Scandinavian Society for the Study of Diabetes 52nd Annual Meeting May Nyborg, Denmark

Transcription

1 Scandinavian Society for the Study of Diabetes 52nd Annual Meeting May Nyborg, Denmark Programme and abstract book SSSD2017_abstract_book.indd 1 09/05/17 17:14

2 Main sponsors Co-sponsors 2 SSSD2017_abstract_book.indd 2 09/05/17 17:14

3 Welcome Welcome to the 52 nd Annual Meeting of the Scandinavian Society for the Study of Diabetes (SSSD) in Nyborg, Denmark. The objective of the Annual Meeting of SSSD is to give diabetes researchers inn the Nordic and neighboring countries an opportunity to meet and exchange and discuss clinical and experimental diabetes research. The main focus of the meeting is the opportunity for scientists to present their own clinical or basic science. It has always been the aim of the annual meetings of o SSSD to enable young researchers to meet and orally present research projects in a friendly yet knowledgeable environment. For the symposia, we have invited lecturers to cover both clinical themes and cutting edge basic science. This year, the annual meeting is held at Hotel Storebælt in Nyborg, Denmark. We have received registrations from 38 young researchers, who will present their workk during the oral presentation sessions. Moreover, a number of Board members, senior researchers and invited speakers will attend the annual meeting. In total, 67 researchers from f Denmark and the other Scandinavian countries will participate. Moreover, the meeting will include Barndiabetesfondens Nordic Prize, P the Young Investigator Awards, the Knud Lundbeck Award Lecture and the Novo Nordisk Foundationn Lecture. We express our warm welcome and hopee that you will enjoy every aspect of the meeting. On behalf of the Board of SSSD The organizers of the SSSD Meeting 2017 Niels Grarup, MD, PhD University of Copenhagen Kurt Højlund, MD, PhD Odense University Hospital 3 SSSD2017_abstract_book.indd 3 09/05/17 17:14

4 Index Programme... 5 General Information Abstracts Oral presentations Oral presentations Oral presentations Oral presentations Oral presentations SSSD2017_abstract_book.indd 4 09/05/17 17:14

5 Programme 52 nd Annual Meeting of the Scandinavian Society for the Study of Diabetes May 2017, Sinatur Hotel Storebælt, Nyborg, Denmark. Friday 19 May :00 12:00 Registration 12:00 13:00 Lunch 13:00 13:10 Opening 13:10 14:30 Symposium 1: Novel insight into metformin and SGLT2 inhibitors mechanism of action Professor Niels Jessen, Department of Biomedicine, Aarhus University, Denmark and Professor Jørgen Rungby, Department of Endocrinology, Bispebjerg University Hospital, Denmark 14:30 15:00 Coffee and Exhibition 15:00 16:40 Oral presentations of scientific abstracts 1 Chairs: Niels Jessen & Bjørn Olav Åsvold 1 1: Peter Breining: Brown adipose tissue is a putative metformin target 1 2: Thomas Bryrup: The effect of metformin on a healthy human gut microbiota 1 3: Johan Palmfeldt: Effect of metformin on protein expression in human muscle biopsies 1 4: Peter Wurtz: Circulating metabolite biomarkers for type 2 diabetes risk on young and middle aged adults: evidence from nmr metabolomics in 18,388 Finns 1 5: Svend Korfitzen: Effects of a naturally occuring dual FFAR agonist on incretins, insulin secretion, lipids and inflammation in obesity and type 2 diabetes 1 6: Ole Lindgård Dollerup: Metabolic effects of nicotinamide riboside in humans a vitamin B3. A randomized placebo controlled trial 1 7: Camilla Sommervoll: Loss of decorin reduces glucose tolerance in high fat, high carbohydrate fed mice 5 SSSD2017_abstract_book.indd 5 09/05/17 17:14

6 1 8: Jens Jacob Lauterlein: Metabolic and molecular consequences of enhanced WNT signaling due to a LRP5 gain of function mutation in humans 1 9: Rikke Kruse Sørensen: Effects of insulin and training on FGF21, its receptors and target genes in obesity and type 2 diabetes 1 10: Hanne Gulseth: Life years lost and risk of cardiovascular complications in type 2 diabetes patients a nationwide cohort study from Norway 16:40 17:00 Coffee and Exhibition 17:00 18:00 Oral presentations of scientific abstracts 2 Chairs: Valdemar Grill & Kurt Højlund 2 1: Jakob V. Schmidt: Individually tailored treatment in type 2 diabetes: a prospective controlled multicenter open label intervention study 2 2: Åsne Bakke: Type 2 diabetes in general practice in Norway, status and time trends 2 3: Jarno L.T. Kettunen: Cclinical characteristics of patients carrying pathogenic HNF1A mutations 2 4: Johnny Ludvigsson: No association between socioeconomic background and development of type 1 diabetes in Sweden The ABIS study. 2 5: Jens Steen Nielsen: Pathophysiology based phenotyping in type 2 diabetes: a clinical classification tool 2 6: Carl J. Drott: CART decreases both islet and pancreatic blood flow, but has no effect on glucose tolerance in anesthetized rats 18:00 18:40 Symposium 2: The German Diabetes Study The German Diabetes Study: Subphenotypes of Diabetes Dr. Julia Szendrödi, German Diabetes Center, University of Düsseldorf, Germany 19:30 Dinner 6 SSSD2017_abstract_book.indd 6 09/05/17 17:14

7 Saturday 20 May :30 10:00 Oral presentations of scientific abstracts 3 Chairs: TBA & Kolbein Gudmundsson 3 1: Søs Skovsø: Peripheral effects of beta cell specific insulin resistance 3 2: Barareh Rasouli: Coffee consumption, genetic susceptibility and the risk of LADA latent autoimmune diabetes in adults 3 3: Elin P. Sørgjerd: Evidence of transcient autoimmun activity preceding diabetes diagnosis in patients classified with type 2 diabetes. the HUNT study. 3 4: Valdemar Grill: A randomized clinical trial testing for optimal beta cell preserving treatment in latent autoimmune diabetes in adults (LADA) 3 5: Sofia Carlsson: Serious life events and the risk of latent autoimmune diabetes in adults and type 2 diabetes 3 6: Johnny Ludvigsson: EDCR (etanercept diamyd combination regimen), a pilot trial to preserve residual beta cell function in children with type 1 diabetes 3 7: Kailash Singh: Increased interleukin 35 levels in long standing type 1 diabetes patients with remaining C peptide 3 8: Paula Fernandez Guerra: Metabolic changes in peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients 3 9: Mariela Mejia: Kinetics of the innate immune cells response in multiple low dose streptozotocin induced type 1 diabetes 10:00 10:30 Coffee and Exhibition 10:30 11:50 Symposium 3: The gut in diabetes The gut: a key to the pathogenesis of type 2 diabetes? Professor Jens Juul Holst, the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Denmark Any evidence that dysbiosis of the intestinal microbiota is diabetogenic? Professor Oluf Borbye Pedersen, the Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Denmark 11:50 12:30 Young Investigator Awards Chair: Bjørn Olav Åsvold 7 SSSD2017_abstract_book.indd 7 09/05/17 17:14

8 An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets Dr. Erna Domsgen, Karolinska Instituttet, Karolinska University Hospital, Sweden and Human gut microbiota host metabolic interactions in insulin resistance Dr. Helle Krogh Pedersen and Dr. Valborg Gudmundsdottir, Technical University of Denmark, Denmark 12:30 13:30 Lunch 13:30 15:00 Oral presentations of scientific abstracts 4 Chairs: Dorte Møller Jensen & Johnny Ludvigsson 4 1: Marianne Vestgaard: In early pregnancy home blood pressure is more than five mmhg lower than routinely measured office blood pressure in women with preexisting diabetes and in healthy women 4 2: Kathrine Kjær: Interval walking intervention for pregnant women diagnosed with gestational diabetes mellitus a randomized controlled pilot study 4 3: Sidse K. Nørgaard: Diastolic blood pressure is a potential modifiable risk factor for preeclampsia in women with type 1 and type 2 diabetes 4 4: Freja B. Kampmann: Is low birth weight associated with food intake related to the development of type 2 diabetes in 14 years old adolescents? 4 5: Nora Grotenfelt: The effect of early vs late gestational diabetes (GDM) on neonatal outcomes among obese women 4 6: Aron Willems: Amino acid transport in adipocytes modulates visceral fat accumulation and diabetes risk 4 7: Morten Frost Nielsen: No association between the bone turnover markers CTX and P1NP and insulin sensitivity or beta cell function in healthy men 4 8: Eva M. Gram Kampmann: A reduced carbohydrate diet high in monounsaturated fats in type 2 diabetes: a six month study of changes in metabolism, liver and cardiovascular function (reduction) 4 9: Cecilie Halkier: The effect of testosterone on insulin mediated signaling to glucose transport and glycogen synthesis in skeletal muscle cells 15:00 15:30 Coffee and Exhibition 8 SSSD2017_abstract_book.indd 8 09/05/17 17:14

9 15:30 16:50 Symposium 4: Health consequences of intrauterine exposure to maternal diabetes Associate Professor Dorte Møller Jensen, Department of Endocrinology, Odense University Hospital, Denmark and Professor Peter Damm, Department of Obstetrics, Copenhagen University Hospital, Denmark Coffee and Exhibition 17:10 17:50 Oral presentations of scientific abstract 5 Chairs: Peter Damm & Niels Grarup 5 1: Anders Edhager: Myocardial proteome during pre diabetes and type 2 diabetes mellitus in zucker diabetic fatty rats 5 2: Zhengkang Luo: Kinetics of the innate immune cells response in kidney tissue of autoimmune induced hyperglycemia in mice 5 3: Nina W. Hansen: Reprogramming adipose tissue stem cells 5 4: Suresh Raju: A method to predict the effects of transcription factor binding sequence variants Barndiabetesfondens Nordic Prize Chair: Johnny Ludvigsson Improved prediction of type 1 diabetes Professor Riitta Veijola, University of Oulu and Oulu University Hospital, Finland 18:40 19:10 General Assembly 19:30 Dinner 9 SSSD2017_abstract_book.indd 9 09/05/17 17:14

10 Sunday 21 May :30 9:50 Symposium 5: Lessons from ANDIS & the Diabetes Impact Study 2013 ANDIS towards precision medicine in diabetes Professor Leif Groop, Department of Clinical Sciences Diabetes and Endocrinology, Lund University, Sweden The Diabetes Impact Study 2013: Trends in the epidemiology of diabetes in Denmark Professor Anders Green, Odense Patient data Explorative Network, University of Southern Denmark, Denmark (on behalf of the Diabetes Impact Study 2013 Research Team) Stretch break :10 Knud Lundbæk Award Chair: Jan Erik Henriksen Personalised medicine in diabetic nephropathy Professor Peter Rossing, Steno Diabetes Center Copenhagen, Denmark 11:10 11:40 Coffee and Exhibition 11:40 12:30 Novo Nordisk Foundation Lecture Chair: Laszlo Hegedüs Functional Genomics in Diabetes Research Professor Susanne Mandrup, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark 12:30 13:00 Closing of the meeting Sandwich 10 SSSD2017_abstract_book.indd 10 09/05/17 17:14

11 General Information Contact information Until (and including) 19 May 2017: Tine Hylle Tel May 2017: Kurt Højlund Tel Niels Grarup Tel Conference venue Hotel Storebælt Østerøvej Nyborg Denmark Tel.: Mail: Website: Hotel rooms If you have requested a hotel room, this has been booked by the hotel on the dates you have registered when registering for the conference. A confirmation has been sent to you from the hotel. The key for your room will be available when you check in at the conference desk/reception at the hotel. Check in: Rooms are available from 14h00 Check out: 11h00 Payment for the room must be made by credit card or cash directly to the hotel upon departure. If you wish to pay by other means of payment, please contact the hotel directly at or before arrival. Payment for hotel rooms for invited speakers (not including speakers invited for presenting abstracts) will be taken care of by the organizers. 11 SSSD2017_abstract_book.indd 11 09/05/17 17:14

12 Conference room All lectures including oral presentations will take place in room Sandholm on the ground floor. Facilities A power point projector, a PC, microphone and pointer will be available in the conference room. The hotel has free wifi. Information about access can be found in every room of the hotel. Presentations You are welcome to forward your presentations prior to the course (at the latest on 19 May 2017) and we will make sure it is ready for your lecture. Otherwise, please hand in your presentation on a USB stick to the organizers during the break prior to your session. Format of lectures (invited speakers and award winners) We kindly ask you to keep the time schedule set out in the programme. Please leave 5 minutes for questions from the audience. The audience will be both junior and senior researchers. Format of oral abstract presentations Your oral presentation should be 10 minutes including 3 minutes for questions from the audience. Language All lectures should be held in English. 12 SSSD2017_abstract_book.indd 12 09/05/17 17:14

