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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

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

Author

  • Malin Fex

Summary, in English

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.

Department/s

  • Diabetes and Celiac Unit

Publishing year

2006

Language

English

Document type

Dissertation

Publisher

Experimental Medical Science, Lund University

Topic

  • Basic Medicine

Keywords

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

Status

Published

Research group

  • Diabetes and Celiac Unit

Supervisor

  • Hindrik Mulder
  • Cecilia Holm

ISBN/ISSN/Other

  • ISBN: 91-85559-40-7

Defence date

10 November 2006

Defence time

09:00

Defence place

Segerfalksalen, Wallenberg Neurocentrum Sölvegatan 17, 22184 Lund

Opponent

  • Miriam Cnop (MD, PhD)