Diabetes and its complications

Kerstin Brismar 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.

Ongoing research

1. IGFBP/IGF system

Regulation and clinical importance as a marker of insulin secretion and resistance, future risk of T2 DM and CVD, regulator of NO synthesis and glucose homeostasis.

• MD PhD Neda Rajamand Ekberg, MD.PhD Maria Sääf

Main Projects:

1. Identify future risk for type2 diabetes and cardiovascular disease

2. Identify risk factors for osteoporosis and future fractures in diabetes

3. Prevent risk for type2 diabetes and cardiovascular disease

Main Projects:

1. Modulation of IGF-1 expression by IGFBP-1

Aim: To investigate the effect of IGFBP-1 on IGF-I regulation at the transcriptional level and whether different tissues exhibit different regulation. Methods; gene and protein expression of IGF-I protein using qPCR analysis, ELISA or RIA in various cell lines.

2. Deducing the role of IGF system in an in vitro model of liver steatosis.

Aim: To investigate whether free fatty acids can modulate IGFBP-1 protein and to identify role of IGFBP1 in lipid accumulation. Methods: study lipid accumulation, free-fatty acid-induced apoptosis, oxidative stress, changes in gene expression, using ´TUNEL assays, FACS analysis and QPCR analysis in an in-vitro model of liver steatosis including the spheroid (collaborating Magnus Ingelman Sundberg).

3. Deducing the role of IGF system in the diagnosis of liver steatosis and progression to fibrosis in humans

4. Deducing the most effective diet to reverse liver steatosis in humans

2. Diet intervention

In diabetes and healthy controls, humans and mice

• MD PhD Neda Rajamand Ekberg 

1. Examine the Effects of Standardized Meals on Postprandial Metabolic, Hormonal and Inflammatory Responses

2. Examine the Effects of Low Fructose Load on Postprandial Metabolic and Inflammatory Responses

• PhD Ismael Valladolid Acebes (in collaboration with Signal Transduction)

Main Projects:

1. Beta Cell Function in a Mouse Model of Western Diet-Induced Diabesity

Aim: To study stimulus-secretion coupling in situ combining electro-and optophysiological novel complex network approaches with the acute mouse pancreas tissue slice preparation. Methods: diet-induced obesity and type-2 diabetes using a western diet during eight weeks in C57bl/6 mice. This project includes: intraperitoneal glucose and insulin tolerance tests; Determination of the dynamic insulin release in isolated pancreatic islets; Membrane potential and calcium dynamics in beta cells from mouse pancreas tissue slices; hormonal characterization in serum; Immunohistochemistry, western blot and qPCR.

2. Role of micro-RNA 210 (mir210) in Diabetes (Sergiu Catrina)

Aim: To investigate whether the lack of mir210 impacts on glucose homeostasis and insulin sensitivity. Methods: mir210 homozygous and heterozygous mutant male and female mice. Phenotypic and genotypic characterization is being performed at the ages of 20, 40 and 60 weeks of age. This project includes: 1) In vivo studies: Glucose tolerance tests (GTTs), insulin secretion during the GTTs measured by ELISA, insulin tolerance tests (ITTs), tissue specific glucose uptake and energy metabolism using the metabolic cages; In vitro studies: Glucose-stimulated insulin secretion in isolated pancreatic islets, qPCR, western blot and immunohistochemistry.

3. New compound with effects on mitochondrial function with anti- inflammatory and antioxidant properties in prevention of diabetes complications

• Gustav Dallner, PhD Michael Tekle, PhD Magnus Bentinger, PhD student Cheng Xu

Modified tocotrienol (Mod-T3) effectively protects the heart after ischemic reperfusion, enhances wound healing of the skin and improves mitochondrial function.

Aim: To develop a new compound (based on tocotrienol) that prevent diabetes complications Methods, Synthesis of the compound, HPLC, db/db mice and WD induced diabetes. in vitro “Scratch assay” as wound healing model, In vivo wound healing model, A FX-24 Seahorse instrument for mitochondrial function analysis of both cells and kidney mitochondria.

Selected Publications

Increase in insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 after supplementation with selenium and coenzyme Q10. A prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens.
Alehagen U, Johansson P, Aaseth J, Alexander J, Brismar K
PLoS ONE 2017 ;12(6):e0178614

Changes in fruit, vegetable and juice consumption after the diagnosis of type 2 diabetes: a prospective study in men.
Olofsson C, Discacciati A, Åkesson A, Orsini N, Brismar K, Wolk A
Br. J. Nutr. 2017 Mar;117(5):712-719

IGFBP1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation.
Lu J, Liu KC, Schulz N, Karampelias C, Charbord J, Hilding A, et al
EMBO J. 2016 09;35(18):2026-44

The receptor for advanced glycation end products and risk of peripheral arterial disease, amputation or death in type 2 diabetes: a population-based cohort study.
Malmstedt J, Kärvestedt L, Swedenborg J, Brismar K
Cardiovasc Diabetol 2015 Jul;14():93

Short and prolonged exposure to hyperglycaemia in human fibroblasts and endothelial cells: metabolic and osmotic effects.
Moruzzi N, Del Sole M, Fato R, Gerdes JM, Berggren PO, Bergamini C, et al
Int. J. Biochem. Cell Biol. 2014 Aug;53():66-76

Increased DNA methylation levels of the insulin-like growth factor binding protein 1 gene are associated with type 2 diabetes in Swedish men.
Gu T, Gu HF, Hilding A, Sjöholm LK, Ostenson CG, Ekström TJ, et al
Clin Epigenetics 2013 Nov;5(1):21 

Coenzyme Q10 prevents peripheral neuropathy and attenuates neuron loss in the db-/db- mouse, a type 2 diabetes model.
Shi TJ, Zhang MD, Zeberg H, Nilsson J, Grünler J, Liu SX, et al
Proc. Natl. Acad. Sci. U.S.A. 2013 Jan;110(2):690-5

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Research areas

Gustav Dallner - Drug development and Coenzyme Q research

Regulated membrane fusion

Sergiu-Bogdan Catrina  - Mechanisms underlying diabetes 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

Interview

Kerstin Brismar took part in the European Parliament seminar "Women Health & Food - Can we do more to meet the challenges of diabetes and heart diseases?" (Nov 2012). Hear her interesting conversation with Anna Maria Corazza Bildt.