after contractile activity in rat skeletal muscle. Effect of adrenaline on glycogen synthesis and activation of glycogen synthase and glycogen phosphorylase. Biochem. J. 344:231-235, 1999.

3. Jones, D.R. and Varela-Nieto, I. Diabetes and the role of inositol-containing lipids in insulin signalling. Mol. Medicine 5, 505-514. 1999. (Review).

4. Kawano Y, Rincon J, Soler A, Ryder JW, Nolte LA, Zierath JR, Wallberg-Henriksson H. Changes in glucose transport and protein kinase Cbeta(2) in rat skeletal muscle induced by hyperglycaemia. Diabetologia. 1999 42:1071-1079.

5. Nave, B.T., Ouwens, M., Withers, D.J., Alessi, D.R. and Shepherd, P.R.: Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427-431, 1999.

6. Sebokova, E., Gasperikova, D., Ouwens, M., Dorrestijn, J., Eckel, J., Msen, A. and Klimes, I.: Defect in long-term activation of phosphatidylinositol 3-kinase by insulin in vivo: studies in insulin-resistant hHTg rats. Endocr. Regul. 33, 49-54, 1999.

7. Song XM, Ryder JW, Kawano Y, Chibalin AV, Krook A, Zierath JR. Muscle fiber type specificity in insulin signal transduction. Am J Physiol. 1999 277:R1690-1696

8. Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Diez MT, Pelaez F, Ruby C, Kendall RL, Mao X, Griffin P, Calaycay J, Zierath JR, Heck JV, Smith RG, Moller DE. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice.Science. 1999 284:974-977.

2000

1. Baynes K.C.R, Beeton C.A., Panayotou G., Stein R., Simpson H., Soos M., Hansen T., O'Rahilly S., Shepherd P.R. and Whitehead J.P..(2000) A novel missense mutation in the p85a phosphoinositide 3-kinase gene found in a pedigree with familial insulin resistance impairs insulin stimulated PI 3-kinase activity Diabetologia 43: 321-331
2. Beeton, C.A., Chance E.M. Foukas, L. & Shepherd P.R. (2000) Comparison of the kinetic properties of the lipid and protein kinase activities of the p110a  and p110b catalytic subunits of class Ia PI 3-kinases Biochemical Journal 350:353-359

3. Chibalin AV, Yu M, Ryder JW, Song XM, Galuska D, Krook A, Wallberg-Henriksson H, Zierath JR. Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: differential effects on insulin-receptor substrates 1 and 2. Proc Natl Acad Sci U S A. 2000 97:38-43.

4. Constantinescu, D. Alexandru, V. Alexandru, M. Raicu, M. Simionescu. Endothelial cell-derived foam cells fail to express adhesion molecules (ICAM-1 and VCAM-1) for monocytes. J Submicrosc Cytol Pathol. 32 (2), 2000.

5. Costache, G. D. Popov, A. Georgescu, M. Cenuse, V.V. Jinga, M. Simionescu. The effects of simultaneous hyperlipemia-hyperglycemia on the mesenteric resistance arteries, myocardium and kidney glomeruli. J. Submicrosc. Cytol. Pathol., 32(1), 47-58, 2000a.

6. Costache, G. D. Popov, A. Georgescu, M. Simionescu. Functional-structural alterations of the resistance arteries in experimental hyperlipemia or hyperglycemia. Proc. Rom. Acad. Ser.B, 1, 31-37, 2000b.

7. Dimitriadis, G. and Newsholme, E.: Integration of some biochemical and physiologic effects of insulin that may play a role in the control of blood glucose concentration. In: LeRoith, Taylor, Olefsky (Editors) "Diabetes mellitus, a fundamental and clinical text", Lippincott Williams and Wilkins, 2nd Edition, pp 161-176, 2000.

8. Dobrian, V. Lazar, C. Sinescu, D. Mincu, M. Simionescu. Diabetic state induces lipid loading and altered expression of lipoprotein lipase in culture monocyte-derived macrophages. Atherosclerosis, 153: 191-201, 2000.

9. Dransfeld, O., Uphues, I., Sasson, S., Schurmann, A., Joost, H.G. and Eckel, J.: Regulation of subcellular distribution of GLUT4 in cardiomyocytes: Rab4A reduces basal glucose transport and augments insulin responsiveness. Exp. Clin. Endocrinol. Diabetes 108, 26-36, 2000.

10. Enrique-Tarancón, G. Y. Castan, N. Morin, L. Marti, A. Abella, M. Camps, R. Casamitjana, M. Palacín, X. Testar, E. Degerman, C. Carpéné, A. Zorzano. Substrates of semicarbazide-sensitive amine oxidase cooperate with vanadate to stimulate tyrosine phosphorylation of IRS proteins, phosphatidylinositol 3-kinase activity and GLUT4 translocation in adipose cells. Biochem. J. 350, 171-180, 2000.

11. Frago L.M., Camarero G., Cańón S., Pańeda C., Sanz C., León Y., Giraldez F. and Varela-Nieto I. Role of diffusible and transcription factors in inner ear development: implications in regeneration. Histol. Histopathol. 15, 657-666. 2000. (Review).

12. Gaster M, Handberg A, Beck-Nielsen H, Schroder HD. Glucose transporter expression in human skeletal muscle fibers. Am J Physiol Endocrinol Metab 2000a Sep;279(3):E529-E538

13. Gaster M, Poulsen P, Handberg A, Schroder HD, Beck-Nielsen H. Direct evidence of fiber type-dependent GLUT-4 expression in human skeletalmuscle. Am J Physiol Endocrinol Metab 2000b May;278(5):E910-E916

14. Georgescu, A. D. Popov. Age-dependent accumulation of advanced glycation endproducts is accelerated in combined hyperlipemia and hyperglycemia, a process attenuated by L-Arginine. J. Am. Aging Assoc. 23:33-40, 2000.

15. Glavan, G., Zorec, R., Babic. K., Sket, D., Zivin, M. (2000) Dopaminergic regulation of Synaptotagmin I and IV mRNAs in Hemiparkinsonian Rats Neuroreport, 11: 1-5.

16. Jinga, A. Gafencu, F. Antohe, E. Constantinescu, C. Heltianu, M. Raicu, I. Manolescu, W. Hunziker, M. Simionescu. Establishment of a pure microvascular endothelial cell line from human placenta. Placenta, 21(4), 325-336, 2000.

17. Kessler, A. E. Tomŕs, D. Immler, H.E. Meyer, A. Zorzano, J. Eckel. Rab 11 is associated with GLUT4-containing vesicles and redistributes in response to insulin. Diabetologia. 43, 1518-1527, 2000.

18. Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, Myers MG Jr, Wallberg-Henriksson H, Zierath JR. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes. 2000 49:284-292.

19. Kurtzhals, P., Schaffer, L., Sorensen, A., Kristensen, C., Jonassen, I., Schmid, C., and Trub, T.: Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49, 999-1005, 2000.

20. Mazura I., Bendlová B., Vaňková M., Včelák J., Perušičová J., Svatoš J., Štefek M., Zvárová J. (2000): Genetic variation at the apo B 3´VNTR in Czech General population and in Czech diabetes mellitus type II patient group. Journal of Human Ecology 12 (1): 19-24.

21. Mohr T, Dela F, Handberg A, Biering-Sorensen F, Galbo H, Kjaer M.: Insulin action and long-term electrically induced training in individuals withspinal cord injuries. Med Sci Sports Exerc 2001 Aug;33(8):1247-1252

22. Morin, N. J.M. Lizcano, E. Fontana, L. Marti, F. Smih, P. Rouet, D. Prevot, A. Zorzano, M. Unzeta, C. Carpéné. Semicarbazide-sensitive amine oxidase substrates stimulate glucose transport and inhibit lipólisis in human adipocytes. Journal of Pharmacology and Experimental Therapeutics 297, 563-572, 2001.

23. Pimentel, B., Sanz, C., Rapp, U., Varela-Nieto, I., de Pablo, F. and de la Rosa, E. C-Raf regulates cell survival and retinal ganglion cell morphogenesis during neurogenesis. J. Neurosci. 20, 3254-3262. 2000.

24. Raicu, S. Florea, G. Costache, D. Popov, M. Simionescu. Clotrimazole inhibits smooth muscle cells proliferation and has a vasodilator effect on resistance arteries. Fundamental and Clinical Pharmacology 14: 477-485, 2000.

25. Rupnik, M. M. Kreft, I., S. K. Sikdar, S. Grilc., R. Romih, G. Zupančič, T. F. J. Martin, and R. Zorec (2000) Rapid Regulated Dense-Core Vesicle Exocytosis Requires the CAPS Protein PNAS 97:5627-5632.

26. Rupnik, M., Kreft, M., Limpel Kržan, M. & Zorec, R. (2000) Millisecond measurements of Ca²⁺ and exocytosis in neuroendocrine and glial cells. Acta Biologica Slovenica 43: 57-61.

27. Ryder JW, Yang J, Galuska D, Rincon J, Bjornholm M, Krook A, Lund S, Pedersen O, Wallberg-Henriksson H, Zierath JR, Holman GD. Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients. Diabetes. 2000 49:647-654.

