Studies in beta cells and adipocytes in the context of obesity and T2D - focusing on PDE3B, OPN and SCFAs

Emilia Heimann

Research output: ThesisDoctoral Thesis (compilation)

301 Downloads (Pure)

Abstract

Type 2 diabetes (T2D) is a heterogeneous disease characterized by altered lipid
parameters and elevated glucose levels, as a direct consequence of impaired
insulin signaling in target tissues and reduced insulin exocytosis from pancreatic
β-cells. Obesity, which dramatically increases worldwide, is associated with
insulin resistance and T2D. In this thesis, we elucidate the effects of hormones and
nutrients on biological responses and regulatory mechanisms in pancreatic β-cells
and adipocytes. The information is scarce with regard to the regulation of cyclic
nucleotide phosphodiesterase 3B (PDE3B) in pancreatic β-cells. We show that
PDE3B is activated in response to glucose, insulin and forskolin, which is coupled
to a decrease, no apparent change or an increase in total phosphorylation of the
enzyme in rat pancreatic β-cells. Furthermore, PDE1A, PDE3, PDE4C, PDE5A,
PDE7A, PDE7B, PDE8A, PDE10A and PDE11A are detected in human
pancreatic islets. Islets from RIP-PDE3B mice, exhibiting β-cell specific
overexpression of the cAMP-degrading enzyme phosphodiesterase 3B (PDE3B)
and dysregulated insulin secretion, show induced OPN protein expression. In
addition, in silico and functional approaches demonstrate that PDE3B and OPN
are connected and follow a similar protein expression pattern in response to e.g.
cAMP-elevating agents and insulin. Little is known regarding the direct effects of
short-chain fatty acids (SCFAs), produced through bacterial fermentation of
dietary fibers, on glucose and lipid metabolism in adipocytes. We show that the
SCFAs propionic acid and butyric acid inhibit cAMP-stimulated lipolysis, a
mechanism that is not dependent on the cAMP-degrading enzyme PDE3B.
Moreover, both SCFAs inhibit basal and insulin-stimulated de novo lipogenesis,
which is associated with increased phosphorylation of acetyl CoA carboxylase, the
rate-limiting enzyme in fatty acid synthesis. Propionic acid and butyric acid are
also able to potentiate insulin-stimulated glucose uptake.
In summary, we demonstrate that agents relevant for β-cell function regulate
PDE3B activity and phosphorylation levels. Based on several strategies, we
demonstrate a connection between PDE3B and OPN, the latter having a protective
role in pancreatic β-cells. Further investigations are required to identify
downstream targets of PDE3B that are involved in the regulation of insulin
exocytosis and also to elucidate the relationship with OPN. Moreover, several
PDEs are present in human pancreatic islets. The majority of these PDEs have
been described as insulin secretagogues in animal models and it is thus promising
to also confirm their presence in humans, as it can be advantageous for the
8
treatment of T2D. SCFAs inhibit fatty acid mobilization and potentiates insulininduced
glucose uptake; observed effects that might be beneficial for preventing
ectopic lipid accumulation, lipotoxicity and insulin resistance. Thus, it remains to
be verified if anti-obesity properties can be conferred to SCFAs.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Insulin Signal Transduction
Supervisors/Advisors
  • Degerman, Eva, Supervisor
  • Stenson, Lena, Supervisor
Award date2014 Jun 4
Publisher
ISBN (Print)978-91-7619-002-9
Publication statusPublished - 2014

Bibliographical note

Defence details

Date: 2014-06-04
Time: 09:00
Place: Grubb lecture hall, BMC, Sölvegatan 19, Lund

External reviewer(s)

Name: Barg, Sebastian
Title: [unknown]
Affiliation: Uppsala University

---

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Free keywords

  • Obesity
  • type 2 diabetes
  • islets of Langerhans
  • adipocytes
  • PDE3B
  • OPN
  • SCFAs

Fingerprint

Dive into the research topics of 'Studies in beta cells and adipocytes in the context of obesity and T2D - focusing on PDE3B, OPN and SCFAs'. Together they form a unique fingerprint.
  • AFC: ANTIDIABETIC FOOD CENTRE

    Adlercreutz, P. (PI), Ahrén, I. L. (PI), Ahrné, S. (Researcher), Alhamimi, S. (Research student), Andersson, K. E. (Researcher), Andersson, K. E. (Research student), Månberger, A. (Researcher), Axling, U. (Researcher), Axling, U. (Research student), Bergenståhl, B. (Researcher), Berger, K. (PI), Björck, I. (PI), Bränning, C. (Research student), Bäckhed, F. (PI), Zanzer, Y. C. (Research student), Danielsson, A. (PI), Danielsson, B. (Research assistant), Degerman, E. (PI), Dejmek, P. (Researcher), Dey, E. (PI), Dougkas, A. (Researcher), Ekström, L. (Research student), Eliasson, A.-C. (PI), Fahlgren, C. (Research engineer), Falck, P. (PI), Falck, P. (Research student), Ghaffarzadegan, T. (Research student), Granfeldt, Y. (Researcher), Grey, C. (Researcher), Gunnerud, U. (Research student), Håkansson, Å. (Researcher), Håkansson, Å. (Research student), Hållenius, F. (Researcher), Hållenius, F. (PI), Haskå, L. (PI), Haskå, L. (Research student), Heimann, E. (Research student), Hellstrand, P. (Researcher), Heyman, L. (Research student), Holm Wallenberg, C. (PI), Holmén-Pålbrink, A.-K. (Research assistant), Holst, O. (Researcher), Immerstrand, T. (Research student), Immerzeel, P. (Researcher), Jakobsdottir, G. (Research student), Jeppsson, B. (Researcher), Johansson, E. (Research student), Johansson, M. (Project coordinator), Johansson, M. (Researcher), Johansson, M. (Research assistant), Johansson, U. (Researcher), Jones, H. (Researcher), Nordberg Karlsson, E. (Researcher), Kovatcheva-Datchary, P. (Researcher), Kulcinskaja, E. (Research student), Landin-Olsson, M. (Researcher), Linninge, C. (Researcher), Marefati, A. (Research student), Marungruang, N. (Research student), Molin, G. (PI), Nilsson, A. (PI), Nilsson, E. (Research engineer), Nilsson, U. (PI), Nyman, M. (PI), Ohlson, E. (Research assistant), Olsson, C. (Researcher), Öste, R. (PI), Östman, E. (PI), Persson, L. (Research engineer), Persson, S. (Researcher), Plaza, M. (Researcher), Prykhodko, O. (Researcher), Radeborg, K. (Researcher), Rayner, M. (PI), Rosén, L. (Research student), Sandahl, M. (Researcher), Sandberg, J. (Research student), Sjöö, M. (PI), Skog, K. (Researcher), Spégel, P. (PI), Stålbrand, H. (Researcher), Sterner, O. (PI), Svensson, J. (Research student), Tareke, E. (PI), Tovar, J. (PI), Turner, C. (PI), Weström, B. (Researcher), Xu, J. (Research student) & Zhong, Y. (Research student)

    2007/07/012018/01/31

    Project: Research

Cite this