Forskningsanslag Populärvetenskaplig sammanfattning

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1 Forskningsanslag 2018 Populärvetenskaplig sammanfattning

2 Diabetesfonden beviljade forskningsprojekt 2018 Populärvetenskaplig beskrivning Projekt DIA , Hindrik Mulder, Lunds Universitet Metabolic control of islet hormone secretion. Bukspottkörtelns β-celler spelar en avgörande roll för utveckling av typ 2-diabetes (T2D). De ansvarar för sviktande insulinfrisättning, som resulterar i hyperglykemi i insulinresistenta individer. Vi studerar hur β-cellers funktion rubbas vid T2D. Därför avser vi att identifiera gener och metabola vägar ansvariga för denna utveckling. Detta möjliggörs av bioinformatiska, integrerade analyser som spänner över gener, mrna, proteiner, metaboliter till kliniska och funktionella data; dessa har samlats i en unik databas över humana pankreatiska öar. Vi kommer särskilt att studera sjukdomsalstrande mekanismer kopplade till T2D riskgenerna MTNR1B och TFB1M, vilka tidigare beskrivits av oss. För detta ändamål kommer vi att använda inducerade pluripotenta stamceller och humana insulin-producerande celler. Genom-redigering kommer att användas för att inducera eller reversera sjukdomsalstrande processer kopplade till dessa diabetesgener. Slutligen kommer vi att bedriva mekanistiska studier av MICU2, som reglerar calcium i mitokondrier, DIMT1, som kontrollerar proteinsyntes, NUDT2, som reglerar insulinfrisättning, samt ARG2, som bryter ned aminosyran arginin. Vi använder knock out-möss och insulin-producerande celler. För funktionella analyser, använder vi RNA-sekvensering, genom-redigering, metabolisk profilering och analys, samt cellulära avbildningsmetoder. Vårt arbete kan ge nya insikter i hur T2D utvecklas och leda till identifiering av nya terapeutiska mål för sjukdomen. Projekt DIA , Juleen Zierath, Karolinska Instituet Discovery of Skeletal Muscle Mediators and Exercise-Induced Adaptations Governing Insulin Sensitivity in Type 2 Diabetes Type 2 diabetes is a life threatening metabolic disease reaching epidemic proportions. We have shown that patients with type 2 diabetes are characterized by insulin resistance in skeletal muscle and that exercise can counteract this defect. Type 2 diabetes shares features of accelerated aging including insulin resistance, defective oxidative metabolism/mitochondrial function and loss of muscle mass. Strikingly, exercise programs mitigates secondary aging and reduces disability and mortality. This program is designed to fill a therapeutic void by identifying and validating exercise-responsive treatment targets to mitigate secondary aging and prevent metabolic disease.

3 We will test the hypotheses that: Discrete molecular targets induced by exercise play a role in skeletal muscle plasticity of substrate metabolism and muscle mass. Skeletal muscle communicates with other organs to confer the beneficial effects of exercise on whole-body health. Many of the adaptive responses of skeletal muscle to exercise training can be mimicked by genetic manipulation and/or drug treatment. The groundbreaking nature of this work leverages a deep dive into exercise biology to discover new inroads into prevention and treatment of type 2 diabetes. The overarching goal is to identify and validate molecules, pathways and ultimately new treatments that confer the benefits of exercise to improve insulin sensitivity, preserve mitochondrial energetics and attenuate loss of strength and power. Projekt DIA , Jorge Ruas, Karolinska Institutet Neurturin, a novel myokine that promotes muscle glucose uptake and oxidative metabolism Physical exercise is a very efficient way to improve systemic energy metabolism, muscle insulin sensitivity, glucose uptake, and oxidative metabolism. Conversely, these are processes that become impaired in diabetic patients. However, it is not always possible to use exercise as a therapeutic approach for reasons that range from patient compliance, to exercise-intolerance inherent to the disease. Therefore, the search for factors that mediate the effects of exercise on glucose homeostasis is of great importance to develop novel antidiabetics. We have identified a muscle-secreted factor named Neurturin (NRTN) using an in vitro system designed to find factors that positively affect the neuromuscular junction. To evaluate the systemic effects of prolonged NRTN secretion from muscle, we generated a skeletal muscle-specific transgenic mouse that expresses NRTN under the human alpha-skeletal actin promoter (HSA- NRTN mice). Surprisingly, the HSA-NRTN mice display a remarkable increase in muscle oxidative metabolism, vascularization, and glucose uptake. This project aims to explore the therapeutic potential of NRTN as an antidiabetic biological. We propose to investigate the mechanism of action of NRTN on skeletal muscle, as well as evaluate its potential as an antidiabetic drug in vivo. Since NRTN is a secreted molecule adapted to signal through the extracellular milieu, this could result in quick translation into human studies once the preclinical validation is completed.

