THE ROLE OF PHOSPHODIESTERASE 3B IN CAMP-MEDIATED REGULATION OF INSULIN SECRETION

Helena Jones

Research output: ThesisDoctoral Thesis (compilation)

537 Downloads (Pure)

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by various combinations of ?-cell failure and insulin resistance leading to hyperglycemia and glucose intolerance. In order to maintain glucose tolerance in the insulin resistance state, increased insulin secretion is a requirement and it is because of inadequate islet adaptation that glucose intolerance develops in T2DM. The pathophysiology of T2DM is not fully understood and more knowledge is needed concerning both insulin action and ?-cell physiology and adaptation. The general aim of this thesis was to investigate the role of ?-cell cAMP-degrading phosphodiesterase 3B (PDE3B) in the regulation of insulin secretion and whole body energy homeostasis. The specific aims were (i) to study the physiological importance of well-regulated ?-cell-cAMP levels for insulin release and whole body energy homeostasis during a long-term metabolic challenge, (ii) to evaluate the role of PDE3B in biphasic insulin secretion and its intracellular localization, and (iii) to investigate the mechanisms for regulation of PDE3B activity in ?-cells. It was previously shown that PDE3B attenuates glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) potentiated-insulin secretion. It is shown here that accurate regulation of ?-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance. This finding is coupled to the novel discovery that PDE3B, shown to localize to the exocytotic machinery, functions as a specific attenuator of cAMP-mediated potentiation of depolarization-induced insulin secretion. Further, we have begun to elucidate the details concerning the regulation of PDE3B activity in ?-cells. Data are presented suggesting that PDE3B activity in ?-cells is intricately regulated by phosphorylation and dephosphorylation, probably by the action of several differentially regulated kinases and phosphatases. In conclusion, this thesis contributes to the knowledge regarding the importance and function of cAMP-mediated regulation of stimulus-secretion coupling in pancreatic ?-cells and demonstrates that dysfunction of cAMP-PDE3B signalling results in a substantially increased sensitivity to the adverse effects of a high-fat diet.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Insulin Signal Transduction
Supervisors/Advisors
  • Stenson, Lena, Supervisor
Award date2007 Oct 19
Publisher
ISBN (Print)978-91-85897-11-7
Publication statusPublished - 2007

Bibliographical note

Defence details

Date: 2007-10-19
Time: 09:00
Place: Lundmarksalen, Astronomi Centrum, Sölvegatan 27, Lund

External reviewer(s)

Name: Tengholm, Anders
Title: Docent
Affiliation: Inst. Medicinsk Cellbiologi, Uppsala Universitet

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<div class="article_info">HA Walz, L Härndahl, N Wierup, E Zmuda-Trzebiatowska, F Svennelid, VC Manganiello, T Ploug, F Sundler, E Degerman, B Ahrén and L Stenson Holst. <span class="article_issue_date">2006</span>. <span class="article_title">Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B.</span> <span class="journal_series_title">J Endocrinol.</span>, <span class="journal_volume">vol 189</span> <span class="journal_pages">pp 629-641</span>.</div>
<div class="article_info">HA Walz, N Wierup, J Vikman, VC Manganiello, E Degerman, L Eliasson and L Stenson Holst. <span class="article_issue_date">2007</span>. <span class="article_title">Beta-cell PDE3B regulates Ca2+-stimulated exocytosis of insulin.</span> <span class="journal_series_title">Cell Signal.</span>, <span class="journal_volume">vol 19</span> <span class="journal_pages">pp 1505-1513</span>.</div>
<div class="article_info">HA Walz, S Resjö, VC Manganiello, E Degerman and L Stenson. <span class="article_issue_date"></span>. <span class="article_title">Regulation of Phosphodiesterase 3B in beta-cells.</span> (manuscript)</div>

Subject classification (UKÄ)

  • Endocrinology and Diabetes

Free keywords

  • cAMP
  • PDE3B
  • exocytosis
  • insulin
  • diabetes
  • Medicine (human and vertebrates)
  • Medicin (människa och djur)
  • diabetologi
  • sekretion
  • Endokrinologi
  • diabetology
  • Endocrinology
  • secreting systems

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