The Ambiguous beta-cell : On the loss of human pancreatic beta-cell identity

Spijker, H.S. (2017)

Doctoral Thesis

Diabetes mellitus is amongst the leading causes of morbidity and mortality worldwide. Insulin-producing pancreatic β-cells are central in establishing adequate glucose regulation and loss of functional β-cells results in the development of diabetes. Although it was previously thought that fully differentiated cells cannot change phenotype, murine studies recently indicated that mature β-cells can change identity into other islet cells under conditions of (metabolic) stress.

We present a novel agarose based microwell culture system that can be used for aggregate formation of human or rodent islet cells. We show that this platform provides reproducible results to study aggregation of primary human islet cells. Using this culture system together with β-cell specific lineage tracing, we find that mature human β-cells can spontaneously lose their identity and convert into glucagon-containing α-cells. We then used human pancreatic tissue from donors with T2DM and matched controls to explore loss of β-cell identity in T2DM. We report that cells indicative of loss of β-cell identity are found more frequently in tissue samples from donors with a history of T2DM. Finally, we show that Pax4 and GLP-1 receptor agonists can partially prevent loss of identity β-cell in our ex vivo model.

• Diabetes mellitus
• Pancreas
• Islet transplantation
• Beta-cell
• Alpha-cell
• Differentiation
• Stem cells

• All authors: Spijker, H.S.
• Supervisor: Koning, E.J.P. de; Rabelink, A.J.
• Co-supervisor: Carlotti, F.
• Committee: Hoeben, R.C.; Pijl, H.; Goumans, M.J.T.H.; Cnop, M.; Apeldoorn, A.A. van
• Qualification: Doctor (dr.)
• Awarding Institution: Nephrology, Medicine / Leiden University Medical Center (LUMC), Leiden University
• Date: 2017-11-07
• ISBN (print): 9789461827968