4 Projekt DIA , Anders Tengholm, Uppsala Universitet Cellular control mechanisms for glucagon secretion Glucagon is critical for normal glucose homeostasis and aberrant secretion of the hormone aggravates the dysregulated glucose control in diabetes patients. The mechanisms regulating glucagon secretion from pancreatic alpha-cells nevertheless remain poorly understood. The proposed studies will use live-cell fluorescence imaging techniques and kinetic secretion assays to elucidate the signalling processes in pancreatic islet cells that regulate glucagon secretion in hypo- and hyperglycaemia. The studies will test the hypothesis that direct (intrinsic) glucosesensing mechanisms in alpha-cells, involving camp and Ca2+-store-operated pathways, regulate secretion during hypoglycaemia, while paracrine signalling from beta- and delta-cells determine the glucagon release pattern during hyperglycaemia. Another aim is to clarify the mechanisms underlying regulation of glucagon secretion by incretin hormones. Results with islets from mice and healthy human donors will be compared with those from diabetic donors and in vitro diabetes models. As a complement to scarcely available human alpha-cells we will explore the utility of glucagon-releasing cells derived from human pluripotent stem cells. Clarification of the cellular control mechanisms for glucagon secretion will provide a basis for correction of hyperglycaemia and restoration of normal glucose counter-regulation in both type 1 and type 2 diabetic patients. Projekt DIA , Anna Krook, Karolinska Universitetet Skeletal muscle contraction-derived factors and metabolites regulating insulin sensitivity. Our research objective is the identification of circulatory factors, metabolites and key signalling pathways regulating skeletal muscle insulin sensitivity. We will use exercise/muscle contraction as a starting point to identify candidates. We will study potential secreted cytokines/myokines, but also focus on changes in metabolites which have received little attention to date. Interesting candidates will be studied for direct effects on skeletal muscle, with the aim to improve reduced insulin-sensitivity in type 2 diabetic skeletal muscle. The ultimate validation of identified candidates is in vivo validation. The focus of this research proposal is to probe the function of signals and metabolites emanating from contracting or exercised skeletal muscle. These factors may have autocrine effects on skeletal muscle itself, but may also function to change whole body metabolism. While type 2 diabetes is associated with insulin resistance, exercise training enhances insulin sensitivity and leads to changes in inflammatory signals in skeletal muscle. Thus, it is important to understand the balance of different immunometabolic signals and how they impact insulin sensitivity. Although, the nature of the skeletal muscle secretome is incomplete, proteomic and metabolomics studies provide evidence that multiple factors are present in circulation, many of which may be of skeletal muscle origin.

5 Projekt DIA , Barbara Cannon, Stockholms Universitet Brite/beige adipocytes - a potential tool against obesity and diabetes? Obesity is not only a significant problem in itself but is also the major inducer of type 2 diabetes. At present there is no satisfactory treatment for obesity and, in reality, little understanding of the cause of obesity. The identification of a novel type of adipocytes, i.e. the brite/beige adipocytes, that possess the ability to increase energy expenditure and that are localized within the white adipose depots themselves, has provided a basis for studying new opportunities. It is the goal of the studies described here to gain insight into the functional significance of the distinct populations of brite/beige adipocytes. Considering the vast implications of the obesity epidemic for development of type 2 diabetes, even modest amelioration of energy balance may be of significance. The studies of brite/beige adipocytes proposed here could represent one means of developing methods to accomplish such amelioration. Projekt DIA , Ulf Smith, Göteborgs Universitet Type 2 Diabetes - novel markers and mechanisms Insulin resistance is recently shown to be an important risk factor for diabetic complications; both macrovascular complications and microvascular kidney disease - the most common cause of kidney transplantations. We have identified mannose as a biomarker of insulin resistance and risk of developing these diabetes-associated complications. We found mannose to be an insulinregulated metabolite mainly from the liver and we have also found that it can play a role in hepatic glucose production. We are also expanding on our recent findings that BMP4 is an important regulator of both white and beige/brown adipogenesis and whole-body energy expenditure preventing development of obesity in mouse models. We have now also found that BMP4 targets peripheral tissues and increases insulin sensitivity in obesity independent of any changes in body weight. Moreover, BMP4 exerts insulin-like effects in liver cells and inhibits key enzymes involved in gluconeogenesis. We are now working to identify cellular mechanisms and examine the possibility to develop agonists. An additional focus is based on our recent findings that the reduced subcutaneous adipogenesis in individuals with genetic predisposition for T2D is due to increased progenitor cell senescence which both inhibits adipogenesis and drives inflammation and insulin resistance. This impairment is associated with a dysregulated TP 53 protein but the molecular mechanisms for this remain to be identified.

6 Projekt DIA , Giovanni Solinas, Göteborgs Universitet Defining the role of specific Class-1 PI3Ks in glucose homeostasis and adiposity to treat obesitydriven diabetes. Class-1 phosphoinositide 3 kinases (PI3K) activity mediate insulin actions in glucose homeostasis and lipolysis. PI3K signaling in hepatic glucose production and adipose tissue lipolysis play opposing roles in the pathogenesis of obesity-driven diabetes; whereas PI3K activity in the liver maintains glucose homeostasis, PI3K inhibition along the brain-adipose axis may promote lipolysis and thermogenesis, reducing adiposity and improving insulin sensitivity in obese individuals. There are four PI3K: PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ whose role in glucose production, lipolysis, and thermogenesis remains largely unresolved. Here we describe a series of experiments aiming at defining the role of each PI3K isoform in glucose homeostasis and in adipose tissue lipolysisthermogenesis. To achieve this aim we will integrate studies using genetically modified mice lacking specific PI3K isoform in selected tissues with primary cell culture studies using primary hepatocytes and adipocytes from mice and humans. Our final goal is to target specific PI3K isoforms implicated in the promotion of adiposity without affecting PI3K isoforms mediating insulin suppression of hepatic glucose production. Because pharmaceutical companies are developing isoform-specific inhibitors of different class-1 PI3K, our results may be readily translated to clinical settings by repurposing specific isoform-selective PI3K inhibitors to the treatment of obesity-driven diabetes. Projekt DIA , Charlotta Ling, Lunds Universitet Can our epigenetics findings be translated to diabetes patients? Over the last 15 years, we have investigated if epigenetics affect type 2 diabetes (T2D). We have identified epigenetic changes in islets, muscle, fat and liver from T2D versus control subjects. We showed that age, obesity, diet and exercise affect the human epigenome. However, it remains unknown if epigenetics cause T2D and if it can be translated to patients. This proposal aims to understand if epigenetic changes cause T2D and will use epigenetic tools for precision medicine. Novel methods will be used on clinical samples. 1. We will use epigenome screens to discover epigenetic changes that cause T2D. We will construct grna libraries based on knowledge of epigenetically regulatory regions in T2D subjects. Cells will be transduced with grna libraries followed by functional readouts and analysis of methylation. 2. We will test if epigenetics can be targeted for treatment of T2D. We will correct unfavorable epigenetic states using epigenome-editing to explore if epigenetics may be targeted for T2D treatment. We will also explore the use of epigenetic inhibitors in T2D.

