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

Summary, in English

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.

• Author: 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
• Department/s: Diabetes; Celiac Disease and Diabetes Unit; Translational Muscle Research; EXODIAB: Excellence of Diabetes Research in Sweden; EpiHealth: Epidemiology for Health
• Publishing year: 2016-06-23
• Language: English
• Pages: 1928-1937
• Publication/Series: Diabetologia
• Volume: 59
• Issue: 9
• Full text: - 21 MB; Download statistics
• Links: http://dx.doi.org/10.1007/s00125-016-4020-6
• Document type: Journal article
• Publisher: Springer
• Topic: Endocrinology and Diabetes
• Keywords: CART peptide; Cocaine- and amphetamine-regulated transcript; Glucagon; Insulin; Islets; Type 2 diabetes
• Status: Published
• Research group: Diabetes; Celiac Disease and Diabetes Unit; Genomics, Diabetes and Endocrinology; LUDC (Lund University Diabetes Centre)
• ISBN/ISSN/Other: ISSN: 0012-186X