What can we learn from β-cell failure biomarker application in diabetes in childhood? A systematic review

Table 1 Overview of the included studies with their corresponding quality assessment

Type 1 diabetes
Ref.	Setting	Target population and sample size	Biomarker	Type of study	Quality (%)
Abdel-Moneim, et al[17], 2020	Egypt	Sample size: 100 subjects; 70 children diagnosed with T1DM and 30 healthy control subjects	Inflammation biomarker (MDA); Oxidative stress biomarker (NO)	Transversal	100
Babar et al[18], 2011	United States	Sample size: 36 children 21 with T1DM (aged 8.3 ± 0.3 yr with a diabetes duration of 4.3 ± 0.4 yr) and 15 group-matched healthy siblings (aged 7.6 ± 0.3 yr)	Vascular inflammatory biomarkers (hs-CRP, homocysteine C-reactive protein)	Transversal	87.5
Cabrera et al[39], 2018	United States	Sample size: 42 pediatric subjects	Innate immunity	Cohort	75.0
Cazeau et al[29], 2016	United States	Sample size: 9 children and adolescents aged 8-15 yr (mean age 12.9 ± 0.9 SD) with a mean T1DM duration of 5.0 ± 2.5 yr were included	Oxidative stress and endothelial dysfunction	Clinical trial/cohort	100
Cree-Green et al[41], 2018	United States	Sample size: 35 youth subjects with T1DM [median age 16-yr-old) and 22 nondiabetic youth subjects of similar age	Insulin resistance	Observational	100
Cummings et al[51], 2018	Canada	Participants (n = 199) were included in the observational arm of the Canadian AdDIT cohort	Urinary inflammatory biomarkers	Retrospective	62.5
Elbarbary et al[33], 2018	Egypt	Sample size: 60 children and adolescents with T1DM (aged ≤ 18 yr with at least 5 yr disease duration). Patients were compared with 30 age- and sex-matched healthy controls	Neopterin	Cross-sectional	75.0
Heier et al[52], 2015	Norway	Sample size: 299 patients with T1DM and 112 healthy controls at baseline and 241 patients and 128 controls at follow-up	AGEs methylglyoxal-derived hydroimidazolone-1 and carboxymethyllysine	Cohort	62.5
Ho et al[53], 2016	Canada	Sample size: Children aged 8 to 17 yr with T1DM for at least 1 yr	Serum C-peptide, HbA1c, serum inflammatory markers (IL-6, IFN-gamma, TNF-alpha, and IL-10), GLP-1 and GLP-2, intestinal permeability	Single-center, randomized, double-blind, placebo-controlled trial	62.5
Hoffman et al[54], 2016	United States	Sample size: 17 adolescents (8 F/9 M; age, 13.1 ± 1.6 yr (mean ± SD); duration, 4.8 ± 3.8 yr, BMI, 20.3 ± 3.1 kg/m2; HbA1c, 8.3% ± 1.2%	Inflammatory (C-reactive protein), oxidative (total anti-oxidative capacity) and endothelial injury (soluble intracellular adhesion molecule 1) markers	Cohort	50.0
Kingery et al[55], 2012	United States	Sample size: 34 patients of European ancestry with new-onset T1DM, aged between 3 and 17 yr (10.70 ± 3.45), at Nationwide Children’s Hospital in Columbus, Ohio	Complement C4A and C4B	Longitudinal	62.5
Lakhter et al[35], 2018	United States	Human experiment. Sample size: 16 healthy non-diabetic children (as a control group) and 19 children diagnosed with T1DM. Animal experiment: Serum was collected weekly from 8-wk-old female NOD mice until diabetes onset	miR-21-5pin Beta cell extracellular vesicle	Human experiment: cross-sectional; Animal experiment: longitudinal	75.0
Marchand et al[56], 2016	France	Sample size: 22 children at onset of T1DM within 2 d of clinical diagnosis (immediate insulin-requiring diabetes with at least one positive autoantibody) and before subcutaneous insulin treatment and sera from 10 control subjects (no obese and nondiabetic child)	miRNA-375	Transversal	62.5
Marek-Trzonkowska et al[57], 2016	Poland	Sample size: 12 children with recently diagnosed T1DM as well as that of untreated subjects	C peptide	Cohort	50.0
Redondo et al[58], 2014	United States	Sample size: 32 lean and 18 obese children (age range: 2-18 yr) with new-onset autoimmune T1DM and followed them for up to 2 yr	Leptin, total and high molecular weight adiponectin, omentin, resistin, chemerin, visfatin, cytokines [interferon-gamma, interleukin (IL)-10, IL-12, IL-6, IL-8, and tumor necrosis factor-alpha] and C-reactive protein	Cohort	62.5