28. Simionescu. M. Structural, biochemical and functional differentiation of the vascular endothelium. In: “Morphogenesis of the endothelium”, W.Risau (ed.), Harwood Academic Publishers, p.1-23, 2000;

29. Sőti Cs. and Csermely, P. (2000) Molecular chaperones and the aging process. Biogerontology, 1, 225-233

30. Till, M., Ouwens, D.M., Kessler, A. and Eckel, J.: Molecular mechanisms of contraction-regulated cardiac glucose transport. Biochem. J. 346, 841-847, 2000.

31. Vrbíková J., Hill M., Stárka L., Vondra K., Šulcová J., Šnajderová M., Cibula D., Pobišová Z., Bendlová B. (2000): An analysis of the relationship between insulin resistance and the activity of steroid C17,20-lyase and 3b-hydroxysteroiddehydrogenase in ovaries and adrenals in women with polycystic ovary syndrome. Exp Clin Endocrinol Diab, 108, 455-462.

32. Whitehead J. P., Soos, M. A., Aslesen, R., O’Rahilly, S., & Jensen, J. Contraction inhibits insulin-stimulated insulin receptor substrate-1/2 associated PI 3-kinase activity, but not PKB activation or glucose uptake in rat muscle. Biochem. J. 349:775-781, 2000.

33. Whitehead J.P., Soos, M.A., Aslesen, R., O Rahilly, S., and Jensen, J.: Contraction inhibits insulin-stimulated insulin receptor substrate-1/2 associated PI 3-kinase activity, but not PKB activation or glucose uptake in rat muscle. Biochem. J. 349, 775-781, 2000.

34. Wiese R, Homan U, M. Kreft, R. Zorec, G. Thiel (2000) Transient and irreversible exocytosis of vesicles in Zea mays coleoptile protoplasts measured in the cell-attached configuration. J. Membrane Biol. 174:15-20.

2001

1. Aslesen, R., Engebretsen, E.M.L., Franch, J. & Jensen, J. Glucose uptake and metabolic stress in rat muscles stimulated electrically with different protocols. J. Appl. Physiol. 91:1237-1244, 2001.

2. Beauloye C, Bertrand L, Krause U, Marsin AS, Dresselaers T, Vanstapel F, Vanoverschelde JL, Hue L. No-flow ischemia inhibits insulin signaling in heart by decreasing intracellular pH. Circ Res. 2001 Mar 16;88(5):513-9.

3. Beauloye C, Marsin AS, Bertrand L, Krause U, Hardie DG, Vanoverschelde JL, Hue L. Insulin antagonizes AMP-activated protein kinase activation by ischemia or anoxia in rat hearts, without affecting total adenine nucleotides. FEBS Lett. 2001 Sep 21;505(3):348-52.

4. Becker C, Sevilla L, Tomas E, Palacin M, Zorzano A, Fischer Y. The endosomal compartment is an insulin-sensitive recruitment site for GLUT4 and GLUT1 glucose transporters in cardiac myocytes. Endocrinology. 2001 Dec;142(12):5267-76.

5. Bendlová B., Vrbíková J., Šaffková J., Stárka L. (2001): Genetické pozadí syndromu polycystických ovárií. Diabetes, metabolism , endocrinology and nutrition (DMEV) 4 (1): 58-62. )

6. Brown R. A. and Shepherd P.R. (2001) Growth factor regulation of the novel class-II PI 3-kinases Biochemical Society Transactions 29 535-537

7. Brumback, A.C., Zorec, R. & Betz, W. J. (2001) Integrins: the missing link. J. Physiol. (Lond) 530.1:1.

8. Burlacu, A. V.Jinga, A.V.Gafencu, M.Simionescu. The severity of the oxidative stress generates different mechanisms of endothelial cell death. Cell and Tissue Research. 306: 409-416, 2001

9. Cervenková K., Belejová M., Veselý J., Chmela Z., Rypka M., Ulrichová J., Modrianský M., Maurel P.: Cell suspensions, cell cultures, and tissue slices – important metabolic in vitro systems. Biomed. Papers, 145, 57-60, 2001.

10. Chibalin AV, Kovalenko MV, Ryder JW, Feraille E, Wallberg-Henriksson H, Zierath JR. Insulin- and glucose-induced phosphorylation of the Na(+),K(+)-adenosine triphosphatase alpha-subunits in rat skeletal muscle. Endocrinology. 2001 Aug;142(8):3474-82.

11. Chmela Z., Veselý J., Lemr K., Rypka M., Hanuš J., Havlíček L., Kryštof V., Michnová L., Fuksová K., Lukeš J.: In vivo metabolism of 2,6,9-trisubstituted purine-derived cyclin-dependent kinase inhibitor bohemine in mice: glucosidation as the principal metabolic route. Drug Metab. Dispos. 29, 326-334, 2001.

12. Cinek, O., Drevinek, P., Sumnik, Z., Bendlova, B., Kolouskova, S., Snajderova, M. and Vavrinec, J.: The CTLA4 +49 A/G dimorphism is not associated with type 1 diabetes in Czech children. Eur. J. Immunogenet. 29, 219-222, 2001.

13. Clement S, Krause U, Desmedt F, Tanti JF, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustel Y, Erneux C, Hue L, Schurmans S. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature. 2001 Jan 4;409(6816):92-7.

14. Conejo, R. and Lorenzo, M. (2001) Insulin signaling leading to proliferation, survival, and membrane ruffling in C2C12 myoblasts. J. Cell. Physiol. 187, 96-108

15. Conejo, R., Valverde, A.M., Benito, M. and Lorenzo, M. (2001) Insulin produces myogenesis in C2C12 myoblasts by induction of NF-KB and down-regulation of AP-1 activities.J. Cell. Physiol. 186, 82-94

16. Csermely, P. (2001a) A nonconventional role of molecular chaperones: involvement in the cytoarchitecture. News in Physiological Sciences. 15, 123-126, IF: 2.3

17. Csermely, P. (2001b) Chaperone-overload as a possible contributor to “civilization diseases”: atherosclerosis, cancer, diabetes. Trends in Genetics, 17, 701-704, IF: 12.9

18. Dimitriadis, G. and Raptis, S.: Thyroid hormone excess and glucose intolerance. Exp. Clin. Endocrinol. Diabetes 109 (Suppl 2), 225-239, 2001.

19. Dostálová, Mačáková J., Riegrová D., Červenková K., Veselý J.: Inhibition of excessive protein phosphorylation in neurones - new hopes for pharmacotherapy of Alzheimer dementia and other neurodegenerative diseases. Homeostasis, 41, 46-48, 2001.

20. Dransfeld O, Rakatzi I, Sasson S, Gruzman A, Schmitt M, Haussinger D, Eckel J. Eicosanoids participate in the regulation of cardiac glucose transport by contribution to a rearrangement of actin cytoskeletal elements. Biochem J. 2001 Oct 1;359(Pt 1):47-54.

21. Emanuelli, B., Peraldi, P., Filloux, C., Chavey, C., Freidinger, K., Hilton, D.J., Hotamisligil, G.S. and VanObberghen, E.: SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J. Biol. Chem. 276, 47944-47949, 2001

22. Fiedler M, Zierath JR, Selen G, Wallberg-Henriksson H, Liang Y, Sakariassen KS. 5-aminoimidazole-4-carboxy-amide-1-beta-D-ribofuranoside treatment ameliorates hyperglycaemia and hyperinsulinaemia but not dyslipidaemia in KKAy-CETP mice. Diabetologia. 2001 Dec;44(12):2180-6.

23. Fontana, E. J. Boucher, L. Marti, J.M. Lizcano, X. Testar, A. Zorzano, C. Carpéné. Amine oxidase substrates mimic several of the insulin effects on adipocyte differentiation in 3T3 F442A cells.Biochem.J. 356, 769-7717, 2001.

24. Ganea, E. "Chaperone-like Activity of alfa-Cristallin and Other Small Heat Shock Proteins", Current Protein & Peptide Science,2, 205, 2001.

25. Gaster M, Schroder HD, Handberg A, Beck-Nielsen H. The basal kinetics parameters of glycogen synthase in human myotubes cultures are not affected by chronic high insulin exposure. Biochemica et Biophysica Acta-Molecular Basis of Disease, 2001, 1537: 211-221

26. Gaster M, Staehr P, Beck-Nielsen H, Schroder HD, Handberg A. GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is insulinresistance in type 2 diabetes a slow, type 1 fiber disease? Diabetes 2001 Jun;50(6):1324-1329

27. Georgescu, A. D. Popov, M. Simionescu. Mechanisms of decreased bradykinin-induced vasodilation in experimental hyperlipemia-hyperglycemia: contribution of nitric oxide and Ca²⁺ activated K⁺ channels. Fundam. Clin. Pharmacol. 15,335-342, 2001.

