Niina Sandholm

Over 500 million people worldwide have diabetes. Diabetic complications such as diabetic kidney disease, eye disease, and cardiovascular diseases affect every second of the patients. Even though these complications pose a massive burden both for the individual and for society, the current treatment can only slow down the progression of these complications rather than curing them. In this project we search for genetic and epigenetic factors predisposing to diabetic complications, as well as for serum proteins that could serve as biomarkers, i.e., predict onset of the complications in order to identify the individuals at risk. Furthermore, combining the genetic, epigenetic, and proteomic data with the health registries and disease outcomes will help us understand the disease processes from genetics to epigenetics to proteomics to the disease.

Lærke Gasbjerg

When you eat, food is digested by the intestines and transferred to the blood. The blood stream transports the digested food to organs of your body which for example need food as an energy source. Eating is therefore essential and when you eat, the blood volumen is increased in the abdominal area to support the digestion and transport digested food. But for some people, this phenomenon leads to symptoms such as dizziness, raised pulse, and fainting. They suffer from low blood pressure called postprandial hypotension and are challenged by eating due to the invalidating symptoms. With this Novo Nordisk Foundation Investigator Grant, I will establish my research group at University of Copenhagen and Rigshospitalet (Copenhagen) and study blood volumen changes in two patient groups with modern imaging techniques (MRI) and also, study the mechanism as well as evaluate treatment options in animals based on hormones that we know are related to blood volume changes during eating.

Sindre Lee-Ødegård

South Asians are at a substantially higher risk of type 2 diabetes mellitus (T2DM) compared with white Europeans, especially when living in regions with a westernized lifestyle. South Asians often develop T2DM 5–10 years earlier than westerns, and at a lower body mass index (BMI). This project aims to consider the complete mechanistic pathway from gene to phenotype explaining T2DM development in migrant south Asians, particularly in those with lower age and BMI. Our results will help to develop ethnic-specific strategies to reduce T2DM-risk. I propose a deep phenotyping study of young Nordic and south Asian women living in Norway, with a history of gestational diabetes placing them at high risk of T2DM. Investigations include among others the hyperinsulinemic euglyemic clamp with c-peptide deconvolution, CT-scans, blood, muscle and fat sampels for multi-omics, and randomized controlled trials including lifestyle interventions, GLP-1-analogs and SGLT2-inhibitors. This will enable new or improved treatments that target T2DM defects more precisely, with fewer side effects.

Alastair Kerr

Excess energy is stored in the adipose tissue as fat to be used when the body demands. In obesity the fat tissue become dysfunctional, leading to a higher uncontrolled release of fat into the circulation. The fat released accumulates in other tissues and drives the development of type-2 diabetes. As type-2 diabetes incidence is estimated to be 10% of the world population by 2030, new treatments are required. Long non-coding RNAs (lncRNAs) are a class of cellular molecules that act in concert with the rest of the cell machinery. The lncRNAs that regulate fat breakdown are not known. I have developed state-of-the-art methods to isolate a lncRNA from a fat cell and discover how it functions mechanistically. Using patient fat tissue data coupled with human stem cell models, I will identify fat breakdown regulating lncRNAs. As many lncRNAs are unique to one type of cell, they offer a precise way to target the fat cell and alter metabolic health.

Petra Sipilä

Androgens are required for the male reproductive tissues. However, in many target tissues the regulation of cell type specific responses to androgen action remain poorly understood. Dramatically declined male fertility with low sperm counts and poor semen quality underlines the compelling need of understanding the process of fine-tuning the androgen response in the epididymis where sperm mature. Androgens signal in cells through androgen receptor. Our studies are aimed at revealing novel mechanisms regulating androgen receptor activity in the epididymis. We will focus on other transcription factors working with androgen receptor, epigenetic marks and post-translational modifications of androgen receptor. With this proposal, we will improve our understanding of the mechanisms of androgen signaling in the epididymis that are relevant for male fertility, in order to uncover targets for novel infertility biomarkers and non-hormonal contraceptive modalities.

