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Linda Ahlkvist

Research project participant

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Novel insights into the regulation of insulin secretion by GLP-1, GIP and glucagon

Author

  • Linda Ahlkvist

Summary, in English

There are many contributing factors to the development of type 2 diabetes, however, failure of beta-cells to sufficiently secrete insulin is the key component. The underlying mechanism of beta-cell failure is not fully established. In this thesis, we examined the role of high glucagon levels, i.e. hyperglucagonemia, for the development of beta-cell dysfunction in pre-diabetic mice. We found that induction of 2 week hyperglucagonemia leads to defective insulin secretion. To enhance beta-cell function, there are several therapeutic strategies. One important strategy is based on the gut incretin hormone glucagon-like peptide 1 (GLP-1), which potently stimulates insulin secretion. In the clinic, GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase 4 (DPP-4), the enzyme responsible for degradation of GLP-1, are currently used. A new concept of GLP-1 based therapies is to increase also endogenous GLP-1 secretion. In this thesis, we explored the importance of meal macronutrient composition for GLP-1 and insulin responses in healthy mice. We found that intake of mixed macronutrients compared to isocaloric glucose leads to a synergistic increase in GLP-1 and insulin levels. We also explored the effects of a novel GPR119 receptor agonist on GLP-1 and insulin levels after meal intake in healthy and glucose intolerant mice. GPR119 activation markedly increased GLP-1 and insulin responses to meal intake, however, only in glucose intolerant mice. Furthermore, we examined the mechanisms behind the effects of DPP-4 inhibition and found that vagal nerve signaling is important for the insulinotropic effects of DPP-4 inhibition. To conclude, the work in this thesis shed new light on possible ways to increase GLP-1 and insulin secretion, on the mechanism behind the effects of DPP-inhibition and on glucagon as a possible factor that may contribute to beta-cell failure.

Department/s

  • Medicine, Lund
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2015

Language

English

Publication/Series

Lund University Faculty of Medicine Doctoral Dissertation Series

Volume

2015:116

Document type

Dissertation

Publisher

Medicine (Lund)

Topic

  • Endocrinology and Diabetes

Keywords

  • Vagus nerve
  • GPR119
  • Insulin resistance
  • Glucagon
  • GIP
  • GLP-1
  • Insulin

Status

Published

Supervisor

  • Bo Ahrén
  • Bilal Omar

ISBN/ISSN/Other

  • ISSN: 1652-8220
  • ISBN: 978-91-7619-195-8

Defence date

20 November 2015

Defence time

09:00

Defence place

Segerfalkssalen, Biomedicinskt Centrum, A10, Sölvegatan 17, Lund

Opponent

  • Peter Flatt (Professor)