The role of proteomics in assessing beta-cell dysfunction and death in type 1 diabetes

ABSTRACT

Introduction: Type 1 diabetes (T1D) is characterized by autoimmune-induced dysfunction and destruction of the pancreatic beta cells. Unfortunately, this process is poorly understood, and the current best treatment for type 1 diabetes is the administration of exogenous insulin. To better understand these mechanisms and to develop new therapies, there is an urgent need for biomarkers that can reliably predict disease stage.

Areas covered: Mass spectrometry (MS)-based proteomics and complementary techniques play an important role in understanding the autoimmune response, inflammation and beta-cell death. MS is also a leading technology for the identification of biomarkers. This, and the technical difficulties and new technologies that provide opportunities to characterize small amounts of sample in great depth and to analyze large sample cohorts will be discussed in this review.

Expert opinion: Understanding disease mechanisms and the discovery of disease-associated biomarkers are highly interconnected goals. Ideal biomarkers would be molecules specific to the different stages of the disease process that are released from beta cells to the bloodstream. However, such molecules are likely to be present in trace amounts in the blood due to the small number of pancreatic beta cells in the human body and the heterogeneity of the target organ and disease process.

KEYWORDS:

• beta cell dysfunction and death
• type 1 diabetes
• neoantigens

Article highlights

• Biomarkers that can accurately predict the early stages of type 1 diabetes are urgently needed to improve our knowledge about the disease mechanism and to develop new therapies.

• Proteomics analysis has provided insights to islet autoimmunity and inflammation, as well as signaling events and regulated processes in type 1 diabetes.

• Immunopeptidomics analyses contributed to the discovery of auto-reactive neoantigens present in type 1 diabetes.

• Peptides derived from alternative splicing along with post-translationally modified and hybrid peptides are targets of the autoimmune response during type 1 diabetes development.

• Nanoproteomics and mass cytometry analyses have enabled to study in great detail the intra- and inter-individual islet variability and immune cell infiltration in islets during insulitis.

• Emerging technologies, such as ion mobility spectrometry, will have a major role in identifying new biomarkers and a better understanding of the disease.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants UC4 DK104166 (to R.G.M, C.E. M., D.L.E, and T.O.M.), UC4 DK104167 and DP3 DK110844 (to W.J.Q), R01 DK60581 and R01 DK 105588 (to R.G.M.) and R01 DK093954 (to C.E.M); VA Merit Award I01BX001733 (to C.E.M.); Fonds National de la Recherche Scientifique (FNRS), Welbio CR-2015A-06, Belgium (to D.L.E.); a JDRF Strategic Research Agreement (to C.E.M and R.G.M.) and gifts from the Sigma Beta Sorority, the Ball Brothers Foundation, the George and Frances Ball Foundation, and the Holiday Management Foundation (to C.E.M and R.G.M.). D.L.E. also received funds from Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115797 (INNODIA), which is supported by the Union’s Horizon 2020 research and innovation program and EFPIA, JDRF and The Leona M. and Harry B. Helmsley Charitable Trust.