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01-09-2016 | Article

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

Authors: Mia Abels, Matteo Riva, Hedvig Bennet, Emma Ahlqvist, Oleg Dyachok, Vini Nagaraj, Liliya Shcherbina, Rikard G. Fred, Wenny Poon, Maria Sörhede-Winzell, Joao Fadista, Andreas Lindqvist, Lena Kask, Ramasri Sathanoori, Marloes Dekker-Nitert, Michael J. Kuhar, Bo Ahrén, Claes B. Wollheim, Ola Hansson, Anders Tengholm, Malin Fex, Erik Renström, Leif Groop, Valeriya Lyssenko, Nils Wierup

Published in: Diabetologia | Issue 9/2016

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.

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Title: CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion
Authors: Mia Abels
Matteo Riva
Hedvig Bennet
Emma Ahlqvist
Oleg Dyachok
Vini Nagaraj
Liliya Shcherbina
Rikard G. Fred
Wenny Poon
Maria Sörhede-Winzell
Joao Fadista
Andreas Lindqvist
Lena Kask
Ramasri Sathanoori
Marloes Dekker-Nitert
Michael J. Kuhar
Bo Ahrén
Claes B. Wollheim
Ola Hansson
Anders Tengholm
Malin Fex
Erik Renström
Leif Groop
Valeriya Lyssenko
Nils Wierup
Publication date: 01-09-2016
Publisher: Springer Berlin Heidelberg
Published in: Diabetologia / Issue 9/2016
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-016-4020-6

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