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

Malin Fex

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

Malin Fex

Celiac Disease and Diabetes Unit

Research output: Thesis › Doctoral 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 language	English
Qualification	Doctor
Awarding Institution	Department of Experimental Medical Science
Supervisors/Advisors	Mulder, Hindrik, Supervisor Holm Wallenberg, Cecilia, Supervisor
Award date	2006 Nov 10
Publisher	Experimental Medical Science, Lund University
ISBN (Print)	91-85559-40-7
Publication status	Published - 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

---

<div class="article_info">Malin Fex, Marloes Dekker Nitert, Nils Wierup, Frank Sundler, Charlotte Ling and Hindrik Mulder. 2006. Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet pp 1-10. Experimetal Medical Sciences, Faculty of Medicine (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. 2003. Hormone-sensitive Lipase Null Mice Exhibit Signs of Impaired Insulin Sensitivity whereas Insulin Secretion Is Intact The Journal of Biological Chemistry, vol 278 pp 36380-36388. Experimental Medical Sciences, Medical Faculty, Lund University.</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. 2004. Hormone-Sensitive Lipase Deficiency in Mouse Islets Abolishes Neutral Cholesterol Ester Hydrolase Activity but Leaves Lipolysis, Acylglycerides, Fat Oxidation, and Insulin Secretion Intact Endocrinology, vol 145 pp 3746-3753. Experimental Medical Sciences, Lund University</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. 2006. A beta-cell-specific Knock out of Hormone-sensitive Lipase results in hyperglycemia and disruption of phasic insulin secretion pp 1-12. Experimental Medical Sciences, Lund University (manuscript)</div>

Subject classification (UKÄ)

Basic Medicine

Free keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Mf_Avhandling_final2

Cite this

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title = "Lipid metabolism in the pancreatic beta-cell. Implications for insulin secretion.",

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.",

keywords = "diabetology, Endokrinologi, sekretion, diabetologi, Endocrinology, secreting systems, Lipid metabolism, Insulin secretion, Beta-cells",

author = "Malin Fex",

note = "Defence details Date: 2006-11-10 Time: 09:00 Place: Segerfalksalen, Wallenberg Neurocentrum S{\"o}lvegatan 17, 22184 Lund External reviewer(s) Name: Cnop, Miriam Title: MD, PhD Affiliation: Universitaire d`Anderlecht, Bruxelles, Belgium --- <div class={"}article_info{"}>Malin Fex, Marloes Dekker Nitert, Nils Wierup, Frank Sundler, Charlotte Ling and Hindrik Mulder. 2006. Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet pp 1-10. Experimetal Medical Sciences, Faculty of Medicine (accepted)</div> <div class={"}article_info{"}>Hindrik Mulder, Maria S{\"o}rhede Winzell, Juan Contreras, Malin Fex, Kristoffer Str{\"o}m, Torkil Plough, Henrik Galbo, Peter Arner, Cecilia Lundberg, Frank Sundler, Bo Ahr{\'e}n and Cecilia Holm. 2003. Hormone-sensitive Lipase Null Mice Exhibit Signs of Impaired Insulin Sensitivity whereas Insulin Secretion Is Intact The Journal of Biological Chemistry, vol 278 pp 36380-36388. Experimental Medical Sciences, Medical Faculty, Lund University.</div> <div class={"}article_info{"}>Malin Fex, Charlotta Olofsson, Ulrika Fransson, Karl Bacos, H{\aa}kan Lindvall, Maria S{\"o}rhede Winzell, Patrik Rorsman, Cecilia Holm and Hindrik Mulder. 2004. Hormone-Sensitive Lipase Deficiency in Mouse Islets Abolishes Neutral Cholesterol Ester Hydrolase Activity but Leaves Lipolysis, Acylglycerides, Fat Oxidation, and Insulin Secretion Intact Endocrinology, vol 145 pp 3746-3753. Experimental Medical Sciences, Lund University</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. 2006. A beta-cell-specific Knock out of Hormone-sensitive Lipase results in hyperglycemia and disruption of phasic insulin secretion pp 1-12. Experimental Medical Sciences, Lund University (manuscript)</div>",

year = "2006",

language = "English",

isbn = "91-85559-40-7",

publisher = "Experimental Medical Science, Lund University",

type = "Doctoral Thesis (compilation)",

school = "Department of Experimental Medical Science",

}

TY - THES

T1 - Lipid metabolism in the pancreatic beta-cell. Implications for insulin secretion.

AU - Fex, Malin

N1 - 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 --- <div class="article_info">Malin Fex, Marloes Dekker Nitert, Nils Wierup, Frank Sundler, Charlotte Ling and Hindrik Mulder. 2006. Enhanced mitochondrial metabolism may account for the adaptation to insulin resistance in islets from C57BL/6J mice fed a high-fat diet pp 1-10. Experimetal Medical Sciences, Faculty of Medicine (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. 2003. Hormone-sensitive Lipase Null Mice Exhibit Signs of Impaired Insulin Sensitivity whereas Insulin Secretion Is Intact The Journal of Biological Chemistry, vol 278 pp 36380-36388. Experimental Medical Sciences, Medical Faculty, Lund University.</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. 2004. Hormone-Sensitive Lipase Deficiency in Mouse Islets Abolishes Neutral Cholesterol Ester Hydrolase Activity but Leaves Lipolysis, Acylglycerides, Fat Oxidation, and Insulin Secretion Intact Endocrinology, vol 145 pp 3746-3753. Experimental Medical Sciences, Lund University</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. 2006. A beta-cell-specific Knock out of Hormone-sensitive Lipase results in hyperglycemia and disruption of phasic insulin secretion pp 1-12. Experimental Medical Sciences, Lund University (manuscript)</div>

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

KW - diabetology

KW - Endokrinologi

KW - sekretion

KW - diabetologi

KW - Endocrinology

KW - secreting systems

KW - Lipid metabolism

KW - Insulin secretion

KW - Beta-cells

M3 - Doctoral Thesis (compilation)

SN - 91-85559-40-7

PB - Experimental Medical Science, Lund University

ER -

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

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

Fingerprint

Cite this