13 Meals breaks, lunches and dinners All meals are included in your registration. Breakfast will be served from 7h30 to 10h30 in the hotel restaurant (ground floor) Coffee, tea, ice water ad libitum from the buffet all day (ground floor) Lunch will be served in the restaurant (one soft drink or beer and ice water are included) (ground floor) Dinner will be served either in the restaurant (ground floor) or in a conference room (first floor) (included are: 3 glasses of wine (or beer/soft drinks) on 19 May 2017 and wine (beer/soft drinks) ad libitum on 20 May 2017). Credit cards and currency exchange The currency is Danish kroner (DKK). ATMs are to be found in many places in Nyborg. Ask at the hotel reception for further information. Transportation Transportation to and from Hotel Storebælt: Direct trains to Nyborg train station from Copenhagen Central Station leave approximately every half hour. Check: From Nyborg train station, you may take a taxi or walk (20 minutes walk). See: route planner google maps Taxis Nyborg Taxa: (+45) The reception will help you reserve taxis, if needed. Price: approx. 50 DKK from the train station to Hotel Storebælt. 13 SSSD2017_abstract_book.indd 13 09/05/17 17:14

14 Travel grants for participants presenting abstracts Travel grants for the meeting are available. The grants (up to 5,000 Norwegian Crowns) are intended to cover a major part of the travelling, accommodation and registration expenses of young colleagues who present an abstract at the meeting. The age limit is 40 years of age (inclusive). The grants can cover a maximum of 75% of the total expenses. More information: Travel reimbursement for invited speakers For reimbursement of your travel and other expenses related to the course, please fill in the form which is to be found at our website and follow the instructions given: invited speakers travel reimbursement Please forward your expense claim at the latest one month after the meeting, i.e. before 19 June Sponsors Main sponsors are: AstraZeneca Novo Nordisk Co sponsors are: Amgen Boehringer Ingelheim Eli Lilly MSD Sanofi Sponsor exhibition is located in room Flintholm on the ground floor next to the coffee buffet. 14 SSSD2017_abstract_book.indd 14 09/05/17 17:14

15 Abstracts Oral presentations (OP) 1 OP 1 1 BROWN ADIPOSE TISSUE IS A PUTATIVE METFORMIN TARGET Peter Breining 1,2, Jonas B Jensen 2, Elias I. O. Sundelin 2, Lars Gormsen 3, Steen Jakobsen 3, Morten Busk 4, Lars Rolighed 5, Peter Bross 6, Paula F. Guerra 6, Lasse K. Markussen 7, Jacob Hansen 7, Steen B. Pedersen 1, Bjørn Richelsen 1, Niels Jessen 2 1 Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark, 2 Department of Clinical Medicine Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus, Denmark, 3 Department of Nuclear Medicine and PET Center, Aarhus University Hospital, Aarhus, Denmark, 4 Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark, 5 Department of Otorhinolaryngology and Department of Surgery P, Aarhus University Hospital, Denmark, 6 Department of Clinical Medicine Research Unit for Molecular Medicine, Aarhus University, Denmark, 7 Department of Biology, University of Copenhagen, Denmark Background: Metformin is the most widely prescribed oral antidiabetic drug worldwide. In spite of well documented beneficial effects on diabetes, target organs that mediate its effects remain to be established. In recent years, active brown adipose tissue (BAT) has been found in the deep neck of adult humans. Under the hypothesis that brown adipose tissue (BAT) is a metformin target tissue we investigated metformin uptake in vivo and studied the in vitro effects of metformin on cultured human brown adipocytes. Material and methods: Tissue specific uptake of metformin was assessed by PET/CT imaging after injection of [(11)C] metformin in mice. Human brown adipose tissue was obtained from elective neck surgery and OCT expression levels in human and murine BAT were determined by qpcr. Oxygen consumption in immortalized brown adipocytes of human origin (TERT hba) during metformin exposure was assessed by Seahorse XF technology. Results: Injection of C11 metformin in mice revealed avid uptake in the interscapular BAT depot. Metformin exposure in BAT was comparable to hepatic exposure. Inhibition of OCT1, OCT2 and MATE1 function did not affect BAT exposure to metformin suggesting OCT3 mediated uptake. Determination of OCT3 mrna expression in BAT supported this assumption. OCT3 levels were >5000 fold higher than other metformin transporter genes in mouse BAT and times higher in the adipose tissue from human deep neck. In vitro incubation of TERT hba cells with metformin inhibited cellular oxygen consumption. This effect was dose dependent with oxygen consumption seemingly settling at a lower rate. Conclusions: Metformin is transported into BAT in mice. This transport is likely mediated through OCT3. OCT3 is present in human brown adipocytes making an effect in human BAT likely. Metformin inhibits mitochondrial respiration in cultured brown adipocytes. Collectively, this suggests BAT as a putative metformin target in humans. 15 SSSD2017_abstract_book.indd 15 09/05/17 17:14

16 OP 1 2 THE EFFECT OF METFORMIN ON A HEALTHY HUMAN GUT MICROBIOTA Thomas Bryrup 1, Cæcilie Thomsen 1, Tue H. Hansen 1, Timo Kern 1, Kristine H. Allin 1, Henrik Vestergaard 1, Torben Hansen 1, Oluf Pedersen 1, Trine Nielsen 1 The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark Background: It has become evident in recent years that patients with type 2 diabetes have an altered bacterial composition of their gut microbiota compared to non diabetic individuals. However, these alterations may be confounded by medication, notably metformin. We investigated changes in gut microbiota composition in response to metformin treatment, independent of the diabetic state. Methods: Twenty six healthy, lean men were enrolled in the study. They underwent a 6 week run in period, a 6 week intervention period with metformin, and a 6 week washout period. Participants were examined five times in the fasting state, with bloodsampling and recording of gastrointestinal symptoms. Examinations took place before and after the run in period, halfway through and immediately after the intervention and after the wash out period. Fecal samples were collected at nine, evenly distributed time points, and bacterial DNA was extracted and subjected to 16S rrna sequencing in order to evaluate gut microbiota composition. Results: Twenty three men completed the intervention. Mean (SD) age was 25.7(2.7) years with a mean BMI of 22.9(2.11) kg/m 2. Plasma B12 and HbA1c concentrations dropped significantly following intervention (p=0.01 and p=0.03 respectively). The relative abundance of 20 operational taxonomic units (OTUs) changed significantly (10% false discovery rate) during the 6 week intervention. Several OTUs of the order Clostridiales were depleted, including one assigned to Intestinibacter bartlettii and two Clostridium spp. In contrast, Alistipes finegoldi of order Bacteroidales and an OTU assigned to genus Escherichia/Shigella were enriched. All OTUs recovered to pre intervention levels within 3 6 weeks of treatment cessation. Changes in gut microbiota composition were accompanied by an increase in self reported intestinal discomfort. Conclusion: Our study demonstrates that metformin treatment changes the gut microbiota composition, independent of the diabetic state. OTU changes are in line with previously described cross sectional findings. Further studies are needed to examine whether metformin exert its glucose lowering effect, and adverse gastrointestinal effects, partly by modifying the gut microbiota. 16 SSSD2017_abstract_book.indd 16 09/05/17 17:14

17 OP 1 3 EFFECT OF METFORMIN ON PROTEIN EXPRESSION IN HUMAN MUSCLE BIOPSIES Johan Palmfeldt 1,2*, Morten Hviid Pedersen 1,2, Niels Jessen 3,, Søren Nielsen 4, Lars Christian Gormsen 2,5, Rima Obeid 6 1 Research unit for Molecular Medicine 2 Department of Clinical Medicine, Aarhus University, Denmark, 3 Department of Clinical Pharmacology, Aarhus University Hospital and Department of Biomedicine, Aarhus University 4 Department of Endocrinology and Internal Medicine, Aarhus University Hospital 5 Department of Nuclear Medicine and PET Centre, Aarhus University Hospital 6 AIAS, Aarhus Institute for Advanced Studies, Aarhus University *E mail: johan.palmfeldt@clin.au.dk Introduction: Metformin is the most widely used drug to treat type 2 diabetes (T2D). Recently, metformin has also shown promise in the areas of anti cancer and anti aging. The effects of metformin have been studied extensively in, for example, rodent liver; however its molecular mechanisms in human tissues are not well explored. Skeletal muscle is a very important tissue for maintaining glucose homeostasis and a potential important target for metformin. Aim: The present study intended at characterizing potential effects of metformin on human muscle. The aim was to locate the proteomic changes in human muscle cells caused by metformin treatment compared with placebo. Methods: 20 patients with T2D were recruited and randomized to receive treatment with either metformin or placebo for 3 months. Muscle biopsies were taken before and after treatment. The samples were homogenized, trypsin digested, and labelled with tandem mass tags (TMT) to allow for relative protein quantification by mass spectrometry. Samples were analysed by nano LC/MS MS on a Q Exactive Plus mass spectrometer (Thermo). Results: We successfully identified and quantified approximately 1,400 proteins. Among these proteins there was a broad selection of structural proteins, receptors and metabolic enzymes of both cytosolic and mitochondrial origin. The top 30 differentially regulated proteins between metformin and placebo group represent various cellular functions. Statistical significant alterations were found in metabolic enzymes but also in the following protein functions: ryanodine receptor mediated calcium release (2 independent proteins), proteasomal activity (3 independent proteins) and protein ADPribosylation (2 independent proteins). These protein functions deserve further studies to pin point their metformin mediated effects in the muscle cells. Conclusions: Treatment with metformin had effects on human muscle tissue proteome; they indicate novel cellular and molecular effects of metformin which go beyond the glucose lowering effect of the drug. 17 SSSD2017_abstract_book.indd 17 09/05/17 17:14

18 OP 1 4 CIRCULATING METABOLITE BIOMARKERS FOR TYPE 2 DIABETES RISK ON YOUNG AND MIDDLE AGED ADULTS: EVIDENCE FROM NMR METABOLOMICS IN 18,388 FINNS. Ari Ahola Olli 1, Johannes Kettunen 2, Mika Ala Korpela 2, Veikko Salomaa 3, Markus Perola 3, Marjo Riitta Järvelin 2, Olli Raitakari 1, Peter Würtz 4 1. University of Turku, Finland 2. University of Oulu, Finland 3. National Institute for Health and Welfare, Helsinki, Finland 4. University of Helsinki, Finland Background: Metabolomic biomarkers of type 2 diabetes risk may reveal etiological pathways and help to identify individuals at risk for disease onset and complications. Many metabolic biomarkers for the diabetes have already been proposed based on metabolomics; however, replication is often lacking and the applicability to risk assessment in young adults remain unclear. Methods: 228 circulating metabolites and lipid measures were quantified using highthroughput NMR metabolomics in 4 population based cohorts (n=18,388; mean age 42; FINRISK 1997, DILGOM 2007, Northern Finland Birth Cohort 1966 and Young Finns Study). Biomarker associations for diabetes incidence (930 cases during 7 15 years follow up) were assessed using logistic regression and meta analysed across the four cohorts. Results: 201 out of the 228 metabolic measures assayed were associated with the risk for diabetes onset in models adjusted age, sex, and baseline glucose (P<0.0008). Odds ratios were >1.5 per 1 SD metabolite concentration for numerous metabolites, including emerging and novel biomarkers such as amino acids, fatty acid measures, triglycerides in VLDL particles, measures of lipoprotein composition, and markers of chronic inflammation. The overall metabolic signature of future diabetes risk was similar to the pattern of metabolic associations with insulin resistance index observed crosssectionally. Most biomarker associations were attenuated after additional adjustment for BMI and fasting insulin, on average ~50% in magnitude, but many biomarkers remained significant. The results were highly consistent across the 4 cohorts, including 15 year risk for diabetes assessed from blood samples drawn from 31 year olds. Biomarker risk scores capturing the overall predictive value of the detailed metabolic profiling are being developed. Conclusion: Numerous metabolites and lipid measures from different metabolic pathways are predictors of future diabetes onset, broadly consistently across different age groups, follow up time, and ascertainment of diabetes status. The diverse metabolic perturbations preceding overt diabetes may potentially be used for early screening of diabetes risk. 18 SSSD2017_abstract_book.indd 18 09/05/17 17:14

19 OP 1 5 EFFECTS OF A NATURALLY OCCURING DUAL FFAR AGONIST ON INCRETINS, INSULIN SECRETION, LIPIDS AND INFLAMMATION IN OBESITY AND TYPE 2 DIABETES Svend S. Korfitzen 1,Karina Vejrum Sørensen 1, Trond Ulven 2, Kurt Højlund 1 1 Department of Endocrinology, Odense University Hospital, Denmark; 2 Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Denmark Background: Recent research has spurred interest in a family of cell surface receptors responsive to free fatty acids (FFAR). In particular, the FFAR4(GPR 120) and FFAR 1(GPR 40) are found in various tissues such as intestinal, pancreatic, immune and brain cells and have been shown to be implicated in energy homeostasis, nutrient sensing, hormone secretion and inflammatory response. Thus these receptors are interesting potential targets for novel treatments of obesity, diabetes and insulin resistance. Pinolenic acid has proved to be a potent agonist of both FFAR4 and FFAR1 and since siberian pine nut oil contains a high amount of pinolenic acid it has been chosen as the intervention product for this unblinded cross over trial. Methods: 10 overweight, non smoking, healthy years old participants will be recruited to participate in a total of three standard fasted 4 hour OGTT with either no oil (screening/baseline), 3g or 6g of hydrolyzed pine nut oil delivered in delayed release capsules given at timepoint 30min. Blood samples will be drawn every 30 minutes throughout the trial. There will be a minimum of 1 week washout between each of the three OGTT trials. Expected results: Glucose tolerance calculated as the area under the curve (AUC) of glucose and OGTT based indices of beta cell function as well as AUC of insulin/c peptide are expected to be improved compared to the baseline OGTT. Measurements of GLP 1, GIP, CCK, PYY are expected to show increased secretion of gut hormones while glucagon, ghrelin, lipids, and inflammatory markers are expected to be equal to or lower than baseline values. Perspectives: Our study is among the first human trials to determine whether hydrolyzed pine nut oil is a viable strategy for managing blood glucose levels in obesity and T2DM. It may prove as a cheaper treatment and with less adverse effects than current pharmaceutical options. 19 SSSD2017_abstract_book.indd 19 09/05/17 17:14

