Neutzsky-Wulff et al. Journal of Translational Medicine 2012, 10:214http://www.translational-medicine.com/content/10/1/214REVIEW Open AccessFuture detection and monitoring of diabetes mayentail analysis of both -cell function and volume:How markers of -cell loss may assistAnita V Neutzsky-Wulff1, Kim V Andreassen1, Sara T Hjuler1, Michael Feigh1, Anne-Christine Bay-Jensen1,Qinlong Zheng2, Kim Henriksen1 and Morten A Karsdal1*Abstract
Disease heterogeneity is as major issue in Type II Diabetes Mellitus (T2DM), and this patient inter-variability mightnot be sufficiently reflected by measurements of glycated haemoglobin (HbA1c).-cell dysfunction and -cell death are initiating factors in development of T2DM. In fact, -cells are known vanishprior to the development of T2DM, and autopsy of overt T2DM patients have shown a 60% reduction in-cell mass.As the decline in -cell function and mass have been proven to be pathological traits in T2DM, methods forevaluating -cell loss is becoming of more interest. However, evaluation of -cell death or loss is currently invasiveand unattainable for the vast majority of diabetes patients. Serological markers, reflecting -cell loss would beadvantageous to detect and monitor progression of T2DM. Biomarkers with such capacities could be neo-epitopesof proteins with high -cell specificity containing post translational modifications. Such tools may segregate T2DMpatients into more appropriate treatment groups, based on their -cell status, which is currently not possible.Presently individuals presenting with adequately elevated levels of both insulin and glucose are classified as T2DMpatients, while an important subdivision of those is pending, namely those patients with sufficient -cell capacityand those without. This may warrant two very different treatment options and patient care paths.Serological biomarkers reflecting -cell health status may also assist development of new drugs for T2DM and aidphysicians in better characterization of individual patients and tailor individual treatments and patientcare protocols.
Keywords: Neo-epitope, Biomarkers, Type II diabetes mellitus, -cell death, BIPED classification, Patient segregation,Personalized treatmentIntroductionType II Diabetes Mellitus (T2DM) is a heterogeneoustype of disease , meaning that affected patients displaya large variability with regards to disease characteristics.This patient heterogeneity is not sufficiently illustratedby the currently available and gold standard biomarkersfor evaluation of T2DM: Fasting plasma glucose (FPG),oral glucose tolerance test (OGTT) and glycated haemo-globin A1c (HbA1c). These markers efficiently reflect* Correspondence: [email protected] contributors1Nordic Bioscience A/S, Herlev Hovedgade 207, DK-2730, Herlev, DenmarkFull list of author information is available at the end of the article
2012 Neutzsky-Wulff et al.; licensee BioMedCreative Commons Attribution License (http:/distribution, and reproduction in any mediumblood glucose status, but they cannot characterizeT2DM patients at a more detailed level, for examplewith regards to pancreatic function, peripheral effects ofinsulin and progression of secondary complications ofthe disease.Hence novel biomarkers with the potential to segre-
gate different T2DM patient subtypes will be imperativeto deliver the best possible treatment to the individualpatient in the future. A new panel of diabetes biomar-kers is needed to identify and characterize these futurepatient subtypes and assign appropriate subtype treat-ments. Also drug development of novel T2DM treat-ments would benefit from biomarkers contributing withmore elaborate pathological information.Central Ltd. This is an Open Access article distributed under the terms of the/creativecommons.org/licenses/by/2.0), which permits unrestricted use,, provided the original work is properly cited.