28. Georgescu, A. D. Popov. Vascular reactivity of the resistance arteries to potassium in combined hyperlipemia-hyperglycemia. Proc. Rom. Acad. 2,111-115, 2001

29. Halse R, Bonavaud SM, Armstrong JL, McCormack JG, Yeaman SJ. Control of glycogen synthesis by glucose, glycogen, and insulin in cultured human muscle cells. Diabetes, 2001, 50: 720-726

30. Halse R, Pearson SL, McCormack JG, Yeaman SJ, Taylor R. Effect of tumor necrosis factor-alpha on insulin action in cultured human muscle cells. Diabetes, 2001, 50: 1102-1109

31. Halvorsen, B., A.C. Rustan, L. Madsen, J. Reseland, R.K. Berge, P. Sletnes, and E.N. Christiansen, Effect of long-chain n-3 and mono-unsaturated fatty acids on fatty acid oxidation and lipid composition in rats. Annals Nutrition & Metabolism, 2001, 45(1): p.

32. Hernandez, R., Teruel, T. and Lorenzo, M. (2001). Akt mediates insulin induction of glucose uptake and up-regulation of GLUT4 gene expression in brown adipocytes. FEBS Lett 494, 225-231

33. Jermendy, Gy. and Csermely, P. (2001) Thiazolidindiones - a new group of oral antidiabetica. Medical Weekly (Hung.), 142, 1547-1554, the publication received the Lajos Markusovszky Award for the best publication of the journal in 2001

34. Kawano Y, Ryder JW, Rincon J, Zierath JR, Krook A, Wallberg-Henriksson H. Evidence against high glucose as a mediator of ERK1/2 or p38 MAPK phosphorylation in rat skeletal muscle. Am J Physiol Endocrinol Metab. 2001 Dec;281(6):E1255-9.

35. Kessler, A., Uphues, I., Ouwens, D.M., Till, M. and Eckel, J.: Diversification of cardiac insulin signaling involves the p85alpha/beta subunits of phosphatidylinositol 3-kinase. Am. J. Physiol. 280, E65-E74, 2001.

36. Kiss, G., Heidegger, M., Somogyi, J., Csermely, P. and Ver, A. (2001) Streptozotocin-induced diabetes alters the oligomerization pattern of acetylcholinesterase in rat skeletal muscle. Diabetologia, 44, 220-223, IF: 5,2

37. Košmelj, K., A. Cedilnik, P. Veranič, G. Zupančič, M. Rupnik, L. K.Bobanovic and R. Zorec (2001) Intergranule Fusion In Rat Pars Intermedia. Image Analysis and Stereology 20:79-85.

38. Laviola L, Belsanti G, Davalli A, Napoli R, Perrini S, Weir GC, Giorgino R, Giorgino F. Effects of streptozotocin diabetes and diabetes treatment by islet transplantation on in vivo insuling signaling in diabetic heart. Diabetes 50:2709-2720, 2001.

39. Magre J, Delepine M, Khallouf E, Gedde-Dahl T, Jr., Van Maldergem L, Sobel E, Papp J, Meier M, Megarbane A, Bachy A, Verloes A, d'Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O'Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J 2001 Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365-370

40. Marti, A. Abella, C. Carpéné, M. Palacín, X. Testar, A. Zorzano. Combined treatment with benzylamine and low doses of vanadate enhances glucose tolerance and reduces hyperglycemia in streptozotocin-induced diabetic rats. Diabetes 50, 2061-2068, 2001.

41. Nardai, G., Braun, L., Csala, M., Mile, V., Csermely, P., Benedetti, A., Mandl, J. and Banhegyi, G. (2001) Protein disulfide isomerase and protein thiol dependent dehydroascorbate reduction and ascorbate aumulation in the lumen of the endoplasmic reticulum. J. Biol. Chem. 276, 8825-8828

42. Newsholme, E. and Dimitriadis, G.: Integration of biochemical and physiologic effects of insulin on glucose metabolism, Exp. Clin. Endocrinol. Diabetes 109 (Suppl 2), 122-134, 2001.

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47. Popov, D. M. Simionescu Structural and transport property alterations of the lung capillary endothelium in diabetes. In: Advances in Microanatomy of Cells and Tissues, Biophysical and Biochemical Correlates, Ed. P.M.Motta, 2001, pp. 405-412.

48. Raptis, S. and Dimitriadis, G.: Oral hypoglycaemic agents: insulin secretagogues, a-glucosidase inhibitors and insulin sensitizers, Exp. Clin. Endocrinol. Diabetes 109 (Suppl 2), 265-287, 2001.

49. Reynet C and Kahn CR. Unbalanced expression of the different subunits of elongation factor 1 in diabetic skeletal muscle. PNAS, 2001, 98: 3422-3427

50. Riegrová D., Dostálová K., Mačáková J., Červenková K., Veselý J.: Embryonal development of stratified areas in central nervous system and its disturbancies – new insights. Homeostasis, 41, 44-46, 2001.

51. Rustan, A.C., and C.A. Drevon, Fatty acids: structures and properties. Encyclopedia  of Life Sciences, 2001, electronic publication at http://www.els.net/

52. Ryder JW, Portocarrero CP, Song XM, Cui L, Yu M, Combatsiaris T, Galuska D, Bauman DE, Barbano DM, Charron MJ, Zierath JR, Houseknecht KL. Isomer-specific antidiabetic properties of conjugated linoleic acid. Improved glucose tolerance, skeletal muscle insulin action, and UCP-2 gene expression. Diabetes. 2001 May;50(5):1149-57.

53. Santalucia T, Moreno H, Palacin M, Yacoub MH, Brand NJ, Zorzano A. A novel functional co-operation between MyoD, MEF2 and TRalpha1 is sufficient for the induction of GLUT4 gene transcription. J Mol Biol. 2001 Nov 23;314(2):195-204

54. Sima, A. C.Stancu, E. Constantinescu, L. Ologeanu, M. Simionescu. The hyperlipemic hamster - a model for testing the anti-atherogenic effect of amlodipine. J. Cell Mol. Med., 5: 153-162, 2001

55. Simionescu, M. Effect of hyperlipemia and hyperglycemia on the vascular endothelium, In: “Vascular endothelium source and target for inflammatory mediators”, NATO ASI Series, Eds. J.Catravas, A.D. Callow, U.S. Ryan, M.Simionescu., 2001, pp. 87- 99.

56. Simionescu, M., D. Popov, A. Sima. Cellular and molecular alterations in diabetes – induced cardiovascular complications studied in an original experimental model, in “Introducere in diabetologia experimentala”, Ed: D.M.Cheta, Romanian Academy Publishing House, 2001.

57. Somogyi, J., Kiss, G., Pentek, E., Csermely, P. and Ver, A. (2001) Diabetes mellitus as a general membrane disease and its consequences. Medical Weekly (Hung.), 142, 1781-1788

58. Song XM, Fiedler M, Galuska D, Ryder JW, Fernstrom M, Chibalin AV, Wallberg-Henriksson H, Zierath JR. 5-aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic ob/ob mice. Diabetologia, 2002, 45: 56-65

59. Soos, M. A., Jensen, J., Brown, R.A., O’Rahilly, S., Shepherd, P.R., & Whitehead, J.P. Class II phosphoinositide 3-kinase is activated by insulin but not by contraction in skeletal muscle. Arch Biochem. Biophys. 396:244-248, 2001.

60. Storgaard H, Song XM, Jensen CB, Madsbad S, Bjornholm M, Vaag A, Zierath JR. Insulin signal transduction in skeletal muscle from glucose-intolerant relatives with type 2 diabetes. Diabetes, 2001, 50: 2770-2778

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2002

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2. Ahrén, B., Simonsson, E., Landin-Olsson, M., Torgeirsson, H., Jansson, P.A., Sandqvist, M., Bĺvenholm, P., Efendic, S., Eriksson, J.W., Dickinson, S. and Holmes, D.: Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4 week study period in type 2 diabetes. Diabetes Care 25, 869-875, 2002.

3. Almind, K., Delahaye, L., Hansen, T., VanObberghen, E., Pedersen, O., and Kahn, C.R.: Characterization of the Met3261Ie variant of phosphatidylinositol 3-kinase p85 alpha. Proc Natl. Acad. Sci. USA 99, 2124-2128, 2002.

4. Alpert, E., Gruzman, A., Totary, H., Kaiser, N., Reich, R. and Sasson, S.: A natural protective mechanism against hyperglycaemia in vascular endothelial and smooth-muscle cells: role of glucose and 12-hydroxyeicosatetraenoic acid. Biochem. J. 362, 413-422, 2002

5. Alpert, E., Totary, H. and Sasson, S.: Cellular mediators of glucose-induced autoregulation of hexose transport. In: Frontiers in Animal Diabetes Research: Muscle Metabolism. (Eds: Zierath, J.R. and Wallberg-Henriksson, H.), Taylor & Francis Books Ltd., London. 2002, pp.155-167

6. Balboa, M., Varela-Nieto, I., Killerman, K. and Dennis, E.A.: Differential expression and regulation of PLA2 enzymes in human astrocytoma cells. FEBS Lett. 531, 12-17, 2002. Number co-editor.