20 OP 1 6 METABOLIC EFFECTS OF NICOTINAMIDE RIBOSIDE IN HUMANS A VITAMIN B3 A RANDOMIZED PLACEBO CONTROLLED TRIAL Ole Lindgård Dollerup1,2,3, Marianne Agerholm1, Mads Svart2, Karolina Sulek1, Hans Stødkilde Jørgensen4, Niels Møller2,3, Jonas Thue Treebak1, Niels Jessen2,5 1Section of Integrative Physiology, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, 3Department of Endocrinology, Aarhus University Hospital, 4The MR Research Centre, Aarhus University Hospital, 5Department of Pharmacology, Aarhus University Hospital Background & aim: Nicotinamide Riboside (NR), a vitamin B3, has anti obesogenic properties and improves insulin sensitivity in rodent models of prediabetes and diabetes. NR treatment increases intracellular nicotinamide adenine dinucleotide (NAD) levels in insulin target tissues concurrent with enhanced activity of NAD dependent sirtuins. The current hypothesis in the field suggests that increased sirtuin mediated deacetylation of transcription factors and mitochondrial proteins increase fat oxidation and improves insulin sensitivity. We aim to determine if NR treatment can improve insulin sensitivity, substrate metabolism and body composition in obese, non diabetic humans. Material and methods: In a randomized, double blinded, placebo controlled trial, 40 obese, healthy, middle aged men receive NR treatment 1 g twice daily or placebo for 12 weeks. We determine the effects of NR treatment on insulin sensitivity by a hyperinsulinemic euglycemic clamp and substrate metabolism by indirect calorimetry and labeled substrates. Alterations in body composition and fat mass distribution are determined by DEXA and MRI scans and measurements of intra hepatic and intramyocellular lipid contents are obtained by MR spectroscopy. Furthermore analysis of mitochondrial function in permeabilized muscle fibers by mitochondrial respirometry, intestinal bacteria composition by 16S rrna sequencing and incretin hormone response during an oral glucose tolerance test will be performed. Results: Baseline characteristics (n=40) are presented as mean (±SD). BMI 32.9 (±2.7) kg/m2, fat percentage 30.7 % (±4,1), age 58.7 (±7.9) range Insulin clamps at baseline have a mean M value of 2.4 (±1.1) mg/kg/min suggesting that the study group is insulin resistant as a whole. Completion of the trial is expected in April 2017 and preliminary data, including the primary endpoint insulin sensitivity, will be ready for presentation shortly hereafter. Conclusions: This is the first human clinical trial investigating the long term effects of NR supplementation on whole body insulin sensitivity, body composition and glucose homeostasis, and the potential role of NR as an anti diabetic agent. 20 SSSD2017_abstract_book.indd 20 09/05/17 17:14

21 OP 1 7 LOSS OF DECORIN REDUCES GLUCOSE TOLERANCE IN HIGH FAT, HIGH CARBOHYDRATE FED MICE Camilla E N Sommervoll 1,2, Jessica Svärd 1,2,3, Therese H Røst 1,3, Christine Haugen 1,3,, Oddrun A Gudbrandsen 4, Johan Fernø 1,2,3, Simon N Dankel 1,2,3, Anne E Mellgren 4,5, Eyvind Rødahl 4,5, Jørn V Sagen 1,2,3 and Gunnar Mellgren 1,2,3 1 Department of Clinical Science, University of Bergen, N 5020 Bergen, Norway; 2 Hormone Laboratory, Haukeland University Hospital, N 5021 Bergen, Norway; 3 KG Jebsen Center for Diabetes Research, Bergen, N 5020 Bergen, Norway; 4 Department of Clinical Medicine, University of Bergen, Norway; 5 Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway Aims/Hypothesis: The small leucine rich proteoglycan decorin (dcn) is a component of the extracellular matrix, and is highly expressed in human adipose tissue. Here we investigated whether loss of decorin in mice results in metabolic alterations, such as changes in body weight and altered glucose tolerance. Methods: We studied the effect of a high fat, high carbohydrate (HFHC) diet (4,73 kcal/g, 45 kcal% fat, 35 kcal% carbohydrates, 20 kcal% protein) (n=10), vs. chow diet (3,85 kcal/g, 10 kcal% fat, 70 kcal% carbohydrates, 20 kcal% protein) (n=8) in male C57Bl/6J wt mice and male dcn knock out (dcnko) mice. The mice were housed individually. During 11 weeks of diet, the body weight was measured once a week. After eight weeks on diet, an intraperitoneal glucose tolerance test was performed. Food pellet weights were measured once each week and consumed amount of food was calculated. The amount of renal adipose tissue was determined by MRI. After euthanasia, blood samples and tissue samples were isolated for biochemistry and gene expression, respectively. Results: The dcnko mice showed an impaired glucose tolerance on HFHC compared to wt littermates (p=0,0043). This difference was not found in mice fed on a chow diet. This effect on glucose metabolism appeared without significant differences in weight gain or renal fat accumulation between the different genotypes on any of the diets. Conclusions: We found that on a HFHC diet, the dcnko mice showed impaired glucose tolerance compared to wt littermates, independent of changes in body weight. Our result suggest that decorin may have a protective role against development of type 2 diabetes. 21 SSSD2017_abstract_book.indd 21 09/05/17 17:14

22 OP 1 8 METABOLIC AND MOLECULAR CONSEQUENCES OF ENHANCED WNT SIGNALING DUE TO A LRP5 GAIN OF FUNCTION MUTATION IN HUMANS Jens Jacob L. Lauterlein, Pernille Hermann, Kurt Højlund, Morten F. Nielsen Department of Endocrinology, Odense University Hospital, Odense, Denmark Background: Variants in genes encoding canonical Wnt pathway signaling molecules (TCF7L2 and HHEX) are associated with type 2 diabetes, but the molecular mechanisms linking canonical Wnt pathway signaling to glucose homeostasis are unclear. The canonical Wnt pathway is activated by binding of ligands to a Frizzled receptor and a Lrp5/6 co receptor, which promotes e.g. bone formation. Gain of function mutations (GoF) in LRP5 cause the LRP5 high bone mass syndrome, but it also appear to promote insulin sensitivity. The aim of the study is to assess whether metabolic and molecular markers of glucose homeostasis and fat metabolism are altered in patients with enhanced canonical Wnt signaling due to LRP5 GoF. Methods: In 15 patients with LRP5 GoF and 15 healthy weight, age and sex matched controls, we examine insulin secretion, insulin sensitivity and substrate metabolism using 1 h intravenous glucose tolerance tests followed by 3 h euglycemichyperinsulinemic clamps combined with indirect calorimetry. Before and after insulin, skeletal muscle and subcutaneous fat biopsies are obtained for measurement of mrna levels, phosphorylation and activity of key enzymes in insulin signalling, and markers of mitochondrial metabolism. Body composition is determined by DXA scan. Expected results: We expect that LRP5 GoF carriers show improved insulin secretion and insulin sensitivity despite a higher fat mass compared to controls, and that the improved insulin sensitivity in LRP5 GoF carriers can be explained by enhanced insulin action on IRS1 PI3K, Akt2 and GYS1 and/or increased markers of mitochondrial metabolism in muscle and/or adipose tissue. Perspectives: This is the first sufficiently powered case control study of the metabolic and molecular consequences of genetically determined enhanced Wnt signaling in humans. The changes observed in glucose and fat homeostasis as well as insulin signaling and mitochondrial metabolism in LRP5 GoF carriers may provide novel insights into the link between genetic variants involved in Wnt signaling and type 2 diabetes. 22 SSSD2017_abstract_book.indd 22 09/05/17 17:14

23 OP 1 9 EFFECTS OF INSULIN AND TRAINING ON FGF21, ITS RECEPTORS AND TARGET GENES IN OBESITY AND TYPE 2 DIABETES Rikke Kruse 1,2, Sara G. Vienberg 3, Birgitte F. Vind 2, Birgitte Andersen 3, Kurt Højlund 1,2 1 The Section of Molecular Diabetes and Metabolism, Department of Clinical Research and Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark; 2 Department of Endocrinology, Odense University Hospital, Odense, Denmark; 3 Diabetes Research Unit, Novo A/S, Måløv, Denmark Aims/hypothesis: Pharmacological doses of FGF21 improve glucose tolerance, lipid metabolism and energy expenditure in rodents. Induced expression and secretion of FGF21 from muscle may increase browning of white adipose tissue (WAT) in a myokinelike manner. Recent studies have reported that insulin and exercise increases FGF21 in plasma. Obesity and type 2 diabetes (T2D) are potentially FGF21 resistant states, but to what extent FGF21 responses to insulin and exercise training are preserved, and whether FGF21, its receptors and target genes are altered remain to be established. Methods: The effects of insulin during euglycaemic hyperinsulinaemic clamps and 10 weeks endurance training on serum FGF21 were examined in patients with T2D and glucose tolerant overweight/obese and lean individuals. Gene expression of FGF21, its receptors and target genes in skeletal muscle and WAT biopsies was evaluated by quantitative real time PCR. Results: Insulin increased serum and muscle FGF21 independent of overweight/obesity or T2D, and with no additional effect of exercise training. The insulin induced increases in serum FGF21 and muscle FGF21 expression correlated tightly (p<0.0001). In WAT, overweight/obesity with and without T2D led to reduced expression of KLB, but increased FGFR1c expression. However, the expression of most FGF21 target genes was unaltered except for reduced CIDEA expression in T2D. Conclusions/interpretation: Insulin induced expression of muscle FGF21 correlates strongly with the raise in serum FGF21, and this response appears intact in overweight/obesity and T2D. FGF21 resistance may involve reduced KLB expression in WAT. However, increased FGFR1c expression or other mechanisms seem to ensure adequate expression of most FGF21 target genes in WAT. 23 SSSD2017_abstract_book.indd 23 09/05/17 17:14

24 OP 1 10 LIFE YEARS LOST AND RISK OF CARDIOVASCULAR COMPLICATIONS IN TYPE 2 DIABETES PATIENTS A NATIONWIDE COHORT STUDY FROM NORWAY Hanne L. Gulseth 1, Johan Bodegard 2, Marcus Thuresson 3, Kåre I. Birkeland 1,4 1 Oslo University Hospital, Oslo, Norway; 2 AstraZeneca Nordic Baltic, Södertälje, Sweden; 3 Statisticon AB, Uppsala, Sweden; 4 University of Oslo, Oslo, Norway. Background: Prevalence of type 2 diabetes (T2D) is increasing in Norway, but little is known about current life years lost and risk of complications compared to the diabetesfree population. This nationwide study aimed to describe life years lost, risks of myocardial infarction, stroke and all cause mortality in pharmacologically treated T2D patients in Norway. Methods: Patients 18 years of age who dispensed any glucose lowering drug during the period were identified from the Norwegian Prescription Database and linked to data extracted from the Norwegian Patient, and Cause of Death registers. Ageadjusted risks of complications in the T2D population was compared with the total Norwegian population. Results: In 2015, a 40 year old T2D patient lost 4.5 years and an 80 year old T2D patient lost one year compared to the diabetes free population. The drop in life years lost inbetween 40 and 80 years was linear. There was no difference between women or men. From 2008 to 2015, a small but significant decrease in age adjusted risks of myocardial infarction, stroke and all cause mortality was observed. However, in 2015 the T2D patients still showed a significant 1.8, 1.8 and 1.2 fold increased age standardized risk of myocardial infarction, stroke and all cause mortality, respectively, compared to the general population. Conclusions: In Norway, type 2 diabetes patients on glucose lowering drug treatment have shorter longevity compared to the general background population, with no difference between women and men. Risk of complications for type 2 patients, important to longevity, has improved slightly over the last years but is still unacceptably high in year SSSD2017_abstract_book.indd 24 09/05/17 17:14