7 3. We will develop epigenetic biomarkers for prediction of T2D, diabetic complications (CVD) and response to treatment. DNA methylation will be analyzed in blood samples from prospective cohorts for T2D, CVD and response to metformin by Illumina arrays. Generating epigenetic therapy for T2D and biomarkers that will predict disease and response to treatment would impact millions of people worldwide. Projekt DIA , Olle Korsgren, Uppsala Universitet Azithromycin Insulin Diet Intervention Trial in children with Type 1 Diabetes. The objective of the Azithromycin Insulin Diet intervention trial (AIDIT: EudraCT Number: ) is to preserve beta cells in children newly diagnosed with Type 1 Diabetes. All participating children (6-16 years old, n=60) will receive standard of care. In addition, children randomized to the AIDIT protocol will receive: 1. Azithromycin, a macrolide antibiotic, for 52 weeks to prevent bacteria-induced inflammation, by its direct anti-bacterial effect and its anti-inflammatory effect. In addition, its prokinetic activity is expected to reduce the reflux from the duodenum to the pancreas. 2. Intensified supervised high dose insulin infusions to achieve increased beta cell rest based on the finding that islets from subjects with T1D can recover upon culture in a non-diabetic but hyperinsulinaemic environment, and on the notion that beta cell stress is an important contributor to beta cell loss. 3. Dietician support Personalized nutritional advice on intake of carbohydrates, fat and protein will be given to in order to reduce insulin resistance. By giving nutritional advices on less volume of the meals, especially of the fluid (maximum 300 ml per meal), and by trying to extend the meal time to at least 20 minutes, the reflux into ductus pancreaticus might be reduced. The effect of the AIDIT protocol will be evaluated with Mixed Meal Tolerance Test (MMT) as well as other secondary endpoints to explore the effect on preservation of beta-cell function after 12 months.

8 Projekt DIA , Bryndis Birnir, Uppsala Universitet GABA regulation of the inflammatory environment. Today, type 1 diabetes (T1D) is a chronic disease that cannot be prevented or cured and insulin injections are required for survival of the patients. Here we study the regulation by the neurotransmitter GABA (gamma-aminobutyric acid) of the inflammatory environment generated by peripheral T cells. GABA activates GABA-A receptors (GABAAR) on T cells. Our recent results demonstrate that GABA, at concentrations present in blood and normally also in the pancreatic islets, effectively regulates release of a vast number of cytokines from peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. But we still do not know the GABA-activated cellular pathways and check-points resulting in inhibition of the cytokine release. We postulate that GABAARs are located together with CRAC/Cav2+ ion channels and intracellular signalling molecules in complexes that include proteins both in the membrane and in the cytoplasm. In this way GABA can activate selective, local pathways that then regulate targeted signalling pathways and gene transcription. GABA concentrations in plasma correlate with expression of cholesterol biosynthesis pathway genes in T cells and six genes in this pathway are down-regulated in T1D. How cholesterol impacts GABA signalling is an important area of our studies. We use state-ofthe-art techniques to study T cells from non-diabetic and T1D donors. Our data will subsequently be used to provide novel targets for therapeutic intervention of T1D. Projekt DIA , Åke Lernmark, Lunds Universitet Dissecting early islet autoimmunity. Islet autoimmunity is triggered early in life. One type of islet autoimmunity is that autoantibodies against insulin (IAA) are the first appearing biomarker for islet autoimmunity in 1-3 year olds with HLA DR4-DQ8. An enterovirusinfection may be the trigger. The second type of islet autoimmunity has a different pattern. GADA first appear also after a different enterovirusinfection but primarily in children with DR3-DQ2. GADA first appeared about after 1-2 years of age, increased to a peak at 3-4 years of age and then staying constant in children with the DR3-DQ2 haplotype. About 60 % of the children developed a second autoantibody within one year. Children who have developed one persistent autoantibody have a 15% risk to be diagnosed with diabetes within 10 years, with two are more autoantibodies the risk is 70%. We test the overall hypothesis that the appearance of additional autoantibodies are genetically controlled and best understood by combining cellular with autoantibody tests. We aim at dissecting the early islet autoimmunity i three specific aims: 1) to combine genetic factors with islet autoantibody including TSPAN7 testing to predict type 1 diabetes in children diagnosed before 15 years of age; 2) to determine in cellular analyses HLA-DR-DQ expression in relation

