Project details

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Type 1 diabetes-induced alterations in islets of Langerhans

Keywords:
Advanced Microscopy beta cell destruction insulitis

Researchers:
dr. B.N.G. Giepmans
P. de Boer

Nature of the research:
Cell Biology/ Medical Biology: - Electron microscopy sample preparation, including ultramicrotomy - Post/pre-embedding immunolabeling - (Confocal) light microscopy - Large-scale electron microscopy5, 7 (www.nanotomy.org)

Fields of study:
cell biology molecular imaging diabetes

Background / introduction
Type 1 diabetes (T1D) is associated with loss of insulin producing beta-cells in the pancreatic islets of Langerhans resulting in impaired glucose uptake of target cells and consequently hyperglycaemia. In some rodent models beta-cell reconstitution from other cell types, called transdifferentiation, is observed either spontaneous or induced1-3. A hallmark of transdifferentiation is the presence of by bihormonal cells. Spontaneous transdifferentiation was only observed in selective near-total cell loss in transgenic mouse model of diphtheria toxin-induced selective beta-cell ablation1. However, using large-scale correlative light and electron microscopy (CLEM)4, 5 we found bihormonal cells in normoglycaemic rats. Furthermore, hormone granules were observed in aberrant exocrine cells and recently effects on the exocrine pancreas in T1D patients was reported6. This raises the intriguing possibility to examine whether transdifferentiation, via endocrine and/or exocrine cells, play a role in early-onset T1D for example to counteract an increased demand of insulin.
Research question / problem definition
Investigate the role of bihormonal cells and/or affected exocrine pancreas in normoglycaemic, diabetic-prone rats and human material in relation to early-onset T1D.
Workplan
Immunolabeling to identify different cell types (incl. bihormonal) in islets of Langerhans of both rat and human material in a CLEM approach.
Quantum dots are used for immune-fluorescence and EM localization7
Analyse large-scale electron microscopy datasets to score the appearance of bihormonal cells, aberrant exocrine cells and/or other abnormalities in both rat and human T1D material versus controls.
References
1. Thorel, F. et al. Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149-1154 (2010).
2. Chera, S. et al. Diabetes recovery by age-dependent conversion of pancreatic delta-cells into insulin producers. Nature 514, 503-507 (2014).
3. Piran, R. et al. Pharmacological induction of pancreatic islet cell transdifferentiation: relevance to type I diabetes. Cell. Death Dis. 5, e1357 (2014).
4. de Boer, P., Hoogenboom, J.. & Giepmans, B. N. Correlated light and electron microscopy: ultrastructure lights up! Nat. Methods 12, 503-513 (2015).
5. Ravelli, R.. et al. Destruction of tissue, cells and organelles in type 1 diabetic rats presented at macromolecular resolution. Sci. Rep. 3, 1804 (2013).
6. Campbell-Thompson, M. L. et al. The influence of type 1 diabetes on pancreatic weight. Diabetologia 59, 217-221 (2016).
7. Kuipers, J., de Boer, P. & Giepmans, B. N. Scanning EM of non-heavy metal stained biosamples: Large-field of view, high contrast and highly efficient immunolabeling. Exp. Cell Res. 337, 202-207 (2015).
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