25 Oral presentations 2 OP 2 1 INDIVIDUALLY TAILORED TREATMENT IN TYPE 2 DIABETES: A PROSPECTIVE CONTROLLED MULTICENTER OPEN LABEL INTERVENTION STUDY Jakob V. Schmidt 1, Jacob V. Stidsen 1, Johnny R. Thomsen 1, Nicolai T. Berendtsen 1, Jens S. Nielsen 1, Jan E. Henriksen 1, Søren G. Friborg 1, Henrik T. Sørensen 2, Reimar W. Thomsen 2, Thomas B. Olesen 1, Michael H. Olsen 1, Henning Beck Nielsen 1 1 Diabetes Research Centre, Department of Endocrinology, Centre for Individualized Medicine in Arterial Diseases, Odense University Hospital, Odense, Denmark; 2 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Background: Current guidelines for treatment of type 2 diabetes (T2D) use a one treatment fits all principle. Our study is designed to examine if targeted treatment based on pathophysiological traits and individual goals may improve diabetes outcomes. Study design: Prospective controlled multicentre intervention study based on the longitudinal cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2). Clinically diagnosed T2D patients in the intervention group will receive individualised treatment initiated by their general practitioner (GP). A matched comparison cohort is derived from patients in the DD2 of comparable T2D patients without intervention. Pathophysiological phenotyping will identify patients with other diabetes forms and WHO defined T2D. The latter will be sub characterized by their beta cell function (BCF) and insulin sensitivity (IS), using the revised homeostatic assessment model, as having either insulinopenic T2D (high IS and low BCF), classical T2D (low IS and low BCF), or hyperinsulinemic T2D (low IS and high BCF). For each T2D sub type a treatment algorithm will target the primary pathophysiological defect. For hypertensive patients antihypertensive treatment is chosen to target the dominating pathophysiological factor identified by impedance cardiography estimating vascular resistance, intravascular volume and cardiac inotropy. Lifestyle intervention, via a personalised e health and faceto face strategy, aims to empower patients to make sustainable increase in daily physical activity and change to a low carbohydrate diet. Status: Currently 83 GP's and four hospital outpatient clinics are included. 757 patients, of expected 1123, have completed the outpatient baseline examination. Follow up examinations are planed after two, four and ten years, for patients with hypertension also after six and twelve months. Perspectives: This study is one of the first to formalize a specific implementation of individualized medicine in treatment of T2D. The clinical perspective is to improve the quality of life and reduce the complications in T2D patients. 25 SSSD2017_abstract_book.indd 25 09/05/17 17:14

26 OP 2 2 TYPE 2 DIABETES IN GENERAL PRACTICE IN NORWAY, STATUS AND TIME TRENDS Åsne Bakke 1, John G. Cooper 1,3, Geir Thue 3,4, Ingvild Dalen 2, Siri Carlsen 1, Svein Skeie 1, Karianne Løvås 4,5, Tone Vonheim Madsen 3, Ellen Oord 3, Anh Thi Tran 6, Anne Karen Jenum 6, Tore Julsrud Berg 7, Tor Claudi 8, Bjørn Gjelsvik 6, Sverre Sandberg Department of Medicine, Stavanger University Hospital, Stavanger, Norway; 2 Department of Biostatistics, Stavanger University Hospital, Norway; 3 Norwegian Quality Improvement of Primary Care Laboratories (Noklus), Haraldsplass Deaconess Hospital, Bergen, Norway; 4 Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway; 5 Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway; 6 Institute of Health and Society, Faculty of Medicine, University of Oslo, Norway; 7 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; 8 Nordlandssykehuset, Bodø, Norway Objective: To give an overview of type 2 diabetes care in general practice in Norway in 2014, assess changes in quality of care between 2005 and 2014 and identify areas of diabetes care that need improvement. Methods: Two cross sectional surveys were performed that identified all patients (n=5463 attending 60 practices in 2005, n=9464 attending 77 different practices in 2014) with type 2 diabetes. Quality of care was based on key recommendations in National guidelines. Data was extracted electronically with manual verification. Results were adjusted for age, sex and regional differences and clustering within GP practices. Results: Between 2005 and 2014 there was a significant reduction in mean HbA1c from 7.14 to 6.99%, blood pressure from 139/79 to 135/78 mmhg and cholesterol from 5.1 to 4.7 mmol/l. Recommended treatment targets were achieved in a significantly higher proportion of patients in 2014 compared with 2005; HbA1c 7.0% in 62.5% vs 54.6%,, blood pressure 135/80 treated/ 140/85 untreated in 50.0% vs. 42.8%, and total cholesterol 4.5 mmol/l in 49.5% vs. 34.1%. We observed an intensification in glucose lowering, antihypertensive and lipid lowering therapy from 2005 to 2014, especially combination therapies. Insulin use declined whereas the proportion of patients receiving metformin or two or more antidiabetic agents increased. Clinical performance measured in terms of screening for important microvascular complications was poor in Screening for all three complications (albuminuria, retinopathy and neuropathy) was only recorded in the case notes of 12.4% of patients and 27.1% lacked any form of documentation of performed microvascular screening. Conclusion: Between 2005 and 2014 there has been significant improvements in risk factor control for patients with type 2 diabetes in general practice in Norway. However screening for microvascular complications remains disturbingly low and we suggest that additional incentives to encourage practitioners to adhere to national guidelines are required. 26 SSSD2017_abstract_book.indd 26 09/05/17 17:14

27 OP 2 3 CLINICAL CHARACTERISTICS OF PATIENTS CARRYING PATHOGENIC HNF1A MUTATIONS Jarno L.T. Kettunen 1,2, Bo Isomaa 2, Leena Sarelin 2, Päivi J. Miettinen 3, Paula Kokko 2, Sanna Maria Virtaniemi 2, Leif C. Groop 4, Tiinamaija Tuomi 1,2,5 1 Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Finland; 2 Folkhälsan Research Centre, Helsinki, Finland; 3 Children s Hospital, University of Helsinki, and Helsinki University Hospital, Finland; 4 Lund University Diabetes Centre, Malmö, Sweden; 5 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. Background: Mutations in the hepatocyte nuclear factor 1A (HNF1A) gene result in HNF1A MODY diabetes characterized by autosomal dominant inheritance and young onset of diabetes with poor insulin response to glucose. While most studies on MODY have focused on comparing the phenotypic features with those in type 1 and type 2 diabetes or unrelated control cohorts, we aim to study more subtle phenotypic effects by comparing mutation carriers and non carriers within large pedigrees. We hypothesize that in line with defective insulin response the mutation carriers would metabolize relatively more fat than glucose resulting in lower BMI, and this might be reflected by their ApoC3 concentrations. Methods: In this intra familial comparative analysis, we have studied 18 year old members of two large pedigrees with HNF1A diabetes, including 64 carriers and 188 non carriers of the p.gly292fs mutation. We will compare their glucose, insulin and free fatty acid (FFA) response during OGTT as well as their apolipoprotein C3 (ApoC3) levels with respect to body mass index, lean body mass, and estimated fat percentage. Expected results: The mutation carriers are expected to have lower BMI and body fat percentage than the non carriers. Yet, the hypothesis suggests that the carriers should express elevated FFA levels and depressed ApoC3 levels. Perspectives: More patients are recruited and genotyped to strengthen the results. Measurements of ApoC3 are scheduled in March. 27 SSSD2017_abstract_book.indd 27 09/05/17 17:14

28 OP 2 4 NO ASSOCIATION BETWEEN SOCIOECONOMIC BACKGROUND AND DEVELOPMENT OF TYPE 1 DIABETES IN SWEDEN THE ABIS STUDY Pär Andersson White 1 Tomas Faresjö 2, Johnny Ludvigsson 1 1 Div of Pediatrics, Dept of Clin Exp Medicine, Linköping University, Sweden; 2 Dept of Health and Medicine, Linköping University, Sweden Background and objectives: Rapid increase of incidence, twin studies, migrant studies, large difference in incidence between populations with similar genetic background but different social situation ( like Finnish and Russian Karelia) prove that change of life style and/or environmental factors play an important role for the development of manifest Type 1 diabetes (T1D). We therefore decided to analyze whether social inequality based on income/change of income, or parents education show any connection to development of T1D. Patients and Methods: ABIS ( All Babies in Southeast Sweden) included (78.6%) out of children born in Southeast Sweden Oct 1 st We compared 113 who had got T1D with the non diabetic children using cox regression analyses and timedependent co variates starting at birth and then step wise from 2 3, 5 6, and 8 years. Education was divided into 3 levels (primary (<10 years), secondary (gymnasium/high school) and university. Income was divided into six groups (percentiles <10,10 25,26 50,51 75,76 90, >90) and the analyses was controlled for heredity for T1D and ethnicity. Results: Neither income, change of income in recent years, nor education of mother or father was significantly related to incidence of T1D. Perspectives: No studies can prove that something does not exist, and our study can be underpowered to be able to show possible associations between income or education when looking into subgroups of patients eg at different ages, in different geographical areas, with consideration taken for different factors like early feeding, serious life events, social vulnerability, degree of physical activity, infectious exposure etc. However, we dare to conclude that in a country like Sweden with relatively low social inequality, social inequality does not seem to be an important factor contributing to the high incidence of T1D. 28 SSSD2017_abstract_book.indd 28 09/05/17 17:14

29 OP 2 5 PATHOPHYSIOLOGY BASED PHENOTYPING IN TYPE 2 DIABETES: A CLINICAL CLASSIFICATION TOOL Thomas B. Olesen1, Jacob V. Stidsen1, Jan E. Henriksen1, Michael H. Olsen2, Reimar W. Thomsen3, Jens S. Nielsen1, Jørgen Rungby4, Sinna P. Ulrichsen3, Klara Berencsi3, Søren G. Friborg1, Ivan Brandslund5, Aneta A. Nielsen5, Jens S. Christiansen 6, Henrik T. Sørensen3, Henning Beck Nielsen1 1Diabetes Research Centre, Department of Endocrinology, Centre for Individualized Medicine in Arterial Diseases, Odense University Hospital, Odense, Denmark; 2Department of Internal Medicine, Holbaek Hospital, and Centre for Individualized Medicine in Arterial; Diseases (CIMA), Odense University Hospital, University of Southern Denmark, Denmark; 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 4Department for Diabetes Research, Gentofte University Hospital, Gentofte, Denmark and Department of Biomedicine, Aarhus University, Aarhus, Denmark; 5Department of Biochemistry, Center Hospital Lillebaelt, Vejle, Denmark; 6Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark; Deceased Background and Aims: Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the prevalence and characteristics of different phenotypes among 5,813 patients with new clinically diagnosed type 2 diabetes in Denmark. Methods: We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid associated diabetes. We then used the homeostatic assessment model (HOMA2) to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), and hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. Results: Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid associated diabetes, and 93.7% had WHO defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (waist 105 cm) and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92 cm) and 17.5 % had CVD (p=0.14 vs. classical diabetes). Hyperinsulinemic patients were severely obese (waist 112 cm) and 25.5% had CVD (p< vs. classical diabetes). Conclusions: Patients diagnosed with type 2 diabetes in the community clinical setting are heterogeneous. In the future, targeted treatment based on pathophysiological characteristics rather than the current one size fits all approach may improve patient prognosis. 29 SSSD2017_abstract_book.indd 29 09/05/17 17:14

30 OP 2 6 CART DECREASES BOTH ISLET AND PANCREATIC BLOOD FLOW, BUT HAS NO EFFECT ON GLUCOSE TOLERANCE IN ANESTHETIZED RATS Carl Johan Drott 1, Daniel Espes 1,2, Leif Jansson 1, Per Ola Carlsson 1,2 1 Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; 2 Department of Medical Sciences, Uppsala University, Uppsala, Sweden Background: Cocaine and amphetamine regulated transcript (CART) is a neurotransmitter and hormone, which is involved in the regulation of e.g. food intake, maintenance of body weight, reward and addiction, stress response, and endocrine function. CART has previously been shown to impair insulin secretion and alter beta cell morphology, both in vivo and in vitro. It was also demonstrated that CART knock out mice became overweight and glucose intolerant. Furthermore, CART affects nervous regulation of the cardiovascular system and helps to modulate vascular tone. The aim of this study was, in view of this, to investigate the effects of CART on the endocrine and exocrine pancreatic circulation and endocrine function. Methods: Blood flow measurements were made with a microsphere technique in anesthetized Sprague Dawley rats after a 1 h infusion with CART (25 µg/h) or saline. Some animals were also given an endothelin A receptor antagonist (BQ123; 100 µg/kg), whereas others were injected with glucose (2 g/kg), a well known stimulator of islet blood flow. Separately anesthetized and CART infused animals were subjected to an intravenous 2 h glucose tolerance test (GTT). Results: We found that total pancreatic, but especially islet, blood flow, was reduced by infusion of CART. Also the normal glucose induced increase in islet blood flow was diminished, albeit still present. No effects on intestinal or renal blood flow were seen after CART infusion. The pancreatic vascular effects were not affected by simultaneous administration of the endothelin A receptor antagonist. No difference in GTT was seen after CART administration compared to control rats. Perspectives: Thus, we found that CART has pronounced vascular constrictive actions restricted to the pancreas, and especially the islet circulation. This was not associated with any changes in the GTT. The mechanisms behind the vascular effects are still unknown, but may reflect a direct action on pancreatic blood vessels. 30 SSSD2017_abstract_book.indd 30 09/05/17 17:14