9 to islet autoantibodies and 3) establish high-sensitivity Luciferase Immuno Precipitation System (LIPS). The assay work without radioactive methionine which hamper progress in the clinic. Projekt DIA , Erik Renström, Lunds Universitet Mechanotransduction is a novel signaling modality in insulin secretion - Role of unorthodox ion channels. Genetics and epidemiology of type 2-diabetes have identified the insulin-producing beta-cell as a central culprit. Future developments rely on the consensus model for glucose-stimulated insulin secretion. However, this model is incomplete and does not fit with all experimental observations. Mechanosensitive PIEZO channels acting in concert with water channels AQUAPORINS could provide the missing link. How? Probably as part of a novel signaling modality, mechanotransduction, that is based on glucose-induced beta-cell swelling, as reported independently by different groups. This increases membrane tension leading to activation of PIEZO channels, which conduct a depolarizing Na+, K+ and Ca2+ conductance that fills a missing gap in the current model. The hypothesis that mechanotransduction affects beta-cell function and type 2-diabetes is investigated using clinical materials from islet donors and RNA sequencing of human islets. Functional studies in human islets, rodents and cell line models will define how PIEZO gene expression is regulated, signals that activate PIEZOs and which beta-cell processes it controls (electrical activity, secretion, gene expression). To this end we use: single-cell electrophysiology, in vivo animal tests, superresolution and confocal immunocytochemistry, microfluorimetry of Ca2+ signals and membrane potential, as well as a novel nanotechnology approach developed in-house to expose beta-cells to mechanical forces in a controlled fashion.

10 Projekt DIA , Ingrid Wernstedt Asterholm, Göteborgs Universitet Adipose Tissue Functionality in the Pathogenesis of Type-2 Diabetes. Dysfunctional adipose tissue increases the risk for type-2 diabetes through impaired energy storage capacity and altered release of adipocyte-derived hormones (adipokines), metabolites and possibly also extracellular vesicles. These pathological changes lead to deleterious ectopic lipid deposition, chronic inflammation and insulin resistance associated with an increased risk for developing type-2 diabetes. In this project, we will focus on mechanisms underlying altered release of adipokines, metabolites and extracellular vesicles, as well as the effects of such factors on whole-body metabolism and pancreatic beta cell functionality. Based on our preliminary data we hypothesize 1) that reduced adipocyte levels of the ER calcium pump SERCA2 mediate many of the pathological changes observed in obese adipose tissue, 2) that acute changes in extracellular succinate levels have profound effect on regulated exocytosis in both adipocytes and pancreatic beta cells and 3) that adiponectin regulates both beta cell hyperplasia and insulin release. To test these hypotheses we will use mouse models, cultured adipocytes, isolated mouse and human islet, and several different methodologies ranging from classical electrophysiology to in vivo studies of metabolism. We believe a successful outcome of this project will provide a firm base for future diabetes research and hopefully lead to new therapeutic targets for the treatment of type-2 diabetes. Projekt DIA , Annika Rosengren, Göteborgs Universitet Diabetes from youth to midlife causes, trends, and consequences. Individuals with type 1 diabetes have markedly increased risk of cardiovascular disease (CVD) compared to non-diabetic individuals. The chief burden of diabetes, however, consists of type 2 diabetes and with increasing rates of severe obesity in young people, type 2 diabetes may well be the predominant type of diabetes also in the young in the future. Through prior work we have established improving prognosis in diabetes, although very few people attain the level of risk factor control that will insure normal survival in type 2 and practically none in type 1. In this project we will combine data in Swedish registers to Estimate the effect of BMI, particularly of severe obesity, in adolescence for the development of early diabetes type 2 in 1.6 million young men Study trends in incidence and prevalence of diabetes type 2 in younger and older persons Compare outcome (CVD, other complications, and mortality) between individuals with type 1

11 and with type 2 diabetes by age Compare birth cohorts of young adults with diabetes type 1 with respect to mortality and early complications from childhood Investigate the effect of socioeconomic disparities on cardiovascular disease and death Through creating new knowledge from combining Swedish registers we can achieve better prevention in the future. Projekt DIA , Charlotta Olofsson, Göteborgs Universitet Molecular and cellular regulation of white adipocyte adiponectin secretion in health and in metabolic disease. The white adipocyte hormone adiponectin protects against development of type 2 diabetes and circulating levels are decreased in diabesity. Although the physiological importance of adiponectin is clear, the molecular and cellular regulation of its secretion remains inadequately investigated. Own research has provided a first model of that adiponectin is secreted via vesicular camp/adrenergically stimulated exocytosis. We have moreover defined controlling mechanisms that are disrupted in adipocytes isolated from obese/diabetic mice. Here we aim to further develop our pathophysiological understanding of how adiponectin secretion is controlled. We will: 1) Characterise the dynamics and molecular control of adiponectin vesicle exocytosis; 2) Define the role of caveolae and exosomes for exocytosis of different adiponectin molecular forms; 3) Determine the role of sympathetic innervation for control of adiponectin secretion. We will combine high-resolution imaging of adiponectin vesicle dynamics and release with electrophysiology and novel molecular biology tools. Adipose tissue targeted gene transfer will allow us to define the molecular regulation, ex vivo and at the systemic level in lean and obese/diabetic mice. Access to human adipose tissue and serum will enable us to verify the translational relevance of our studies. The research described in this proposal will hopefully pave the way for successful future prevention and treatment of metabolic disease.

