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

Table 3 Overview of the articles included that studied insulin resistance and Beta cell mass

Ref.	Setting	Biomarker	Insulin resistance	Beta cell mass	Insulin sensitivity
Type 1 diabetes
Abdel-Moneim, et al[17], 2020	Egypt	MDA; NO	IR was studied by measuring HbA1c and fasting glucose plasma levels, which were higher in the studied population	Not analyzed	Not reported
Babar et al[18], 2011	United States	hs-CRP, Homocysteine	IR was analyzed indirectly by measuring the flow-mediated dilatation of the brachial artery, which had a positive relation with higher levels of Hb1A	Not analyzed	Not reported
Cabrera et al[39], 2018	United States	Innate immunity activity (circulating activated regulatory T cells (CD4+/CD45RA−/FOXP3high)	IR was indirectly analyzed by the rate of C-peptide decline	Not analyzed	Not reported
Cazeau et al[29], 2016	United States	Endothelial function/ dysfunction: (ECFCs: CD34+, CD133+, CD45-). Oxidative stress: TAOC, hs-CRP, EPCs	IR was analyzed by indirect biomarkers that relate to high levels of HbA1c such as adiponectin and hs-CRP	Not analyzed	Not reported
Cree-Green et al[41], 2018	United States	hs-CRP, adiponectin, leptin and C-peptide	IR was assessed by insulin sensitivity four-phase HE clamp - glucose and glycerol rate of appearance, rate of disappearance and metabolic clearance rate over the last 30 min of each phase of the clamp	Not analyzed	IS was assessed with a four-phase HE clamp: a bolus of 4.5 mg/kg 6,6-2; H2-glucose followed by a continuous infusion at 0.03 mg/kg/min 6,6-2H2-glucose was paired with a primed (1.6 mmol/kg) then constant (0.11 mmol/kg/min), infusion of 2H5-glycerol. During the last 30 min of each of the four clamp phases, four samples, each 10 min apart, were drawn for glucose, glycerol, free fatty acid and insulin concentrations
Elbarbary et al[33], 2018	Egypt	Neopterin	IR was indirectly analyzed with biomarkers related to higher levels of HbA1c such as dyslipidemia, hs-CRP and also fasting blood glucose	Not analyzed	Not reported
Lakhter et al[35], 2018	United States	miR-21-5pin Beta cell extracellular vesicle	Not reported	Not analyzed	Not reported
Vorobjova et al[32], 2019	Estonia	Inflammation markers; Association with Enterovirus infection; Immunity	IR was analyzed by indirect biomarkers that relate to high levels of HbA1c such as leptin	Not analyzed	Not reported
Type 1 and 2 diabetes
Aburawi et al[30], 2016	United Arab Emirates	sICAM-1, sVCAM-1, IL-6, TNF-α, hs-CRP	IR was analyzed by indirect biomarkers that relate to high levels of HbA1c such as adiponectin	Not analyzed	Not reported
Type 2 diabetes
Arenaza et al[36], 2017	Spain	miRNA expression in circulating exosomes and in peripheral blood mononuclear cells	IR was measured by the HOMA, which has been shown to be a reliable method in pediatric population.	Not analyzed	IS was indirectly measured by the amount of total, visceral and abdominal as well as hepatic and pancreatic adiposity.
Bacha et al[40], 2014	United States	Leptin, IL-6, VCAM-1, ICAM-1, E-selectin	IR was measured by OGTT (1.75 g/kg, maximum 75 g Trutol), which was performed with glucose, insulin and C-peptide determination at 215, 0, 15, 30, 60 and 120 min	Not analyzed	IS analysis was measured using intravenous crystalline insulin, which was infused at a constant rate of 80 mU/m2/min, and plasma glucose was clamped at 100 mg/dL (5.6 mmol/L) with a variable rate infusion of 20% dextrose
