CLINICAL MEDICINE GROUP
We are working to improve clinical characterization of diabetes and we are analyzing health registries and biobanks to find new diabetes genes and risk factors.
Using exome sequencing in a Norwegian family, we have discovered the genetic basis of
SHORT syndrome; short stature, lipodystrophy, diabetes and insulin resistance. The cause is a hot spot mutation in the PIK3R1 gene encoding p85, a protein regulating fundamental cellular processes such as metabolism, proliferation, and survival. We also found that the mutation leads to impaired interaction between p85a and IRS-1, and reduced AKT-mediated insulin signaling. Normal PI3K activity is critical for adipose differentiation and insulin signaling; mutated PIK3R1 therefore provides a unique link between lipodystrophy, growth, and insulin signalling. The paper (Chudasama et al., American J Human Genetics, 2013) was awarded “Best Scientific Article of 2013” at the Faculty of Medicine, UoB.
- Taking advantage of our large registry of MODY type diabetes as a source for unexplained disease mechanisms, we have revealed that SUMOylation is a novel mechanism for regulation of the diabetes-associated enzyme glucokinase (Aukrust et al., J Biological Chemistry, 2013). We also discovered that protein destabilization, aggregation and degradation are novel mechanisms for how GCK-MODY (MODY2) develops (Negahdar et al., Molecular and Cellular Endocrinology, 2014).
- Due to the group leader´s research stay 2012-13 at Broad Institute of Harvard and MIT, three collaborative studies have already manifested in papers in high-profile journals:
- Using next-generation panel sequencing of around 4,000 individuals and then comparing the results to genetic findings in the Norwegian MODY Registry, we found that a substantial proportion of individuals in the general population carry low-frequency, nonsynonymous variants in the MODY genes. This finding has wide-reaching implications for how to predict a person’s risk for developing MODY, or other Mendelian diseases (Flannick et al., Nature Genetics, 2013).
- By genotyping or sequencing of ~150,000 individuals from several population-based cohorts including the Norwegian HUNT biobank, we identified 12 rare protein-truncating variants in SLC30A8, encoding the pancreatic islet zinc transporter ZnT8. Carriers of these rare variants in SLC30A8 showed reduced risk of type 2 diabetes and reduced glucose levels. This opens up the possibility of reducing diabetes risk or treating the disease by new drugs that turn off SLC30A8 (Flannick et al., Nature Genetics, 2013).
- By exome sequencing 4000 individuals from Mexico, we discovered that the rare mutation E508K in HNF1A causes a phenotype that can be misdiagnosed as type 2 diabetes. In our lab, we showed that the variant affects HNF1A function by reducing transcriptional activity. Moreover, this effect was in-between that of normal variants and mutations associated with MODY3, a dominant form of diabetes that we have studied for years. The paper (Estrada, Aukrust, Bjørkhaug et al., JAMA, 2014) was commented in the New York Times.
Head of group: Professor PÅL R. NJØLSTAD
- Professor C. Ronald Kahn MD, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
- Professor Tiinamaija Tuomi MD PhD, University of Helsinki, Helsinki, Finland
- Consultant physician Torild Skrivarhaug MD PhD, Oslo University Hospital, Oslo, Norway
- Ass. Professor Daniel Macarthur PhD, Massachussets General Hospital, Boston, MA, USA
- Professor Leif Groop MD PhD, Researcher Ola Hansson, Lund University, Malmø, Sweden
- Professor Mark I. McCarthy MD PhD, Professor Anna L. Gloyn PhD, Oxford University, Oxford, UK
- Professor Andrew Hattersley MD PhD, Professor Sian Ellard PhD, University of Exeter, Exeter, UK
- Ass. Professor Jose Florez MD PhD, Researcher Jason Flannick PhD, Broad Institute of Harvard and MIT, Cambridge, MA, USA
- Professor Camilla Stoltenberg MD PhD, Researcher Lars Christian Stene PhD, Researcher Gun Peggy Knutsen PhD, Norwegian Institute of Public Health, Oslo, Norway
KG Jebsen center for Diabetes research, Children and Youth Hospital, 6th floor, Block 2, Haukelandsbakken 15, N-5021 Bergen, NORWAY