Ryba-Stanisławowska et al[59], 2014	Poland	Sample size: 47 young patients (mean age; 14.25 ± 3.50 yr) diagnosed with T1DM. Control group consisted of 28 age- and sex- matched individuals	IL-12, IL-18. Blood glucose levels, lipid status, C-reactive protein, HbA1c	Transversal	62.5
Singh et al[60], 2017	United States	Sample size: 220 adolescents and children, half of which had lived with T1DM for an average of 7 years and half of which were healthy siblings	Leucine-rich alpha-2-glycoprotein, CD14, AZGP1, NAGA, CTSD, GM2A, GNS, CTSS	Cases and controls prospective	50.0
Şiraz et al[61], 2017	Turkey	Sample size: 80 patients who had T1DM for at least 5 yr and who had no chronic complications or an autoimmune disorder	Fetuin-A, Hb1Ac	Transversal	62.5
Thorsen et al[20], 2014	England	Sample size: 482 cases and 479 sibling frequencies matched on age and sample year distribution were included	Five different inflammatory chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8)	Cases and controls	100
Vorobjova et al[32], 2019	Estonia	Sample size: 72 patients (median age 10.1 yr) who had undergone small bowel biopsy were studied	Inflammation markers. Association with Enterovirus infection. Immunity	Longitudinal	87.5
Wołoszyn-Durkiewicz et al[19], 2019	Poland	NA	Advanced glycation end-products and their receptors, adhesive molecules, pro- and anti-inflammatory cytokines, growth factors or enzymes, such as N-acetyl-β-D-glucosaminidase	Review	25.0
Zhang et al[62], 2014	United States	NA	Autoantibodies [pancreatic islet antigens (insulin, glutamic acid decarboxylase and/or tyrosine phosphatase islet antigen 2)]	Review	37.5
Type 1 and 2 diabetes
Aburawi et al[30], 2016	United Arab Emirates	Sample size: 181 subjects; 79 patients with T1DMs, 55 patients with T2DM and 47 control subjects	Endothelial dysfunction biomarkers (sICAM-1, and sVCAM-1). Inflammation biomarkers Interleukin-6, tumor necrosis factor-α, high-sensitivity C reactive protein	Transversal	100
Krapfenbauer[63], 2017	Austria	NA	Novel protein chip technology	Review	50.0
Roberts et al[64], 2012	Australia	NA	Glucose in respiratory fluids	Review	12.5
Type 2 diabetes
Arenaza et al[36], 2017	Spain	Sample size: 84 children (age 8-12-yr-old) with high risk of T2DM. Control (n = 42) or intervention (exercise) (n = 42) group	microRNA expression in circulating exosomes and in peripheral blood mononuclear cells	Randomized control trial	87.5
Arslanian et al[65], 2019	United States	Sample size: 662 patients between 10-yr-old to 18-yr-old with DM for 2 yr (median duration 8 mo) with overweight or obesity	OGTT glucose response curve	Cohort	62.5
Bacha et al[40], 2014	United States	Sample size: 90 obese adolescents (37 normal glucose tolerant, 27 with prediabetes and 26 T2DM); Mean age for adolescents with T2DM was 15.1 ± 0.4 yr and duration of diabetes was 10.8 ± 2.5 mo	Inflammatory markers (Leptin, Interleukin-6, VCAM-1, ICAM-1, E-selectin)	Transversal	87.5
Barbosa-Cortés et al[31], 2017	Mexico	Sample size: 52 children (leukemia n = 26, lymphoma n = 26), who were within the first 5 yr after cessation of therapy. Median age of the subjects was 12.1 yr	Leptin. Adiponectin. Vascular cell adhesion molecule, intercellular cell adhesion molecule	Cohort	100
Berezin[66] 2016	Ukraine	NA	Growth differentiation factor-15	Review	25.0
Blum et al[21], 2014	United States	Animal experiment: Sample: Mouse strains: C57BL/6, Lep ob/ob, Lepr db/db, Ins2akita, Insulin2-Cre transgenic mice, Ucn3-GFP transgenic mice	Urocorti3	Cohort	50.0
Burke et al[67], 2017	United States	Animal experiment: Sample: 9-wk-old C57BL/6j and 5-wk-old male db/ and db/db mice	B-cell dedifferentiation biomarkers	Cohort	37.5
