β Cell-intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion

被引:29
作者
Barella, Luiz F. [1 ]
Rossi, Mario [1 ]
Zhu, Lu [1 ]
Cui, Yinghong [1 ]
Mei, Fang C. [2 ]
Cheng, Xiaodong [2 ]
Chen, Wei [3 ]
Gurevich, Vsevolod V. [4 ]
Wess, Jurgen [1 ]
机构
[1] NIDDK, Mol Signaling Sect, Lab Bioorgan Chem, Bldg 8A,Room B1A-05,8 Ctr Dr, Bethesda, MD 20892 USA
[2] Univ Texas Hlth Sci Ctr Houston, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA
[3] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[4] Vanderbilt Univ, Dept Pharmacol, 221 Kirkland Hall, Nashville, TN 37235 USA
关键词
ACTIVATION; RECEPTORS; RELEASE;
D O I
10.1172/JCI126309
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
beta-Arrestin land 2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic p cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating beta cell function and whole-body glucose homeostasis. Initially, we inactivated the Barr1 gene in beta cells of adult mice (beta-barr1-KO mice). beta-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, 2 widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in perifused KO islets in vitro. Additional in vivo and in vitro studies demonstrated that Barri enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. Pull-down and coimmunoprecipitation experiments showed that Barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote Barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These findings suggest that strategies aimed at promoting Barr1 signaling in beta cells may prove useful for the development of efficacious antidiabetic drugs.
引用
收藏
页码:3732 / 3737
页数:6
相关论文
共 27 条
[1]   Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes [J].
Ahren, Bo .
NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (05) :369-385
[2]   RGS4 is a negative regulator of insulin release from pancreatic β-cells in vitro and in vivo [J].
de Azua, Inigo Ruiz ;
Scarselli, Marco ;
Rosemond, Erica ;
Gautam, Dinesh ;
Jou, William ;
Gavrilova, Oksana ;
Ebert, Philip J. ;
Levitt, Pat ;
Wess, Juergen .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (17) :7999-8004
[3]   Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1 [J].
Drucker, Daniel J. .
CELL METABOLISM, 2018, 27 (04) :740-756
[4]   Loss of Lkb1 in Adult β Cells Increases β Cell Mass and Enhances Glucose Tolerance in Mice [J].
Fu, Accalia ;
Ng, Andy Cheuk-Him ;
Depatie, Chantal ;
Wijesekara, Nadeeja ;
He, Ying ;
Wang, Gen-Sheng ;
Bardeesy, Nabeel ;
Scott, Fraser W. ;
Touyz, Rhian M. ;
Wheeler, Michael B. ;
Screaton, Robert A. .
CELL METABOLISM, 2009, 10 (04) :285-295
[5]   A critical role for β cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo [J].
Gautam, Dinesh ;
Han, Sung-Jun ;
Hamdan, Fadi F. ;
Jeon, Jongrye ;
Li, Bo ;
Li, Jian Hua ;
Cui, Yinghong ;
Mears, David ;
Lu, Huiyan ;
Deng, Chuxia ;
Heard, Thomas ;
Wess, Jurgen .
CELL METABOLISM, 2006, 3 (06) :449-461
[6]  
Gu GQ, 2002, DEVELOPMENT, V129, P2447
[7]  
Gurevich V. V., 2014, CURR PROTOC PHARM, V67
[8]   Direct Activation of Epac by Sulfonylurea Is Isoform Selective [J].
Herbst, Katie J. ;
Coltharp, Carla ;
Amzel, L. Mario ;
Zhang, Jin .
CHEMISTRY & BIOLOGY, 2011, 18 (02) :243-251
[9]   Epac2: A Molecular Target for Sulfonylurea-Induced Insulin Release [J].
Hinke, Simon A. .
SCIENCE SIGNALING, 2009, 2 (85) :pe54
[10]   Establishment of new clonal pancreatic β-cell lines (MIN6-K) useful for study of incretin/cyclic adenosine monophosphate signaling [J].
Iwasaki, Masahiro ;
Minami, Kohtaro ;
Shibasaki, Tadao ;
Miki, Takashi ;
Miyazaki, Jun-ichi ;
Seino, Susumu .
JOURNAL OF DIABETES INVESTIGATION, 2010, 1 (04) :137-142