31 Oral presentations 3 OP 3 1 PERIPHERAL EFFECTS OF BETA CELL SPECIFIC INSULIN RESISTANCE Søs Skovsø (SS), Derek A. Dionne (DAD), Hong Li (HL), Daria Hutchinson (DH), Xiaoke Hu (XH), James D. Johnson (JDJ). Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences. University of British Columbia, Canada Type 2 diabetes is associated with obesity, insulin resistance, and eventually significant beta cell failure and loss. Insulin resistance may be tissue specific, a concept that has previously been examined through employment of various Insulin receptor knockout mouse models, including the BIRKO mice. This model employed a Cre recombinase controlled by RIP. Unfortunately, since the generation of the original BIRKO mice, the rat insulin 2 promoter has been shown to delete floxed alleles in both beta cells and the brain. We therefore generated a new mouse model to re address the function of insulin receptors specifically in beta cells Insrf/f:Ins1 Cre mice. We confirmed beta cell specific Insr gene deletion in at least 95% of beta cells, with no deletion in the brain. Interestingly, in contrast to the original BIRKO mouse model, we observed a minor improvement in the glucose tolerance of low fat diet fed male Insrf/f:Ins1 Cre mice in comparison to littermate controls at 9 weeks, an effect which neutralized with age. In low fat diet fed females, this minor improvement was present from 9 weeks to 9 months of age. Interestingly, female Insrf/f:Ins1 Cre mice fed a low fat diet also had increased basal insulin levels at 7, 16, and 28 weeks of age, along with a subtle effect on body weights. At 9 weeks of age, low fat diet fed Insrf/f:Ins1 Cre males had increased glucose stimulated insulin secretion when compared to littermate controls. Collectively, these data are consistent with the concept that insulin inhibits its own secretion, at least initially. Our data suggest that early beta cell specific modulation of insulin secretion via insulin receptor deletion on beta cells can have peripheral consequences for body weight regulation and glucose tolerance. Together, these data provide new information about the function of beta cell insulin receptors and will provide more insight into the pathogenesis of type 2 diabetes. 31 SSSD2017_abstract_book.indd 31 09/05/17 17:14

32 OP 3 2 COFFEE CONSUMPTION, GENETIC SUSCEPTIBILITY AND THE RISK OF LADA LATENT AUTOIMMUNE DIABETES IN ADULTS Bahareh Rasouli 1, Lars Alfredsson 1, Tomas Andersson 1,2, Per Ola Carlsson 3, Leif Groop 4,5, Josefin Edwall Löfvenborg 1, Mats Martinell6, Petter Storm 4, Tiinamaija Tuomi 5,7, Sofia Carlsson 1 1 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2 Center for Occupational and Environmental Medicine, Stockholm County Council, Sweden; 3 Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 4 Department of Clinical Sciences in Malmö, Clinical Research Centre, Lund University, Malmö, Sweden; 5 6 Finnish Institute of Molecular Medicine, Helsinki University, Helsinki, Finland; Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; 7 Division of Endocrinology, Abdominal Center, Helsinki University Hospital, Research Program for Diabetes and Obesity, University of Helsinki, and Folkhälsan Research Center, Helsinki, Finland Background: Coffee consumption is inversely associated with the risk of type 2 diabetes (T2D). In contrast, an increased risk of latent autoimmune diabetes in adults (LADA) has been reported in high coffee consumers, primarily of more autoimmune forms of LADA. Our aim was to study coffee consumption in relation to risk of LADA and T2D, taking into account HLA genotype. Methods: Analyses were based on newly diagnosed cases recruited from ANDIS (All New Diabetes in Scania), comprising 433 LADA and 1426 T2D cases and 885 randomly selected population controls. Information on coffee consumption was collected by validated food frequency questionnaire. On the basis of HLA genotype, participants were categorized into high risk (DR4 DQ8, DR4/3 DQ8, DR3/4, DR3/3, DR4/4, and DQA1*0501 DQB1*0201), and other (DR3/X, DR4/X, DR4 DQ7, and DRX/X). Odds ratios (OR) with 95% confidence intervals (CI) were calculated and adjusted for age, sex, BMI, education, smoking, and alcohol intake. Interaction between coffee consumption and high risk HLA was assessed by attributable proportion due to interaction (AP). Results: Coffee intake was associated with an increased risk of LADA in carriers of high risk HLA (OR per cup/day; 1.14, 95% CI; ); whereas no association were seen in non carriers (1.01, 95% CI; ). Individuals exposed to both high coffee consumption ( 4 cups/day) and high risk HLA had an OR of 4.55 (95% CI; ) with AP estimated at 0.48 (95% CI; ); implying that 48% of the LADA cases among heavy coffee consumers with high HLA risk was attributable to interaction between these factors. We could also confirm that coffee intake was associated with a reduced T2D risk (OR per cup/day; 0.92, 95% CI; ). Conclusions: Our findings suggest that coffee consumption may promote autoimmune diabetes in genetically susceptible individuals. This novel finding may have important public health implications given the widespread use of coffee. 32 SSSD2017_abstract_book.indd 32 09/05/17 17:14

33 OP 3 3 EVIDENCE OF TRANSCIENT AUTOIMMUN ACTIVITY PRECEDING DIABETES DIAGNOSIS IN PATIENTS CLASSIFIED WITH TYPE 2 DIABETES. THE HUNT STUDY. Elin P Sørgjerd 1, Bjørn Olav Åsvold 1,2, Per M Thorsby 3 and Valdemar Grill 2,4 1. HUNT Research Centre, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, the Norwegian University of Science and Technology, Norway; 2. Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 3. Hormone Laboratory, Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; 4. Department of Cancer Research and Molecular Medicine, Faculty of Medicine and Health Sciences, the Norwegian University of Science and Technology, Trondheim, Norway. Background: Type 2 diabetes (T2D) is heterogeneous, and phenotype, prognosis and efficacy of treatment can vary greatly between individuals. In this context, we examined the possibility of transcient autoimmunity in T2D, defined as signs of autoimmune activity preceding, but no longer present after, diabetes diagnosis. Further we studied if transcient autoimmunity was associated with clinical characteristics. Methods: We used data and serum samples from the second (HUNT2, ) and third (HUNT3, ) surveys of the Nord Trøndelag Health Study (HUNT). We included 836 individuals diagnosed with T2D between HUNT2 and HUNT3. Classification criteria of T2D were autoantibody negativity (GADA and IA 2A) and no insulin use within one year after diagnosis. From these individuals, serum samples from HUNT2 (prior to diabetes diagnosis) were assayed for GADA, IA 2A, ZnT8A and IAA. Further, individuals who were found to be autoantibody positive prior to diagnosis were tested for ZnT8A and IAA in serum collected in HUNT3. Results: Among 836 individuals, 23 (2.8%) were positive for at least one autoantibody before T2D diagnosis. Only one of them tested positive for ZnT8A in HUNT3, and none tested positive for IAA. Autoantibody positive individuals had higher non fasting glucose before diagnosis (5.8 vs 5.4 mmol/l, p=0.043 at HUNT2) and were younger at the time of diagnosis (53 vs. 61 years of age, p <0.001) than autoantibody negative individuals. Autoantibody positive individuals also tended to have lower insulin production (fasting C peptide 808 vs. 984 pmol/l), lower beta cell function (HOMA2 %B 59.8 vs 76.9) and higher HbA1c (7.2 vs 6.7%) after diagnosis (HUNT3), but these differences were not statistically significant. Conclusion: To our knowledge we are the first to demonstrate transcient evidence of autoimmune activity prior to diagnosis in a subgroup of T2D. This subgroup seems to be diagnosed at a younger age and might have reduced beta cell function and poorer glycemic control than its counterparts. 33 SSSD2017_abstract_book.indd 33 09/05/17 17:14

34 OP 3 4 A RANDOMIZED CLINICAL TRIAL TESTING FOR OPTIMAL BETA CELL PRESERVING TREATMENT IN LATENT AUTOIMMUNE DIABETES IN ADULTS (LADA) Valdemar Grill, Ingrid Hals, Hanne Fiskvik Fleiner, Nina Reimers, Marianne Astor, Karin Filipsson, Anneli Björklund Background and aims: The optimal beta cell preserving treatment of LADA patients is presently uncertain. This is due to a lack of randomized clinical trials in LADA. We aimed to compare the effect on beta cell function during either insulin or sitagliptin, a DDP 4 inhibitor, when added to ongoing treatment with metformin. Methods: Inclusion criteria included GADA positivity, age years, no clinical need for insulin treatment and a diagnosis of diabetes made < 3 years before participation in the study. Further, HbA1C at inclusion was to be less than 60 but more than 5% above upper limit of normal. Patients were stratified by age, BMI and degree of GADA positivity (high/low). Beta cell function was evaluated by C peptide glucagon tests which were performed after a 48 h temporary withdrawal of study medication. Results: In a study population of 53 participants the mean age at randomization was 53 years and BMI 27.7 kg/m 2. These parameters and others (male/female participation, HbA1c, fasting C peptide) were similar between arms of the study. HbA1c did not differ significantly between baseline and after 9 months of intervention (baseline 52.2 ± 1.4 mmol/mol, at 9 months, 50.8 ± 2.1 mmol/mol in the insulin, 50.6 ± 1.8 mmol/mol and 44.9 ± 1.8 mmol/mol in the sitagliptin arm). Stimulated C peptide after 9 months of intervention was similar in the insulin and sitagliptin arm (incremental C peptide 0.31 ± 0.04 nmol/l in the insulin, 0.31 ± 0.05 nmol/l in the sitaglitin arm). These findings did not negate a time dependent negative effect of autoimmunity in the study population (taken as a whole); this was manifested by a decrease in stimulated C peptide from 0.97 ± 0.09 to 0.82 ± 0.09 nmol/l in those with the highest titer of GADA (p< 0.02 for difference baseline vs 9 months). Conclusions: This is the first randomized study to compare in LADA patients the effects on beta cell function of early insulin treatment vs. a DDP 4 inhibitor, the latter being a conventional treatment alternative in non insulin dependent diabetes. The results do not give evidence favoring early insulin during the time frame studied. Follow up of the study population is underway to answer the question whether a longer observation period would detect differences between the arms of treatment. 34 SSSD2017_abstract_book.indd 34 09/05/17 17:14

35 OP 3 5 SERIOUS LIFE EVENTS AND THE RISK OF LATENT AUTOIMMUNE DIABETES IN ADULTS AND TYPE 2 DIABETES Sofia Carlsson 1, Bahareh Rasouli 1, Tomas Andersson 1 2, Per Ola Carlsson 3, Rebecka Hjort 1, Josefin Edwall Löfvenborg 1, Mats Martinell 4, Leif Groop 5, Tiinamaija Tuomi Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2. Center for Occupational and Environmental Medicine, Stockholm County Council, Sweden. 3. Department of Medical Sciences, Uppsala University, Uppsala, Sweden 4. Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden 5. Department of Clinical Sciences in Malmö, Clinical Research Centre, Lund University, Malmö, Sweden and Finnish Institute of Molecular Medicine, Helsinki University, Helsinki, Finland 6. Division of Endocrinology, Abdominal Center, Helsinki University Hospital, Research Program for Diabetes and Obesity, University of Helsinki, and Folkhälsan Research Center, Helsinki, Finland Background: It has been suggested that serious life events (SLE) may trigger or promote type 1 diabetes in children. Studies in adults are lacking and so are studies on interaction of SLE with genetic factors. We aimed to investigate SLE in relation to the risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes while taking into account HLA genotype. Methods: Analysis were based on 425 incident cases of LADA and 1417 incident cases of type 2 diabetes from the ANDIS/ANDiU studies and 1702 population based controls. Self reported information on SLE including conflicts, divorce, illness/accidents, death and financial problems experienced during the 5 years preceding diagnosis/index year was used. Odds ratios and 95% confidence intervals were calculated by logistic regression and adjusted for BMI, family history of diabetes, smoking, physical activity and education. Results: Overall there was no association between experience of any SLE and neither LADA (OR 0.86, 95% CI ) nor type 2 diabetes (OR 1.00, 95% CI ). Results were similar for the individual events as well as in separate analysis of men and women. Similar results were seen in more autoimmune LADA (GADA >median); OR [any SLE] 0.88, 95% CI and in carriers of high risk HLA DR4 DQ8 genotype; OR [SLE] 0.89, 95% CI Conclusion: Our findings indicate that experience of a serious life including the death of a family member, divorce or financial problems is not associated with an increased risk of type 2 diabetes or LADA, neither overall nor in genetically susceptible individuals. 35 SSSD2017_abstract_book.indd 35 09/05/17 17:14

