Type 1 diabetes (T1D) is an autoimmune disease, whereas type 2 diabetes (T2D) results from insulin resistance and beta cell dysfunction. Previously, the onset of these two separate diseases was easily distinguished, with children being most at risk for T1D and T2D occurring in overweight adults. However, the dramatic rise in obesity, coupled with the notable increase in T1D, has created a large overlap in these previously discrete patient populations. Delayed diagnosis of T1D can result in severe illness or death, and rapid diagnosis of T1D is critical for the efficacy of emerging therapies. However, attempts to apply next-generation platforms have been unsuccessful for detecting diabetes biomarkers. Here we describe the development of a plasmonic gold chip for near-infrared fluorescence–enhanced (NIR-FE) detection of islet cell–targeting autoantibodies. We demonstrate that this platform has high sensitivity and specificity for the diagnosis of T1D and can be used to discover previously unknown biomarkers of T1D.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Smyth, S. & Heron, A. Diabetes and obesity: the twin epidemics. Nat. Med. 12, 75–80 (2006).
Karvonen, M. et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 23, 1516–1526 (2000).
EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 355, 873–876 (2000).
International Diabetes Federation (IDF). Diabetes in children: epidemiology. Pediatr. Diabetes 8 (S8), 10–18 (2007).
Patterson, C.C. et al. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 373, 2027–2033 (2009).
Maahs, D.M., West, N.A., Lawrence, J.M. & Mayer-Davis, E.J. Epidemiology of type 1 diabetes. Endocrinol. Metab. Clin. North Am. 39, 481–497 (2010).
Liese, A.D. et al. The burden of diabetes mellitus among US youth: prevalence estimates from the SEARCH for Diabetes in Youth Study. Pediatrics 118, 1510–1518 (2006).
Imperatore, G. et al. Projections of type 1 and type 2 diabetes burden in the U.S. population aged <20 years through 2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care 35, 2515–2520 (2012).
Jones, K.L. Role of obesity in complicating and confusing the diagnosis and treatment of diabetes in children. Pediatrics 121, 361–368 (2008).
Zeitler, P. Approach to the obese adolescent with new-onset diabetes. J. Clin. Endocrinol. Metab. 95, 5163–5170 (2010).
Michels, A.W. & Eisenbarth, G.S. Immune intervention in type 1 diabetes. Semin. Immunol. 23, 214–219 (2011).
Greenbaum, C.J., Schatz, D.A., Haller, M.J. & Sanda, S. Through the fog: recent clinical trials to preserve beta-cell function in type 1 diabetes. Diabetes 61, 1323–1330 (2012).
Orban, T. et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378, 412–419 (2011).
Greenbaum, C.J., Palmer, J.P., Kuglin, B. & Kolb, H. Insulin autoantibodies measured by radioimmunoassay methodology are more related to insulin-dependent diabetes mellitus than those measured by enzyme-linked immunosorbent assay: results of the Fourth International Workshop on the Standardization of Insulin Autoantibody Measurement. J. Clin. Endocrinol. Metab. 74, 1040–1044 (1992).
Liu, E. & Eisenbarth, G.S. Accepting clocks that tell time poorly: fluid-phase versus standard ELISA autoantibody assays. Clin. Immunol. 125, 120–126 (2007).
Valdez, S.N. & Poskus, E. Autoimmune diabetes mellitus: the importance of autoantibodies for disease prediction and diagnostic support. Curr. Immunol. Rev. 6, 299–313 (2010).
Bottazzo, G.F., Florin-Christensen, A. & Doniach, D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 304, 1279–1283 (1974).
Bingley, P.J., Bonifacio, E. & Mueller, P.W. Diabetes Antibody Standardization Program: first assay proficiency evaluation. Diabetes 52, 1128–1136 (2003).
Bingley, P.J. et al. Measurement of islet cell antibodies in the Type 1 Diabetes Genetics Consortium: efforts to harmonize procedures among the laboratories. Clin. Trials 7, S56–S64 (2010).
