Anders Rosengren, MD PhD
Type 2 diabetes (T2D) is an escalating health problem of enormous proportions. The disease poses a heavy burden on health care systems in both developed and developing countries. Current therapy is insufficient, as evident from the devastating complications in kidneys, eyes and the cardiovascular system. Finding more effective treatment is therefore a great priority.
Our research aims to alleviate this problem by combining clinical investigations, bioinformatics and experimental studies. The integration of all these aspects in the research group provides very interesting opportunities for translational research and drug target identification. "Detailed Mapping of Type 2 diabetes" (DIACT) is a longitudinal patient study that constitutes the major platform of the research group. Newly diagnosed patients with T2D are recrutied from ANDIS (All New Diabetics in Scania) into DIACT, and they undergo comprehensive clinical profiling every 6 months. The study will continue for many years.
The clinical profiling captures different aspects of the pathophysiology. We also obtain global genetic, gene expression ant metabolite data to identify biomarkers associated with the pathophysiological components. The longitudinal design facilitates the distinction between causal and reactive changes.
In the next step, we use network analysis and other bioinformatics approaches to integrate genetic and gene expression data from patient samples and human tissues and to identify disease genes. Candidate genes identified from these analyses are studied in-depth experimentally to characterize the underlying cellular disease mechanisms. The strength of this strategy is highlighted by our recent identification of SFRP4 (Mahdi et al., Cell Metabolism 2012) and ADRA2A (Rosengren et al., Science 2010) as novel disease genes for T2D.
An attractive strategy for expanding the therapeutic options is drug repositioning, which implies finding new indications for approved drugs or for the thousands of compounds that have passed toxicology tests but not yet reached clinical use. One potential benefit with repositioning is that the road to clinical implementation can be considerably shorter compared with de novo drug development. We use a method for drug repositioning that is based on comparing the gene networks that are perturbed in T2D with a large library of gene expression signatures from drugs. The aim is to find drugs that can reverse entire networks of perturbed disease genes. Candidate drugs are then investigated experimentally.
Finally, the most interesting drug targets and candidate compounds as identified from the network analyses and the repositioning approach are studied in the patient cohort as explorative plase II studies. This workflow enables us to start with the patient setting, bring the most relevant findings to the laboratory for mechanistic studies and then translate these findings back to the patients. As an example, we are currently conducting a phase II study investigating the effects of the ADRA2A antagonist yohimbine in patients with a T2D risk variant in ADRA2A.
In addition to the biological studies we are investigating psychological/motivational aspects of T2D. We believe that a combination of improved self-management and new pharmacological approaches is needed to more effectively treat T2D and that studying both aspects in the same study can be highly interesting. The DIACT study provides unique opportunities to explore how biological factors, lifestyle and psychological factors interact and affect disease progression and how motivation to lifestyle changes can be improved. The psychological aspects will be studied using internet-based interventions.
Patients with T2D undergo a comprehensive clinical profiling every 6 months to analyse the pathophysiological components. This information is combinded with global genetic, gene expression and metabolite data to identify molecular networks associated with the pathophysiology. Candidate genes identified from these analyses are studied mechanistically. The most interesting drug targets and candidate compounds are then investigated in the patients. The vision is to obtain clinically useful signatures for pathophysiological components to guide more precise therapeutic interventions and to identify novel anti-diabetic compounds targeted at the underlying disease mechanisms. An important face of the cohort is to also study motivational/psychological aspects of T2D.
Last updated: December 16, 2013
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