12 Projekt DIA , Johnny Ludvigsson, Linköpings Universitet Innovative approaches to preserve residual insulin, especially Intra-lymphatic Autoantigen Injection Therapy, in Type 1 diabetes. Trots daglig intensiv behandling leder T1D till både livshotande komplikationer. Om kvarvarande insulinsekretion kan bevaras blir sjukdomen mildare.gad-vaccination gav lovande resultat i så k Fas II-studier och tecken på toleransutveckling iimmunförsvaret., men Fas III studie gav otillräcklig effekt. Bayesian analys visar att GAD-alum med >97% sannolikhet har effet ( C Beam et al Diabetologia 2017) och fortsatta försök rekommenderas. I en öppen studie (EDCR) på 10 svenska barnkliniker har 20 nyinsjuknade T1D patienter behandltas med Etanercept (Enbrel), en TNF-alfa-inhibitor,i kombination med GADalum 20 mikrog sc x 2. Uppföljning pågår. DIAGNODE-1 är ett pilotprojekt där vi studerar säkerhet, effekt på immunförsvar och förmåga att bilda insulin hos 12 patienter med T1D i åldern år. Parallellt med Vitamin D 2000 enh/d Dag har de fått 4 mikrog GAD-alum direkt i lymfkörtel Dag 30,60,90. Uppföljning efter 6,15, 30 månader. Resultaten har varit uppmuntrande med Th2- deviation, tecken på T-cellsregulation, och efter15 mån har faste-c-peptid i genomsnitt varit närmast oförändrat, C-peptid AUC efter MMTT sjunkit ca 15% ( dvs mindre än hälften av förväntat), medan insulinbehov och HbA1c har sjunkit. Vi har nu påbörjat DIAGNODE-2, en dubbelblind randomiserad placebokontrollerad studie med 106 patienter med i övrigt samma design som DIAGNODE-1. Betydelse: Skulle vi lyckas rädda viss kvarvarande insulinsekretion, så vore det ett stort framsteg till stor klinisk nytta. Projekt DIA , Eva Degerman, Lunds Universitet What is the role for the insulin signaling system in the inner ear-implications for insulin resistance and diabetes. We will evaluate the role for the inner ear, the organ for hearing and balance, as a target for insulin action and diabetes. For that purpose we will [1] map insulin signaling networks in the inner ear [2] evaluate the impact of diabetes on inner ear fluid homeostasis in mice [3] initiate studies on inner ears in patients with diabetes. Expertise in different areas will meet in this project to work at the interface of cellular signaling, diabetes and the inner ear applying a range of techniques. We will [1] use human tissues and a unique auditory cell-line to map insulin signaling networks in the inner ear using immunohistochemistry, Tirf microscopy, and western blot in combination with biochemical assays and molecular biology tools [2] evaluate the impact of diabetes on inner ear fluid homeostasis in mice using endolymphatic hydrops, a hallmark of inner ear dysfunction as readout and MRI as method. Diabetes will be studied in relation to risk factors for inner ear dysfunction like noise, high levels of vasopressin and selected phosphodiesterase inhibitors and

13 in relation to drugs of relevance for prevention [3] put an inne ear perspective to novel subgroups of diabetes (Ahlqvist et al, Lancet). A new target for insulin action will be explored which will have impact on basic knowledge of inner ear ion and fluid homeostasis. The most important aspect is to highlight the inner ear in the context of hearing and balance impairments in patients with diabetes. Projekt DIA , Unn-Britt Johansson, Sophiahemmet Högskola Att leva med typ 1 diabetes och att tillämpa stresshanteringsstrategier som utgår ifrån Acceptance and Commitment Therapy. Endast 21 % av personer med typ 1 diabetes når målet för glukoskontroll, HbA1c < 52 mmol/mol. Tidigare forskning visar att typ 1 diabetes har en avgörande påverkan på välbefinnandet och att det finns en ökad förekomst av bl.a. stress, oro, och depression hos de som lever med sjukdomen. I flera studier, liksom i nationella och internationella riktlinjer ges uppmaning om ökat engagemang kring de psykologiska aspekterna av att leva med diabetes. I nuläget finns ett fåtal kvalitativa studier som djupare beskriver hur det är att leva som vuxen med typ 1 diabetes och det finns ett tydligt behov av att utveckla metoder som syftar till att underlätta livet för dem som lever med typ 1 diabetes. Acceptance And Commitment Therapy (ACT) är en psykologisk behandlingsform som fått ökad uppmärksamhet de senaste åren. Det övergripande syftet är att i en RCT-studie utvärdera effekterna av ett ACT-baserat stresshanteringsprogram för vuxna personer med typ 1 diabetes (n=70)och i en kvalitativ intervjustudie (n=20) beskriva erfarenheter och upplevelser av hur det är att leva som vuxen med typ 1 diabetes. Ytterligare ett syfte är att psykometriskt utvärdera (n=120) den svenska versionen av självskattningsformuläret Acceptance and Action Diabetes Questionnaire (AADQ) som mäter acceptans för diabetesrelaterade tankar och känslor. I RCT-studien görs mätningar av HbA1c, egenvård, stress och livskvalitet före och efter programmet samt vid flera uppföljningar upp till 5 år. Projekt DIA , Ulf Risérus, Uppsala Universitet Liver fat and de novo lipogenesis as novel targets for dietary treatment of type 2 diabetes and prediabetes. Fatty liver precedes liver disease and predicts type 2 diabetes. Hepatic de novo lipogenesis synthesize fatty acids from glucose. Dysregulation of this key metabolic pathway promotes fatty liver, hepatic insulin resistance and dyslipidemia. As lipogenesis is induced by both refined carbohydrates and saturated fat, but inhibited by polyunsaturated fatty acids (PUFA), we hypothesized that such specific dietary therapy for up to 2 years effectively reduces liver fat and thereby improve the multiple hepatic metabolic disorders typical for type 2 diabetes. Persons with prediabetes and diabetes will be randomized to one of three groups; 1) Anti-lipogenic diet

