title: CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion.
abstract: 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.
  
  
  
  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. Ca(2+) oscillation patterns and exocytosis were studied in mouse islets.
  
  
  
  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 Ca(2+) 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.
  
  
  
  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.
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Abels
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Matteo
authors.initials: M
authors.lastname: Riva
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Hedvig
authors.initials: H
authors.lastname: Bennet
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Ahlqvist
authors.affiliation: Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden.
authors.forename: Oleg
authors.initials: O
authors.lastname: Dyachok
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Vini
authors.initials: V
authors.lastname: Nagaraj
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Liliya
authors.initials: L
authors.lastname: Shcherbina
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Rikard G
authors.initials: RG
authors.lastname: Fred
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Wenny
authors.initials: W
authors.lastname: Poon
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Sörhede-Winzell
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Joao
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lindqvist
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Kask
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Ramasri
authors.initials: R
authors.lastname: Sathanoori
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Marloes
authors.initials: M
authors.lastname: Dekker-Nitert
authors.affiliation: The Yerkes Research Center of Emory University, Atlanta, GA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kuhar
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Ahrén
authors.affiliation: Department of Cell Physiology and Metabolism, University Medical Centre, Geneva, Switzerland.
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Department of Medical Cell Biology, Uppsala University Biomedical Centre, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Tengholm
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Fex
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Renström
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden.|Steno Diabetes Center A/S, Gentofte, Denmark.
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.affiliation: Lund University Diabetes Centre, Skåne University Hospital, Lund and Malmö, Sweden. nils.wierup@med.lu.se.|Lund University Diabetes Centre, Skåne University Hospital, Department of Clinical Sciences in Malmö, Unit of Neuroendocrine Cell Biology, Lund University, Clinical Research Centre 91:12, Jan Waldenströms gata 35, 20502, Malmö, Sweden. nils.wierup@med.lu.se.
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020013:Calcium Signaling / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology*; D004594:Electrophysiology; D005089:Exocytosis / Q000235:genetics / Q000502:physiology; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D007328:Insulin; D009419:Nerve Tissue Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D005934:Glucagon; D005947:Glucose
keywords: CART peptide; Cocaine- and amphetamine-regulated transcript; Glucagon; Insulin; Islets; Type 2 diabetes