Leiden University Scholarly Publications

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Ellenbroek, J.H. (2015)

Pancreatic β- and α-cell adaptation in response to metabolic changes

Doctoral Thesis
Insulin-producing pancreatic _-cells are essential to maintain blood glucose levels within a narrow range. _-cells can adapt to an increased insulin demand by enhancing insulin secretion via increased _-cell function and/or increased _-cell mass. Inadequate _-cell adaptation leads to hyperglycemia and eventually diabetes mellitus. Therefore, it is critical to understand how the _-cell mass is regulated. We investigated _- and _-cell adaptation in response to different metabolic changes. We found that _-cell adaptation in response to insulin resistance in mice, rats, and deceased organ donors was regionally heterogeneous throughout the pancreas. We also observed that the glucagon-producing _-cell mass adapts to metabolic changes, resulting in the maintenance of the _- to _-cell ratio. Furthermore, we show that treatment of normoglycemic mice with a glucagon-like-peptide-1 receptor agonist improved _-cell function and that this is associated with a decrease in _-cell mass in order to...Show moreInsulin-producing pancreatic _-cells are essential to maintain blood glucose levels within a narrow range. _-cells can adapt to an increased insulin demand by enhancing insulin secretion via increased _-cell function and/or increased _-cell mass. Inadequate _-cell adaptation leads to hyperglycemia and eventually diabetes mellitus. Therefore, it is critical to understand how the _-cell mass is regulated. We investigated _- and _-cell adaptation in response to different metabolic changes. We found that _-cell adaptation in response to insulin resistance in mice, rats, and deceased organ donors was regionally heterogeneous throughout the pancreas. We also observed that the glucagon-producing _-cell mass adapts to metabolic changes, resulting in the maintenance of the _- to _-cell ratio. Furthermore, we show that treatment of normoglycemic mice with a glucagon-like-peptide-1 receptor agonist improved _-cell function and that this is associated with a decrease in _-cell mass in order to maintain normoglycemia. In mice fed a high-fat, low-carbohydrate ketogenic diet beta-cell adaptation failed, resulting in symptoms that are associated with diabetes in humans. Finally, we developed three high-throughput culture platforms for human islets to assess _-cell function that can be used in future studies to identify novel mechanisms involved in _- and _-cell adaptation.Show less
Beta-cell adaptation
Insulin resistance
Alpha-cell
Beta-cell
Pancreas
Diabetes mellitus
Endocrinology
All authors
Ellenbroek, J.H.
Supervisor
Koning, E.J.P. de; Rabelink, T.J.
Co-supervisor
Carlotti, F.
Qualification
Doctor (dr.)
Awarding Institution
Leiden University Medical Center (LUMC), Leiden University
Date
2015-03-25
ISBN (print)
9789461089298

Funding

Sponsorship
The research presented in this thesis was supported by the Diabetes Cell Therapy Initiative consortium, the Dutch Diabetes Research Foundation, the DON foundation, the Bontius Foundation and an unrestricted research grant from Novo Nordisk.