7. Barnes, B. R., J. W. Ryder, T. L. Steiler, L. G. D. Fryer, D. Carling, and J. R. Zierath. Isoform-specific regulation of 5' AMP-activated protein kinase in skeletal muscle from obese Zucker (fa/fa) rats in response to contraction. Diabetes 51: 2703-2708, 2002

8. Belejová M., Červenková K., Urbánek K., Veselý J.: Cell cycle control and chemical inhibitors of cyclin-dependent kinases. Acta Med. Martiniana, 2, 15-21, 2002.

9. Björnholm, M., L. Al-Khalili, A. Dicker, E. Näslund, S. Rössner, J. R. Zierath, and P. Arner. Insulin signal transduction and glucose transport in human adipocytes: Effects of obesity and low calorie diet. Diabetologia 45: 1128-1135, 2002

10. Brrrrs, O., Sharikabad, M.N. and Jensen, J.: Sarcolemmal beta-adrenoceptors determined in rat ventricular heart biopsies with (-)-[³H]CGP-12177. Pharmacol. Toxicol. 91,166-173, 2002.

11. Burén, J., Liu, H-X., Jensen, J. and Eriksson, J.W.: Dexamethasone impairs glucose transport and insulin signalling by depletion of IRS-1, PI3-kinase and Protein kinase B in primary cultured rat adipocytes. Eur. J. Endocrinol. 146, 419-429, 2002.

12. Camarero, G., Villar, A., Contreras, J., Fernández, C., Pichel, J., Avendańo, C. and Varela-Nieto, I.: Cochlear abnormalities in insulin-like growth factor-1 mouse mutants. Hear. Res. 3925, 1-10, 2002.

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14. Ceddia, R. B., H. A. Koistinen, J. R. Zierath and G. Sweeney. Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J. 16: 1163-1176, 2002

15. Cheta, D. (ed.) “NEW INSIGHTS INTO EXPERIMENTAL DIABETES”, Romanian Academy Publishing House, Bucharest, 2002.

16. Conejo, R. and Lorenzo, M.: Differential insulin signaling involved in skeletal muscle development. Anal. Real Acad. Nac. Farm. 68, 231-250, 2002.

17. Conejo, R., De Alvaro, C., Benito, M., Cuadrado, A. and Lorenzo, M.: Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-kappaB through an AKT/P70S6K/p38-MAPK pathway. Oncogene 21, 3739-3753, 2002.

18. Conroy, S.J., Green, I., Dixon, G., Byrne, P.M., Nolan, J., AbdelWahab, Y.H.A., McClenaghan, N., Flatt, P.R. and Newsholme, P.: Evidence for a sustained increase in clonal beta-cell basal intracellular Ca2+ levels after incubation in the presence of newly diagnosed type-1 diabetic patient sera. Possible role in serum-induced inhibition of insulin secretion. J. Endocrinol. 173, 53-62, 2002

19. Constantinescu, E., D. Alexandru, V. Alexandru. An ex vivo model to study the monocyte-endothelial cell interaction in the prelesional stage of experimentally-induced atherogenesis in hamster. J Submicr. Cytol. Pathol 34: 115-124, 2002

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22. Csermely, P. and Yahara, I. (2002) Heat shock proteins. In: Molecular Pathomechanisms and New Trends in Drug Research (Eds.: Gy. Kéri and I. Tóth), Taylor and Francis, London and New York, pp. 67-75.

23. Csermely, P., Nardai, G. and Sőti, Cs. (2002) Redox regulation in protein folding and chaperone function, In: Redox regulation (eds.: A. Pompella, G. Banhegyi and M. Wellman-Rousseau), NATO Science Series, I/347, 273-280.

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25. Dietze, D., Koenen, M., Röhrig, K., Horikoshi, H., Hauner, H. and Eckel, J.: Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes. Diabetes 51, 2369-2376, 2002.

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29. Flachs, P., Novotny, J. Baumruk, F., Bardová, K., Bourova, L., Miksik, I., Sponarova, J., Svoboda, P. and Kopecky, J.: Impaired noradrenaline-induced lipolysis in white fat of aP2-Ucp1 transgenic mice is associated with changes in G-protein levels. Biochem. J. 364, 369-376, 2002.

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34. Gasperikova D., Demáková E., Ukropec J., Klimes I. and Seböková E.: Insulin resistance in hereditary hypertriglyceridemic rat is associated with an impairment of D-6 desaturase expression in liver. Ann. NY Acad. Sci. 967, 446-453, 2002.

35. Gaster M, Petersen I, Hojlund K, Poulsen P, Beck-Nielsen H. The diabetic phenotype is conserved in myotubes established from diabetic subjects: evidence for primary defects in glucose transport and glycogen synthase activity. Diabetes 51, 921-927, 2002

36. Gedde-Dahl, A., Kulseth, M.A., Ranheim, T., Drevon, C.A. and Rustan, A.C.: Reduced secretion of triacylglycerol in CaCo-2 cells transfected with intestinal fatty acid-binding protein. Lipids 37, 61-68, 2002.

37. Georgescu, A., D. Popov, L. Vladimirescu. Effect of blocking the intercellular communication junctions on the contractile response of the resistance arteries, Current Problems in Cellular and Molecular Biology, VI: 85-90, 2002, ed: A. Ardelean et. al.

38. Giorgino, F.: Defects in intermediate insulin signaling in skeletal muscle: phophatidylinositol (PI) 3-kinase and glucose transport. In: Frontiers in Animal Diabetes Research: Muscle Metabolism. (Eds.: E. Shafrir, J. R. Zierath, H. Wallberg-Henriksson.) OPA Overseas Publishers Association, Amsterdam, 2002.

39. Graham, J., Hagopian, W.A., Kockum, I., Li, L.S., Sanjeevi, C.B., Lowe, R.M., Schaefer, J.B., Sarhami, M., Day, H.L., Landin-Olsson, M., Palmer. J.P., Janer-Villanueva, M., Hood, L., Sundkvist, G., Lernmark, Ĺ., Breslow, N., Dahlquist, G. for the Swedish Childhood Diabetes Study Group and Blohmé, G. for the Diabetes Incidence in Sweden Study Group (Arnqvist, H., Bolinder, J., Björk, E., Eriksson, J.W., Sundkvist, G.) Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 51, 1346-1355, 2002.

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41. Hamer, I., Foti, M., Emkey, R., Philippe, J., Maeder, C., Kahn, C.R., and Carpentier, J.-L.: An arginine to cysteine²⁵² mutation in insulin receptors from a patient with severe insulin resistance inhibits receptor internalization but preserves signaling events. Diabetologia 45, 657-667, 2002.

42. Hart LM, Nijpels G, Dekker JM, Maassen JA, Heine RJ, van Haeften TW 2002 Variations in insulin secretion in carriers of gene variants in IRS-1 and -2 Diabetes 51:884-887

43. Hart, L.M., van Haeften, T.W., Dekker, J.M., Bot, M., Heine, R.J. and Maassen, J.A. Variations in insulin secretion in carriers of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K(+) channel in the beta-cell. Diabetes 51, 3135-3138, 2002

44. Heltianu, C., G. Costache, K.Azibi, L.Poenaru, M.Simionescu. Endothelial nitric oxide synthase gene polymorphism in Fabri disease. Clin. Genetics 61: 423-429, 2002

45. Hoffmann, T.K., Bojar, H., Eckel, J., van Lierop, A., Balz, V., Friebe-Hoffmann, U., Hauser, U. and Bier, H.: Effects of tamoxifen on human squamous cell carcinoma lines of the head and neck. Anticancer Drugs 13: 521-531, 2002.

46. Horman, S., Browne, G.J., Krause, U., Patel, J.V., Vertommen, D., Bertrand, L., Lavoinne, A., Hue, L., Proud, C.G. and Rider, M.H.: Activation of AMP-activated protein kinase leads to the phosphorylation of elongation factor 2 and an inhibition of protein synthesis. Curr. Biol. 12, 1-20, 2002.

47. Hue, L., Beauloye, C., Marsin, A.-S., Bertrand, L., Horman, S. and Rider, M.H.: Insulin and ischemia stimulate glycolysis by acting on the same targets through different and opposing signaling pathways. J. Mol. Cell Cardiol., 34, 1091-1097, 2002.

48. Jansson, P-A., Eliasson, B., Lindmark, S. and Eriksson, J.W.: Endocrine abnormalities in healthy first-degree relatives of type 2 diabetes patients - potential role of steroid hormones and leptin in the development of insulin resistance. Eur. J. Clin. Invest. 32, 172-178, 2002.

49. Jensen, J. Brennesvik, E., Bergersen, L.H., Oseland, H., Jebens, E., and Brřrs, O.: Cell surface beta-adrenoceptors in rat soleus muscle strips and biopsies determined with (-)-[³H]CGP-12177. Pflügers Arch. 444, 213-219, 2002.

50. Kahleova, R., Palyzova, D., Zvara, K., Zvarova, J., Hrach, K., Novakova, I., Hyanek, J., Bendlova, B. and Kozich, V.: Essential hypertension in adolescents: Association with insulin resistance and with metabolism of homocysteine and vitamins. Am. J. Hypertension 15, 857-864, 2002.

