Diabetes and its complications
Kerstin Brismar has overall responsibility for clinical studies including epidemiology and treatment investigations on the cause of diabetes complications and also responsible for the studies on the IGF-system as markers of disease including diabetic complications. Kerstin Brismar has as a group leader overall responsibility for the research projects on diabetes complications and is supervisor or co-supervisor for the PhD students.
Department of Molecular Medicine and Surgery
Karolinska University Hospital Solna, L1:00
SE-171 76 Stockholm
Summary of Research
The research of my group has been focused on the cause of type2 diabetes and diabetes complications, and the regulation of growth factors especially that of the growth factor IGF/IGFBP system.
We have shown that high glucose causes capillary hypoxia and loss of adaptation to hypoxia via destabilization of HIF-1alfa during hypoxia. The studies of IGFBP-1 resulted in that this protein became an important method to diagnose malnutrition, insulin sensitivity and beta-cell function and the risk to develop diabetes complications such as cardiovascular event, neuropathy and foot ulcers. IGFBP-1 also became a predictor of future development of type2 diabetes as well as a method to evaluate the response to life style intervention and need for insulin in type2 diabetes. Investigations on IGF-I have demonstrated that this protein is an important marker for growth hormone and first phase insulin release and an indicator of nutritional status.
Analyses of the interaction between IGF-I, the transcription factor HIF-1α and its target gene growth factor VEGF have demonstrated that IGF-I stimulates expression of both these factors. Both HIF-1α and free radicals increase the production of IGFBP-1 which impairs the IGF-I activity. IGFBP-1 has also IGF- independent effects on proliferation and cell migration and in endothelial cells it stimulates NO production.
In healthy subjects with and without family history of type2 diabetes IGFBP-1 can be used as a marker of endothelial function.
At present the work is concentrated on the importance of oxidative stress for development of diabetes complications demonstrating the importance of both endogenous and exogenous antioxidants for prevention of diabetes complications especially neuropathy, nephropathy, endothelial dysfunction and chronic foot ulcers. This research line also involves identification of subjects with increased risk to develop type2 diabetes and studies on prevention of impaired glucose tolerance via different lifestyle modifications including diets, antioxidants as well as development of new drugs, polyisoprenoid epoxides, for induction of endogenous antioxidants synthesis.
We use different mice models to study the effect of diet and exercise on development and prevention of insulin resistance and diabetes with focus on the brain, pancreas, adipose tissue, liver and muscle.
The group has collaborations with top laboratories and universities in Denmark, England, Italy, Poland, Germany, China, USA, as well as other research groups at Karolinska Institutet and The Science of Life Laboratories. Around 15 people are working on these projects in the laboratory or clinic at Karolinska University Hospital.
1. Studies on the mechanisms behind diabetes complications focusing on hyperglycemia, hypoxia and the IGF-system including the mechanisms behind glucose effects on HIF-1α and Notch 1 activity in humans and animal models of diabetes. Responsible project leaders: Sergiu-Bogdan Catrina, Elisabete Forsberg, Jing Wang, Kerstin Brismar.
2. Importance of antioxidants to control oxidative stress in diabetes. This project includes the study of different antioxidant system including Coenzyme Q (CoQ) and its relation to diabetes as well as the possibility to increase the endogenous antioxidant response to reactive oxygenic species. It also includes i) the development of new drugs stimulating the antioxidant defense and ii) the effect of treatment with antioxidants such as Carnosine, CoQ, polyisoprenoid epoxides with focus on wound healing, neuropathy and nephropathy as well as the immune response. Responsible project leaders: Gustav Dallner, Magnus Bentinger, Michael Tekle, Elisabete Forsberg, Jacob Grünler, Kerstin Brismar.
3. New imaging platform as a model to study the cause and prevention of diabetes complications. In this project we use a mouse eye model to study in collaboration with P-O Berggren's group the effect of hyperglycemia and hypoxia on angiogenesis, capillary leakage and nerve generation in transplanted pancreatic islets,. With this model we have the possibility to study the effect of treatment with antioxidants and normalization of HIF-1α activity. Responsible project leaders: Sergiu-Bogdan Catrina, Elisabete Forsberg, Kerstin Brismar.
4. Human clinical studies on the causes of diabetes complications: including genetic studies and prospective population studies of patients with type 1 and type 2 diabetes. Responsible project leaders: Harvest F Gu, Sergiu-Bogdan Catrina, Michael Alvarsson, Neda Rajamand-Ekberg, Kerstin Brismar.
|Project leaders||Area of research|
|Gustav Dallner||Drug development and Coenzyme Q research|
|Christina Bark||Regulated membrane fusion|
|Sergiu-Bogdan Catrina||Mechanisms underlying diabetes complications|
|Harvest F Gu||Genetic and functional analyses in diabetes, obesity and diabetic complications|
|Jacob Grünler||Inflammatory processes in development of atherosclerosis in diabetics|
|Magnus Bentinger||Synthesis of new compounds with the ability to stimulate the endogenous antioxidant defense|
|Michael Tekle||Development of methods to determine lipid, protein and DNA oxidation. Study of biological effects of new drugs with antioxidant properties|
|Neda Rajamand Ekberg||Clinical studies of different composites of meals in type 1- and type 2-diabetes. Clinical studies on PCOS in type 1 diabetes|
|Michael Alvarsson||Clinical studies on β-cell rest and the HPA-axis on metabolic control in diabetic, clinical studies on the effects of physical activities in patients with type 2-diabetes. Clinical studies on PCOS in type 1-diabetes|
|Marie Degerblad||Clinical studies on the effects of physical activities in patients with type 2-diabetes|