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CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion
Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
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2016 (Engelska)Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, nr 9, s. 1928-1937Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
2016. Vol. 59, nr 9, s. 1928-1937
Nyckelord [en]
CART peptide, Cocaine- and amphetamine-regulated transcript, Glucagon, Insulin, Islets, Type 2 diabetes
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
URN: urn:nbn:se:uu:diva-303027DOI: 10.1007/s00125-016-4020-6ISI: 000380668800017PubMedID: 27338624OAI: oai:DiVA.org:uu-303027DiVA, id: diva2:970762
Forskningsfinansiär
Vetenskapsrådet, 521-2012-2119 522-2008-4216 K2009-55X 21111-01-4 521-2010-3490 325-2012-6778 6834Vetenskapsrådet, 349-2006-237 EXODIAB 2009-1039Novo NordiskCrafoordska stiftelsenÅke Wibergs StiftelseStiftelsen Lars Hiertas MinneMagnus Bergvalls StiftelseKnut och Alice Wallenbergs Stiftelse, KAW 2009.0243DiabetesförbundetHjärt-LungfondenEU, Europeiska forskningsrådetTillgänglig från: 2016-09-14 Skapad: 2016-09-14 Senast uppdaterad: 2017-11-21Bibliografiskt granskad

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Dyachok, OlegTengholm, Anders
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