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THE ROLE OF PHOSPHODIESTERASE 3B IN CAMP-MEDIATED REGULATION OF INSULIN SECRETION

Jones, Helena LU (2007) In Dissertation Series 2007:133.
Abstract
Type 2 diabetes mellitus (T2DM) is characterized by various combinations of ?-cell failure and insulin resistance leading to hyperglycemia and glucose intolerance. In order to maintain glucose tolerance in the insulin resistance state, increased insulin secretion is a requirement and it is because of inadequate islet adaptation that glucose intolerance develops in T2DM. The pathophysiology of T2DM is not fully understood and more knowledge is needed concerning both insulin action and ?-cell physiology and adaptation. The general aim of this thesis was to investigate the role of ?-cell cAMP-degrading phosphodiesterase 3B (PDE3B) in the regulation of insulin secretion and whole body energy homeostasis. The specific aims were (i) to study the... (More)
Type 2 diabetes mellitus (T2DM) is characterized by various combinations of ?-cell failure and insulin resistance leading to hyperglycemia and glucose intolerance. In order to maintain glucose tolerance in the insulin resistance state, increased insulin secretion is a requirement and it is because of inadequate islet adaptation that glucose intolerance develops in T2DM. The pathophysiology of T2DM is not fully understood and more knowledge is needed concerning both insulin action and ?-cell physiology and adaptation. The general aim of this thesis was to investigate the role of ?-cell cAMP-degrading phosphodiesterase 3B (PDE3B) in the regulation of insulin secretion and whole body energy homeostasis. The specific aims were (i) to study the physiological importance of well-regulated ?-cell-cAMP levels for insulin release and whole body energy homeostasis during a long-term metabolic challenge, (ii) to evaluate the role of PDE3B in biphasic insulin secretion and its intracellular localization, and (iii) to investigate the mechanisms for regulation of PDE3B activity in ?-cells. It was previously shown that PDE3B attenuates glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) potentiated-insulin secretion. It is shown here that accurate regulation of ?-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance. This finding is coupled to the novel discovery that PDE3B, shown to localize to the exocytotic machinery, functions as a specific attenuator of cAMP-mediated potentiation of depolarization-induced insulin secretion. Further, we have begun to elucidate the details concerning the regulation of PDE3B activity in ?-cells. Data are presented suggesting that PDE3B activity in ?-cells is intricately regulated by phosphorylation and dephosphorylation, probably by the action of several differentially regulated kinases and phosphatases. In conclusion, this thesis contributes to the knowledge regarding the importance and function of cAMP-mediated regulation of stimulus-secretion coupling in pancreatic ?-cells and demonstrates that dysfunction of cAMP-PDE3B signalling results in a substantially increased sensitivity to the adverse effects of a high-fat diet. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Docent Tengholm, Anders, Inst. Medicinsk Cellbiologi, Uppsala Universitet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
cAMP, PDE3B, exocytosis, insulin, diabetes, Medicine (human and vertebrates), Medicin (människa och djur), diabetologi, sekretion, Endokrinologi, diabetology, Endocrinology, secreting systems
in
Dissertation Series
volume
2007:133
pages
115 pages
publisher
Medical Faculty, Lund University
defense location
Lundmarksalen, Astronomi Centrum, Sölvegatan 27, Lund
defense date
2007-10-19 09:00:00
ISSN
1652-8220
ISBN
978-91-85897-11-7
language
English
LU publication?
yes
additional info
HA Walz, L Härndahl, N Wierup, E Zmuda-Trzebiatowska, F Svennelid, VC Manganiello, T Ploug, F Sundler, E Degerman, B Ahrén and L Stenson Holst. 2006. Early and rapid development of insulin resistance, islet dysfunction and glucose intolerance after high-fat feeding in mice overexpressing phosphodiesterase 3B. J Endocrinol., vol 189 pp 629-641.
HA Walz, N Wierup, J Vikman, VC Manganiello, E Degerman, L Eliasson and L Stenson Holst. 2007. Beta-cell PDE3B regulates Ca2+-stimulated exocytosis of insulin. Cell Signal., vol 19 pp 1505-1513.
HA Walz, S Resjö, VC Manganiello, E Degerman and L Stenson. . Regulation of Phosphodiesterase 3B in beta-cells. (manuscript)
id
d525dd69-91f9-441f-9736-abf46422fcea (old id 598984)
date added to LUP
2016-04-01 16:18:58
date last changed
2019-05-21 13:09:04
@phdthesis{d525dd69-91f9-441f-9736-abf46422fcea,
  abstract     = {{Type 2 diabetes mellitus (T2DM) is characterized by various combinations of ?-cell failure and insulin resistance leading to hyperglycemia and glucose intolerance. In order to maintain glucose tolerance in the insulin resistance state, increased insulin secretion is a requirement and it is because of inadequate islet adaptation that glucose intolerance develops in T2DM. The pathophysiology of T2DM is not fully understood and more knowledge is needed concerning both insulin action and ?-cell physiology and adaptation. The general aim of this thesis was to investigate the role of ?-cell cAMP-degrading phosphodiesterase 3B (PDE3B) in the regulation of insulin secretion and whole body energy homeostasis. The specific aims were (i) to study the physiological importance of well-regulated ?-cell-cAMP levels for insulin release and whole body energy homeostasis during a long-term metabolic challenge, (ii) to evaluate the role of PDE3B in biphasic insulin secretion and its intracellular localization, and (iii) to investigate the mechanisms for regulation of PDE3B activity in ?-cells. It was previously shown that PDE3B attenuates glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) potentiated-insulin secretion. It is shown here that accurate regulation of ?-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance. This finding is coupled to the novel discovery that PDE3B, shown to localize to the exocytotic machinery, functions as a specific attenuator of cAMP-mediated potentiation of depolarization-induced insulin secretion. Further, we have begun to elucidate the details concerning the regulation of PDE3B activity in ?-cells. Data are presented suggesting that PDE3B activity in ?-cells is intricately regulated by phosphorylation and dephosphorylation, probably by the action of several differentially regulated kinases and phosphatases. In conclusion, this thesis contributes to the knowledge regarding the importance and function of cAMP-mediated regulation of stimulus-secretion coupling in pancreatic ?-cells and demonstrates that dysfunction of cAMP-PDE3B signalling results in a substantially increased sensitivity to the adverse effects of a high-fat diet.}},
  author       = {{Jones, Helena}},
  isbn         = {{978-91-85897-11-7}},
  issn         = {{1652-8220}},
  keywords     = {{cAMP; PDE3B; exocytosis; insulin; diabetes; Medicine (human and vertebrates); Medicin (människa och djur); diabetologi; sekretion; Endokrinologi; diabetology; Endocrinology; secreting systems}},
  language     = {{eng}},
  publisher    = {{Medical Faculty, Lund University}},
  school       = {{Lund University}},
  series       = {{Dissertation Series}},
  title        = {{THE ROLE OF PHOSPHODIESTERASE 3B IN CAMP-MEDIATED REGULATION OF INSULIN SECRETION}},
  url          = {{https://lup.lub.lu.se/search/files/4635069/598985.pdf}},
  volume       = {{2007:133}},
  year         = {{2007}},
}