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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

Stimulus-Section Coupling in Endocrine Cell Models

Author

  • Lotta Andersson

Summary, in English

Detailed understanding of biological systems governing specific mechanisms and pathways is essential in the development of novel disease therapies. Stimulus-secretion coupling in hormone secreting cells is a complex system of pathways that link activation of cellular processes by i.e. nutrients to the release of hormone. Stimulus-secretion coupling in the insulin secreting beta-cell is intensely researched to improve our understanding of type 2 diabetes (T2D), a perpetually growing global pandemic. Such research requires availability of model systems that are metabolically and functionally faithful to the cell type they represent.

In my research I have characterized, evaluated and applied cell models for metabolic research in endocrine cells. In studies I and II cellular function in response to nutrient stimuli in human and murine beta cell models and isolated islets was evaluated. In these studies I investigated functional aspects such as insulin secretion as well as metabolic changes such as changes in intracellular metabolite levels, oxygen consumption rates and energy production. I found that the response was qualitatively similar in human and rat beta cell models. The same was found when comparing a clonal rat beta cell model to isolated rat islets. Hence, I concluded that the similarities outweigh the differences and as such the in vitro models investigated lend themselves useful in metabolic studies, but with the recommend use of primary material for confirmation of key findings.

Stimulus-secretion coupling has been widely studied in the beta cell, providing extensive knowledge on the mechanisms governing insulin secretion elicited by various nutrients. In study III and IV, I used established alpha, beta and L-cell models to investigate similarities and differences in stimulus-secretion coupling in different endocrine cell types. In study III, an important difference in mitochondrial shuttles was found between alpha and beta cells, highlighting the malate-aspartate shuttle to be critical for glucagon secretion. These findings were subsequently verified in mouse islets. In study IV, a striking difference in the activity of glutamate dehydrogenase was found between L and beta cells.

Accumulation of glycogen in the beta cell has been associated with T2D. In study V, I investigated the potential role of glycogen metabolism in beta cells and its potential role in regulation of insulin secretion. This study revealed glycogen metabolism to be active and accumulation of glycogen to occurs in response to elevated glucose levels both in a clonal cell line and human islets. Moreover, perturbation of glycogen metabolism was shown to decrease insulin secretion in vitro.

Stimulus-secretion coupling is highly complex as is the pathogenesis of T2D. These studies highlight how well-characterized metabolic models may be used to further the understanding of stimulus secretion coupling in endocrine cells.

Department/s

  • Diabetes - Molecular Metabolism
  • LUDC (Lund University Diabetes Centre)-lup-obsolete
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2015

Language

English

Publication/Series

Lund University Faculty of Medicine Doctoral Dissertation Series

Volume

2015:144

Document type

Dissertation

Publisher

Department of Clinical Sciences, Lund University

Topic

  • Cell Biology
  • Biochemistry and Molecular Biology

Status

Published

Research group

  • Diabetes - Molecular Metabolism
  • LUDC (Lund University Diabetes Centre)-lup-obsolete

Supervisor

  • Peter Spégel
  • Hindrik Mulder

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-7619-224-5

Defence date

18 December 2015

Defence time

13:00

Defence place

Lilla Aulan, Jan Waldenströmsgata 5, SUS, Malmö

Opponent

  • Pierre Maechler (Ph.D.)