CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion
2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 9, 1928-1937 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2016. Vol. 59, no 9, 1928-1937 p.
CART peptide, Cocaine- and amphetamine-regulated transcript, Glucagon, Insulin, Islets, Type 2 diabetes
Endocrinology and Diabetes
IdentifiersURN: urn:nbn:se:uu:diva-303027DOI: 10.1007/s00125-016-4020-6ISI: 000380668800017PubMedID: 27338624OAI: oai:DiVA.org:uu-303027DiVA: diva2:970762
FunderSwedish Research Council, 521-2012-2119 522-2008-4216 K2009-55X 21111-01-4 521-2010-3490 325-2012-6778 6834Swedish Research Council, 349-2006-237 EXODIAB 2009-1039Novo NordiskThe Crafoord FoundationÅke Wiberg FoundationLars Hierta Memorial FoundationMagnus Bergvall FoundationKnut and Alice Wallenberg Foundation, KAW 2009.0243Swedish Diabetes AssociationSwedish Heart Lung FoundationEU, European Research Council