Christian Benedict

Through advanced sleep-tracking technologies and continuous glucose monitoring applied under free-living conditions, my project will help decipher to which extent broken sleep, an umbrella term describing sleep patterns hallmarked by short sleep duration, low-quality sleep, late bedtime, and irregular sleep timing, impacts daily blood glucose profiles in 240 individuals with overweight or obesity. My project will also be the first to study whether day-to-day variations in the length and depth of the most restorative sleep stage, slow-wave sleep, matter for daytime blood glucose control in people with unhealthy weight, as previously demonstrated in small experiments involving metabolically healthy normal-weight adults. We also hypothesize that blood glucose surges occurring near sleep onset, indicative of late eating, alter the restorative power of subsequent nighttime sleep, with possible negative implications for brain health. Understanding the interaction between sleep, glucose control, and brain health in this population at risk for type 2 diabetes may inform the development of interventions to improve sleep and blood glucose management and potentially benefit brain health.

Anna Wredenberg

Cellular metabolism describes the chemical reactions in our cells that sustain life. Of key importance in these reactions is the mitochondrial network, a dynamic structure inside our cells. Mitochondria are maybe best known for their role in energy metabolism, converting the food we eat into usable energy. But many other cellular pathways, such as glucose, lipid, amino acid, or nucleotide metabolism, enter or pass through mitochondria. It is therefore not surprising that mitochondrial dysfunction is a common feature not only in numerous rare inherited diseases but is also a contributing factor in several more common conditions. There are no effective treatment strategies for mitochondrial dysfunction, mainly due to our lack of understanding some basics of mitochondrial biology, but also because of the complexity of the cellular metabolism. This project will identify and target cellular pathways to improve the diagnosis and treatment of mitochondrial dysfunction.

Jørgen Wojtaszewski

This proposal combines in depth investigation of human physiological traits with state-of-art global molecular analyses (omics technology). It concerns aspects to the metabolic action of the hormone insulin, – both when insulin fails to work properly (insulin resistance) and when conditions make insulin work better than normal (insulin sensitization). Our proposal will illuminate molecules that are causing these changes. In this way, we will gain insight to understand insulin resistance – a condition preceding diseases like type 2 diabetes – as well as insight enabling us to enhance insulin sensitivity. We will also explore the value of our analytical platform to be used in stratifying people according to their individual molecular profile (phosphoproteomics) for treatment and prevention strategies – personalized medicine.

Stefano Romeo

Fatty liver disease (FLD) ranges from simple liver fat accumulation to more severe conditions like inflammation, fibrosis and ultimately cirrhosis and cancer. Despite all the efforts, to date there is no approved drug treatment against this disease. Obesity is the strongest environmental risk factor for FLD. However, some individuals, despite being obese, do not have hepatic fat accumulation or, even more surprisingly, although with liver fat, do not progress towards the more severe stages of FLD. Our aim is to understand the protection against FLD and its progression in obese individuals by: A) unravelling the mechanisms behind the beneficial effect of genetic variants protecting against FLD; B) identifying novel protective genetic variants; and C) identifying specific lipid species and metabolic pathways protecting against disease progression. This will finally allow us to identify novel targets and compounds to effectively treat FLD in a framework of precision medicine.

Maria Peleli-Pedersen

Many people suffer today from having a ‘fatty’ and therefore sick liver which is often associated to obesity and cardiovascular diseases. More than 2 million people die per year from liver diseases. Therefore, finding new more specialized and personalized treatments is imperative. Three different liver cell types are involved in ‘fatty liver disease’ but how exactly they interact is poorly understood. Hydrogen sulfide (H2S) is a small endogenously produced molecule and lower levels of H2S is a causative factor to liver disease. The more we understand the role and the exact cellular sources of H2S in the liver, the better treatments we can create. We will inhibit the production of H2S in these three different cell types by creating sophisticated mouse and cellular models. We will also use samples from patients suffering from ‘fatty liver disease’. This approach will help us design more targeted and personalized treatments for patients having a fatty liver and associated pathologies.