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

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

doi:10.1007/s00125-016-4020-6

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

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 TengholmMalin Fex, Erik Renström, Leif Groop, Valeriya Lyssenko, Nils Wierup

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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.

Original language	English
Pages (from-to)	1928–1937
Number of pages	10
Journal	Diabetologia
Volume	59
Issue number	9
DOIs	https://doi.org/10.1007/s00125-016-4020-6
Publication status	Published - 2016 Jun 23

Subject classification (UKÄ)

Endocrinology and Diabetes

Free keywords

CART peptide
Cocaine- and amphetamine-regulated transcript
Glucagon
Insulin
Islets
Type 2 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00125-016-4020-6

9992839Accepted author manuscript, 21.3 MB

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Abels, M., Riva, M., Bennet, H., Ahlqvist, E., Dyachok, O., Nagaraj, V., Shcherbina, L., Fred, R. G., Poon, W., Sörhede-Winzell, M., Fadista, J., Lindqvist, A., Kask, L., Sathanoori, R., Dekker-Nitert, M., Kuhar, M. J., Ahrén, B., Wollheim, C. B., Hansson, O., ... Wierup, N. (2016). CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion. Diabetologia, 59(9), 1928–1937. https://doi.org/10.1007/s00125-016-4020-6

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title = "CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion",

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.",

keywords = "CART peptide, Cocaine- and amphetamine-regulated transcript, Glucagon, Insulin, Islets, Type 2 diabetes",

author = "Mia Abels and Matteo Riva and Hedvig Bennet and Emma Ahlqvist and Oleg Dyachok and Vini Nagaraj and Liliya Shcherbina and Fred, {Rikard G.} and Wenny Poon and Maria S{\"o}rhede-Winzell and Joao Fadista and Andreas Lindqvist and Lena Kask and Ramasri Sathanoori and Marloes Dekker-Nitert and Kuhar, {Michael J.} and Bo Ahr{\'e}n and Wollheim, {Claes B.} and Ola Hansson and Anders Tengholm and Malin Fex and Erik Renstr{\"o}m and Leif Groop and Valeriya Lyssenko and Nils Wierup",

year = "2016",

month = jun,

day = "23",

doi = "10.1007/s00125-016-4020-6",

language = "English",

volume = "59",

pages = "1928–1937",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "9",

}

Abels, M, Riva, M, Bennet, H, Ahlqvist, E, Dyachok, O, Nagaraj, V, Shcherbina, L, Fred, RG, Poon, W, Sörhede-Winzell, M, Fadista, J, Lindqvist, A, Kask, L, Sathanoori, R, Dekker-Nitert, M, Kuhar, MJ, Ahrén, B , Wollheim, CB , Hansson, O, Tengholm, A, Fex, M , Renström, E, Groop, L, Lyssenko, V & Wierup, N 2016, 'CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion', Diabetologia, vol. 59, no. 9, pp. 1928–1937. https://doi.org/10.1007/s00125-016-4020-6

TY - JOUR

T1 - CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion

AU - Abels, Mia

AU - Riva, Matteo

AU - Bennet, Hedvig

AU - Ahlqvist, Emma

AU - Dyachok, Oleg

AU - Nagaraj, Vini

AU - Shcherbina, Liliya

AU - Fred, Rikard G.

AU - Poon, Wenny

AU - Sörhede-Winzell, Maria

AU - Fadista, Joao

AU - Lindqvist, Andreas

AU - Kask, Lena

AU - Sathanoori, Ramasri

AU - Dekker-Nitert, Marloes

AU - Kuhar, Michael J.

AU - Ahrén, Bo

AU - Wollheim, Claes B.

AU - Hansson, Ola

AU - Tengholm, Anders

AU - Fex, Malin

AU - Renström, Erik

AU - Groop, Leif

AU - Lyssenko, Valeriya

AU - Wierup, Nils

PY - 2016/6/23

Y1 - 2016/6/23

N2 - 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.

AB - 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.

KW - CART peptide

KW - Cocaine- and amphetamine-regulated transcript

KW - Glucagon

KW - Insulin

KW - Islets

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=84976325962&partnerID=8YFLogxK

U2 - 10.1007/s00125-016-4020-6

DO - 10.1007/s00125-016-4020-6

M3 - Article

C2 - 27338624

AN - SCOPUS:84976325962

SN - 0012-186X

VL - 59

SP - 1928

EP - 1937

JO - Diabetologia

JF - Diabetologia

IS - 9

ER -

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

Abstract

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

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The role of CART in islet function

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