Schlosser, M., Mueller, P.W., Torn, C., Bonifacio, E. & Bingley, P.J. Diabetes Antibody Standardization Program: evaluation of assays for insulin autoantibodies. Diabetologia 53, 2611–2620 (2010).
Yu, L. et al. Distinguishing persistent insulin autoantibodies with differential risk: nonradioactive bivalent proinsulin/insulin autoantibody assay. Diabetes 61, 179–186 (2012).
Törn, C. et al. Diabetes Antibody Standardization Program: evaluation of assays for autoantibodies to glutamic acid decarboxylase and islet antigen-2. Diabetologia 51, 846–852 (2008).
Tabakman, S.M. et al. Plasmonic substrates for multiplexed protein microarrays with femtomolar sensitivity and broad dynamic range. Nat. Commun. 2, 466 (2011).
Zhang, B. et al. Multiplexed cytokine detection on plasmonic gold substrates with enhanced near-infrared fluorescence. Nano Research 6, 113–120 (2013).
Achenbach, P. et al. Combined testing of antibody titer and affinity improves insulin autoantibody measurement: Diabetes Antibody Standardization Program. Clin. Immunol. 122, 85–90 (2007).
Roberts, M.J., Bentlye, M.D. & Harris, J.M. Chemistry for peptide and protein PEGylation. Adv. Drug Deliv. Rev. 54, 459–476 (2002).
Oak, S., Phan, T.T., Gilliam, L.K., Hirsch, I.B. & Hampe, C.S. Animal insulin therapy induces a biased insulin antibody response that persists for years after introduction of human insulin. Acta Diabetol. 47, 131–135 (2010).
Naserke, H.E., Dozio, N., Ziegler, A.G. & Bonifacio, E. Comparison of a novel micro-assay for insulin autoantibodies with the conventional radiobinding assay. Diabetologia 41, 681–683 (1998).
Ljungberg, U.K. et al. The interaction between different domains of staphylococcal protein A and human polyclonal IgG, IgA, IgM and F(ab′)2: separation of affinity from specificity. Mol. Immunol. 30, 1279–1285 (1993).
Wabl, M., Cascalho, M. & Steinberg, C. Hypermutation in antibody affinity maturation. Curr. Opin. Immunol. 11, 186–189 (1999).
Lakowicz, J.R. Radiative decay engineering 5: metal-enhanced fluorescence and plasmon emission. Anal. Biochem. 337, 171–194 (2005).
We thank the patient volunteers. We thank P.J. Utz and D. Wilson for helpful discussions. We thank M. Gong, J. Wu and L. Zhang for help with experiments; we thank C. Yan for help with the scatter plot for diabetes autoantibodies. This work was supported by grants from the Stanford C-IDEA program (US National Institutes of Health grant 1 RC4 TW008781-01), the US National Institutes of Health DP2OD006740 (to B.J.F.) and the Juvenile Diabetes Research Foundation 17-2013-528 (to B.J.F.) and the National Cancer Institute of the US National Institutes of Health (5R01CA135109-02) and the Stanford SPARK program (to H.D.). B.Z. acknowledges support from the Stanford Bio-X SIGF fellowship. R.B.K. received unrestricted fellowship support from Genentech and the Child Health Research Institute at Stanford. B.J.F. is a Bechtel Endowed Faculty Scholar.
Stanford University and the authors have filed patents for both the technology and the use of the technology to detect islet cell–targeting autoantibodies with the US Patent and Trademark Office and via the Patent Cooperation Treaty.
About this article
Cite this article
Zhang, B., Kumar, R., Dai, H. et al. A plasmonic chip for biomarker discovery and diagnosis of type 1 diabetes. Nat Med 20, 948–953 (2014). https://doi.org/10.1038/nm.3619
Optical Properties of Electrically Active Gold Nanoisland Films Enabled with Interfaced Liquid Crystals
Nature Communications (2020)
Graphically encoded suspension array for multiplex immunoassay and quantification of autoimmune biomarkers in patient sera
Biosensors and Bioelectronics (2019)
Biosensors and Bioelectronics: X (2019)
High-throughput multiplexed autoantibody detection to screen type 1 diabetes and multiple autoimmune diseases simultaneously