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

被引：23

作者：

Abels, Mia ^{[1
,2
]}

Riva, Matteo ^{[1
,2
]}

Bennet, Hedvig ^{[1
,2
]}

Ahlqvist, Emma ^{[1
,2
]}

Dyachok, Oleg ^{[3
]}

Nagaraj, Vini ^{[1
,2
]}

Shcherbina, Liliya ^{[1
,2
]}

Fred, Rikard G. ^{[1
,2
]}

Poon, Wenny ^{[1
,2
]}

Sorhede-Winzell, Maria ^{[1
,2
]}

Fadista, Joao ^{[1
,2
]}

Lindqvist, Andreas ^{[1
,2
]}

Kask, Lena ^{[1
,2
]}

Sathanoori, Ramasri ^{[1
,2
]}

Dekker-Nitert, Marloes ^{[1
,2
]}

Kuhar, Michael J. ^{[4
]}

Ahren, Bo ^{[1
,2
]}

Wollheim, Claes B. ^{[5
]}

Hansson, Ola ^{[1
,2
]}

Tengholm, Anders ^{[3
]}

Fex, Malin ^{[1
,2
]}

Renstrom, Erik ^{[1
,2
]}

Groop, Leif ^{[1
,2
]}

Lyssenko, Valeriya ^{[1
,2
,6
]}

Wierup, Nils ^{[1
,2
,7
]}

机构：

[1] Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden

[2] Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden

[3] Uppsala Univ, Dept Med Cell Biol, Biomed Ctr, Uppsala, Sweden

[4] Emory Univ, Yerkes Res Ctr, Atlanta, GA 30322 USA

[5] Univ Med Ctr, Dept Cell Physiol & Metab, Geneva, Switzerland

[6] Steno Diabet Ctr AS, Gentofte, Denmark

[7] Lund Univ, Clin Res Ctr 91 12, Ctr Diabet, Skane Univ Hosp,Dept Clin Sci Malmo,Unit Neuroend, Jan Waldenstroms Gata 35, S-20502 Malmo, Sweden

来源：

DIABETOLOGIA | 2016年 / 59卷 / 09期

基金：

瑞典研究理事会;

关键词：

CART peptide; Cocaine- and amphetamine-regulated transcript; Glucagon; Insulin; Islets; Type; 2; diabetes; AMPHETAMINE-REGULATED TRANSCRIPT; CYTOPLASMIC CA2+; ENDOCRINE PANCREAS; BETA-CELLS; COCAINE; RAT; OSCILLATIONS; EXPRESSION; RECEPTORS; RELEASE;

D O I：

10.1007/s00125-016-4020-6

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1928 / 1937

页数：10

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