Exocytosis Protein DOC2B As a Biomarker of Type 1 Diabetes

Overview

Journal J Clin Endocrinol Metab

Publisher Oxford University Press

Specialty Endocrinology

Date 2018 Mar 6

PMID 29506054

Citations 11

Authors

Arianne Aslamy

Eunjin Oh

Miwon Ahn

Abu Saleh Md Moin

Mariann Chang

Molly Duncan

Jeannette Hacker-Stratton

Mohamed El-Shahawy

Fouad Kandeel

Linda A DiMeglio

Debbie C Thurmond

Affiliations

Soon will be listed here.

Abstract

Context: Efforts to preserve β-cell mass in the preclinical stages of type 1 diabetes (T1D) are limited by few blood-derived biomarkers of β-cell destruction.

Objective: Platelets are proposed sources of blood-derived biomarkers for a variety of diseases, and they show distinct proteomic changes in T1D. Thus, we investigated changes in the exocytosis protein, double C2 domain protein-β (DOC2B) in platelets and islets from T1D humans, and prediabetic nonobese diabetic (NOD) mice.

Design, Patients, And Main Outcome Measure: Protein levels of DOC2B were assessed in platelets and islets from prediabetic NOD mice and humans, with and without T1D. Seventeen new-onset T1D human subjects (10.3 ± 3.8 years) were recruited immediately following diagnosis, and platelet DOC2B levels were compared with 14 matched nondiabetic subjects (11.4 ± 2.9 years). Furthermore, DOC2B levels were assessed in T1D human pancreatic tissue samples, cytokine-stimulated human islets ex vivo, and platelets from T1D subjects before and after islet transplantation.

Results: DOC2B protein abundance was substantially reduced in prediabetic NOD mouse platelets, and these changes were mirrored in the pancreatic islets from the same mice. Likewise, human DOC2B levels were reduced over twofold in platelets from new-onset T1D human subjects, and this reduction was mirrored in T1D human islets. Cytokine stimulation of normal islets reduced DOC2B expression ex vivo. Remarkably, platelet DOC2B levels increased after islet transplantation in patients with T1D.

Conclusions: Reduction of DOC2B is an early feature of T1D, and DOC2B abundance may serve as a valuable in vivo indicator of β-cell mass and an early biomarker of T1D.

Citing Articles

DOC2b enrichment mitigates proinflammatory cytokine-induced CXCL10 expression by attenuating IKKβ and STAT-1 signaling in human islets.

Bhowmick D, Ahn M, Bhattacharya S, Aslamy A, Thurmond D Metabolism. 2025; 164:156132.

PMID: 39805534 PMC: 11798586. DOI: 10.1016/j.metabol.2025.156132.

Biological functions of extracellular vesicle double C2-like domain beta in cervical cancer.

Eswaran S, Bhat S, Upadhya D, Mascarenhas R, Kabekkodu S Sci Rep. 2025; 15(1):477.

PMID: 39747389 PMC: 11695970. DOI: 10.1038/s41598-024-84643-2.

Pancreatic β-cells package double C2-like domain beta protein into extracellular vesicles via tandem C2 domains.

Esparza D, Lima C, Abuelreich S, Ghaeli I, Hwang J, Oh E Front Endocrinol (Lausanne). 2024; 15:1451279.

PMID: 39497805 PMC: 11532064. DOI: 10.3389/fendo.2024.1451279.

Spontaneous Akt2 deficiency in a colony of NOD mice exhibiting early diabetes.

Herve J, Haurogne K, Allard M, Sourice S, Lindenbaum P, Bach J Sci Rep. 2024; 14(1):9100.

PMID: 38643275 PMC: 11032318. DOI: 10.1038/s41598-024-60021-w.

TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis.

Hao X, Lv Y, Li D, Bai F, Gong J, Pan G J Transl Med. 2024; 22(1):6.

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References

Klement G, Yip T, Cassiola F, Kikuchi L, Cervi D, Podust V . Platelets actively sequester angiogenesis regulators. Blood. 2008; 113(12):2835-42. PMC: 2661866. DOI: 10.1182/blood-2008-06-159541. View

Li J, Cantley J, Burchfield J, Meoli C, Stockli J, Whitworth P . DOC2 isoforms play dual roles in insulin secretion and insulin-stimulated glucose uptake. Diabetologia. 2014; 57(10):2173-82. DOI: 10.1007/s00125-014-3312-y. View

Reuwer A, Nieuwland R, Fernandez I, Goffin V, van Tiel C, Schaap M . Prolactin does not affect human platelet aggregation or secretion. Thromb Haemost. 2009; 101(6):1119-27. View

