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

Abels, Mia, Riva, Matteo, Bennet, Hedvig, Ahlqvist, Emma, Dyachok, Oleg, Nagaraj, Vini, Shcherbina, Liliya, Fred, Rikard G., Poon, Wenny, Sorhede-Winzell, Maria, Fadista, Joao, Lindqvist, Andreas, Kask, Lena, Sathanoori, Ramasri, Dekker-Nitert, Marloes, Kuhar, Michael J., Ahren, Bo, Wollheim, Claes B., Hansson, Ola, Tengholm, Anders, Fex, Malin, Renstrom, Erik, Groop, Leif, Lyssenko, Valeriya and Wierup, Nils (2016) CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion. Diabetologia, 59 9: 1928-1937. doi:10.1007/s00125-016-4020-6


Author Abels, Mia
Riva, Matteo
Bennet, Hedvig
Ahlqvist, Emma
Dyachok, Oleg
Nagaraj, Vini
Shcherbina, Liliya
Fred, Rikard G.
Poon, Wenny
Sorhede-Winzell, Maria
Fadista, Joao
Lindqvist, Andreas
Kask, Lena
Sathanoori, Ramasri
Dekker-Nitert, Marloes
Kuhar, Michael J.
Ahren, Bo
Wollheim, Claes B.
Hansson, Ola
Tengholm, Anders
Fex, Malin
Renstrom, Erik
Groop, Leif
Lyssenko, Valeriya
Wierup, Nils
Title CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion
Journal name Diabetologia   Check publisher's open access policy
ISSN 1432-0428
0012-186X
Publication date 2016-09-01
Year available 2016
Sub-type Article (original research)
DOI 10.1007/s00125-016-4020-6
Open Access Status Not yet assessed
Volume 59
Issue 9
Start page 1928
End page 1937
Total pages 10
Place of publication Heidelberg, Germany
Publisher Springer Verlag
Collection year 2017
Language eng
Formatted 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 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.
Keyword CART peptide
Cocaine- and amphetamine-regulated transcript
Glucagon
Insulin
Islets
Type 2 diabetes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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School of Chemistry and Molecular Biosciences
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