51. Kamp GA, Ouwens DM, Hoogerbrugge CM, Zwinderman AH, Maassen JA, Wit JM 2002 Skin fibroblasts of children with idiopathic short stature show an increased mitogenic response to IGF-I and secrete more IGFBP-3. Clin Endocrinol (Oxf) 56:439-447

52. Karamessinis, P.M., Tzinia, A.K., Kitsiou, P.V., Stetler-Stevenson, W.G., Michael, A.F., Fan, W., Zhou, B., Margaritis, L.H. and Tsilibary, E.C.: Proximal tubular epithelial cell integrins respond to high glucose by altered cell-matrix interactions and differentially regulate matrixin expression. Lab. Invest. 82, 1081-1093, 2002.

53. Klimes I. and Šeböková E.: Preface. Lipids and insulin resistance. Ann. NY Acad. Sci 967, xiii-xv, 2002.

54. Koaka, J., Kainantová, L., Seböková, E., Kvetnanský, R., Klimes, I., Chrousos, G. and Pacák, K.: Endocrine regulation of subcutaneous fat metabolism during cold exposure in humans. Ann. NY Acad. Sci. 967, 500-505, 2002.

55. Koistinen, H. A., and J. R. Zierath. Regulation of glucose transport in human skeletal muscle. Annals of Medicine, 34: 1-9, 2002

56. Kopecky, J., Flachs, P., Bardová, K., Brauner P., Pražák, T., and Šponarová, J.: Modulation of lipid metabolism by energy metabolism in adipocytes: Implications for insulin sensitivity. Ann. N.Y. Acad. Sci. 967, 1-15, 2002.

57. Krause, U., Bertrand, L. and Hue, L.: Control of p70 ribosomal protein S6 kinase and acetylCoA carboxylase activity by AMP-activated protein kinase and protein phosphatases in isolated rat hepatocytes. Eur. J. Biochem., 269, 3751-3759, 2002.

58. Krause, U., Bertrand, L., Maisin, L., Rosa, M. and Hue, L.: Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes. Eur. J. Biochem., 269, 3742-3750, 2002.

59. Lauritzen H.P., Reynet C., Schjerling P., Ralston E., Thomas S., Galbo H. and Ploug T. Gene gun bombardment mediated expression and translocation of EGFP-tagged GLUT4 in skeletal muscle fibers in vivo. Pflügers Archiv -Eur. J. Physiol. 444, 710-721, 2002

60. Ledwig, D., Müller, H., Bischoff, H. and Eckel, J.: Early acarbose treatment ameliorates resistance of insulin-regulated GLUT4 trafficking in obese Zucker rats. Eur. J. Pharm. 445, 141-148, 2002.

61. Lorenzo, M., Teruel, T, Hernandez, R., Kayali, A.G. and Webster N.J.G.: PLCgamma participates in insulin stimulation of glucose uptake through activation of PKCzeta in brown adipocytes. Exp. Cell Res. 278, 146-157, 2002.

62. Luiken, D.P.Y. Koonen, J. Willems, A. Zorzano, C. Becker, Y. Fischer, N.N. Tandon, G. J. van der Vusse, A. Bonen, J.C. Glatz. Insulin stimulates long-chain fatty acid utilization by rat cardiac myocytes through cellular redistribution of FAT/CD36. Diabetes 51, 3113-3119, 2002.

63. Maassen JA 2002 Mitochondrial diabetes: Pathophysiology, clinical presentation, and genetic analysis. Am J Med Genet 115:66-70

64. Maassen JA, Janssen GM, Lemkes HH 2002 Mitochondrial diabetes mellitus. J Endocrinol Invest 25:477-484

65. Maassen, JA: Mitochondrial diabetes, diabetes and the thiamine-responsive megaloblastic anaemia syndrome and MODY-2. Diseases with common pathophysiology? Panminerva Med 44:395-400, 2002

66. Madsen, L., Guerre-Millo, M., Flindt, E.N., Berge, K., Tronstad, K.J., Bergene E., Sebokova, E., Rustan, A.C., Jensen, J., Mandrup, S., Kristiansen, K., Klimes, I., Staels, B. and Berge, R.K.: Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance. J. Lipid Res. 43, 742-750, 2002.

67. Manduteanu, I., M.Voinea, M.Capraru, E.Dragomir, M.Simionescu. A novel atribute of enoxaparin: Inhibition of monocyte adhesion to endothelial cells by a mechanism involving cell adhesion molecules. J. Exp. Clin. Pharmacology, 65:32-38, 2002

68. Maran, A., Crepaldi, C., Tiengo, A., Grassi, G., Vitali, E., Pagano, G., Bistoni, S., Calabrese, G. Santeusanio, F., Leonetti, F., Ribaudo, M., Di Mario, U., Annuzzi, G., Genovese, S., Riccardi, G., Previti, M., Cucinotta, D., Giorgino, F., Bellomo, A., Giorgino, R., Poscia, A., Varalli, M.: Continuous subcutaneous glucose monitoring in diabetic patients: a multi-center analysis. Diabetes Care 25, 347-352, 2002.

69. Marsin, A.-S., Bouzin, C., Bertrand, L. and Hue, L.: The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J. Biol. Chem., 277, 30778-30783, 2002.

70. Meisse, D., Van de Casteele, M., Beauloye, C., Hainault, I., Kefas, B.A., Rider, M.H., Foufelle, F. and Hue, L.: Sustained activation of AMP-activated protein kinase induces c-Jun-N-terminal kinase activation and apoptosis in liver cells. FEBS Lett, 526, 38-42, 2002.

71. Müller, H., Deckers, K. and Eckel, J.: The fatty acid translocase (FAT)/CD36 and the glucose transporter GLUT4 are localized in different cellular compartments in rat cardiac muscle. Biochem. Biophys. Res. Commun. 293, 665-669, 2002.

72. Mulligan, C., Rochford, J., Denyer, G., Stephens, R., Yeo, G., Freeman, T., Siddle, K. and O'Rahilly, S. Microarray analysis of insulin and IGF-1 receptor signalling reveals the selective up-regulation of the mitogen HB-EGF by IGF-1. J. Biol. Chem. 277, 42480-42487, 2002

73. Nardai G., Korcsmaros, T. and Csermely, P. (2002) Reduction of the endoplasmic reticulum accompanies the oxidative damage of diabetes mellitus, In: Redox regulation (eds.: A. Pompella, G. Banhegyi and M. Wellman-Rousseau), NATO Science Series, I/347, 281-289.

74. Nardai, G. and Csermely, P. (2002) Protein folding in diabetes. In: New Insights in Experimental Diabetes, ed.: D. Cheta, Romanian Academy Publishing House, Bucharest., pp. 120-131.

75. Nardai, G., Csermely, P. and Sőti, Cs. (2002) Chaperone function and chaperone overload in the aged, Exp. Gerontol, 37, 1255-1260

76. O’Rourke, L. and Shepherd, P.R.: Biphasic regulation of extracellular-signal-regulated protein kinase by leptin in macrophages: role in regulating STAT3 Ser(727) phosphorylation and DNA binding. Biochem. J. 364, 875-879, 2002

77. O'Rourke L., Gronning L. M., Yeaman S. J. and Shepherd P. R. (2002) Glucose dependent regulation of cholesterol ester metabolism in macrophages by insulin and leptin. J. Biol. Chem. 277, 42557-42562, 2002

78. Ouwens DM, de Ruiter ND, van der Zon GC, Carter AP, Schouten J, van der BC, Kooistra K, Bos JL, Maassen JA, van Dam H 2002 Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38. EMBO J 21:3782-3793

79. Paneda, C., Gorospe, I., Herrera, B., Nakamura, T., Fabregat, I. and Varela-Nieto, I.: Liver cell proliferation requires MAT 2A mRNA up-regulation. Hepatology 35, 1381-1391, 2002.

80. Pannacciulli, N., De Pergola, G., Giorgino, F., Giorgino, R.: A family history of Type 2 diabetes is associated with increased plasma levels of C-reactive protein in non-smoking healthy adult women. Diabetic Med. 19, 689-692, 2002.

81. Poberaj I, M. Rupnik, M. Kreft, S. K. Sikdar and R. Zorec Modeling excess retrieval in rat melanotroph membrane capacitance records. Biophys. J. 82, 226-232, 2002.

82. Popov, D., G. Costache, A. Georgescu, M. Enache. Beneficial effects of L-arginine supplementation in experimental hyperlipemia – hyperglycemia in the hamster, Cell and Tissue Research, 308: 109-120, 2002.

83. Popov, D., G. Costache, A. Georgescu. Altered vascular reactivity of the resistance arteries: lessons from the hyperlipemic-hyperglycemic hamster model, in “New Insights into Experimental Diabetes”, Ed: D.M.Cheta, Romanian Academy Publishing House, 2002, pp.173-209.

84. Pundziute-Lyckĺ, A., Dahlquist, G., Nyström, L., Arnqvist, H.J., Björk, E., Blohmé, G., Bolinder, J., Eriksson, J.W., Sundkvist, G., Östman, J. and the Swedish Childhood Diabetes Study Group: The incidence of Type 1 diabetes has not increased but shifted to a younger age at diagnosis in the 0-34 years group in Sweden 1983 to 1998, Diabetologia, 45, 783-791, 2002.

