Research Group HöPPENER

Faculty of Medicine, University Medical Centre Utrecht, Dept. of Metabolic & Endocrine Diseases
Contact: Dr. Jo Höppener
E-mail: j.w.m.hoeppener@umcutrecht.nl
Website: http://www.metabole-ziekten.nl/

General research focus: Type 2 diabetes mellitus

In our research group we study a crucial pathogenic factor in type 2 diabetes mellitus (DM2, 'ouderdomssuikerziekte'), i.e. “β-cell failure”.
DM2 is the most common metabolic disease worldwide (estimated number of patients: > 200 million) and its prevalence is rapidly increasing. Although known as an age-related disease, its prevalence is increasing mainly in the relatively younger age groups, together with that of overweight/obesity, which is an important risk factor for DM2. DM2 and obesity are associated with insulin resistance, meaning reduced sensitivity of target tissues for the metabolic actions of insulin. However, this does not lead to hyperglycemia (DM, inappropriately elevated blood glucose levels) as long as the body is able to make enough insulin to compensate for this insulin resistance. Hyperglycemia only develops when the overall insulin production by the β-cells in the pancreas becomes insufficient (hence: β-cell failure). In fact, this impaired insulin production is the actual reason for the hyperglycemia which characterizes DM.

A specific histopathological feature of DM2, detected at autopsy in ± 90% of the patients, is islet amyloid. This is an extracellular, fibrillar protein deposition in the pancreatic islets of Langerhans, which is accompanied by β-cell death. The building block of these amyloid fibrils in the pancreatic islets is the protein IAPP (Islet Amyloid PolyPeptide), which like insulin is produced by the pancreatic islet β-cells.
The major research theme of our group is the role of human IAPP, and particularly its (pre-)fibrillary depositions, in islet ß-cell dysfunction in DM2. To this end we have generated and characterized a transgenic mouse model, in which the amyloidogenic human IAPP (of 37 amino acids) is expressed in the pancreatic islet ß-cells (mouse and rat IAPP can nót form amyloid fibrils). Particularly when insulin resistance is induced (as in overweight/obesity), islet amyloid develops in these mice and contributes to the pathogenesis of DM2, as shown by decreased insulin – and increased blood glucose levels. Probably the islet amyloid develops as a consequence of increased IAPP production, which accompanies increased insulin production to compensate for insulin resistance. Thus, this unique animal model can be used for pioneering research with respect to both the pathogenesis, diagnosis and therapy of DM2, with the focus on the role of amyloid formation in the pancreatic islets of Langerhans and its relation to death of the insulin-producing islet β-cells.
Such pathological protein aggregation also occurs in age-related neurodegenerative diseases (e.g. Alzheimer's dementia [AD], Parkinson's disease, Creutzfeldt Jakob disease), and in this regard our results may also be relevant for those diseases.

The human IAPP mice developing islet amyloid enable in vivo and ex vivo (using isolated pancreatic islets) studies into the mechanisms and cellular consequences of islet amyloidosis (financed by the Dutch Diabetes Research Fund and The Netherlands Metabolomics Center). In addition to studying the role of specific candidate genes, we also use large scale screening methods (gene expression profiling with microarrays and metabolomics using mass spectrometry) for identification of mRNAs, proteins and other metabolites, and thus eventually mechanisms, involved in protein aggregation-induced cell death and organ dysfunction. In collaboration with national and international companies, our hIAPP transgenic mice are used to develop anti-amyloid therapy for DM2.

Techniques: transgenic mice, cell- and islet culture, (immuno)histochemistry, light- and electron microscopy, image-analysis, transcriptomics (micro-array analysis), metabolomics.

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