Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention

被引：89

作者：

Nakayasu, Ernesto S. ^{[1
]}

Syed, Farooq ^{[2
,3
]}

Tersey, Sarah A. ^{[2
,3
,10
,11
]}

Gritsenko, Marina A. ^{[1
]}

Mitchell, Hugh D. ^{[1
]}

Chan, Chi Yuet ^{[1
]}

Dirice, Ercument ^{[4
,5
]}

Turatsinze, Jean-Valery ^{[6
]}

Cui, Yi ^{[7
,9
]}

Kulkarni, Rohit N. ^{[4
,5
]}

Eizirik, Decio L. ^{[6
]}

Qian, Wei-Jun ^{[1
]}

Webb-Robertson, Bobbie-Jo M. ^{[1
,8
]}

Evans-Molina, Carmella ^{[2
,3
]}

Mirmira, Raghavendra G. ^{[2
,3
,10
,11
]}

Metz, Thomas O. ^{[1
]}

机构：

[1] Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA

[2] Indiana Univ Sch Med, Ctr Diabet & Metab Dis, Indianapolis, IN 46202 USA

[3] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA

[4] Brigham & Womens Hosp, Joslin Diabet Ctr, Dept Med, Dept Islet Cell & Regenerat Biol, Boston, MA USA

[5] Harvard Stem Cell Inst, Boston, MA USA

[6] ULB, Med Fac, ULB Ctr Diabet Res, Brussels, Belgium

[7] Pacific Northwest Natl Lab, Environm & Mol Sci Lab, Richland, WA 99352 USA

[8] Pacific Northwest Natl Lab, Comp & Analyt Div, Richland, WA 99352 USA

[9] MIT, Media Lab, Cambridge, MA 02139 USA

[10] Univ Chicago, Kovler Diabet Ctr, Chicago, IL 60637 USA

[11] Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA

来源：

CELL METABOLISM | 2020年 / 31卷 / 02期

基金：

美国国家卫生研究院; 欧盟地平线“2020”;

关键词：

BETA-CELL LINE; DIFFERENTIATION FACTOR 15; ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; INTEGRIN ACTIVATION; COMBINATION THERAPY; INSULIN-SECRETION; PROGNOSTIC MARKER; MASS-SPECTROMETRY; MESSENGER-RNA;

D O I：

10.1016/j.cmet.2019.12.005

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Type 1 diabetes (T1D) results from the progressive loss of beta cells, a process propagated by pro-inflammatory cytokine signaling that disrupts the balance between pro- and anti-apoptotic proteins. To identify proteins involved in this process, we performed comprehensive proteomics of human pancreatic islets treated with interleukin-1 beta and interferon-gamma, leading to the identification of 11,324 proteins, of which 387 were significantly regulated by treatment. We then tested the function of growth/differentiation factor 15 (GDF15), which was repressed by the treatment. We found that GDF15 translation was blocked during inflammation, and it was depleted in islets from individuals with T1D. The addition of exogenous GDF15 inhibited interleukin-1 beta+interferon-gamma-induced apoptosis of human islets. Administration of GDF15 reduced by 53% the incidence of diabetes in NOD mice. Our approach provides a unique resource for the identification of the human islet proteins regulated by cytokines and was effective in discovering a potential target for T1D therapy.

引用

页码：363 / +

页数：18

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