85. Ravussin, E., Klimes, I., Sebökova, E. and Howard, B.: Lipids and insulin resistance: What we have learned at the Fourth International Smolenice Symposium.Ann. NY Acad. Sci. 967, 576-580, 2002.

86. Reig N, Chillaron J, Bartoccioni P, Fernandez E, Bendahan A, Zorzano A, Kanner B, Palacin M, Bertran J. The light subunit of system b(o,+) is fully functional in the absence of the heavy subunit. EMBO J. 21, 4906-4914, 2002.

87. Rossmeisl, M., Barbatelli, G., Flachs, P., Brauner, P., Zingaretti, M.C., Marelli, M., Janovská, P., Horáková, M., Syrový, I., Cinti, S. and Kopecký, J.: Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo. Eur. J. Biochem. 269,19-28, 2002.

88. Rypka M., Veselý J., Chmela Z., Riegrová D., Červenková K., Havlíček L., Lemr K., Hanuš J., Černý B., Lukeš J., Michalíková K.: In vitro biotransformation of 2,6,9-trisubstituted purine-derived cyclin-dependent kinase inhibitor bohemie by mouse liver microsomes. Xenobiotica, 32, 1017-1031, 2002.

89. Seboková E., Kürthy M., Mogyorosi T., Nagy K., Demáková E., Ukropec J., Koranyi L. and Klimes I.: Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance. Ann. NY Acad. Sci. 967, 424-430, 2002

90. Selisko, T., Vcelak, J., Bendlova, B., Graessler, J., Schwarz, P., Schulze, J.: Mutations and intronic variants in the HNF-1beta gene in a group of German and Czech Caucasians with type 2 diabetes mellitus and progressive diabetic nephropathy. Exp. Clin. Endocrinol. Diabetes 110,145-147, 2002.

91. Sima, A., C. Stancu. Modified lipoproteins accumulate in human coronary atheroma. J. Cell. Mol. Med., 6: 110-111, 2002.

92. Sima, A., Experimental atheroma formation in the coronary artery of the hyperlipemic hamster J. Cell. Mol. Med., 6: 276-277, 2002.

93. Simionescu, M. Vascular endothelium: more complex than previously thought, In: “Entering an unseen world: the rise of modern cell biology”, Eds: C.L. Moberg, P. Siekevitz, Rockefeller University Press, 2002.

94. Simionescu, M., A. Gafencu, F. Antohe: Transcytosis of Plasma Macromolecules in Endothelial Cells: A Cell Biology Survey. Microscopy Research and Technique 57: 269-288, 2002.

95. Simionescu, M., C. Stancu, G. Costache, A. Sima. Endothelial cell response to hyperlipemia: activation – dysfunction - injury; the protective role of simvastatin. Vasc. Pharmacol. 38: 275-282, 2002

96. Simionescu, M., D. Popov, A. Sima. Cellular and molecular alterations in diabetes – induced cardiovascular complications studied in an original experimental model, in “ “New Insights into Experimental Diabetes”, Ed: D.M.Cheta, Romanian Academy Publishing House, 2002, pp. 210- 222.

97. Simonikova, P., Wein, S., Gasperíková, D., Ukropec, J., Mertík, M., Klimes I. and Seböková, E.: Comparison of the extrapancreatic action of ł-linolenic acid and fish oil in the high fat diet-induced insulin resistance. Endocrine Regulation 36, 135-140, 2002.

98. Song, X.M., M. Fiedler, D. Galuska, J. W. Ryder, M. Fernström, A. V. Chibalin, H. Wallberg-Henriksson, and J. R. Zierath. 5-aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 45: 56-65, 2002

99. Sőti Cs. and Csermely, P. (2002) Chaperones come of age. Cell Stress and Chaperones 7, 186-190

100. Sőti, Cs. and Csermely, P. (2002) Chaperones and aging: their role in neurodegeneration and other civilizational diseases. Neurochem. International., 41, 383-389.

101. Sőti, Cs., Rácz, A. and Csermely, P. (2002) A nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90: N-terminal nucleotide binding unmasks a C-terminal binding pocket. J. Biol. Chem. 277, 7066-7075

102. Sramkova, D., Kunesova, M., Hainer, V., Hill, M., Vcelak, J. and Bendlova, B.: Is a Pro12Ala Polymorphism of the PPARă2 Gene Related to Obesity and Type 2 Diabetes Mellitus in the Czech Population? Ann. N.Y. Acad. Sci. 967, 265-273, 2002.

103. Strologo LD, Pras E, Pontesilli C, Beccia E, Ricci-Barbini V, De Sanctis L, Ponzone A, Gallucci M, Bisceglia L, Zelante L, Jimenez-Vidal M, Font M, Zorzano A, Rousaud F, Nunes V, Gasparini P, Palacin M, Rizzoni G. Comparison between SLC3A1 and SLC7A9 Cystinuria Patients and Carriers: A Need for a New Classification. Am. Soc. Nephrol. 13, 2547-2553, 2002.

104. Surinya, K.H., Molina, L., Soos, M.A., Brandt, J., Kristensen, C. and Siddle, K.: Role of insulin receptor dimerization domains in ligand binding, co-operativity and modulation by anti-receptor antibodies. J. Biol. Chem. 277, 16718-16725, 2002

105. Svensson, M. and Eriksson, J.W.: No direct link between albumin excretion rate and insulin resistance - a study in type 1 diabetes patients with mild nephropathy. Horm. Metab. Res. 34, 254-259, 2002.

106. Svensson, M., Yu, Z-W. and Eriksson, J.W.: A small reduction in glomerular filtration is accompanied by insulin resistance in type 1 diabetes patients with diabetic nephropathy. Eur. J. Clin. Invest. 32, 100-109, 2002.

107. Tomás, E., A. Zorzano, N.B. Ruderman. Exercise and Insulin Signaling: A Historical Perspective Appl. Physiol. 93, 765-772, 2002.

108. Treins, C., GiorgettiPeraldi, S., Murdaca, J., Semenza, G.L. and VanObberghen, E.: Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J. Biol. Chem. 277, 27975-27981, 2002

109. Tsuchida, H., M. Björnholm, M. Fernström, P.X. Johansson, H. Wallberg-Henriksson, J. R Zierath, S. Lake, and A. Krook. Gene expression of the p85? regulatory subunit of phosphatidylinositol 3-kinase in skeletal muscle from type 2 diabetic subjects. Pfügers Archiv. Eur. J. Physiol. 445: 25-31, 2002

110. Tzinia, A., Kitsiou, P., Talamagas, A., Georgopoulos, A. and Tsilibary, E.C.: Effects of collagen IV on neuroblastoma cell matrix-related functions. Exp. Cell. Res. 274, 69-177, 2002.

111. Ukropec, J., Klimes, I., Gasperíková, D., Demáková, E., Drevon, C.A., Reseland, J.E. and Seböková E.: An increase in peroxisomal fatty acid oxidation is not sufficient to prevent tissue lipid accumulation in hHTg rats. Ann. NY Acad. Sci. 967, 71-79, 2002.

112. Urbanavicius V.: Treatment effect on type 2 diebetes mellitus glucose, glycated hemoglobin HbA1c, insulin sensitivity and fat mass. Lietuvos endokrinologija (Endocrinology of Lithuania) 10, 8-11, 2002

113. Vankova, M., Vrbikova, J., Hill, M., Cinek, O. and Bendlova, B.: Association of insulin gene VNTR polymorphism with polycystic ovary syndrome. Ann. N.Y. Acad. Sci 967, 558-565, 2002.

114. Varela-Nieto, I., de la Rosa, E., Valenciano, A. and Leon, Y. Cell death in the nervous system: lessons from insulin and insulin-like growth factors. Mol. Neurobiol. Invited review. 2002.

115. Vesely J., Hajdúch M.: Brain cyclin-dependent kinase 5 (Cdk5). II. Interaction of Cdk5 with cytoskeletal structures. (Czech) Biol. listy, 67, 147-156, 2002.

116. Vesely J., Mačáková J., Dostálová K., Riegrová D.: Nadměrná fosforylace proteinů v rozvoji Alzheimerovy nemoci se zřetelem na nové perspektivy její farmakoterapie. (Czech) Psychiatrie, 6, 17-21, 2002.

117. Vesely J., Mačáková J., Dostálová K., Riegrová D.: Significance of reelin for the development of the central nervous system. I. Membrane receptors for reelein. (Czech). Cs. fysiol., 51, 16-20, 2002.

118. Vesely J.: Mechanisms of arterial hypertension after transplantation and renal surgery. (Czech) Cas. lek. ces., 141, 535-539, 2002.

119. Vesely J.: Methods used to define salt sensitivity of blood pressure. (Czech) Vnitr. lek., 48, 241-247, 2002.

120. Vesely J.: Obesity, hyperinsulinemia, and hypertension. In: J. Veselý: Pressure diuresis and arterial hypertension (Tlaková diuréza a arteriální hypertenze). Epava, Olomouc, Czech Republic 2002. Pp. 87-197.