Can et al[68], 2016	Turkey	Sample size: 43 (18 males, 25 females) MetS adolescents between the ages of 13 and 17 yr (14.70 ± 1.15) and 43 lean controls were matched for age and sex	High-sensitive C-reactive protein, haptoglobin, α2-macroglobulin, platelet factor-4, fetuin-A, serum amyloid P and α1-acid glycoprotein	Transversal	62.5
Carlbom et al[34], 2017	Sweden	Sample size: 39 participants. 31 individuals with T2DM divided in 4 groups based on their current DM treatment. Control group with 8 participants	Functional Beta cell mass	Clinical trial	75.0
Cui et al[69], 2018	China	Human experiment: Sample size: 183 children and adults with obesity; Animal experiment: Obese ob/ob mice (3-wk-old to 4-wk-old), diabetic db/db mice (8-wk-old) and age-matched male C57BL/6J wild-type mice	Circulating microRNAs (miR-486, miR-146b and miR-15b),	Observational	62.5
DeBoer[70] 2013	United States	NA	Fasting insulin, adiponectin, retinol-binding protein 4	Review	-
Dentelli et al[27], 2013	Germany	Sample size: 25 patients with T2DM and 15 non-diabetic participants who underwent abdominal surgery (gallbladder removal, in situ colorectal cancer) were included. Non-diabetic participants were used as controls	Adipose-derived stem cell pluripotentiality	Transversal	75.0
Fanjul et al[71], 2010	France	Sample size: Human pancreases (n56) were harvested from brain- dead adult donors between 24 and 64-yr-old	Epithelial-mesenchymal transition biomarkers	Retrospective	50.0
Garanty-Bogacka et al[44], 2011	Poland	Sample size: 50 obese children and adolescents (boys and girls), aged 8 yr to 18 yr	High-sensitive C-reactive protein, interleukin-6, fibrinogen, white blood count, glucose, insulin, insulin resistance index, glycosylated hemoglobin, lipids as well as systolic and diastolic blood pressure	Cohort	50.0
Garnett et al[72], 2010	Australia	Sample size: 108 (54 each treatment arm) 10-yr-old to 17-yr-old with clinical features of insulin resistance and/or prediabetes	Insulin sensitivity	Randomized controlled clinical trial	37.5
Hansen et al[73], 2014	Denmark	NA	Iron	Review	25.0
Ishida et al[74], 2017	United States	Animal experiment: B6.BKS(D)-Leprdb/J heterozygous mice (db/+) were purchased from The Jackson Laboratory (Sacramento, CA) and bred to homozygosity to obtain wild-type, db/+, and db/db mice	Blood glucose and plasma insulin	Cohort	50.0
Jaberi-Douraki et al[75], 2014	Canada	NA	Autoantibodies (Auto-antigen-2)	Review	25.0
Janem et al[43], 2017	United States	Sample size: 3 pediatric cohorts ages 10-19 years were studied: lean (normal weight-C), obese (Ob) and obese with T2DM	Salivary glucose. Nitric oxide, CRP and IL-1B	Cohort	62.5
Kaya et al[76], 2017	Turkey	Sample size: 50 obese adolescents with IR were included in the study	Serum lipids, adiponectin, and interleukin-6 levels	Transversal	75.0
Kim-Muller et al[38], 2016	United States	Animal experiment. Groups: Mice were maintained in a mixed 120J-C57BL/6 background. Sample size calculations were based on the variance observed in prior experiments. No randomization or blinding was used	B cell dedifferentiation markers; Impaired mitochondrial function	Observational	87.5
Kim et al[77], 2016	United States	Sample size: 277 obese adolescents without diabetes completed a 2-h OGTT and were categorized to either a monophasic or a biphasic group	In vivo insulin sensitivity, insulin secretion, and β-cell function relative to insulin sensitivity	Observational	62.5
Kuo et al[78], 2016	United States	Animal experiment: Mice lacking the three FoxO isoforms in pancreas (TKO) using Tg (Ipf1-cre)1Tuv transgenics to excise the floxed Foxo1, Foxo3a, and Foxo4 genes	FoxO1, FoxO3a, and FoxO4	Longitudinal	62.5
Mastrangelo et al[79], 2016	Spain	Sample size: 60 prepubertal obese children (30 girls/30 boys, 50% IR and 50% non-IR in each group, but with similar BMIs)	47 metabolites (Taurodeoxycholate, LysoPC, LysoPE, LysoPS, acetylcarnitine, biliverdin, pyruvate, lactate, alanine, proline, valine, isoleucine, tryptophan, tyrosine, arginine, aspartate, glutamate)	Transversal	62.5
