Erythropoietin protects against diabetes through direct effects on pancreatic β cells

被引：104

作者：

Choi, Diana ^{[1
,2
]}

Schroer, Stephanie A. ^{[2
]}

Lu, Shun Yan ^{[2
]}

Wang, Linyuan ^{[2
,3
]}

Wu, Xiaohong ^{[2
]}

Liu, Yunfeng ^{[5
,6
]}

Zhang, Yi ^{[5
,6
]}

Gaisano, Herbert Y. ^{[5
,6
]}

Wagner, Kay-Uwe ^{[7
,8
]}

Wu, Hong ^{[9
]}

Retnakaran, Ravi ^{[1
,4
,5
,10
]}

Woo, Minna ^{[1
,2
,3
,4
,5
,11
,12
]}

机构：

[1] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada

[2] Univ Toronto, Ontario Canc Inst, Toronto, ON M5S 1A1, Canada

[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A1, Canada

[4] Univ Toronto, Div Endocrinol & Metab, Toronto, ON M5S 1A1, Canada

[5] Univ Toronto, Dept Med, Toronto, ON M5S 1A1, Canada

[6] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A1, Canada

[7] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA

[8] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA

[9] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, David Geffen Sch Med, Los Angeles, CA 90095 USA

[10] Mt Sinai Hosp, Leadership Sinai Ctr Diabet, Toronto, ON M5T 3L9, Canada

[11] St Michaels Hosp, Dept Med, Toronto, ON M5B 1W8, Canada

[12] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2010年 / 207卷 / 13期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

INSULIN-RESISTANCE; GROWTH-HORMONE; RECEPTOR; EXPRESSION; STAT5; ASSOCIATION; ACTIVATION; APOPTOSIS; DELETION; ANEMIA;

D O I：

10.1084/jem.20100665

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

A common feature among all forms of diabetes mellitus is a functional beta-cell mass insufficient to maintain euglycemia; therefore, the promotion of beta-cell growth and survival is a fundamental goal for diabetes prevention and treatment. Evidence has suggested that erythropoietin (EPO) exerts cytoprotective effects on nonerythroid cells. However, the influence of EPO on pancreatic beta cells and diabetes has not been evaluated to date. In this study, we report that recombinant human EPO treatment can protect against diabetes development in streptozotocin-induced and db/db mouse models of type 1 and type 2 diabetes, respectively. EPO exerts antiapoptotic, proliferative, antiinflammatory, and angiogenic effects within the islets. Using beta-cell-specific EPO receptor and JAK2 knockout mice, we show that these effects of EPO result from direct biological effects on. cells and that JAK2 is an essential intracellular mediator. Thus, promotion of EPO signaling in. cells may be a novel therapeutic strategy for diabetes prevention and treatment.

引用

页码：2831 / 2842

页数：12

共 54 条

[1] Transgenic expression of dominant-negative fas-associated death domain protein in β cells protects against fas ligand-induced apoptosis and reduces spontaneous diabetes in nonobese diabetic mice [J].

Allison, J ;

Thomas, HE ;

Catterall, T ;

Kay, TWH ;

Strasser, A .

JOURNAL OF IMMUNOLOGY, 2005, 175 (01) :293-301

[2] INSULIN-DEPENDENT DIABETES-MELLITUS AS AN AUTOIMMUNE-DISEASE [J].

BACH, JF .

ENDOCRINE REVIEWS, 1994, 15 (04) :516-542

[3] Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia [J].

Bernal-Mizrachi, E ;

Wen, W ;

Stahlhut, S ;

Welling, CM ;

Permutt, MA .

JOURNAL OF CLINICAL INVESTIGATION, 2001, 108 (11) :1631-1638

[4] Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet β cells [J].

Bernal-Mizrachi, E ;

Fatrai, S ;

Johnson, JD ;

Ohsugi, M ;

Otani, K ;

Han, ZQ ;

Polonsky, KS ;

Permutt, MA .

JOURNAL OF CLINICAL INVESTIGATION, 2004, 114 (07) :928-936

[5] Activation of STAT5 during EPO-directed suppression of apoptosis [J].

Bittorf, T ;

Seiler, J ;

Lüdtke, B ;

Büchse, T ;

Jaster, R ;

Brock, J .

CELLULAR SIGNALLING, 2000, 12 (01) :23-30

[6] Discovering erythropoietin's extra-hematopoietic functions: Biology and clinical promise [J].

Brines, M. - ;

Cerami, A. .

KIDNEY INTERNATIONAL, 2006, 70 (02) :246-250

[7] Stimulation of pancreatic β-cell proliferation by growth hormone is glucose-dependent:: signal transduction via Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) with no crosstalk to insulin receptor substrate-mediated mitogenic signalling [J].

Cousin, SP ;

Hügl, SR ;

Myers, MG ;

White, MF ;

Reifel-Miller, A ;

Rhodes, CJ .

BIOCHEMICAL JOURNAL, 1999, 344 :649-658

[8] Anemia and diabetes in the absence of nephropathy [J].

Craig, KJ ;

Williams, JD ;

Riley, SG ;

Smith, H ;

Owens, DR ;

Worthing, D ;

Cavill, I ;

Phillips, AO .

DIABETES CARE, 2005, 28 (05) :1118-1123

[9]

DAMEN JE, 1993, BLOOD, V82, P2296

[10]

DeFronzo RA, 1997, DIABETES REV, V5, P177

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