121. Vrbikova, J., Bendlova, B., Hill, M., Vankova, M., Vondra, K. and Starka, L.: Insulin sensitivity and beta-cell function in women with polycystic ovary syndrome. Diabetes Care 25, 1217-1222, 2002.

122. Zhyvoloup, A., I Nemazanyy, O. Babych, G. Panasyuk, N. Pobigailo, M. Vudmaska, V. Naidenov, O.Kukharenko, S. Palchevskii, L. Savinska, G. Ovcharenko, F. Verdier, T. Valovka, T.Fenton, H. Rebholz, M.Wang, P. Shepherd, G. Matsuka, V. Filonenko, and I. T. Gout Molecular cloning of CoA synthase: the missing link in CoA biosynthesis Molecular cloning of CoA synthase: a missing link in CoA biosynthesis. J. Biol. Chem. 277, 22107-22110, 2002

123. Zierath, J. R. and H. Wallberg-Henriksson. From receptor to effector: Insulin signal transduction in skeletal muscle from type II diabetic patients. Ann. N.Y. Acad. Sci. 967:120-134, 2002

124. Zierath, J. R. Exercise training-induced changes in insulin signaling in skeletal muscle. J. Appl. Physiol. 93:765-777, 2002

125. Zorzano, A., E. Tomŕs, M. Camps, A. Gumŕ, M. Palacín. Muscle GLUT4 traffic and insulin resistant-states. In "Muscle metabolism" 2002. Volume 4: “Fontiers in Animal Diabetes Research”. Editor, J.R. Zierath & H. Wallberg-Henriksson. Taylor & Francis. London and New York. pp 297-312.

2003

1. Beauloye, C., Marsin, A.-S., Bertrand, L., Vanoverschelde, J.L., Rider, M.H. and Hue, L.: The stimulation of heart glycolysis by increased workload does not require AMP-activated protein kinase but a wortmannin-sensitive mechanism. FEBS Lett., in press

2. Ben-Romano, R., A. Rudich, D. Torok, S. Vanounou, K. Riesenberg, F. Schlaeffer, A. Klip and N. Bashan. Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors. AIDS, in press

3. Björnholm, M. A.R. He, A. Attersand, S. Lake, S.C.H. Liu, G.E. Lienhard, S. Taylor, P. Arner, and J.R. Zierath. Absence of functional insulin receptor substrate-3 (IRS-3) gene in humans. Diabetologia in press

4. Burén, J., Liu, H-X., Lauritz, J. and Eriksson, J.W.: High glucose and insulin in combination cause IRS-1 and IRS-2 depletion and PKB desensitization in primary cultured rat adipocytes. Potential implications for insulin resistance in type 2 diabetes. Eur. J. Endocrinol., in press.

5. Burén, J., Lindmark, S., Renström, F. and Eriksson, J.W.: In vitro reversal of hyperglycemia normalizes insulin action in fat cells from type 2 diabetes patients. Is cellular insulin resistance caused by glucotoxicity in vivo. Metabolism, in press.

6. Borg, H., Arnqvist, H., Björk, E., Bolinder, J., Eriksson, J.W., Nyström, L., Jeppsson, J-O. and Sundkvist, G.: Evaluation of the new ADA and WHO criteria for classification of diabetes mellitus in young adult people (15-34 yr) in the Diabetes Incidence Study in Sweden (DISS). Diabetologia, in press.

7. Cervenková K., Belejová M., Chmela Z., Rypka M., Riegrová D., Michnová L., Michalíková K., Šúrová I., Brejcha A., hanuš J., Černý B., Fuksová K., Havlíček L., Veselý J.: In vitro glycosidation potential towards olomoucine-type cyclin-dependent kinase inhibitors in rodent and primate microsomes. Physiol Res., in press

8. Chowdhury, H.H., Kreft, M. and Zorec, R. Distinct effect of actin cytoskeleton disassembly on exo- and endocytic events in a membrane patch of rat melanotrophs J. Physiol. (Lond), in press

9. Chowdhury, H.H., Kreft, M. and Zorec, R. Rapid insulin-induced exocytosis in white rat adipocytes. Eur. J. Physiol., in press

10. Cinek, O., Drevinek, P., Sumnik, Z., Bendlova, B., Sedláková, P., Kolouskova, S., Snajderova, M., Vavrinec, J.: NeuroD polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in the Czech children. Diabetes Research and Clinical Practice – in press

11. Eriksson, J.W., Burén, J., Svensson, M., Olivecrona, T. and Olivecrona, G.: Postprandial regulation of blood lipids and adipose tissue lipoprotein lipase activity in type 2 diabetes patients and healthy control subjects. Atherosclerosis, in press.

12. Forst, T., Eriksson, J.W., Strotmann, H-J., Brunelle, R., Bai, S., Hottgenroth, A. and Gudat, U.: The influence of preprandial administration of Insulin Lispro in comparison to oral treatment with glibenclamide on blood glucose control and beta cell function in early type 2 diabetes. Exp. Clin. Endocrinol. Diabetes, in press.

13. Frago, L.M., Cańon, S., de la Rosa, E., León, Y. and Varela-Nieto, I. Programmed cell death in the developing inner ear is balanced by nerve growth factor and insulin-like growth factor-1. J. Cell Sci. in press

14. George, S., Johansen, A., Soos, M.A., Mortensen, H., Gammeltoft, S., Saudek, V., Siddle, K., Hansen, L. and O'Rahilly, S. Deletion of V335 from the L2 domain of the insulin receptor results in a conformationally abnormal receptor which is unable to bind insulin and causes Donohue's syndrome in a human subject. Endocrinology, in press

15. Glodeanu, A., A. Sima. A linear kinetic approach and near equilibrium thermodynamics of serum parameters from atherosclerosis - induced animals treated with drugs. Rom. J. Physics, in press

16. Grano, M., Mori, G., Minielli, V., Colucci, S., Vaira, S., Giannelli, G., Martemucci, S., Giorgino, F., Zallone, A.Z.: HGF and M-CSF modulate the adhesion of MDA-231 breast cancer cells by increasing osteopontin secretion. J Biol. Regulators Homeostat. Agents, in press

17. Henricsson, M., Nyström, L., Blohmé, G., Östman, J., Cullberg, K., Svensson, M., Schölin, A., Arnqvist, H., Björk, E., Bolinder, J., Eriksson, J.W. and Sundkvist, G.: The prevalence of retinopathy 10 years after diagnosis of diabetes in young adults in Sweden. A nationwide population-based investigation from The Diabetes Incidence Study in Sweden (DISS). Diabetes Care, in press.

18. Kitsiou, P., Tzinia, A., Stettler-Stevenson, W., Michael, A.F., Fan, W., Zhou, B. and Tsilibary, E.C.: Glucose-induced phenotypic modulation in glomerular epithelial cells. Am. J. Physiol., in press

19. Kreft, M., V. Kuster, S. Grilc, M. Rupnik, I. Milisav, and R. Zorec: Synaptotagmin-I increases the probability of vesicle fusion at low [Ca2+] in pituitary cells. Am. J. Physiol. in press

20. Krian, M. M. Stenovec, M. Kreft, T. Pangrlil, S. Grilc, P. G. Haydon and R. Zorec Calcium-dependent exocytosis of atrial natriuretic peptide from astrocytes. J.Neurosci. in press

21. Krimanova, O., Šeböková, E. and Klimeš I.: The effect of losartan on the Na+/Ca2+ exchanger in the left ventricle of the insulin resistant and hypertensive hHTg rat. Gen. Physiol. Biophys., in press

22. Lake, S., A. Krook, and J. R. Zierath. Analysis of insulin signaling pathways through genomic approaches: Mapping mechanisms for insulin resistance in Type II diabetes mellitus. Exp Clin Endocrinol Diabetes, in press

23. Lindmark, S., Wiklund, U., Bjerle, P. and Eriksson, J.W. Does the autonomic nervous system play a role in the development of insulin resistance? A study on heart rate variability in first-degree relatives of type 2 diabetes patients compared to control subjects. Diabet. Med., in press

24. Morin, V. Visentin, D. Calisse, L. Marti, A. Zorzano, X. Testar, P. Valet, Y. Fischer, C. Carpéné Intracellular signals involved in the effects of insulin-like growth factors and neuregulins on myofiber formation. J. Pharmacol. Exp. Therap., in press

25. Noyman, I., Marikovsky, M., Sasson, S., Strak, A.H., Bernath, K., Seger, R. and Madar, Z.: Hyperglycemia reduces nitric oxide synthase and glycogen synthase activity in endothelial cells. Nitric oxide, in press

26. Rakatzi, I., Dransfeld, O., Seipke, G. and Eckel, J.: The novel insulin analog Lys^B3,Glu^B29 insulin preferentially activates the IRS-2 signaling pathway in muscle cells, Diabetes, in press

27. Schreyer, S., Ledwig, D., Rakatzi, I., Klöting, I. and Eckel, J.: Insulin receptor substrate-4 is expressed in muscle tissue without acting as a substrate for the insulin receptor, Endocrinology, in press