Corbett J, Wang J, Sweetland M, Lancaster Jr J, McDaniel M . Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide. J Clin Invest. 1992; 90(6):2384-91. PMC: 443394. DOI: 10.1172/JCI116129. View

Figliolini F, Cantaluppi V, De Lena M, Beltramo S, Romagnoli R, Salizzoni M . Isolation, characterization and potential role in beta cell-endothelium cross-talk of extracellular vesicles released from human pancreatic islets. PLoS One. 2014; 9(7):e102521. PMC: 4100900. DOI: 10.1371/journal.pone.0102521. View

Witas H, Rozalski M, Watala C, Mlynarski W, Sychowski R, Bodalski J . Do determinants of platelet function co-segregate with genetic markers of type 1 diabetes mellitus?. Platelets. 2006; 10(2-3):169-77. DOI: 10.1080/09537109976257. View

Wicker L, Clark J, Fraser H, Garner V, Gonzalez-Munoz A, Healy B . Type 1 diabetes genes and pathways shared by humans and NOD mice. J Autoimmun. 2005; 25 Suppl:29-33. DOI: 10.1016/j.jaut.2005.09.009. View

Oh E, Stull N, Mirmira R, Thurmond D . Syntaxin 4 up-regulation increases efficiency of insulin release in pancreatic islets from humans with and without type 2 diabetes mellitus. J Clin Endocrinol Metab. 2014; 99(5):E866-70. PMC: 4010690. DOI: 10.1210/jc.2013-2221. View

Ramalingam L, Oh E, Thurmond D . Doc2b enrichment enhances glucose homeostasis in mice via potentiation of insulin secretion and peripheral insulin sensitivity. Diabetologia. 2014; 57(7):1476-84. PMC: 4055500. DOI: 10.1007/s00125-014-3227-7. View

10.

Malachowska B, Tomasik B, Szadkowska A, Baranowska-Jazwiecka A, Wegner O, Mlynarski W . Altered platelets' morphological parameters in children with type 1 diabetes – a case-control study. BMC Endocr Disord. 2015; 15:17. PMC: 4391729. DOI: 10.1186/s12902-015-0011-8. View

11.

Ke B, Oh E, Thurmond D . Doc2beta is a novel Munc18c-interacting partner and positive effector of syntaxin 4-mediated exocytosis. J Biol Chem. 2007; 282(30):21786-97. DOI: 10.1074/jbc.M701661200. View

12.

Ziegler A, Rewers M, Simell O, Simell T, Lempainen J, Steck A . Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013; 309(23):2473-9. PMC: 4878912. DOI: 10.1001/jama.2013.6285. View

13.

Ye S, Karim Z, Al Hawas R, Pessin J, Filipovich A, Whiteheart S . Syntaxin-11, but not syntaxin-2 or syntaxin-4, is required for platelet secretion. Blood. 2012; 120(12):2484-92. PMC: 3448260. DOI: 10.1182/blood-2012-05-430603. View

14.

Miyazaki M, Emoto M, Fukuda N, Hatanaka M, Taguchi A, Miyamoto S . DOC2b is a SNARE regulator of glucose-stimulated delayed insulin secretion. Biochem Biophys Res Commun. 2009; 384(4):461-5. DOI: 10.1016/j.bbrc.2009.04.133. View

15.

Eizirik D, Mandrup-Poulsen T . A choice of death--the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia. 2002; 44(12):2115-33. DOI: 10.1007/s001250100021. View

16.

Stull N, Breite A, McCarthy R, Tersey S, Mirmira R . Mouse islet of Langerhans isolation using a combination of purified collagenase and neutral protease. J Vis Exp. 2012; (67). PMC: 3490250. DOI: 10.3791/4137. View

17.

Van Belle T, Taylor P, von Herrath M . Mouse Models for Type 1 Diabetes. Drug Discov Today Dis Models. 2010; 6(2):41-45. PMC: 2855847. DOI: 10.1016/j.ddmod.2009.03.008. View

18.

Watkins R, Evans-Molina C, Terrell J, Day K, Guindon L, Restrepo I . Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes. Transl Res. 2015; 168:96-106.e1. PMC: 4839287. DOI: 10.1016/j.trsl.2015.08.010. View

19.

Sims E, Chaudhry Z, Watkins R, Syed F, Blum J, Ouyang F . Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes. Diabetes Care. 2016; 39(9):1519-26. PMC: 5001142. DOI: 10.2337/dc15-2849. View

20.

Fisher M, Watkins R, Blum J, Evans-Molina C, Chalasani N, DiMeglio L . Elevations in Circulating Methylated and Unmethylated Preproinsulin DNA in New-Onset Type 1 Diabetes. Diabetes. 2015; 64(11):3867-72. PMC: 4613977. DOI: 10.2337/db15-0430. View