Neelankal et al[80], 2017	United States	Animal experiment: Pancreatic B cell line mouse insulinoma 6	Insulin. GLUT-2, Pdx1	Transversal	62.5
Park et al[81], 2016	Korea	Sample size: 214 children 7-9 yr of age	Persistent organic pollutants	Cohort	62.5
Rachdi et al[82], 2014	France	Animal experiment: mBACTgDyrk1A mice	DYRK1A	Cohort	-
Santoro et al[83], 2014	United States	Sample size: 80 adolescents (age 13.30 ± 3.31 yr; BMI 33.0 ± 6.79 kg/m2)	Cytokeratin 18	Transversal	62.5
Serbis et al[84], 2018	United States	Sample size: 88 children with obesity divided into two groups according to 1h-GL during an OGTT: group 1 (n = 57) consisted of those with 1h-GL < 8.6 mmol/L and group 2 (n = 31) of those with 1h-GL ≥ 8.6 mmol/L	HOMA-IR, Matsuda index and Cederholm insulin sensitivity index. Adiponectin, leptin, visfatin and interleukin-6 together with lipid levels	Transversal	62.5
Sheng et al[37], 2016	China	Animal experiment C57BLKS/J-Leprdb/Leprdb (db/db) and C57BLKS/J-Leprdb/m (db/m) male mice from the Shanghai Laboratory Animal Center, Chinese Academy of Sciences (SLAC, CAS)	B-cell dedifferentiation	Longitudinal	87.5
Solimena et al[42], 2018	Germany	Sample size: 103 organ donors, including 84 non-diabetic and 19 type 2 diabetic individuals, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance and 20 with recent-onset diabetes (< 1 yr)	Genes including TMEM37, which inhibited Ca2+ influx and insulin secretion in beta cells, and ARG2 and PPP1R1A	Retrospective	62.5
Spagnuolo et al[23], 2010	Italy	Sample size: 34 children (25 males; median age 10.8 ± 3.4 yr) with severe obesity; Groups: Normal glucose tolerance (n = 10), Impaired glucose tolerance (n = 24) and T2DM (n = 7)	Systemic and bowel inflammation markers	Transversal	75.0
Stansfield et al[28], 2016	United States	Sample size: 575 adolescents aged 14-18 yr (52% female, 46% black population)	Leptin. Adiponectin. C-reactive protein	Transversal	87.5
Tenenbaum and Fisman[85], 2012	Israel	NA	PPAR isoforms	Review	NA
Walker et al[25], 2014	Italy	Sample size: 33 children (mean BMI 28.1 ± 5.1 kg/m2 and mean age 11.6 ± 2.2 yr) with confirmed NAFLD. Biopsy samples of abdominal and liver were simultaneously collected	WAT inflammation biomarkers; Liver fibrosis biomarkers	Transversal	100
Walsh et al[24], 2018	Canada	Sample size: 66 boys and 136 girls aged 14-18 yr (15.4 ± 1.4 yr), who volunteered for the HEARTY trial	Glucose, HOMA-B, HOMA-IS, HbA1c, insulin	Randomized controlled trial	50.0
White et al[22], 2013	United States	Sample size: 3 individuals with diabetes and 5 nondiabetic control subjects	Insulin, vimentin, glucagon	Transversal	50.0
Xu et al[16], 2017	China	Animal experiment: Male Sprague-Dawley rats. 5 experimental groups: Normal control group. Model control group. Ginseng oligopeptides: Low-dose group, Medium-dose group, High-dose group	Antioxidant biomarkers; NF-KB, Bax, cleaved Caspase-3 and Bcl2	Clinical trial	100

NA: Not available; T1DM: Type 1 diabetes mellitus; SD: Standard deviation; F: Female; M: Male; BMI: Body mass index; HbA1c: Glycated hemoglobin; IR: Insulin resistance; OGTT: Oral glucose tolerance test; TKO: Total knock out; NAFLD: Nonalcoholic fatty liver disease; CRP: C-reactive protein; IL: Interleukin; IFN: Interferon; TNF: Tumor necrosis factor; hs-CRP: High-sensitivity C-reactive protein; NO: Nitric oxide; GL: Glucose; HOMA-IR: Homeostatic Model Assessment of Insulin Resistance; VCAM: Vascular cell adhesion molecule; ICAM: Intracellular cell adhesion molecule; MDA: Malondialdehyde; AGE: Advanced glycation end-product; AdDIT: Adolescent type 1 Diabetes cardio-renal Intervention Trial; MetS: Metabolic syndrome; HOMA-B: Homeostasis model assessment-B cell; HOMA-IS: Homeostatic model assessment of insulin sensitivity; WAT: White adipose tissue; PPAR: Proliferator-activated receptor.