14 relatively low in carbohydrates and saturated fat, but high in PUFA 2) 'Healthy Nordic diet' low in saturated fat, but higher in fiber-rich carbohydrates 3) Control group (initial dietary advice, usual care ). Liver fat will be determined by MRI. Changes in liver fat will be linked to changes in DNL and measures of insulin sensitivity and glucose metabolism. To gain metabolic insights of potential diet-induced mechanisms, we will also investigate changes in gut microbiota, lipidome and conduct genetic studies to gain information on individual responses to diets. Besides potentially large clinical benefits of potential importance for long-term treatment of type 2 diabetes, this study could provide new knowledge how modulations of liver fat and DNL may translate into metabolic improvements. Projekt DIA Albert Salehi, Lunds Universitet VDAC1 a common denominator of β-cell and endothelial cell dysfunction in T2D with its complications. β-cell failure precipitates T2D in insulin-resistant obesity. β- and endothelial cell (EC) dysfunction results from glucotoxic episodes during the years of prediabetes. We show that glucotoxicity impairs ATP production in β-cells and ECs, due to overexpression and cell surface mistargeting of the mitochondrial membrane protein VDAC1. This causes ATP loss, whose attenuation with VDAC1 inhibitors restores cell function. Daily injections of a VDAC1 inhibitor prevent the onset of hyperglycemia in db/db mice. Amyloid precursor protein (APP) is present in β-cells and ECs. Neuronal surface expression of VDAC1 is seen early in Alzheimer s disease (AD), having comorbidity with T2D. Therefore, our main AIMS are: 1) To clarify the mechanisms of VDAC1 mistargetting to the plasma membrane under glucotoxic condition. 2) To elucidate the putative implication of APP and amyloid-beta (Aβ) in β-cell and in EC dysfunction in relation to VDAC1 by measuring APP and Aβ generation after glucotoxicity in human islets and islets of diabetes protected TRL4-KO mice. 3) To study the role of APP in impaired glucose-stimulated insulin secretion in islets during glucotoxicity using APP-knockout mice and in APP-silenced ECs. 4) To characterize membrane translocation of VDAC1 in β-cells and its impact on beta-cell dysfunction and progression of diabetes in APP/PS1 mice, a model of AD/T2D. The proposed studies should contribute to novel therapies for the prevention of T2D and its organ complications. Projekt DIA , Olof Idevall Hagren, Uppsala Universitet Regulation of beta cell function through its primary cilium. Primary cilia are present on most cells, and defects in cilia structure or function are the cause of ciliopathies, a group of diseases that present with obesity and often associate with type-2

15 diabetes. The role of primary cilia in the regulation of neuronal cell function is well characterized, but very little is known about its role in other post-mitotic cells, including those of the pancreatic islets of Langerhans. In this project, we will develop tools that enable direct measurements of cilia signaling in cells of the intact islets, and by combining these with high resolution live cell imaging determine the role of these structures in the regulation of islet cell function. We hypothesize that the primary cilia function as sensory antennas within the islets that facilitate long-range communication both between endocrine cells of the islet and between endocrine cells and intra-islet neurons, and that this facilitation is of importance for synchronizing and regulating hormone secretion. The aim of this study is to determine the role of primary cilia in the regulation of islet cell function. Projekt DIA , Katarina Hjelm, Uppsala Universitet Utveckling och test av modell för vård och utbildning av utlandsfödda personer med Typ 2 diabetes samt stöd för anhöriga. Diabetes typ 2 utgör en pandemi främst drabbande sårbara grupper som migranter. Våra tidigare studier har visat skillnader i uppfattningar om hälsa/sjukdom mellan utlands-och svenskfödda personer. Svensk vård har inte upplevts svara mot utlandsföddas personers behov. Syfte: att i samverkan med vårdpersonal utveckla/testa en modell för undervisning/vård i en interventionsstudie (RCT) med 3 års uppföljning och att undersöka stöd av anhöriga. Baserat på tidigare studier testas hypoteserna att utlandsfödda med typ 2 diabetes har lägre kunskaper/riskmedvetenhet om diabetes vilket inverkar på benägenheten till egenvård och undervisning utgående från individen kan ändra detta. En strukturerad intervjuundersökning (tolk vid behov) och HbA1C värde av samtliga kända utlandsfödda med typ 2 diabetes med svenska kontroller har genomförts som baslinjemätning och underlag för modell som nu testas i olika grupper. Undervisningen genomförs med tolk och videofilmas för studium av kommunikationen. Resultatet följs med samma metod som i baslinjemätningen och fokusgruppsintervjuer efter avslutad undervisning, 3 mån,1 och 3 år därefter. Anhöriga intervjuas individuellt. Studier saknas där undervisning av personer med utländsk härkomst utvärderats liksom bevis för vilken undervisningsmetod som ger bäst effekt och behövs då Sverige är ett mångkulturellt land med ökande kontakter med utlandsfödda i vården. Anhöriga är en underutnyttjad/behövd resurs i vården men inverkan på egenvården är ej studerat.

