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CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion

Abels, Mia LU ; Riva, Matteo LU ; Bennet, Hedvig LU ; Ahlqvist, Emma LU ; Dyachok, Oleg; Nagaraj, Vini LU ; Shcherbina, Liliya LU ; Fred, Rikard G. LU ; Poon, Wenny LU and Sörhede-Winzell, Maria LU , et al. (2016) In Diabetologia 59(9). p.1928-1937
Abstract

Aims/hypothesis: Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart−/− mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. Methods: CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca2+ oscillation patterns and... (More)

Aims/hypothesis: Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart−/− mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. Methods: CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca2+ oscillation patterns and exocytosis were studied in mouse islets. Results: We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca2+ signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis. Conclusions/interpretation: We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.

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published
subject
keywords
CART peptide, Cocaine- and amphetamine-regulated transcript, Glucagon, Insulin, Islets, Type 2 diabetes
in
Diabetologia
volume
59
issue
9
pages
10 pages
publisher
Springer Verlag
external identifiers
  • scopus:84976325962
  • wos:000380668800017
ISSN
0012-186X
DOI
10.1007/s00125-016-4020-6
language
English
LU publication?
yes
id
9aa0a0ed-e63e-4197-9edc-0dff545938ae
date added to LUP
2016-07-21 12:35:52
date last changed
2017-09-02 00:01:00
@article{9aa0a0ed-e63e-4197-9edc-0dff545938ae,
  abstract     = {<p>Aims/hypothesis: Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart<sup>−/−</sup> mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. Methods: CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca<sup>2+</sup> oscillation patterns and exocytosis were studied in mouse islets. Results: We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca<sup>2+</sup> signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis. Conclusions/interpretation: We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.</p>},
  author       = {Abels, Mia and Riva, Matteo and Bennet, Hedvig and Ahlqvist, Emma and Dyachok, Oleg and Nagaraj, Vini and Shcherbina, Liliya and Fred, Rikard G. and Poon, Wenny and Sörhede-Winzell, Maria and Fadista, Joao and Lindqvist, Andreas and Kask, Lena and Sathanoori, Ramasri and Dekker-Nitert, Marloes and Kuhar, Michael J. and Ahrén, Bo and Wollheim, Claes B. and Hansson, Ola and Tengholm, Anders and Fex, Malin and Renström, Erik and Groop, Leif and Lyssenko, Valeriya and Wierup, Nils},
  issn         = {0012-186X},
  keyword      = {CART peptide,Cocaine- and amphetamine-regulated transcript,Glucagon,Insulin,Islets,Type 2 diabetes},
  language     = {eng},
  month        = {06},
  number       = {9},
  pages        = {1928--1937},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion},
  url          = {http://dx.doi.org/10.1007/s00125-016-4020-6},
  volume       = {59},
  year         = {2016},
}