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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Mia Abels
  • Matteo Riva
  • Hedvig Bennet
  • Oleg Dyachok
  • Vini Nagaraj
  • Rikard G. Fred
  • Wenny Poon
  • Maria Sörhede-Winzell
  • Joao Fadista
  • Lena Kask
  • Ramasri Sathanoori
  • Marloes Dekker-Nitert
  • Michael J. Kuhar
  • Anders Tengholm
Organisations
External organisations
  • Uppsala University
  • Emory University
  • Steno Diabetes Center Copenhagen
  • Skåne University Hospital
  • University Medical Center, Geneva
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • CART peptide, Cocaine- and amphetamine-regulated transcript, Glucagon, Insulin, Islets, Type 2 diabetes
Original languageEnglish
Pages (from-to)1928–1937
Number of pages10
JournalDiabetologia
Volume59
Issue number9
Publication statusPublished - 2016 Jun 23
Publication categoryResearch
Peer-reviewedYes

Total downloads

No data available

Related research output

Abels, M., 2016, Lund: Lund University, Faculty of Medicine. 85 p.

Research output: ThesisDoctoral Thesis (compilation)

View all (1)