Neutzsky-Wulff et al. Journal of Translational Medicine 2012, 10:214 Page 2 of 16http://www.translational-medicine.com/content/10/1/214Obvious candidates in a novel biomarker panel arethose reflecting the health or death of -cells . -cellsare the focal point in both Type I Diabetes Mellitus(T1DM) and T2DM, because of their capacity to pro-duce and secrete insulin. In both types of diabetes, -cells are lost [3,4]. The vast majority of T1DM patientsdisplay a dramatic loss of -cells as a consequence of acell-mediated autoimmune attack on the -cells, withconsequent insulin deficiency and chronic hypergly-caemia . At time of diagnosis, T1DM patients havehad their -cell mass reduced by 70-80% . Patientssuffering from T1DM are often lean and display ahealthy phenotype when their insulin deficiency is prop-erly treated. This is in contrast to T2DM patients, whooften are overweight or obese and display a metabolicphenotype, which complicates the overall pathology.Loss of -cells is an initiating event in development ofT2DM and may occur gradually and long before the dis-ease is diagnosed . A 40% reduction in -cell masshas been observed in obese individuals with impairedfasting glucose (IFG), and a 60% reduction has beenobserved in patients suffering from overt T2DM [4,6].Furthermore, a strong correlation between decline in -cell area and development of T2DM has been estab-lished in patients suffering from pancreatic disorders .These findings clearly indicate that when the -cell massdeclines considerably, the body can no longer upholdnormal glucose regulation, with development of T2DMas consequence.It is often not well established how current and novel
drugs for management of T2DM affect the -cells at amore detailed level, despite the apparent need for im-proving this aspect of the disease. Biomarkers reflecting-cell death and -cell mass could aid in evaluation ofpositive and/or negative effects on -cells inflicted bydifferent types of drugs, and novel -cell biomarkerscould therefore be advantageous in future drug develop-ment programs.The ability to detect -cell loss could facilitate progno-
sis of disease development of T2DM at a much earlierpoint in time than any of the currently used diabetesbiomarkers such as FPG, OGTT and HbA1c. In addition,different sub-groups of T2DM patients are highly likelyto lose -cells at different rates, and these differencesmay require different treatment regimens for individualpatients . Serological biomarkers reflecting -celldeath and -cell volume would therefore be valuabletools for disease prognosis, early diagnosis and tailoringtreatment to the individual.Today, evaluations of -cell mass are only rarely per-
formed, as this currently requires obtaining biopsies,which is an invasive procedure to the patient. Post-mortem histological evaluations of -cell mass can beperformed, but these examinations will not elucidatedecline in -cell mass during disease. Furthermore,histological assessment of -cell death is complicated bythe fact that dead cells are rapidly removed from the is-lets by macrophages . Serological biomarkers reflect-ing -cell mass or -cell death have the strong advantageof being non-invasive, and such markers could, likeHbA1c, be used as continuous evaluation of disease de-velopment and disease management.Potential serological biomarkers reflecting -loss could
be specific neo-epitopes of -cell related proteins. When-cells are being lost by apoptosis or necrosis , site-specific cleavage of -cell specific proteins is expected toarise from cleavage by particular proteases, creating neo-epitopes for measurement in serum. By this mechanisma particular protein fingerprint is generated, and investi-gations of this specific protein fingerprint could provideinformation about pathological processes . Measure-ments of neo-epitopes have in several diseases beenshown to correlate with disease pathology [9-15], asgeneration of specific neo-epitopes arise from specificpathological processes [8,16,17]. An incomplete list of-cell proteins that might be of interest as novel bio-markers could include insulin, amylin, incretin recep-tors, special neuronal proteins and proteins which act asautoantigens in T1DM.In the current review we describe how new biomarkers
reflecting -cell loss are desired to better identify peopleat risk of developing T2DM, to diagnose the diseaseearlier than is possible with current biomarkers, to bettercharacterize affected patients, to optimize individualtreatment, and to evaluate the effects of drugs on -cells.We will in this paper describe the pursuit of novel -cellneo-epitope biomarkers that could improve the clinicaldiagnosis and management of diabetes.
Overview of T2DMT2DM is a major cause of morbidity and mortality inthe industrialized world, and cardiovascular complica-tions affect as many as 50% of all T2DM patients .The global prevalence of T2DM is rapidly increasing,and the number of people diagnosed with the diseaseworldwide has more than doubled over the past threedecades, primarily due to a dramatic increase in numberof obese people, as obesity is a major risk factor for de-velopment of T2DM . Previously T2DM was consid-ered a disease of the elderly, however, with increasingnumbers of obese individuals of all ages, including chil-dren and adolescents, T2DM is now observed at all ages. It is estimated that the prevalence of both type Iand type II diabetes was 285 million in 2010, and thisnumber is expected to increase to around 440 million by2030, which represents 7.7% of the total adult populationof the world aged 2079 years . Of the total popula-tion of diagnosed diabetics, at least 90% suffer from