Coupling mechanisms of insulin secretion - roles of mitochondrial metabolism and cAMP.

Ulrika Krus

Research output: ThesisDoctoral Thesis (compilation)

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Abstract

Type 2 diabetes is a disease that increases tremendously in the western world. It is characterized by insulin resistance and defects in insulin secretion. Insulin resistance is tightly linked to obesity, and usually precedes the onset of type 2 diabetes. When insulin resistance develops, the pancreatic beta-cells compensate by in¬creasing their secretion of insulin, causing hyperinsulinemia. This state may not be a major risk factor per se; in fact, many people develop severe insulin resistance and hyperinsulinemia without ever acquiring diabetes. However, beta-cells in some individuals, perhaps genetically predisposed, are unable to increase their secretion sufficiently to meet the new requirements. This leads to hyperglycemia, the main hallmark of diabetes. To be able to treat diabetes, the defects in the beta-cells causing impaired insulin secretion must be elucidated.

The aim of this thesis was to investigate the mechanisms of insulin secretion, and especially what couples glucose stimulation of the beta-cell to insulin secretion.

We have found that anaplerosis via pyruvate carboxylase is essential for both phases of glucose-stimulated insulin secretion, presumably via generation of an increased ATP/ADP ratio. Further, we discovered that expression of PDK1 is upregulated in INS-1 832/13 cells cultured at high concentrations of glucose, and that knock-down of PDK1 enhances insulin secretion. Both these findings prove that mitochondrial metabolism is important for insulin secretion, and points to the involvement of pyruvate cycling. We have also showed that PKA signaling is stimulated by glucose, and that inhibition of PKA decreases glucose-stimulated insulin secretion in INS-1 832/13 cells.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Mulder, Hindrik, Supervisor
Award date2006 Dec 15
Publisher
Print ISBNs91-85559-67-9
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-12-15
Time: 09:15
Place: Segerfalkssalen, Wallenberg neurocentrum, Sölvegatan 17

External reviewer(s)

Name: Wollheim, Claes
Title: professor
Affiliation: University of Geneva, Switzerland

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<div class="article_info">Ulrika Fransson, Anders Rosengren, Frans Schuit, Erik Renström and Hindrik Mulder. <span class="article_issue_date">2006</span>. <span class="article_title">Anaplerosis via pyruvate carboxylase is required for the fuel-induced rise in the ATP:ADP ratio in rat pancreatic islets</span> <span class="journal_series_title">Diabetologia</span>, <span class="journal_volume">vol 49</span> <span class="journal_pages">pp 1578-86</span>. <span class="journal_distributor">Springer-Verlag</span></div>
<div class="article_info">Ulrika Fransson, Elna Hallgard, Mary Sugden and Hindrik Mulder. <span class="article_issue_date"></span>. <span class="article_title">Knock-down of Pyruvate Dehydrogenase Kinase 1 in INS-1 832/13 Cells Increases Insulin Secretion</span> (manuscript)</div>
<div class="article_info">Shumin Yang, Ulrika Fransson, Lillian Fagerhus, Lena S Holst, Hans Hohmeier, Erik Renström and Hindrik Mulder. <span class="article_issue_date">2004</span>. <span class="article_title">Enhanced cAMP Protein Kinase A Signaling Determines Improved Insulin Secretion in a Clonal Insulin-Producing A-Cell Line (INS-1 832/13)</span> <span class="journal_series_title">Molecular Endocrinology</span>, <span class="journal_volume">vol 18</span> <span class="journal_pages">pp 2312-20</span>. <span class="journal_distributor">The Endocrine society</span></div>

Subject classification (UKÄ)

  • Basic Medicine

Keywords

  • secreting systems
  • Endocrinology
  • pyruvate dehydrogenase kinase
  • beta-cells
  • pyruvate carboxylase
  • diabetology
  • Endokrinologi
  • sekretion
  • diabetologi
  • diabetes

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