Center for Diabetes Research

Clinical Medicine

We are working to find new genetic risk factors for diabetes and the complications of the disease, while developing and implementing targeted and improved treatment for diabetes. Based on functional studies and records, we recruit patients with hereditary diabetes types for in-depth examinations to identify phenotype, heredity, comorbidity and treatment options.

A fundamental amazement about subjects and patients has always been central to the research at the Center for Diabetes Research. Founder of the center, Prof. Emeritus Oddmund Søvik, knew well that the important questions were to be found in the clinic, and that systematic research was key to find good answers. Under his leadership, the first diabetes register in Norway was established. The register, at its earliest beginnings, consisted of a single hole-sheet system, but has over the years been modernized and digitized, giving rise to the registers we know today. In Bergen we archive research data with clinical information and associated biobank from over 250 Norwegian families with hereditary diabetes forms in the MODY register under the leadership of Professor Pål R. Njølstad.

An amazing development in medical genetics over the past decade has enabled research on a different scale than before. Based on our large Norwegian patient registries and cohorts, we have a unique starting point for studying diabetes at population level, between populations, but also finding answers to deeper research questions in more rare types of diabetes. Bergen is therefore a leader in the field of epidemiological and genetic research in the diabetes field, thanks in part to the MODY register.

It is crucial that as a clinician, the hereditary forms of type 1 and type 2 diabetes are diagnosed and separated because the treatment and follow-up of the patients is different. Patients with rare forms of diabetes and diabetes syndrome should have personalized treatment to the cause of their diabetes, be it a transcription factor or ion channel that has been affected. Some patients may replace insulin with tablets while others may stop treatment completely. Some gene changes will cause more organ systems to be affected, and a syndromic diabetes and these will need follow-up for comorbid conditions. Beyond this, it is important that family members are looked after so that they receive genetic counseling and genetic testing as the hereditary component is often strong.

Ongoing research projects
We are conducting a study in which we map patients with gene variants of unknown significance (VUS) into genes that produce MODY 1, 3 and 5. These are patients enrolled in the MODY registry, which have previously been examined with genetic testing due to of clinical suspicion of monogenic diabetes without a safe response. In other words, you do not know about their remorse associated with diabetes or innocence. Patients are called in for thorough clinical and physiological examinations and a response to low-dose sulfonylureas is investigated to get closer. Family members are also offered gene tests to find out if diabetes and the gene variant are associated with each other.

Research results:
Several of the 14 MODY types that have been identified so far, but also new diabetes syndromes, are described first here at the Center for Diabetes Research, which ensures that patients receive optimal follow-up and correct treatment. An important finding derived from this was that children with newborn diabetes could release painful insulin injections, and should be treated with sulfonylureas (Sagen et al, NEJM, 2004). Ten-year follow-up of these patients demonstrated that treatment is safe and provides lasting and improved blood glucose control over insulin (Bowman et al, Lancet DE, 2018). This article received the "Best Scientific Article" the same year by the Norwegian Pediatric Association. Another study has linked newborn diabetes to cognitive disorders that depend on the genotype of the patient (Svalastoga et al, Diabetes Care, 2020). This can ensure that children receive interdisciplinary follow-up for their comorbidity early.

By using exome sequencing in a Norwegian family, we have discovered the genetic cause of SHORT syndrome; short growth, lipodystrophy, diabetes and insulin resistance. The reason is a hot spot mutation in the PIK3R1 gene encoding P85, a protein that regulates basic cellular processes such as metabolism and growth. We also found that the mutation leads to decreased interaction between p85a and IRS-1, and reduced AKT-mediated signaling of insulin. Normal PI3K activity is essential for adipose differentiation and insulin signaling; Mutated PIK3R1 therefore provides a unique link between lipodystrophy, growth and insulin signaling. The article (Chudasama et al., American J Human Genetics, 2013) was named "Best Scientific Article of 2013" by the Faculty of Medicine, UiB.

By taking advantage of our large registries of MODY-type diabetes, we have discovered that SUMOylation is a novel mechanism for regulating the diabetes-associated enzyme glucokinase (Aukrust et al, J Biological Chemistry, 2013.). We have found that destabilization, aggregation, and degradation of proteins encoded by diabetic genes are novel mechanisms for how GCK-MODY (MODY2) develops (Negahdar et al., Molecular and Cellular Endocrinology, 2014).

A new collaboration has been initiated with the Broad Institute of Harvard and MIT. This has so far resulted in three studies:

1. Using Next Generation Sequencing Panel Sequencing of 4000 Population Studies in the United States, and then Comparing Results with Genetic Findings In the Norwegian MODY Register, we found that a significant proportion of people in the general population are carriers of rare variants in MODY genes. This finding has far-reaching implications for how to predict a person's risk of developing MODY, or other Mendelian inherited diseases (Flannick et al., Nature Genetics, 2013).

2. When genotyping or sequencing ~ 150,000 individuals from several population-based cohorts including the Norwegian HUNT study, we identified 12 rare variants in SLC30A8, which encode the zn transporter ZnT8. Carriers of these rare variants showed reduced risk of type 2 diabetes as well as decreased glucose levels. This opens up the possibility of reducing the risk of diabetes or treating the disease with new drugs that turn off SLC30A8 (Flannick et al., Nature Genetics, 2013).

3. By exome sequencing of 4000 people from Mexico, we discovered that the rare mutation E508K in the MODY gene HNF1A (MODY3). We found that this affects the normal function of HNF1A by reducing the factor's ability to turn on other genes. The important thing about the study is that one can now find subtypes of type 2 diabetes, and that these may be the subject of personalized medicine since one knows that the sulfonylurea tablet is best at MODY3, a hereditary form of diabetes that we have studied for many years. The article (Estrada, Aukrust, Bjørkhaug et al., JAMA, 2014) was commented on in the New York Times.

Group leader: PÅL R. NJØLSTAD


What do we do?

  • Genetic assessment for referred patients with suspected monogenic diabetes or hyperinsulinism
  • Use genetics, functional and physiological studies to tailor treatment for patients with monogenic diabetes
  • Clinical characterization of patients with:
    • Clinical examination
    • Glucose Load Tests
    • MRI / Ultrasound abdomen
    • Structural / Functional MRI of the brain
    • Autonomic Neuropathy Assessment
    • Gastroenterological assessment including exocrine pancreatic function
    • Psychological investigation
    • Mapping of motor development

Registers / cohorts

  • Children Diabetes Registry
  • Adult Diabetes Registry
  • MODY registry
  • Mother-Child-Study-cohort

Biobank Haukeland