36 OP 3 6 EDCR (ETANERCEPT DIAMYD COMBINATION REGIMEN), A PILOT TRIAL TO PRESERVE RESIDUAL BETA CELL FUNCTION IN CHILDREN WITH TYPE 1 DIABETES. Johnny Ludvigsson 1, Ann Karin Albin 2, Carl Göran Arvidsson 3, Annelie Carlsson 4, Ragnar Hanas 5, Helena Elding Larsson 6,Björn Rathsman 7, Stefan Särnblad 8, Tore Vigård 6 Rosaura Casas 1,Ulf Samuelsson 1 1 Div of Pediatrics, Dept of Clin Exp Medicine, Linköping university, Sweden; 2 Pediatric clinic, Helsingborgs lasarett, Helsingborg, Sweden, Pediatric clinic, 3 Pediatric clinic, Västerås Hospital, Västerås, Sweden, 4 Pediatric clinic, Skåne University Hospital, Lund, Sweden, Pediatric clinic, 5 Central Hospital Uddevalla, Sweden, 6 Pediatric clinic, Skåne University Hospital, Malmö, Sweden, 7 Sachsska Pediatric clinic, Södersjukhuset, Stockholm, 8 Pediatric clinic, University Hospital, Örebro, Sweden Background and objectives: Residual beta cell function in Type 1 diabetes (T1D) is clinically very important. Interventions so far have had too serious risks/adverse and/or not been efficacious. Meta analyses suggests a 98% probability that GAD alum sc preserves beta cell function, but insufficiently. TNF alfa inhibition has impressive effect in rheumatoid arthritis and Inflammatory Bowel Disease. One small study in T1D, 6 months follow up, showed efficacy. Vitamin D might improve efficacy. Thus, we combined GAD alum, Etanercept and Vitamin D in a pilot trial aiming to preserve residual insulin secretion in recent onset T1D, study the immune response and evaluate safety. Patients and Methods: EDCR is an open labeled multi center study pilot trial which has enrolled 20 T1D patients, 7 girls and 13 boys, aged (mean + SD): ( ) years, with a diabetes duration of (44 118) days. Baseline fasting C peptide was ( ) nmol/l, C peptide AUC after Mixed Meal Tolerance Test ( ) nmol/l, insulin dose ( ) U/kg,24 hrs, and HbA1c (35 55) mmol/mol. All were GADA positive, median ( ) RU/ml. The patients got from Day Vitamin D (Calciferol) 2000 U /d per os, Day 1 90 Etanercept ( TNF alfa inhibitor) 0.8 mg given sc once a week and 20 μg Diamyd sc in Day 30 and 60. Follow up 30 months. Results: All patients have finished their Etanercept treatment. No treatment related Serious Adverse Events have occurred and only some mild adverse events, transient GAD injection site reactions. Several patients have required low insulin doses. The group will have passed 6month follow up and results can be presented May Perspectives: Our studies are expected to reveal whether treatment with Vitamin D+ Etanercept (TNF alfa inhibition) + GAD alum sc is safe, suggests preservation of residual beta cell function. If so this will lead to further trials. 36 SSSD2017_abstract_book.indd 36 09/05/17 17:14

37 OP 3 7 INCREASED INTERLEUKIN 35 LEVELS IN LONG STANDING TYPE 1 DIABETES PATIENTS WITH REMAINING C PEPTIDE Kailash Singh 1, Daniel Espes 1,2, Stellan Sandler 1 and Per Ola Carlsson 1,2. 1 Departments of Medical Cell Biology and 2 Medical Sciences, Uppsala University, Uppsala, Sweden. Aim/hypothesis: Many patients with long standing type 1 diabetes (T1D) have remaining functional β cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after 10 year duration of disease. Methods: 113 patients ( 18 years of age) with T1D and with disease duration of 10 years were recruited at Uppsala University Hospital. Residual β cell function was determined with an ultrasensitive C peptide ELISA. Circulating cytokines including IL 35 was determined in plasma. Additional blood samples were collected from 14 of the identified C peptide positive patients and 12 of the C peptide negative patients, as well as from 15 healthy controls, and were used for immediate investigation of peripheral blood mononuclear cells. Results: The blood concentration of the cytokine IL 35 was markedly lower in C peptide negative patients, and this was associated with a simultaneous decrease in the proportion of IL 35 + regulatory T cells, IL 35 + regulatory B cells and IL 35 producing CD8 + Foxp3 + T cells. IL 35 has previously been shown to maintain the phenotype of regulatory T cells, block the differentiation of T helper 17 cells, and thereby dampen immune assaults to β cells. We found that the proportions of IL 17a + cells among the regulatory T cells, CD4 + T cells and CD8 + T cells were lower in the C peptide positive patients. Conclusion: Patients with remaining endogenous β cell function after more than 10 years duration of T1D differs immunologically from other patients with long standing T1D. In particular, they have a much higher IL 35 production. 37 SSSD2017_abstract_book.indd 37 09/05/17 17:14

38 OP 3 8 METABOLIC CHANGES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TYPE 1 DIABETES PATIENTS Paula Fernandez Guerra 1, Simone Rask 2, Troels K Hansen 2, Margrethe Kjeldsen 2, Peter Bross 1, Johan Palmfeldt 1 1 Research Unit for Molecular Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; 2 Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark. Background: Peripheral blood mononuclear cells (PBMCs) constitute a heterogeneous cell population that can mirror systemic changes within the body and provide biomarkers of disease. PBMCs are readily available and can be used to study cellular and mitochondrial function. The Seahorse Metabolic Analyzer measures metabolic rates: extracellular acidification rate (ECAR) reflecting glycolysis leading to lactate production, and oxygen consumption rate (OCR) reflecting mitochondrial respiration. We hypothesized that changes in metabolic rates in PBMCs are associated with symptoms and severity of type 1 diabetes. Such changes can be caused by differential expression of intracellular proteins that can be used as biomarkers of disease. Aim: To study metabolic rates in PBMCs from type 1 diabetic patients by integrating data from metabolic rates by Seahorse and mass spectrometry based proteomics. Methodology: We have studied six patients with type 1 diabetes, classified according to their levels of glycated hemoglobin (HbA1c): well regulated (HbA1c 53 mmol/mol) and poorly regulated (HbA1c 69 mmol/mol). Eleven non diabetic individuals, age and gender matched, were analyzed as controls. PBMCs were isolated in 8 ml Cell Preparation Tubes (CPT) after 12 hours fasting. PBMCs were analyzed fresh to measure metabolic rates by Seahorse or frozen for future protein analysis by mass spectrometry. Results: After adjusting for severity of disease, we observed changes in glycolytic reserve. Glycolytic reserve is the capacity of the cells to increase the glycolysis rate towards lactate production, in response to increases in energy demand. Poorlyregulated patients showed an increase of 30% compared to well regulated patients (pvalue 0.03). Glycolytic reserve and HbA1c levels have a positive Pearson correlation (r = 0.92). This indicates higher metabolic plasticity in PBMCs with long term increased blood glucose levels. Perspectives: Our studies are expected to reveal whether PBMCs from type 1 diabetic patients display metabolic changes and to what extent intracellular proteins/enzymes are deregulated in these cells. 38 SSSD2017_abstract_book.indd 38 09/05/17 17:14

39 OP 3 9 KINETICS OF THE INNATE IMMUNE CELLS RESPONSE IN MULTIPLE LOW DOSE STREPTOZOTOCIN INDUCED TYPE 1 DIABETES Mariela Mejia 1, Charlotte Soläng 1, Zhengkang Luo 1, Martin Blixt 1, Stellan Sandler 1 and Kailash Singh 1 Department of Medical Cell Biology, BMC, Uppsala University, Uppsala, Sweden Aim: In Type 1 Diabetes (T1D), the insulin producing cells are destructed by autoimmune mechanisms. It has been hypothesized that the very first autoimmune response in T1D onset involves the innate immune cells, which further activate the adaptive immune cells to attack on cells. Despite intense research in the field of T1D, the kinetics of innate immune response in T1D remains elusive. Therefore, we determined the proportion of innate immune cells in early development of T1D in a murine model of T1D. Methods: The proportions of innate immune cells in pancreatic draining lymph nodes (PDLNs), thymi and spleens of Multiple low dose streptozotocin (MLDSTZ) induced T1D mice and control mice were determined by flow cytometry on days 3, 7, 10 and 21 after the first injection of STZ. Results: On day 3, the proportions of CD11b CD11c + antigen presenting cells (APCs) were higher in both PDLNs and thymi, but the proportions of plasmacytoid dencritic cells (pdcs) were higher in PDLNs (on day 3) and spleen (on day 10) of MLDSTZ mice than control mice. Furthermore, the proportions of cross presenting CD8 + APCs were higher in PDLNs (on days 3 and 10), thymus (on day 3) and in spleen (on day 10) of MLDSTZ mice than control mice. Moreover, the proportion of tolerogenic CD11b + CD11c + APCs were first increased in both PDLNs and spleen on day 7 but decreased on day 10 of MLDSTZ mice, which suggest a loss of tolerance in the early development of T1D. The proportions of neutrophils and B 1 lymphocytes were increased in PDLNs and spleen on day 10 of MLDSTZ mice. Conclusion: Our data illustrate compelling evidence for the involvement of innate immune cells in the early development of T1D. Furthermore, these results indicate that tolerogenic APCs should be investigated in the treatment of T1D. 39 SSSD2017_abstract_book.indd 39 09/05/17 17:14

40 Oral presentations 4 OP 4 1 IN EARLY PREGNANCY HOME BLOOD PRESSURE IS MORE THAN FIVE MMHG LOWER THAN ROUTINELY MEASURED OFFICE BLOOD PRESSURE IN WOMEN WITH PREEXISTING DIABETES AND IN HEALTHY WOMEN 1,2,7 Marianne Vestgaard, 1,2 Sidse Nørgaard, 4 Lene Ringholm, 5 Dorte Møller Jensen, 6 Lise Lotte Torvin Andersen, 1,3,7 Peter Damm, 1,2,7 Elisabeth R. Mathiesen 1 Center of Pregnant Women with Diabetes, Rigshospitalet, 2 Department of Endocrinology, Rigshospitalet, 3 Department of Obstetrics, Rigshospitalet, 4 Steno Diabetes Center Copenhagen, Gentofte, 5 Department of Endocrinology, Odense University Hospital, 6 Department of Obstetrics, Odense University Hospital, 7 The Institute of Clinical Medicine, Faculty of Health and Medical Sciences. Aim: To determine the association between home blood pressure (BP) and office BP in early pregnancy in women with preexisting diabetes in comparison with healthy women. Methods: Ninety nine women with diabetes (64 with type 1 and 35 with type 2) and 65 healthy women measured home BP for three days with three measurements both in the morning and in the evening with an automatic device (Microlife BP 3A Plus) at median 71 days and 90 days of pregnancy, respectively. Home BP was similar on the first and the following days of measurement in women with diabetes and in healthy women (p=0.53 and p=0.94), and therefore a mean of all 18 measurements was used. Office BP was measured once after five minutes resting, and if values were above 140/90 mmhg further measurements were done. Results: In women with diabetes home BP and office BP were 111 ± 9/69 ± 7 and 119 ± 12/76 ± 8 mmhg, mean (± SD), respectively. The values for healthy pregnant women were 101 ± 5/63 ± 5 and 109 ± 12/73 ± 7 mmhg with upper normal limits for home BP of 111/74 mmhg (mean + 2 SD). The white coat effect was 8/7 mmhg and 8/10 mmhg, respectively. Both home BP and office BP were higher among women with diabetes compared with healthy pregnant women (all p<0.01). Four (4%) women with diabetes were on antihypertensive therapy. Conclusion: In early pregnancy both women with diabetes and healthy women has a white coat effect exceeding five mmhg. The upper normal limit of home BP was 111/74 mmhg. 40 SSSD2017_abstract_book.indd 40 09/05/17 17:14

41 OP 4 2 INTERVAL WALKING INTERVENTION FOR PREGNANT WOMEN DIAGNOSED WITH GESTATIONAL DIABETES MELLITUS A RANDOMIZED CONTROLLED PILOT STUDY Kathrine Kjær 1, Lise Lotte T. Andersen 3, Christina Vinter 3, Dorte M. Jensen 2, Jens S. Nielsen 2 1 Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark; 2 Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Odense, Denmark; 3 Department of Obstetrics and Gynecology, Odense University Hospital, Denmark Background: Gestational Diabetes Mellitus (GDM) is hyperglycemia diagnosed in pregnancy with no evidence of pre existing diabetes, affecting around 2 3% of all pregnant women in Denmark. The condition is characterized by insulin resistance and is phenotypically similar to type 2 diabetes (T2D). It is well documented that physical activity (PA) can improve glucose control and fitness level in people with T2D and in pregnant women in general, while only a limited number of studies examine the effects of PA for GDM patients. Interval Walking Training (IWT) is a careful type of nonsupervised PA, which consists of repeatedly cycles of 3 minutes of slow and fast walking. IWT can improve glucose regulation in people with T2D, and we aim to study, whether IWT has similar effects in GDM patients. Methods: All subjects (n=20) will follow the hospital provided standard GDM treatment including diet counseling, home blood glucose measurements, exercise advice and if needed insulin treatment. Following screening, subjects will be randomized to either an IWT or a standard care group. The IWT group, will additional to standard care, be encouraged to conduct three interval walking sessions per week (40 50min/session) over six weeks. IWT sessions are supervised and controlled using the smartphone application Interwalk. Interwalk use an on board fitness test to individualize training session intensity and session guidance. For all subjects, continuous blood glucose measurement (48 h), blood pressure, body weight and height, physical activity level (5 days with accelerometers) and fitness level (6 minutes walking test) is measured before and after the six week intervention. Expected results: Six weeks of IWT is expected to improve glycemic control and maintain physical fitness level for women with GDM. AS IWT is a careful type of PA, a high degree of compliance is expected and implementation as a regular advice in pregnant women with GDM should be feasible. 41 SSSD2017_abstract_book.indd 41 09/05/17 17:14