28. Shackleton, S., Hamer, I., Foti, M., Zumwald, N., Maeder, C. and Carpentier, J.-L.: Role of two diisoleucine-like motifs in insulin receptor anchoring to microvilli. J. Biol. Chem., in press

29. Simionescu, M. Vascular endothelium: more complex than previously thought, In: “Entering an unseen world: the rise of modern cell biology”, Eds: C.L. Moberg, P. Siekevitz, Rockefeller University Press, in press

30. Sőti, Cs., Sreedhar, A.S. and Csermely, P. (2003) Apoptosis, necrosis and cellular senescence: chaperone occupancy as a potential switch. Aging Cell, in press

31. Teruel, T., Hernandez, R., Benito, M. and Lorenzo, M.: Rosiglitazone and retinoid acid induce uncoupling protein-1 in a p38 mitogen activated protein kinase dependent manner in fetal primary brown adipocytes. J. Biol. Chem. in press

32. Vesely J., Mačáková J., Dostálová K., Riegrová D., Červenková K.: Significance of reelin for the development of the central nervous system. II. Cyclin-dependent kinase 5 in the reelin signaling cascade. (Czech) Cs. fysiol., 51, in press

33. Yu, M., N.K. Stepto, L.D.G. Fryer, A.V. Chibalin, D. Carling, A. Krook, J. A. Hawley and J. R. Zierath. Metabolic and mitogenic signal transduction in skeletal muscle after intense aerobic exercise in highly trained humans. J. Physiol. Lond. in press

34. Zorzano, A. Abella, L. Marti, C. Carpéné, M. Palacín, X. Testar. Semicarbazide-sensitive amine oxidase activity exerts insulin-like effects on glucose metabolism and insulin-signaling pathways in adipose cells. Biochim. Biophys. Acta, in press

35. Zorzano, P. Kaliman, A. Gumà, M. Palacín. Tyramine stimulates glucose uptake in insulin-sensitive tissues in vitro and in vivo via its oxidation by amine oxidases. Cellular Signalling, in press

6.2. CONFERENCES AND WORKSHOPS

2000

· WG 5 « Cardiovascular » : Bucarest – Romania – 28 November 2000, organisers : P. Shepherd, M. Simionescu (approx. 50 participants).

· WG 2 « Glucose transport » : Barcelona – Spain – 21 December 2000 (participants : J. Eckel, A. Zorzano, A. Guma).

2001

· WG 2 « Glucose and other transport processes and ageing » Kerkrade – The Netherlands – 22-23 May 2001 (organisers: J. Eckel, H. Joost, approx. 100 participants).

2002

· WG 1 « Genetics of diabetes, obesity and ageing » Prague – Czech Republic – 16 February 2002 (organisers: B. Bendlova, T. Maassen, approx. 50 participants).

· WG 5 « Cardiovascular dysfunction » Bucharest – Romania – 10-13 October 2002 (organiser: M. Simionescu, approx. 150 participants).

· WG 2+4 « Clinical and experimental insulin resistance/glucose transporter trafficking » Bari – Italy – 15-16 November 2002 (organiser: F. Giorgino, approx. 80 participants).

6.3. WEB-SITE

http://www.webio.hu/workshop/cost/

The web-site of the Action provides a general information about COST, and about the Action. It gives all the details of the preceeding COST Action, COST B5. The site lists the participating laboratories and gives a survey of their research interests as well as techniques and scientific reagents used to promote cooperation.

6.4. SCIENTIFIC AND TECHNICAL COOPERATION

6.4.1. Within COST B17

Organization of Working Groups, short term scientific missions and informal exchanges ensured a wide cooperation with COST Action B17. Most importantly, the cooperation was extending much beyond the laboratories participating in the Management Committee, and various Working Groups, but also involved several other key labs from the participating countries. The common practice of the Action to invite many young scientists to the WG meetings and workshops of the Action became an effective tool to disseminate the results of the Action as well as to promote scientific cooperation much beyond the originators of the Action.

6.4.2. With other EU organizations

There is a continuing interest and efforts to link the Action with other COST/6^th Framework Actions of the EU. There are two 6^th Framework programmes originated by members of the Action connected to the work of WG 1 (genetics of diabetes) as well as WG 2 (glucose transport). COST Action 918 is working on "Body weight and energy expenditure: functional foods". Delegates of COST B17 participated on the MC meeting of COST 918 and plans for a close cooperation were outlined to utilize the different approaches taken by the two Actions for the examination and extension of obesity-related genes.

6.4.3. Outside the EU

Key members of the respective scientific areas from the USA and other countries are constantly invited members of COST B17 WG meetings and workshops. There is an increasing cooperation with the laboratories represented by these scientists. Several 6^th Framework Aging actions are cooperating with members of COST B17.

6.5. TRANSFER OF RESULTS

6.5.1. Projects

As an important development of the Action two projects has been adopted by COST B17:

· “Chaperone-inducer drug-candidates to improve the chronic consequences of diabetes” (Hungary)

· “Molecular characterization of AP50, a new component of insulin receptor signaling” (Switzerland)

These projects received local funding after the recommendation of the Action and represent efforts to find novel therapeutic approaches to cure and/or ease the consequences of diabetes.

6.5.2. Drug development companies and SME-s

WG 4 “Drugs and new preventive therapeutic approaches to improve glucose metabolism and clinical insulin resistance” will make special efforts to coordinate the R&D research activities of the Action and to ensure an efficient transfer of results to the medical practice. European SME-s working in the field were already invited to the 2002 meeting of WG 4 in Bari.

A few examples of concrete applied research programs

· J. Zierath’s lab is developing a target validation program within our group that can be of benefit to both academic, biotec and pharma. This is more of a technology platform, rather than a scientific development, but it is driving the academic value of our projects higher.

· Peter Csermely is a P.I. of a 2 million USD Hungarian grant aiming to develop drug candidates against diabetes complications in collaboration with several SME-s in Hungary and elsewhere.

· Mr. Arie Gruzman, a Ph.D. student in Shlomo Sasson’s laboratory participates in a research project in my laboratory that is aimed at developing novel antihyperglycemic drugs. His efforts and research in synthesizing new molecules and testing them in vitro and in vivo have led to a registration of a patent on these novel molecules.

· Robert Zorec was asked to chair a Scientific Steering Committe for a Slovenian pharmaceutical company

Besides these, members of B17 are in contact with the following firms:

· Arexio

· Bioiberica

· Biorex

· Biovitrum

· Ely Lilly

· GSK

· Laboratorios Vita

· Merck

· N-Gene

· Novartis

· Novo-Nordisk

· Pfizer

· Provital

· Richter Gedeon

· Rodaris

· Thiamedica

· Xcellsyz

· Youngs

6.6. INORMATION OF THE PUBLIC AND INFLUENCE ON POLITICS

Members of COST B17 are actively seeking public appearances in newspapers, TV-s and radio-s to explain their major findings to the public. Some of the appearances:

· research focus on Ubc9 as a GLUT4 regulatory protein has been mentioned in local Bari and Italian national newspapers and TVs.

· the COST B17 meeting in Bari on Trafficking of Glucose Transporters and Insulin Signaling Proteinsh has been covered by several regional TVs and one Italian national newspaper

· the Hungarian project adopted by COST B17 was widely quoted in Hungarian media (TV, radio etc.) and in New Scientist (Ready, steady, evolve; New Scientist 175, 28-30, 2002)

· medical newspapers published a reference and an interview with Isabel Varela-Nieto, when they published the paper on inner ear defects in Igf-1 nul mouse

· J.A. Maassen contributes to the general public journal Voeding Nu (Diet Now) in the Netherlands

· V. Urbanavicius has been promoting network activity in 4 newspaper, and one TV appearances in Lithuania

· in Czech Republic info on the Action is available on the web pages of the Ministry of Education, Youth and Sports (http://www.msmt.cz) and of the Research and Developmental Council of the Government of the CR (http//wtd.vlada.cz)

· Dr. Marko Kreft from Robert Zorec’s lab is a producer in a TV programme on a Slovenian national TV Station on Cell Biology and Biotehcnology, emphasizing the field of adipocyte research

The MC, the chairman and the WG-s are taking all available opportunities to influence the development of the European Research Area by showing the importance of COST cooperation as well as the field of diabetes and aging research. Some of the actions:

· To optimise the interaction between the COSTB17 program and societies representing patients with diabetes, dr. Maassen together with the newly elected president of International Diabetes Federation-Europe, Dr. W. Wientjens, have taken the initiative to focus research goals better to the needs of the people suffering from diabetes. This contact via the IDF-Europe also opens avenues to those members of the European Parlement with special interest for diabetes and its impact on health care within the European Community.

· Peter Csermely participates in discussions on the establishment of a European Research Council.

7. Economic dimension

7.1. TOTAL MANPOWER PER YEAR

2000: 90 person-year

2001: 389 person-year

2002: 415 person-year

2003: … person-year (N.A.)

2004: … person-year (N.A.)

Total: 894 person-year

7.2. FUNDS RECEIVED FROM THE COMMISSION

(in euros)

Year	Secretariat	Publications	Worshops - Seminars	MC meetings	Short term scientific mis.	Other	Total
2000				40960