Project
The role of IAPP / islet amyloid in type 2 diabetes mellitus
Major research theme: the role of IAPP (islet amyloid polypeptide) in pancreatic islet ß-cell dysfunction in type 2 diabetes mellitus.
Insulin insufficiency is the cause of the hyperglycemia in type 2 diabetes. Histopathologically, type 2 diabetes is characterized by fibrillary protein depositions (amyloid) in the pancreatic islets of Langerhans. Amyloid has been associated with islet ß-cell death. The building block of the amyloid fibrils is the ß-cell protein IAPP.
We want to investigate the role of IAPP/islet amyloid in the pathogenesis of type 2 diabetes. We have generated and characterized a transgenic mouse model, in which human IAPP is expressed in the islet ß-cells. When insulin resistance is induced, islet amyloid develops in these mice and contributes to the pathogenesis of type 2 diabetes by reducing the insulin producing capacity (Höppener et al., 1999, 2000, 2006, also see Figure 1).
More recent data have shown that amyloid fibril formation from human IAPP kills islet ß-cells. This cytotoxic effect is likely to be mediated by interactions between human IAPP aggregates and cellular membranes (Sparr et al., 2004; Engel et al., 2006, 2008).
Our research is financially supported by the Dutch Diabetes Research Foundation and the Netherlands Metabolomics Center.
Group
The following people are working on this project:
Key publications:
Höppener JW et al., Diabetologia 1999
Höppener JW et al., New England J Medicine 2000
Sparr E et al., FEBS Lett 2004
Engel MF et al., J Mol Biol 2006
Höppener JW et al., Int J Biochem Cell Biol 2006
Engel MF et al., PNAS USA 2008
Figure 1
When transgenic mice with islet ß-cell expression of the gene encoding the amyloidogenic human IAPP are cross-bred to leptin-deficient ob/ob mice, obesity develops (left: a human IAPP transgenic mouse; right: a human IAPP transgenic ob/ob mouse). This is associated with insulin resistance, IAPP overproduction and formation of amyloid deposits in the pancreatic islets. The degree of islet amyloidosis correlates with reduced insulin production and severity of the diabetes. Upper panels: immunohistochemical staining for insulin (brown); lower panels: histochemical staining for amyloid (pink). Reprinted with permission from Scan 3/00 (2-monthly publication from the University Medical Center Utrecht, Utrecht, The Netherlands).
last update: 18-2-2011