Barbosa-Cortés et al[31], 2017	México	Leptin, adiponectin, VCAM, ICAM	IR was measured directly measured based on the fasting insulin and glucose concentrations using the Homeostatic Model Assessment of Insulin Resistance [HOMA-IR = (fasting insulin (μU/ml) × fasting glucose (mmol/L)/22.5)] and indirectly by measuring serum levels of leptin and adiponectin	Not analyzed	Not reported
Carlbom et al[34], 2017	Sweden	Functional Beta cell mass	IR was measured using the HOMA-IR	Intravenous arginine test and a glucose potentiated arginine test, which are considered the gold standard to assess the functional B-cell mass; Beta cell mass was analyzed using [11C]5-hydroxytryptophan positron emission tomography	IS was assessed using the HOMA2-S calculator previously calibrated so that 100% represents values obtained from young healthy adults
Dentelli et al[27], 2013	Germany	Adipose-derived stem cell pluripotentiality	Not reported	Not analyzed	Not reports
Kim-Muller et al[38], 2016	United States	Impaired mitochondrial function (Aldehyde dehydrogenase 1 isoform A3, Foxo1, MafA)	Not reported	Not analyzed	Not reported
Sheng et al[37], 2016	China	B-cell dedifferentiation (Glut2, Pdx1, Nkx6.1, MafA, Foxo1, GLP-1, PKC)	IR was assessed by glucose tolerance tests. The mice were fasted for 12 h then they were injected intraperitoneally with 1 g kg−1 glucose. The glucose measurements were taken up to 2 h after injection	Pancreatic sections were analyzed by immunohistochemistry	Not reported
Spagnuolo et al[23], 2010	Italy	C-reactive protein, NO, Fecal calprotectin	OGTT was performed with a load of 1.75 g/kg/body weight of glucose (maximum 75 g) after a 12 h overnight fast	Not analyzed	IS was estimated by the HOMA-IR index from fasting glucose and insulin concentrations according to the following formula: insulin (mU/L) × glucose (mmol/L)/22.5
Stansfield et al[28], 2016	United States	Leptin, adiponectin, C-reactive protein	IR was assessed using HOMA-IR. It was calculated by use of the formula: insulin (pmol/L) × glucose (mmol/L)/22.5.25	Not analyzed	Not reported
Walker et al[25], 2014	Italy	C-reactive protein, TNF-a, IL-6, Crown like structures (CLS) in SAT	IR was assessed by standard OGTT performed with 1.75 g of glucose per kg of body weight (up to 75 g), and glucose and insulin were measured at 0, 30, 60, 90 and 120 min	Not analyzed	IS was estimated by the HOMA
Xu et al[16], 2017	China	Superoxide dismutase activity, MDA and glycated serum protein levels	IR was assessed performing OGTT and HOMA-IR model	Beta cell mass was analyzed with histopathology. For light microscopy, the fixed tissue samples were dehydrated through a graded ethanol series, embedded in paraffin and cut into 7 μm-thick sections with HE stain using a routine protocol	Not reported

TAOC: Total plasma antioxidant capacity; hs-CRP: High-sensitivity C-reactive protein; HOMA-IR: Homeostatic Model Assessment of Insulin Resistance; ECFC: Endothelial colony-forming cells; MDA: Malondialdehyde; NO: Nitric oxide; IR: Insulin resistance; HbA1c: Glycated hemoglobin; EPC: Endothelial progenitor cell; IS: Insulin sensitivity; miR: microRNA; s: soluble; ICAM: Intracellular cell adhesion molecule; IL: Interleukin; VCAM: Vascular cell adhesion molecule; TNF: Tumor necrosis factor; miRNA: MicroRNA; OGTT: Oral glucose tolerance test; HE: Hematoxylin and eosin; HE clamp: Hyperinsulinemic-euglycemic clamp; HOMA2-S: Homeostatic Model Assessment to assess insulin sensitivity; SAT: subcutaneous adipose tissue.