Reseach at the Department related to Wallenberg Centre for Molecular Medicine
Endocrinology with Metabolic Diseases
Metabolic Disorder Including Diabetes
There is a strong link between increased body weight and risk of developing type 2 diabetes mellitus (T2DM). In particular abdominal obesity is linked to increased risk various diseases. A key to organ dysfunction may be an inability to store fat in “safe” gluteofemoral depots leading to ectopic accumulation of fat in liver, pancreas, skeletal muscle, and heart. We want to gain a deeper understanding of the underlying mechanisms leading to adverse effects of lipid accumulation in specific organs, with a focus on accumulation of toxic lipid intermediates and its reversibility. Our studies include interventions focused on improving insulin sensitivity that can be crucial for reducing the risk for T2DM and other obesity-related diseases. This is linked to in-depth analyses of intermediary metabolism in collaboration with the Swedish Metabolomics Centre in Umeå and experimental research together with other researchers within the area of metabolism and diabetes.
Contact: Professor Tommy Olsson
Protein misfolding has gained increased interest as an important part in the pathogenesis of neurodegerative diseases. Lately a prion-like process has been described for ALS, where intra-neuronal misfolded SOD1 acts as a prion and induce SOD1 misfolding in neighbour motor neurones, leading to motoneuron degradation.
In transthyretin (TTR) amyloid (ATTR) disease, extracellular protein misfolding is the cause of the disease, where misfolded TTR-monomers resemble into amyloid fibrils. As in other neurodegenerative diseases, both wild type and variant protein misfold and accumulate into fibrils.
Hereditary ATTR amyloidosis caused by the Val30Met mutation is widespread in Northern Sweden. Interestingly, the mutation gives rise to two distinct phenotypes of the disease, one characterised by an early onset and neuropathy, and the other by late onset and cardiomyopathy in combination with neuropathy. The trait has a low penetrance, approximately 10% by the age of 60 in contrast to clustering areas in Japan and Portugal, where the penetrance is close to 100% for the same mutation.
The centre for hereditary amyloidosis in Umeå has been in the forefront on research into hereditary ATTR amyloidosis. We introduced 1990 the first effective treatment, liver transplantation for the disease. We have since then participated in the development of additional treatment modalities, including TTR stabilisers, and gene silencing by si-RNAs.
In collaboration with Prof Per Westermark, Uppsala University Hospital, we have identified two distinct forms of amyloid fibrils that are closely related to our 2 phenotypes of V30M ATTR amyloidosis, a finding that imply the existence of alternative pathways for ATTR formation. Another research group has recently confirmed this alternative pathway that includes proteolysis of the TTR tetramer before dissociation and amyloid formation.
We have good collaboration with research groups from a various countries, including the USA, France and Japan. Our research is basically clinical, but we are also active in examine the genetic background for the 2 phenotypes and fibril compositions identified in our ATTR V30M population as well as development of diagnostic methods. The variation in phenotype and low penetrance of the trait in our population give us a unique opportunity to identify factors with an impact on penetrance of the trait and disease phenotype, factors that are important for development of treatment for ATTR amyloidosis, and protein misfoldning diseases.
Contact: Professor Ole Suhr
VIP and VIPVIZA
The Västerbotten Intervention Programme (VIP) is a population based screening and cardiovascular disease prevention program on-going within usual health care in the County of Västerbotten since 1990. VIP collects data on an individual level including bio-banked material for innovative risk factor identification, investigations of pathogenesis and new treatment strategies, as well as measured clinical data and comprehensive socioeconomic and lifestyle information. The data is also linked to regional and national registers on morbidity and mortality.
Embedded in VIP is VIPVIZA, a large RCT that targets the whole spectrum from low/intermediate to high risk individuals and evaluates the potential of image based information of silent atherosclerosis, as visualized through carotid ultrasonography, to optimize clinical risk communication, adherence among practitioners and patients to prevention guidelines and in the long run to reduce the burden of CVD.
Quantitative and qualitative methods are used to address the knowledge gap regarding modification by individuals’ psychometric characteristics on pathogenetic mechanisms and the link between risk factors and diseases outcomes. The results are expected to be valid and relevant also for other clinical settings.
VIP is the main contributor to the large biobank in Umeå. VIP as well as VIPVIZA enables studies of biomarkers in e.g. atherosclerosis and metabolic diseases/diabetes.
Contact: Professor Ulf Näslund