Final Report Summary - ICEBERG (Discovery of Type 2 Diabetes Targets)
My research is focused on understanding the mechanisms that contribute to the development of insulin resistance in Type 2 diabetes. Type 2 diabetes arises from insulin resistance in skeletal muscle, adipose tissue and liver, combined with a progressive impairment in insulin secretion from the pancreas. Clinically, defects in these tissues contributes to the abnormally high glucose levels in people with Type 2 diabetes because the tissues cannot properly break down and utilize sugar and fats as energy. Skeletal muscle insulin resistance appears years before the clinical onset of Type 2 diabetes. Consequently, if insulin sensitivity can be maintained, Type 2 diabetes can be prevented. Genetic, epigenetic and lifestyle factors cause insulin resistance. Yet, the specific genes and molecules that influence insulin sensitivity are incompletely resolved. The outcome of our research is applicable to questions related to integrative medicine and human health and may be also directly applied to drug discovery programs in the biotechnology sector.
My strategy is to apply discovery and validation platforms to identify targets important for glucose homeostasis and Type 2 diabetes pathogenesis. By identifying the molecular mechanisms controlling insulin sensitivity, it will be possible to develop pharmacological and physiological (for example exercise and diet) intervention strategies aimed to improve glucose homeostasis in people with Type 2 diabetes, as well as at risk populations. My group is utilizing technology platforms and well-validated, clinically relevant material to identify regulatory factors that contribute to the development of Type 2 diabetes and insulin resistance.
From the ERC funded research, we have evidence that environmental factors can modify the expression of genes through DNA methylation potentially in any tissue, which suggests that DNA methylation is a more dynamic process than previously appreciated. We could show that exercise and obesity, two major life style factors which influence insulin resistance and Type 2 diabetes, in an opposing manner affect DNA methylation of promoters of key genes regulating glucose and lipid metabolism. Thus, DNA methylation provides a mechanism by which environmental factors, including diet and exercise, can modify genetic predisposition to disease. We have also elucidated mechanisms how insulin regulates glucose uptake into skeletal muscle and identified a specific glucose transporter involved. We also found that specific insulin signalling proteins are defective in muscle from Type 2 diabetic patients but could be restored after endurance exercise-training. A central area for my research group is the regulation of metabolism by the enzyme diacylglycerol kinase, which we found to be linked to skeletal muscle insulin resistance. Currently we are placing major efforts to further understand the role(s) of a family of these enzymes in regulation of lipid and glucose metabolism. Apart from insulin, an important metabolic sensor that drives glucose uptake and lipid oxidation is the AMP-activated protein kinase (AMPK). We have determined the importance of AMPK for sugar uptake and fat burning in skeletal muscle, and we have recently provided evidence that AMPK acts as a sensor that translates fasting- and exercise-induced adaptations in skeletal muscle to modulate mitochondrial function.
The most important impact of my project is the unique translational approach we take, whereby we start with clinically driven questions that are based in the field of life sciences and that are related to the pathogenesis of Type 2 diabetes. Most researchers in this field start with interesting discoveries of biology, which may be unrelated to the clinical conditions. Our approach starts with the clinical problem, we resolve the complex biology, and we develop new approaches to prevent and cure insulin resistance in Type 2 diabetes.
My strategy is to apply discovery and validation platforms to identify targets important for glucose homeostasis and Type 2 diabetes pathogenesis. By identifying the molecular mechanisms controlling insulin sensitivity, it will be possible to develop pharmacological and physiological (for example exercise and diet) intervention strategies aimed to improve glucose homeostasis in people with Type 2 diabetes, as well as at risk populations. My group is utilizing technology platforms and well-validated, clinically relevant material to identify regulatory factors that contribute to the development of Type 2 diabetes and insulin resistance.
From the ERC funded research, we have evidence that environmental factors can modify the expression of genes through DNA methylation potentially in any tissue, which suggests that DNA methylation is a more dynamic process than previously appreciated. We could show that exercise and obesity, two major life style factors which influence insulin resistance and Type 2 diabetes, in an opposing manner affect DNA methylation of promoters of key genes regulating glucose and lipid metabolism. Thus, DNA methylation provides a mechanism by which environmental factors, including diet and exercise, can modify genetic predisposition to disease. We have also elucidated mechanisms how insulin regulates glucose uptake into skeletal muscle and identified a specific glucose transporter involved. We also found that specific insulin signalling proteins are defective in muscle from Type 2 diabetic patients but could be restored after endurance exercise-training. A central area for my research group is the regulation of metabolism by the enzyme diacylglycerol kinase, which we found to be linked to skeletal muscle insulin resistance. Currently we are placing major efforts to further understand the role(s) of a family of these enzymes in regulation of lipid and glucose metabolism. Apart from insulin, an important metabolic sensor that drives glucose uptake and lipid oxidation is the AMP-activated protein kinase (AMPK). We have determined the importance of AMPK for sugar uptake and fat burning in skeletal muscle, and we have recently provided evidence that AMPK acts as a sensor that translates fasting- and exercise-induced adaptations in skeletal muscle to modulate mitochondrial function.
The most important impact of my project is the unique translational approach we take, whereby we start with clinically driven questions that are based in the field of life sciences and that are related to the pathogenesis of Type 2 diabetes. Most researchers in this field start with interesting discoveries of biology, which may be unrelated to the clinical conditions. Our approach starts with the clinical problem, we resolve the complex biology, and we develop new approaches to prevent and cure insulin resistance in Type 2 diabetes.