16 Projekt DIA , Marju Orho Melander, Lunds Universitet An integrative multi-omics approach to understand causal inferences between gut microbiome and cardio-metabolic health in two large longitudinal Malmö cohorts. AIMS: To clarify the relation between diet intakes, genetic factors, circulating metabolites and proteins and gut microbiota composition, diversity and functionality (GMCDF), and how they relate to risk of type 2 diabetes, cardiometabolic disease (CMD) traits and cardiovascular complications (CVD) in two large population based cohorts; the Malmö Offspring Study (MOS, N2020=5-6000, to date 3300) and SCAPIS-Malmö (N=4526). METHODS: We investigate how dietary factors are connected to GMCDF and how GMCDF associates with CMD risk traits and incidence of T2D and CVD. By GWAS we identify genetic variants that associate with GMCDF and metabolite levels, and by Mendelian Randomization (MR) we study causal connections between GMCDF, metabolites and T2D, CMD and CVD. By integrative deep learning we elucidate connections in multi-omic data and their usefulness in predictive abilities. TIMEPLAN: Metagenomics completed 2019 (SCAPIS-Malmö) and 2020 (MOS). First prospective data Multi-omics completed Prospective studies (N~10,000) with replication in Scapis-Uppsala (N~5000). NOVELTY AND IMPORTANCE: Gut microbiome variation in overall healthy population has remained under-investigated and prospective studies are lacking. Integration of multi-omics data for MR analyses and deep-learning approaches have not been earlier used to investigate GM. This project provides insights into the hierarchy of mechanisms and causal inferences that may link GM to T2D CMD and CVD. Projekt DIA , Martina Persson, Karolinska Institutet Insulinresistens, fettväv och hjärt-kärlfunktion hos unga individer med typ 1 diabetes. Trots modern diabetesvård är medellivslängden avsevärt kortare för individer med typ 1 diabetes. Den ledande dödsorsaken är hjärtkärlsjukdom. Att behandla högt blodtryck, höga blodfetter och ev njurpåverkan är viktiga åtgärder för att minska risken för hjärtkärlsjukdom. Gemensamt för dessa riskfaktorer är insulinresistens. Insulinresistens är också en oberoende riskfaktor för hjärtkärlsjukdom vid diabetes, även då hänsyn tagits till blodsockerkontroll etc. Hos individer utan typ 1 diabetes medför fetma, ffa fetma centralt i buken, insulinresistens. Fetma blir allt vanligare hos barn/ungdomar med typ 1 diabetes. Hur total och regional fettvävsmassa påverkar insulinkänsligheten vid diabetes är dock oklart.tarmens bakterieflora (mikrobiom) är också mycket betydelsefull för insulinkänsligheten. Vid typ 1 diabetes och/eller fetma är mikrobiomet förändrat. I modern diabetesbehandling eftersträvas nära normala blodsocker med så liten variabilitet som möjligt. Det är svårt att uppnå. Evidens för att minskad

17 blodsockervariabilitet medför minskad risk för hjärt-kärlkomplikationer saknas. I det aktuella forskningsprogrammet avser vi att hos unga individer med typ 1 diabetes undersöka; a) hur totala och central fetma påverkar insulinkänsligheten och dess effekter b) hur blodsockervariabilitet påverkar hjärtfunktion och blodkärlen c) om behandling med antidiabetika (metformin) och/eller synbiotika (mikrobiom+fibrer) kan förbättra insulinkänslighet och minska fettvävsmassa. Projekt DIA , Jens Lagerstedt, Lunds Universitet Lipoproteins in diabetes and myocardial infarction. Individuals with diabetes have a two- to three-fold increased risk of cardiovascular disease, and two-thirds of patients with myocardial infarction have either diabetes or impaired glucose regulation. Metabolic inflexibility with increased utilization of fatty acids as the oxidative energy source has been proposed to contribute to the impaired cardiac function, and has also been linked to worsened outcome in the reperfusion phase after an ischemic event. The mechanism for this is not clear and requires further research. There is also a need to find intervention strategies to reduce the severity of myocardial infarctions. We have shown that the apolipoprotein A-I (ApoA-I, the major protein of high-density lipoprotein HDL), and a peptide derived from the ApoA-I sequence (RG54 peptide), prevents hyperglycemia by activation of glucose uptake by skeletal and cardiac muscle, and by priming pancreatic beta cells for improved glucose-stimulated insulin secretion. In addition, clinical formulations of ApoA- I with phospholipids has recently shown promise in the treatment of myocardial infarction. With relevance for individuals at high cardiometabolic risk and/or with diabetes, we aim to investigate the biology and therapeutic potential of the RG54 peptide in restoring metabolic flexibility in the heart and in reducing severity of myocardial infarction, as well as to explain the mechanism-of-action of ApoA-I protein and RG54 peptide on improved insulin secretion and islet function. Projekt DIA , Carina Sparud Lundin, Göteborgs Universitet Comparative effectiveness of transitional care models for adolescents with Type 1 diabetes in the transition to adulthood: The STEPSTONES-DIAB project. The transfer of young people with type 1 diabetes (T1D) to adult care occurs during a critical period of life, while many young people with T1D have unsatisfactory glycemic control. The preparation to take over responsibility for their health and self-care as well as increasing their participation in care are important aspects for strengthening people's own ability, an important component of person-centered care. STEPSTONES-DIAB aims to evaluate the effectiveness of

