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The role of CART in islet function

Abels, Mia LU (2016)
Abstract
Diminished insulin secretion and dysregulated glucagon secretion are key features of type 2 diabetes (T2D). The overall aim of this thesis was to study the role of cocaine- and amphetamine-regulated transcript (CART) in islet cell function and how CART regulates glucose homeostasis. We found that CART is expressed in human islet cells and that its expression is increased in patients with T2D, as well as in mouse models of T2D. Rat islet CART expression was regulated by glucose and beta cell CART expression was normalised by insulin treatment in diabetic rats. Furthermore, CART increased insulin secretion from both mouse and human islets in a glucose-dependent fashion. This could partly be explained by increased beta cell exocytosis,... (More)
Diminished insulin secretion and dysregulated glucagon secretion are key features of type 2 diabetes (T2D). The overall aim of this thesis was to study the role of cocaine- and amphetamine-regulated transcript (CART) in islet cell function and how CART regulates glucose homeostasis. We found that CART is expressed in human islet cells and that its expression is increased in patients with T2D, as well as in mouse models of T2D. Rat islet CART expression was regulated by glucose and beta cell CART expression was normalised by insulin treatment in diabetic rats. Furthermore, CART increased insulin secretion from both mouse and human islets in a glucose-dependent fashion. This could partly be explained by increased beta cell exocytosis, altered intracellular Ca2+ oscillation pattern as well as improved synchronisation of Ca2+ oscillations between islet cells. Importantly, CART increased insulin secretion and glucose elimination in vivo in mice. We also showed that CART decreased glucagon secretion in mouse and human islets, as well as in vivo in mice, and that CART reduced exocytosis in alpha cells. To mimic the situation in patients, with increased beta cell CART expression, we generated transgenic mice with beta cell-specific CART overexpression (CARTtg) and studied the impact of increased beta cell CART expression on glucose homeostasis in vivo. Under basal conditions, CARTtg mice were normoglycaemic and normoinsulinemic, but when challenged by streptozotocin treatment or a high fat diet, and in ageing, CARTtg mice displayed increased insulin secretion compared with wild-type littermates. This was accompanied by improved glucose elimination in streptozotocin-treated and aged mice, but not in high fat diet-fed mice, which instead displayed mild insulin resistance. Moreover, viral overexpression of CART in INS-1 (832/13) cells increased insulin secretion. Finally, we found that adipocytes from CARTtg mice had altered metabolism, suggesting that CART may be a mediator of cross-talk between beta cells and adipose tissue. Collectively, our data imply that CART has an important role in beta cell function and in regulation of glucose homeostasis. Hence, the potential for CART-based therapies in T2D should be evaluated. (Less)
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author
supervisor
opponent
  • professor Rorsman, Patrik, University of Oxford, United Kingdom and University of Gothenburg, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Cocaine- and amphetamine-regulated transcript, CART, Diabetes, T2D, Human islets, Glucagon, Insulin, Adipocyte
pages
85 pages
publisher
Lund University, Faculty of Medicine
defense location
CRC Aula, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö.
defense date
2016-11-18 09:00
ISBN
978-91-7619-357-0
language
English
LU publication?
yes
id
62266522-158e-406c-a138-e9d52d6d2433
date added to LUP
2016-10-28 10:55:52
date last changed
2016-10-31 14:38:41
@phdthesis{62266522-158e-406c-a138-e9d52d6d2433,
  abstract     = {Diminished insulin secretion and dysregulated glucagon secretion are key features of type 2 diabetes (T2D). The overall aim of this thesis was to study the role of cocaine- and amphetamine-regulated transcript (CART) in islet cell function and how CART regulates glucose homeostasis. We found that CART is expressed in human islet cells and that its expression is increased in patients with T2D, as well as in mouse models of T2D. Rat islet CART expression was regulated by glucose and beta cell CART expression was normalised by insulin treatment in diabetic rats. Furthermore, CART increased insulin secretion from both mouse and human islets in a glucose-dependent fashion. This could partly be explained by increased beta cell exocytosis, altered intracellular Ca<sup>2+</sup> oscillation pattern as well as improved synchronisation of Ca<sup>2+</sup> oscillations between islet cells. Importantly, CART increased insulin secretion and glucose elimination <i>in vivo</i> in mice. We also showed that CART decreased glucagon secretion in mouse and human islets, as well as <i>in vivo</i> in mice, and that CART reduced exocytosis in alpha cells. To mimic the situation in patients, with increased beta cell CART expression, we generated transgenic mice with beta cell-specific CART overexpression (CARTtg) and studied the impact of increased beta cell CART expression on glucose homeostasis <i>in vivo</i>. Under basal conditions, CARTtg mice were normoglycaemic and normoinsulinemic, but when challenged by streptozotocin treatment or a high fat diet, and in ageing, CARTtg mice displayed increased insulin secretion compared with wild-type littermates. This was accompanied by improved glucose elimination in streptozotocin-treated and aged mice, but not in high fat diet-fed mice, which instead displayed mild insulin resistance. Moreover, viral overexpression of CART in INS-1 (832/13) cells increased insulin secretion. Finally, we found that adipocytes from CARTtg mice had altered metabolism, suggesting that CART may be a mediator of cross-talk between beta cells and adipose tissue. Collectively, our data imply that CART has an important role in beta cell function and in regulation of glucose homeostasis. Hence, the potential for CART-based therapies in T2D should be evaluated.},
  author       = {Abels, Mia},
  isbn         = {978-91-7619-357-0},
  keyword      = {Cocaine- and amphetamine-regulated transcript,CART,Diabetes,T2D,Human islets,Glucagon,Insulin,Adipocyte},
  language     = {eng},
  pages        = {85},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {The role of CART in islet function},
  year         = {2016},
}