Lipid metabolism in the pancreatic beta-cell. Implications for insulin secretion.

Research output: ThesisDoctoral Thesis (compilation)

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Abstract

We have investigated the role of lipid metabolism with regard to beta-cell function and insulin secretion. Lipids are known to play a crucial functional role in the pancreatic beta-cell, where they are essential for adequate hormone release, but may also exert a long-term toxic effect, leading to beta-cell dysfunction. Our studies in mice, where insulin resistance and glucose intolerance was induced by high fat diet, showed that beta-cells compensate by increasing mitochondrial mass and hence shift oxidation from glucose to other fuels, such as amino acids and free fatty acids. This process is likely a means to maintain euglycemia, and if it fails diabetes will evolve. We have studied the consequences of a targeted inactivation of a key enzyme in lipolysis: hormone sensitive lipase (HSL). To this end, both a global knock out of HSL and a beta-cell specific KO of the enzyme (beta-HSL KO) were created. In theory, disruption of HSL could cause an accumulation of lipids, inducing cellular toxicity, as well as having an effect on overall energy homeostasis. Additionally, insulin secretion from beta-cells could be compromised due to abrogation of an essential lipid signal normally provided by HSL. In the global KO of HSL, we found that ablation of HSL causes insulin resistance in skeletal muscle, adipose tissue and liver; accumulation of diglyceride was observed in adipose tissue. However, lack of HSL did not have an effect on insulin secretion in the global KO mouse of HSL. This may be due to compensatory mechanisms. By contrast, in our beta-HSL KO, an ablation of the protein made a strong impact on insulin secretion both in vivo and in vitro. beta-HSL KO mice were hyperglycemic, and the first phase of insulin secretion was selectively affected. Furthermore, an increase in adipose mass in beta-HSL KO mice, accompanied by a rise in plasma leptin levels, as well as increased peripheral insulin sensitivity, indicates crosstalk between tissues involved in metabolic control. We hereby conclude that HSL is a key enzyme in overall glucose homeostasis. Its pivotal role may be attributed to the provision of lipid-derived signals essential for control of insulin release.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Mulder, Hindrik, Supervisor
  • Holm Wallenberg, Cecilia, Supervisor
Award date2006 Nov 10
Publisher
Print ISBNs91-85559-40-7
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-11-10
Time: 09:00
Place: Segerfalksalen, Wallenberg Neurocentrum Sölvegatan 17, 22184 Lund

External reviewer(s)

Name: Cnop, Miriam
Title: MD, PhD
Affiliation: Universitaire d`Anderlecht, Bruxelles, Belgium

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<div class="article_info">Malin Fex, Marloes Dekker Nitert, Nils Wierup, Frank Sundler, Charlotte Ling and Hindrik Mulder. <span class="article_issue_date">2006</span>. <span class="article_title">Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet</span> <span class="journal_pages">pp 1-10</span>. <span class="journal_distributor">Experimetal Medical Sciences, Faculty of Medicine</span> (accepted)</div>
<div class="article_info">Hindrik Mulder, Maria Sörhede Winzell, Juan Contreras, Malin Fex, Kristoffer Ström, Torkil Plough, Henrik Galbo, Peter Arner, Cecilia Lundberg, Frank Sundler, Bo Ahrén and Cecilia Holm. <span class="article_issue_date">2003</span>. <span class="article_title">Hormone-sensitive Lipase Null Mice Exhibit Signs of Impaired Insulin Sensitivity whereas Insulin Secretion Is Intact</span> <span class="journal_series_title">The Journal of Biological Chemistry</span>, <span class="journal_volume">vol 278</span> <span class="journal_pages">pp 36380-36388</span>. <span class="journal_distributor">Experimental Medical Sciences, Medical Faculty, Lund University.</span></div>
<div class="article_info">Malin Fex, Charlotta Olofsson, Ulrika Fransson, Karl Bacos, Håkan Lindvall, Maria Sörhede Winzell, Patrik Rorsman, Cecilia Holm and Hindrik Mulder. <span class="article_issue_date">2004</span>. <span class="article_title">Hormone-Sensitive Lipase Deficiency in Mouse Islets Abolishes Neutral Cholesterol Ester Hydrolase Activity but Leaves Lipolysis, Acylglycerides, Fat Oxidation, and Insulin Secretion Intact</span> <span class="journal_series_title">Endocrinology</span>, <span class="journal_volume">vol 145</span> <span class="journal_pages">pp 3746-3753</span>. <span class="journal_distributor">Experimental Medical Sciences, Lund University</span></div>
<div class="article_info">Malin Fex, Gunther Haemmmerle, Nils Wierup, Marloes Dekker Nitert, Matilda Rehn, Michael Ristow, Rudolf Zechner, Frank Sundler, Cecilia Holm and Hindrik Mulder. <span class="article_issue_date">2006</span>. <span class="article_title">A beta-cell-specific Knock out of Hormone-sensitive Lipase results in hyperglycemia and disruption of phasic insulin secretion</span> <span class="journal_pages">pp 1-12</span>. <span class="journal_distributor">Experimental Medical Sciences, Lund University</span> (manuscript)</div>

Subject classification (UKÄ)

  • Basic Medicine

Keywords

  • diabetology
  • Endokrinologi
  • sekretion
  • diabetologi
  • Endocrinology
  • secreting systems
  • Lipid metabolism
  • Insulin secretion
  • Beta-cells

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