18 different transitional care models in adolescents with T1D to empower them to become active partners in their care. The study is conducted at three hospitals in Stockholm, Sweden. In two hospitals 140 patients will be randomized to either a structured, person-centered transition program over a 2-year period or to usual care. The third hospital with a dedicated youth clinic will serve as a comparison group, 70 patients will be included at the youth clinic. This type of youth clinic is unique in Sweden and has not previously been evaluated. Outcome measures is empowerment, participation and responsibility in care, health status, glycemic control as well as the participants' experiences of care during transfer. Projekt DIA , Johanna Lanner, Karolinska Institutet Mitocentric approach to improve limb muscle function in peripheral artery disease associated with type II diabetes. Comorbidities of type II diabetes (T2D) are major health concerns worldwide, including peripheral artery disease (PAD). PAD induces an ischemic injury that manifests as muscle dysfunction that can lead to long-term disability. There is a need of novel therapeutic approaches directed at counteracting the muscle myopathy of T2D-associated PAD. Recent findings pinpoint mitochondrial dysfunction as a pathological link between T2D and PAD in skeletal muscle. By including patients with T2D-associated PAD and mouse-models, we here aim to identify mitochondrial sites that contribute to the progression of diabetes-associated PAD. A unique combination of in vivo and in vitro techniques will be used to study altered mitochondrial function, e.g. live confocal imaging in single mouse muscle fibers for compartment-specific realtime quantifiable measurements of reactive oxygen species; respirometry to assess oxygen consumption and substrate utilization, and multiplex kinase activity and RNA-seq to identify functional molecular targets and gene expression differences, respectively, in muscle mitochondria. Moreover, we will manipulate the identified mitochondrial sites in the attempt to improve skeletal muscle function in diabetes-associated PAD. Our results will identify novel mitochondrial targets in the search for new therapeutic interventions to improve muscle function in diabetes-associated PAD, which ultimately can contribute to increased quality of life for the afflicted patients. Projekt DIA , Olov Rolandsson, Umeå Universitet Intervention med kost, motion och metabol kontroll för att förhindra insjuknande i allvarlig neurokognitiv sjukdom hos personer med typ 2 diabetes och lätt nedsatt minnesfunktion en pilotstudie. Individer med typ 2 diabetes har en nästan fördubblad risk att utveckla demenssjukdomar jämfört med personer utan diabetes. Om individer med typ 2 diabetes dessutom har en mild minnesstörning föreligger ökar risken ytterligare för att utveckla demenssjukdomar. Man tror att

19 den ökade risken förmedlas via en kombination av höga blodsockernivåer, högt blodtryck, höga blodfettsnivåer, låg fysisk aktivtet och övervikt. Vårt nationella nätverk söker medel för att genomföra en pilotstudie med en multifaktoriellt intervention med medelhavskost, ett individualiserat program för att öka fysisk aktivitet samt optimal diabetesbehandling bland personer som har typ 2 diabetes och samtidig mild minnesstörning. Pilotstudien omfattar 150 personer som rekryteras och randomiseras till interventionsgrupp eller till en kontrollgrupp som får sedvanlig information och behandling av sin typ 2 diabetes. Syftet med pilotstudien är att studera om vi kan rekrytera dessa personer, ifall deltagarna utför interventionen under ett år och kan bibehålls i studien efter två år samt om interventionen har effekt på metabola markörer och minnesfunktion efter tre år. Om pilotstudien är framgångsrik kommer vi genomföra en fullskalig studie och om den blir framgångsrik så kommer det att medföra en bibehållen livskvalitet, längre liv och minskad risk för följdsjukdomar hos personer med typ 2 diabetes och mild minnesstörning. Studien kommer att vara världsunik avseende frågeställning och målgrupp. Projekt DIA , Anna Möllsten, Umeå Universitet Physical, psychological and socioeconomic effects of childhood onset diabetes in Sweden - longitudinal register-based studies. We study time trends of childhood-onset type 1 diabetes and its most serious complication, endstage renal disease. We will further analyse physical, psychological and socio-economic longterm effects on patients and families to identify potentially preventable factors in a population perspective. We analyse determinants of survival and diabetes- and non-diabetes-related causes of death. We investigate the economic burden of disease. We study and improve statistical methods for case-control data. The projects use a longitudinal nationwide database involving about childhood-onset diabetes cases with maximum follow-up of 40 years and for each case 4 matched controls. The Swedish Childhood Diabetes Register is linked to a number of official registers: the Renal register, the Cause of Death register, the National Patient register, the Prescribed Drug register, the Cancer register and the Integrated Database for Labour Market Research. We use GAM-modelling for time trend analyses, standard case-control/cohort analyses, Cox regression and life table analyses, linear fixed effect probability for career development and propensity score models for confounding. The project group is multidisciplinary and involves experts in paediatrics, nephrology, epidemiology, health economics and statistics. This unique database and team will continue to yield new populationbased knowledge on the consequences of this increasingly common chronic childhood-onset disease.

20 Projekt DIA , Anna Lindholm Olinder, Karolinska Institutet Personcentrerad vård till barn och ungdomar med typ 1 diabetes. Barn och unga med diabetes i Sverige behandlas med multipla dagliga insulininjektioner eller med insulinpump. Rekommenderad nivå för glukoskontroll hos barn och ungdomar är HbA1c< 48 mmol/mol. Otillfredsställande glukoskontroll under tonåren ökar risken för diabetesrelaterade komplikationer senare i livet. Trots stora tekniska framsteg inom behandlingen, når mindre än 30 % av ungdomar med typ 1 diabetes det rekommenderade HbA1c-målet. Oavsett typ av behandling är ett aktivt engagemang från patienten och dennes vårdgivare avgörande för möjligheten att uppnå god glukoskontroll. Behovet av att studera och utvärdera olika undervisningsmetoder är stort. Vi avser, att i en randomiserad interventionsstudie för unga kvinnor (15-20 år), utvärdera en teoribaserad undervisningsmetod, GSD-Y. GSD-Y syftar till att stärka den egna förmågan att hantera sin diabetes. Att ha en behandling man trivs med kan underlätta. I en tvärsnittsstudie undersöks behandlingstillfredsställelse hos barn med diabetes i åldern 4-13 år och deras föräldrar, samt eventuella samband mellan behandlingstillfredsställelse och glukoskontroll, typ av behandling, diabetesduration och livskvalitet. Att använda sociala medier som komplement till mottagningsbesök för ungdomar med diabetes kan underlätta egenvården. I en randomiserad studie avser vi att testa om virtuell diabetesmottagning leder till förbättrad glukoskontroll, ökad behandlingstillfredställelse och bättre livskvalitet, hos ungdomar med diabetes.