42 OP 4 3 DIASTOLIC BLOOD PRESSURE IS A POTENTIAL MODIFIABLE RISK FACTOR FOR PREECLAMPSIA IN WOMEN WITH TYPE 1 AND TYPE 2 DIABETES 1,2 Sidse K. Nørgaard, BSc, 1,2,3 Marianne Vestgaard, MD, 1,2,3 Björg Asbjornsdóttir, MD, 5 Lene Ringholm, MD, PhD, 1,3,4 Peter Damm, MD, DMSc, 1,2,3 Elisabeth R. Mathiesen, MD, DMSc 1 Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark; 2 Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark; 3 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4 Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark; 5 Steno Diabetes Center Copenhagen, Gentofte, Denmark E mail: sidsenorgaard@hotmail.com Fax number: Aim: To assess the prevalence of pregnancy related hypertensive disorders and to identify early clinical, modifiable predictors of preeclampsia in women with type 1 and type 2 diabetes. Methods: A population based cohort study of 494 women with pre existing diabetes (307 type 1 and 187 type 2 diabetes), included at their first antenatal visit (11±6 weeks of gestation (mean±sd)) from 2012 to The prevalence of microalbuminuria, diabetic nephropathy, retinopathy, chronic hypertension, gestational hypertension and preeclampsia was recorded. Predictors of preeclampsia present at first antenatal visit were sought identified. Results: At the first antenatal visit HbA1c was 6.9±2.3 % (50.8±10.1 mmol/mol) vs. 6.8±2.6 % (48.7±13.7 mmol/mol) and blood pressure 120±12/76±8 mmhg vs. 122±14/79±10 mmhg, (p=0.16/p=0.001), in women with type 1 and type 2 diabetes, respectively. The prevalence of microalbuminuria was 6% (6% vs. 6%), diabetic nephropathy 1% (1% vs. 2%) and chronic hypertension (without diabetic nephropathy or microalbuminuria) 6% (3% vs. 10%, p=0.003). Preeclampsia developed in 8% (9% vs. 7%) and gestational hypertension in 8% (9% vs. 6%). Univariate analysis identified nulliparity, presence of retinopathy, diabetic nephropathy including microalbuminuria and blood pressure as predictors of preeclampsia. At the first antenatal visit, presence of diabetic microangiopathy (nephropathy, microalbuminuria and/or retinopathy) and diastolic blood pressure, were independently, positively associated with the development of preeclampsia. Conclusion: The prevalence of pregnancy induced hypertensive disorders was comparable between type 1 and type 2 diabetes. At the first antenatal visit, diastolic blood pressure was the only independent, potentially modifiable risk factor for preeclampsia, in women with pre existing diabetes. 42 SSSD2017_abstract_book.indd 42 09/05/17 17:14

43 OP 4 4 IS LOW BIRTH WEIGHT ASSOCIATED WITH FOOD INTAKE RELATED TO THE DEVELOPMENT OF TYPE 2 DIABETES IN 14 YEARS OLD ADOLESCENTS? Freja B. Kampmann 1,2,3,4, Louise G. Grunnet 2, Thorhallur I. Halldorsson 4, 5, Anne A. Bjerregaard 4, Charlotta Granstrøm 4, Marin Strøm 4,6, Allan A. Vaag 2,5, Inge Tetens 1,8, Sjurdur F. Olsen 4 1 Division for Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Søborg, Denmark; 2 Department of Endocrinology Diabetes and Metabolism, Rigshospitalet, Copenhagen Denmark; 3 The Danish Diabetes Academy, Odense, Denmark; 4 Centre for Fetal Programming, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 5 Faculty of Food Science and Nutrition, University of Iceland, Reykjavik, Iceland; 6 Faculty of Natural and Health Sciences, University of the Faroe Islands, Torshavn, Faroe Islands; 7 Astrazeneca, Sweden; 8 Vitalization Centre for Good Older Lives, Department of Nutrition, Sports & Exercise, University of Copenhagen, Denmark Background: Individuals born small for gestational age (SGA) are at increased risk of developing type 2 diabetes (T2D) later in life. Dietary habits play a substantial role in the etiology of T2D and several studies have found SGA individuals having preferences towards energy dense food. However, limited evidence is available on the association between food intake in adolescents in relation to being born SGA at term. Aim: We aimed to examine if SGA individuals have a higher intake of unfavorable foods and/or a lower intake of favorable foods associated with the development of T2D, when compared to individuals born normal for gestational age (NGA). Material and methods: Food intake of , 14 years old offspring from the Danish National Birth Cohort was obtained by a validated food frequency questionnaire. SGA was defined by BW for gestational age (GA) z score < 10percentile (n = 1470) and NGA as BW for GA z score between 10 90percentile (n = 14137). Data were stratified for gender and analyzed by multiple regression analysis, adjusted for energy intake, parental socioeconomic status (SES) at birth and for maternal smoking during pregnancy. Main results: When adjusted for energy intake, girls born SGA had a significantly higher intake of added sugar and red meat and a lower intake of dietary fiber, vegetables, PUFA, total N 3, LA, and total N 6 compared to NGA girls (p < 0.05). After adjusting for parental SES and maternal smoking all dietary intakes except from red meat and dietary fiber were still significantly different between SGA and NGA girls. However we found no significant differences in dietary intake between SGA and NGA boys. Conclusion: Our results suggest that being born SGA may influence food intake in adolescent girls in an unhealthy manner in relation to the development of T2D. 43 SSSD2017_abstract_book.indd 43 09/05/17 17:14

44 OP 4 5 THE EFFECT OF EARLY VS LATE GESTATIONAL DIABETES ON NEONATAL OUTCOMES AMONG OBESE WOMEN Nora E Grotenfelt 1,2, Kristiina Rönö 2, Johan G Eriksson 1,3, Anita Valkama 1,3, Jelena Meinilä 3, Hannu Kautiainen 3,4, Saila B Koivusalo 2. 1 Folkhälsan Research Center, Helsinki, Finland; 2 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki; 3 Unit of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Finland; 4 Department of General Practice and Primary Health Care, University of Eastern Finland, Finland Aims/hypothesis: Gestational diabetes (GDM) diagnosed early in pregnancy (early GDM) can be seen as a marker of an increased metabolic burden possibly affecting the fetus for a longer time period compared with GDM diagnosed in the second trimester (late GDM). The aim of this study was to characterize obese women according to timing of GDM diagnosis, and to assess this in relation to neonatal outcomes. Methods: Women at high risk for GDM over 18 years of age, planning pregnancy or pregnant at <20 weeks, with a pre pregnancy body mass index (BMI) >30 kg/m 2 were divided according to the results of a 75 g two hour oral glucose tolerance test performed at 13.1 weeks of gestation and repeated at 23.4 weeks if normal at first testing. Primary outcomes were offspring birth weight and large for gestational age (LGA). Secondary outcomes were Apgar scores, birth injuries, neonatal hypoglycemia, and need for intensive neonatal care. Results: Out of a total of 361 women, 164 (45.4%) were diagnosed with GDM. Of these, 133 (81.1%) were diagnosed with early GDM and 31 (18.9%) with late GDM. The offspring of women with GDM had a higher birth weight (p=0.019) and standardized birth weight (p=0.023) compared with the offspring of women with normal glucose tolerance. No statistically significant differences in offspring birth weight or risk for LGA were seen between early and late GDM. Instead, risk for LGA was associated with pre pregnancy BMI (p<0.04) and gestational weight gain (p= 0.01). Conclusion: No differences in neonatal outcomes were detected between early and late GDM. The exposure associated with early GDM might be counteracted by early treatment of hyperglycemia and confounded by maternal adiposity. 44 SSSD2017_abstract_book.indd 44 09/05/17 17:14

45 OP 4 6 AMINO ACID TRANSPORT IN ADIPOCYTES MODULATES VISCERAL FAT ACCUMULATION AND DIABETES RISK Aron Willems 1,2, Regine Jersin 1,2, André G. Madsen 1,2, Jan Inge Bjune 1,2, Johan Fernø 1,2, Even Fjære 3, Ståle Ellingsen 3, Lise Madsen 3, Gunnar Mellgren 1,2, Jørn V Sagen 1,2, Simon Dankel 1,2 1 Hormone Laboratory Research Group, Haukeland university hospital, Bergen, Norway; 2 KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway 3 NIFES (National Institute of Nutrition and Seafood Research), Bergen, Norway Aims/hypothesis: Visceral adiposity is a major contributor to type 2 diabetes and cardiovascular disease in our modern society. Metabolomic studies have provided new clues to the critical metabolic pathways in obesity and type 2 diabetes, pointing in particular to altered amino acid metabolism. Adipose tissue has been found to regulate circulating amino acid concentrations, and we recently reported the amino acid transporter ASC 1 as a marker for fat storing white adipocytes. We here aimed to demonstrate a novel role for amino acid uptake in visceral adipocyte fat storage and whole body glucose homeostasis. Methods: We took a translational approach including gene expression analysis of human adipose tissue biopsies of morbidly obese and lean patients, measurement of amino acid uptake and mitochondrial respiration in primary human and murine adipocyte cultures, overfeeding experiments in transgenic zebrafish, and type 2 diabetes genotype gene expression association (eqtl). Results: We found 2 fold higher ASC 1 mrna in visceral compared to subcutaneous adipocytes, and a strong inverse relationship with cardiometabolic risk factors, including TAG/HDL ratio and HOMA IR. ASC 1 mrna showed reduced levels in obesity and upregulation after bariatric surgery. Inhibition of ASC 1 activity in primary human and ME3 murine adipocytes significantly reduced uptake of the neutral amino acid serine, and strongly suppressed mitochondrial oxygen consumption. Finally, genetic risk for type 2 diabetes significantly associated with ASC 1 mrna expression in visceral, but not subcutaneous, adipose tissue. Conclusions: ASC 1 is most highly expressed in visceral adipocytes, where it prevents visceral fat storage likely through its function to promote adipocyte uptake of neutral amino acids and mitochondrial respiration. ASC 1 and amino acid transport in adipocytes are new promising targets for precision therapeutics against cardiometabolic diseases. 45 SSSD2017_abstract_book.indd 45 09/05/17 17:14

46 OP 4 7 NO ASSOCIATION BETWEEN THE BONE TURNOVER MARKERS CTX AND P1NP AND INSULIN SENSITIVITY OR BETA CELL FUNCTION IN HEALTHY MEN Morten Frost 1, Jens Jacob Lauterlein 1, Henning Beck Nielsen 1, and Kurt Højlund 1 1 Department of Endocrinology, Section for Molecular Diabetes & Metabolism, Odense University Hospital and Institute of Clinical Research, University of Southern Denmark, Denmark. Background: Bone turnover is lover in diabetes mellitus, but insulin appears to promote bone formation, and insulin resistance could impair cellular glucose uptake, reducing bone formation and resorption. Furthermore, hyperglycaemia seems to decrease osteoblast and osteoclast activity. Additionally, it has been suggested that bone metabolism influences insulin secretion. The objectives of this study were firstly to explore if bone turnover markers (BTMs) were directly associated with insulin secretion and sensitivity and secondly to determine if BTMs predict incident changes in insulin secretion and sensitivity. Methods: Healthy, glucose tolerant men were identified among RISC study participants. Baseline insulin sensitivity (M/I value) based on hyperinsulinaemic euglycaemic clamp (HEC), insulin secretion during an IVGTT, and baseline and 3 year follow up beta cell glucose sensitivity and rate sensitivity based on 2h oral glucose tolerance tests (OGTT) were used. Fasting and insulin stimulated (120 min) markers of bone formation (P1NP) and resorption (CTX) were measured. Association between insulin sensitivity or indices of beta cell function and BTMs were assessed using regression analyses with/without adjustment for age and BMI. Results: Among the 584 men initially included in the study, 8 were excluded due to diabetes diagnosed on the basis of the OGTT. The age of the non diabetic study population was 42 (36 49) years. Mean weight, height and BMI were 83.7 kg (12.6), 178 cm (7), and 26.2 kg/m 2 (3.5), respectively. Both CTX and P1NP were inversely associated with fasting p glucose in the complete study population before and after adjustment for potential confounders. Insulin sensitivity determined using the OGTT was directly associated with both BTMs before but not after adjustment for BMI. Neither of the BTMs was associated with HEC based measurements of insulin sensitivity in unadjusted models. Insulin secretion during an IVGTT was associated with BTMs neither before nor after adjustments, and total insulin secretion during an OGTT was associated with levels of P1NP only in unadjusted models. Baseline levels of BTMs were not associated with alterations in insulin secretion or sensitivity assessed at 3 years. Vitamin D levels had no impact on the results. Conclusions: Baseline BTMs were neither associated with insulin sensitivity (assessed using HEC and OGTT) nor insulin secretion capacity (based in IVGTT and OGTT). BTMs did not predict changes in insulin sensitivity or secretion. This study is not supporting an effect of bone turnover on insulin secretion and sensitivity in healthy, non diabetic men. 46 SSSD2017_abstract_book.indd 46 09/05/17 17:14

