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

Ulrika Krus

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

Ulrika Krus

Diabetes - öpatofysiologi

Forskningsoutput: Avhandling › Doktorsavhandling (sammanläggning)

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Popular Abstract in Swedish
Typ 2 diabetes är en sjukdom som ökar lavinartat i västvärlden. Dess främsta kännetecken är insulinresistens och defekter i insulinsekretion. Insulinresistens är kopplat till fetma, och framträder ofta långt innan man utvecklar typ 2 diabetes. När man blir insulinresistent kompenseras detta av att betacellerna i de langerhanska öarna i bukspottskörteln producerar mer insulin, vilket leder till hyperinsulinemi. Detta tillstånd behöver inte utgöra en riskfaktor i sig själv, många utvecklar allvarlig insulinresistens och hyperinsulinemi utan att någonsin få typ 2 diabetes. Emellertid har vissa personer betaceller som inte klarar av att öka produktionen av insulin tillräckligt mycket för att kompensera för insulinresistensen, något som kan orsakas av genetiska faktorer. Detta leder till hyperglykemi, vilket är definitionen på diabetes. För att kunna behandla diabetes måste man klarlägga vilka defekter i betacellerna som orsakar den försämrade insulinutsöndringen.

Syftet med den här avhandlingen var att undersöka mekanismer för insulinutsöndring, och speciellt att utröna vad som kopplar glukosstimulering av betacellen till insulinutsöndring. Vi har upptäckt att anapleros via pyruvatkarboxylas är nödvändigt för både första och andra fasen i glukosstimulerad insulinfrisättning, och att det förmodligen sker genom en ökning av ATP/ADP ration. Vidare har vi funnit att uttrycket av PDK1 är uppreglerat i INS-1 832/13 celler som odlats i höga glukoskoncentrationer, och att hämning av PDK1 förbättrar insulinutsöndringen. Båda dessa upptäckter visar att mitokondriell metabolism är viktigt för insulinutsöndring, och tyder på att olika kretslopp för pyruvat är inblandat. Vi har också visat att PKA-signalering stimuleras av glukos, och att inhibering av PKA leder till försämrad insulinsekretion i INS-1 832/13 celler.

Originalspråk	engelska
Kvalifikation	Doktor
Tilldelande institution	Institutionen för experimentell medicinsk vetenskap
Handledare	Mulder, Hindrik, handledare
Tilldelningsdatum	2006 dec. 15
Förlag	Experimental Medical Science, Lund University
ISBN (tryckt)	91-85559-67-9
Status	Published - 2006

Bibliografisk information

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

---

<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>

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@phdthesis{c40b33e070fc4786b332806527fe6c85,

title = "Coupling mechanisms of insulin secretion - roles of mitochondrial metabolism and cAMP.",

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.",

keywords = "secreting systems, Endocrinology, pyruvate dehydrogenase kinase, beta-cells, pyruvate carboxylase, diabetology, Endokrinologi, sekretion, diabetologi, diabetes",

author = "Ulrika Krus",

note = "Defence details Date: 2006-12-15 Time: 09:15 Place: Segerfalkssalen, Wallenberg neurocentrum, S{\"o}lvegatan 17 External reviewer(s) Name: Wollheim, Claes Title: professor Affiliation: University of Geneva, Switzerland --- <div class={"}article_info{"}>Ulrika Fransson, Anders Rosengren, Frans Schuit, Erik Renstr{\"o}m 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 Renstr{\"o}m 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>",

year = "2006",

language = "English",

isbn = "91-85559-67-9",

publisher = "Experimental Medical Science, Lund University",

school = "Department of Experimental Medical Science",

}

TY - THES

T1 - Coupling mechanisms of insulin secretion - roles of mitochondrial metabolism and cAMP.

AU - Krus, Ulrika

N1 - 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 --- <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>

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

KW - secreting systems

KW - Endocrinology

KW - pyruvate dehydrogenase kinase

KW - beta-cells

KW - pyruvate carboxylase

KW - diabetology

KW - Endokrinologi

KW - sekretion

KW - diabetologi

KW - diabetes

M3 - Doctoral Thesis (compilation)

SN - 91-85559-67-9

PB - Experimental Medical Science, Lund University

ER -

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

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