47 OP 4 8 A REDUCED CARBOHYDRATE DIET HIGH IN MONOUNSATURATED FATS IN TYPE 2 DIABETES: A SIX MONTH STUDY OF CHANGES IN METABOLISM, LIVER AND CARDIOVASCULAR FUNCTION (REDUCTION) Eva M. Gram Kampmann 1, Camilla D. Hansen 2, Michael H. Olsen 3, Aleksander Krag 2, Bjørn S. Madsen 2, Henning Beck Nielsen 1 1 Endocrinological Dept. M, Odense University Hospital; 2 Medical Gastrointestinal and Hepatological Dept. S, Odense University Hospital; 3 Cardiology Section, Department of Internal Medicine, Holbaek Hospital / Centre for individualized Medicine in Arterial Diseases, OUH, University of Southern Denmark Aim: Lately, attention has increasingly been directed towards low carbohydrate diets (LCD) for patients with diabetes mellitus type 2 (DM2). There is confusion amongst researchers and health professionals whether a LCD is appropriate diet for these patients or not. Recent studies suggest that LCM is safe and effective over short term, with significant improvements in weight and glycemic control compared to other diets. However, there is still a lack of understanding of pathophysiology and metabolic changes in reported research. The aim of this study is to investigate impact of six months of LCD with high fraction of fat, compared to a regular diabetic diet (RDD), on glycemic control, dyslipidemia, fat distribution, and complications associated with diabetes. Also, impact on endothelial dysfunction, non alcoholic fatty liver disease (NAFLD) associated with diabetes, gut dysbiosis and quality of life will be evaluated. Material and methods: With continuous enrollment, 135 patients with DM2 will be randomized 2:1 to either a ketogenic LCD or RDD for six months. Anthropologic measurements, fat distribution evaluated with DEXA, endothelial function assessed through ultrasound measured flow mediated vasodilation, retinal vessel geometry, NAFLD evaluated through liver biopsy (histology and mass spectrometry to evaluate lipidomics, metabolomics, proteomics and mirna) and shear wave and transient elastrography will be conducted before and after six months of diet. Blood biochemistry associated with diabetes and liver disease as well as microbiota analyzes with genome (16S), meta transcription and metabolome studies will be evaluated. The participants quality of life will be assessed through Diabetes 39 (D 39). A biobank with stored material (blood, hair, sputum, urine and feces) will be established. Perspectives: It is expected that the trial will lead to several publications in leading journal in the field of Endocrinology and Hepatology. This study is expected to impact future guidelines and daily clinical practice both in diabetology, hepatology and cardiovascular medicine. 47 SSSD2017_abstract_book.indd 47 09/05/17 17:14

48 OP 4 9 THE EFFECT OF TESTOSTERONE ON INSULIN MEDIATED SIGNALING TO GLUCOSE TRANSPORT AND GLYCOGEN SYNTHESIS IN SKELETAL MUSCLE CELLS Cecilie Halkier 1, Rugivan Sabaratnam 1,2, Rikke Kruse 1,2, Kurt Højlund 1,2 1 Section of Molecular Diabetes & Metabolism group, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; 2 Department of Endocrinology, Odense University Hospital, Odense, Denmark. Background: Testosterone levels in men decline as a consequence of ageing. Clinical trials with elderly obese men with/without T2D have shown that up to 50% have lower testosterone levels compared to non diabetic controls. Low testosterone levels have been associated with unfavourable changes in body composition, including reduced insulin sensitivity, increased adiposity and decreased muscle mass. Testosterone therapy is believed to increase insulin sensitivity, muscle mass, mitochondrial biogenesis, lipid oxidation and reduce the amount of adipose tissue. More specific it is thought to increase signalling through the IGF 1/Pi3K/Akt pathway, the basal glucose uptake and glycogen levels as well as to decrease signalling through the myostatin/smad pathway. Moreover testosterone therapy is believed to change the skeletal muscle fiber type composition. Here we aim to characterize 1) whether testosterone has a sensitizing effect on insulinmediated signalling to glucose transport and glycogen synthesis via the IRS 1/PI3K/Akt pathway in C2C12 myotubes with and without lipid induced insulin resistance and 2) if testosterone induces changes in fiber type composition by transcriptional regulation of specific myosin isoforms. Methods: Lipid induced insulin resistance in cultured myotubes will be used as a model of insulin resistant conditions. The myotubes are exposed to testosterone (10 nm or 100 nm) for 16 hours. Proteins involved in the IRS 1/PI3K/Akt pathway, including glucose transport and glycogen synthesis, are investigated using immunoblotting. Measurements of glucose uptake are preformed using mass spectrometry for metabolome profiling. Measurements of mrna levels of myosin isoforms representing the major skeletal muscle fiber types MYH1, MYH2, MYH7 are investigated by qrt PCR. Expected results: The above mentioned experiments are expected to reveal if testosterone treatment of myotubes has beneficial sensitizing effects on insulinmediated signaling to glucose transport and glycogen synthesis. Moreover this study is expected to identify whether testosterone regulates assertive changes in fiber type composition by transcriptional control of specific myosin isoforms in C2C12 myotubes. 48 SSSD2017_abstract_book.indd 48 09/05/17 17:14

49 Oral presentations 5 OP 5 1 MYOCARDIAL PROTEOME DURING PRE DIABETES AND TYPE 2 DIABETES MELLITUS IN ZUCKER DIABETIC FATTY RATS Anders V. Edhager 1, Jonas A. Povlsen 2, Bo Løfgren 2, Hans Erik Bøtker 2, Johan Palmfeldt 1 1) Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; 2) Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark Background: Recent findings show that early stage type 2 diabetes mellitus (T2DM) has been associated with protection against ischemia reperfusion (IR) injury in the diabetic rat heart, however the molecular mechanisms are not fully explored and understood. Objective: The objective of the current study was to identify changes in metabolic pathways in the myocardial proteome induced at the pre diabetic state, onset and late T2DM in Zucker Diabetic Fatty (ZDF) rats by large scale label free proteomics, and thereby elucidate contributing molecular factors to the decreased sensitivity towards IRinjury seen at early stage T2DM. Materials and methods: ZDF rats (fa/fa) and their age matched heterozygote lean controls (fa/+) were studied at stage 6, 12, and 24 weeks corresponding to a prediabetic state, onset of and late T2DM, respectively (n=3 in each group). ZDF rats were sacrificed, the heart removed, and the tissue proteins were subjected to quantitative proteomics using mass spectrometry. Results and conclusion: Overall, 841 proteins were identified and quantified at all three stages. After statistical analysis 90, 75, and 124 proteins were considered differentially abundant at 6, 12, and 24 weeks, respectively. They comprise proteins involved in the mitochondrial energy machinery such as the fatty acid oxidation and electron transport chain. Subsequent pathway analysis revealed fatty acid metabolism to be affected already at the pre diabetic state together with the proteasome, which were found as the most enriched pathways. At onset of T2DM the most enriched pathways were the mitochondrion, glutathione S transferases, and the regulatory proteins, and at late T2DM, the mitochondrion and fatty acid metabolism. The results show progressive changes of the central energy metabolism of the diabetic rat heart as T2DM progresses, which may be involved in the decreased sensitivity towards IR injury. 49 SSSD2017_abstract_book.indd 49 09/05/17 17:14

50 OP 5 2 KINETICS OF THE INNATE IMMUNE CELLS RESPONSE IN KIDNEY TISSUE OF AUTOIMMUNE INDUCED HYPERGLYCEMIA IN MICE Zhengkang Luo 1, Sonya Varli 1, Emma Enström 1, Lina Thorvaldson 1, Martin Blixt 1, Peter Hansell 1,Stellan Sandler 1 and Kailash Singh 1. 1 Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Aims/hypothesis: Diabetic nephropathy (DN) is one of the complications of diabetes mellitus. In DN the kidney tissue is damaged by immune attack. Immune cells such as innate and adaptive immune cells play a pivotal role in the development of DN. Despite intensive research in the field of DN, the dynamics of innate immune cells in the early development of DN is not clear. Herein, we determined the proportion of innate immune cells in kidney tissues of murine model of type 1 diabetes (T1D). Methods: Multiple low dose streptozotocin (MLDSTZ) model was used in this study. Blood glucose was measured on days 0, day 3, day 7, day 10 and day 21 and mice were euthanized on days 7, 10 and 21 after the first injection of STZ, and kidneys were removed. The single cell suspensions of these kidneys were prepared and used for flow cytometric analyses. The ratios of Albumin/Creatinine were determined in the urine samples. Results: The ratio of Albumin/Creatinine was increased in urine of MLDSTZ mice than control mice from day 10 and onwards. The proportions of neutrophils and plasmacytoid dendritic cells were not altered among the groups. However, the proportion of CD11c + dendritic cells was increased on day 7 and day 10 in kidneys of MLDSTZ mice than vehicle treated mice. Furthermore, the proportion of tolerogenic CD11c + CD11b + dendritic cells was first increased on day 7, but decreased on day 10 in kidneys of MLDSTZ mice, which suggest a loss of immune tolerance in the early development of DN. Conclusion: Our results demonstrate the kinetic of innate immune cells response in the early development of DN. Furthermore, our results indicate that tolerogenic CD11c + CD11b + dendritic cells may exert immune protection in the early development of DN, which should be further investigated in the treatment of DN. 50 SSSD2017_abstract_book.indd 50 09/05/17 17:14

51 OP 5 3 REPROGRAMMING ADIPOSE TISSUE STEM CELLS Nina W. Hansen 1, Rasmus Ribel Madsen 1, Benjamin Schmid 2, Bjørn Holst 2, Allan Vaag 1,4, Ninna S. Hansen 3, Camilla Scheele 3, Charlotte Brøns 1,3 1 Department of Endocrinology (Diabetes and Metabolism), Rigshospitalet, Copenhagen, Denmark 2 Bioneer A/S, Hørsholm, Denmark; 3 Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark; 4 AstraZeneca, Sweden Background/Aim: Impaired adipocyte maturation characterizes adipose tissue from low birth weight (LBW) individuals at increased risk of developing type 2 diabetes (T2D). We hypothesize that adipose tissue dysfunction in T2D may be brought on by non genetic factors, such as DNA methylation during embryonic and fetal development. Preadipocytes from 12 LBW and 13 normal birth weight (NBW) individuals have been reprogrammed to induced pluripotent stem cells (ipsc) with the purpose of generating a model for early adipocyte development. The cells have subsequently undergone a differentiation pathway to 1) mesenchymal stem cells (MSC) and 2) adipocytes. The aim of this study is to develop a protocol for the differentiation of MSCs and adipocytes from ipscs and to investigate the expression of specific adipogenic transcription factors/markers during adipocyte development. Methods: Primary adipose precursor cells were isolated from subcutaneous biopsies from LBW and NBW individuals and reprogrammed by plasmid transfection of genes encoding a combination of specific transcription factors. A protocol for mesenchymal differentiation of ipscs was subsequently tested and adapted. Further differentiation to adipocytes, and qpcr to quantify differential expression of adipogenic differentiation factors at specific time points, are being initiated. Expected Results: Measures of mrna (C/EBPs, PPARγ1, PPARγ2, FABP4, leptin) are expected to 1) exhibit differential expression profiles during adipocyte development coherent with the level of adipogenic differentiation and 2) to identify abnormalities in early adipocyte development related to the LBW phenotype. Perspectives: Further studies to characterize the developmental programming of adipose tissue stem cells in both LBW and NBW individuals with the future prospect of identifying determining stages during embryonic and fetal development of significance to the potential development of T2D. 51 SSSD2017_abstract_book.indd 51 09/05/17 17:14

52 OP 5 4 A METHOD TO PREDICT THE EFFECTS OF TRANSCRIPTION FACTOR BINDING SEQUENCE VARIANTS Suresh Raju 1, Sari Viitala 2, Suvi Kuosmanen 3, Ale Närvänen 2, Sami Heikkinen 1 1 Institute of Biomedicine, School of Medicine, 2 School of Pharmacy, and 3 A. I. Virtanen Institute for Molecular Sciences, School of Medicine, University of Eastern Finland, Kuopio, Finland Background: Single nucleotide polymorphisms (SNPs) in the DNA binding sequences have been shown to alter the binding affinity of transcription factors (TFs). Recent genome wide association studies (GWAS) have identified many SNPs associated with the risk of type 2 diabetes (T2D) that especially localize in the non coding regions of the genome, and are therefore likely to locate in the regulatory regions of genes. We provide here a systematic characterization of the DNA binding sequence variants for a known T2D risk gene TCF7L2 using a semi high throughput, non radioactive method in microarray format called Microdot ELISA. Methods: The mutated oligo sequences for the TCF7L2 binding core (20 bp) that have single and select multiple variant sets (227 oligos) were generated and arrayed onto an avidin coated glass slide as double stranded, 5 biotinylated oligos. Background fluorescence was measured using POPO dye and, after applying in vitro translated TCF7L2 protein, specific fluorescence was measured using a primary antibody for TCF7L2 and a labeled secondary antibody. Processed fluorescence intensities provided a basis for predicting of allelic effects on TCF7L2 binding for any genetic variant that compared well with a well known computational method HOMER. Subsequent relevance based filtering identified potential TCF7L2 regulatory SNPs (rsnps) among human diseaserelated SNPs. Results and Discussions: We experimentally identified a core sequence for TCF7L2 that is highly sensitive to variation. The developed method and associated data analysis has yielded 30 potential rsnps that might alter the expression of TCF7L2 target genes and thereby have an effect on disease etiology. For variant effect scoring, our method is comparable to methods that are directly derived from good quality ChIP seq data, and therefore it could provide an alternative for TFs for which the fully representative consensus binding motif is otherwise hard to obtain. 52 SSSD2017_abstract_book.indd 52 09/05/17 17:14

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