Metabolic and biological changes in children with obesity and diabetes

Table 1 Characteristics of study findings and identified metabolomic profiles in 13 clinical studies

No.	Ref.	Major finding
1	Perng et al[36], 2020	BCAA levels and products of BCAA catabolism were higher in males than females with comparable BMI z-score; In multivariate analyses, HOMA-IR in males correlated positively with BMI z-score and a metabolic signature containing BCAA, uric acid, and long-chain acylcarnitines and negatively with byproducts of complete fatty acid oxidation
2	Hosking et al[14], 2019	In longitudinal analysis, IR was associated with reduced concentrations of BCAA, 2-ketobutyrate, citrate and 3-hydroxybutyrate, and higher concentrations of lactate and alanine
3	Suzuki et al[44], 2019	HOMA-IR was positively correlated with valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, threonine, lysine, alanine, tyrosine, glutamate, proline, arginine, ornithine, total free amino acids and aspartate; Blood uric acid levels were positively correlated with leucine and glutamate, and negatively correlated with serine, glycine, and asparagine
4	Perng et al[34], 2018	BCAA and androgen hormone metabolite patterns are related to changes in metabolic parameters in a sex-specific manner during early adolescence
5	Xia et al[37], 2018	Disrupted arginine and proline metabolism associated with phthalate exposure might contribute to the development of overweight and obesity in school-age children
6	Moran-Ramos et al[38], 2017	Principal component analysis showed a serum amino acid signature composed of arginine, leucine/isoleucine, phenylalanine, tyrosine, valine and proline significantly associated with obesity and serum triglycerides
7	Goffredo et al[39], 2017	A branched-chain amino acid-related metabolic signature characterizes obese adolescents with non-alcoholic fatty liver disease
8	Hellmuth et al[40], 2016	Tyrosine alterations in association with insulin resistance precede alteration in BCAA metabolism
9	Mastrangelo et al[43], 2016	The majority of metabolites differing between groups were lysophospholipids (15) and amino acids (17), indicating inflammation and central carbon metabolism as the most altered processes in impaired insulin signaling
10	Lee et al[41], 2015	Obese children presented significantly higher levels of BCAAs and several acylcarnitines and lower levels of acyl-alkyl phosphatidylcholines; Baseline BCAAs were significantly positively correlated with both HOMA-IR and continuous metabolic risk score at the 2-year follow-up
11	Butte et al[42], 2015	BCAAs and their catabolites, propionylcarnitine and butyrylcarnitine, were significantly elevated in obese children; Lower lysolipids and dicarboxylated fatty acids were seen in obese children; Steroid derivatives were markedly higher in obese children, as were markers of inflammation and oxidative stress
12	Perng W et al[33], 2014	BCAA and androgen metabolites were associated with adiposity and cardiometabolic risk during mid-childhood
13	Newbern et al[35], 2014	BCAA levels and byproducts of BCAA catabolism are higher in obese teenage boys than girls of comparable BMI z-score; A metabolic signature comprising BCAA and uric acid correlates positively with HOMA-IR in males and TG to HDL ratio in females and inversely with adiponectin in males but not females

BCAA: Branched-chain amino acid; BMI: Body mass index; HDL: High-density lipoprotein; HOMA: Homeostatic model assessment; IR: Insulin resistance; TG: Triglycerides.

Table 2 Plasma amino acid values (μmol/L) during childhood

Amino acid	6 mo 50th (10th-90th) quantile value	2 yr 50th (10th-90th) quantile value	6 yr 50th (10th-90th) quantile value	16 yr 50th (10th-90th) quantile value
Alanine	248 (182-396)	229 (173-349)	234 (182-319)	370 (240-482)
Arginine	72 (43-120)	70 (46-90)	76 (50-99)	96 (68-128)
Asparagine	41 (31-56)	38 (29-56)	42 (31-67)	55 (37-81)
Aspartic acid	7 (4-18)	6 (3-8)	4 (3-6)	4 (2-5)
Citrulline	26 (14-32)	28 (17-35)	30 (23-37)	30 (23-39)
Cystine	38 (21-53)	41 (27-52)	44 (33-54)	48 (36-61)
Glutamic acid	56 (31-113)	52 (25-81)	39 (13-65)	25 (11-46)
Glutamine	583 (474-737)	580 (473-692)	604 (493-724)	680 (551-797)
Glycine	207 (138-276)	207 (138-276)	213 (144-282)	252 (183-322)
Histidine	76 (61-91)	76 (61-91)	78 (63-93)	92 (77-107)
Isoleucine	53 (39-76)	55 (4-78)	54 (40-69)	60 (47-74)
Leucine	115 (77-153)	111 (79-147)	110 (86-136)	128 (101-159)
Lysine	129 (87-171)	130 (88-172)	139 (96-181)	200 (157-242)
Methionine	55 (25-103)	19 (13-22)	20 (14-25)	26 (20-34)
Ornithine	53 (38-78)	35 (24-60)	37 (25-50)	47 (37-62)
Phenylalanine	52 (38-78)	49 (39-65)	49 (40-61)	57 (47-74)
Proline	93 (151-265)	128 (93-220)	127 (93-201)	184 (113-271)
Serine	126 (98-160)	121 (97-154)	118 (96-155)	130 (101-177)
Taurine	59 (39-111)	55 (39-80)	53 (41-69)	53 (41-66)
Threonine	102 (61-162)	91 (61-115)	94 (65-125)	131 (104-188)
Tryptophan	54 (34-73)	54 (35-73)	56 (37-76)	74 (54-87)
Tyrosine	60 (43-108)	55 (40-77)	55 (39-65)	65 (46-87)
Valine	196 (135-260)	199 (147-255)	199 (165-234)	233 (178-275)

Table 3 Insulin, glucose/insulin, and homeostasis model assessment of insulin resistance levels during childhood

Group	Insulin	Glucose/insulin	HOMA-IR
Prepubertal
≤ 7.5 yr	2.9 (1.6-10.9)	29 (12-50)	0.6 (0.3-1.4)
> 7.5 yr	5 (1.7-9.6)	20 (10-47)	1.1 (0.3-2.0)
Pubertal
Girls	6.7 (1.8-16.9)	12 (7.9-44)	1.6 (0.3-2.6)
Boys	7.3 (2.2-12.9)	16 (8.0-44)	1.1 (0.3-2.4)

G/Ins: Glycemia/insulin ratio; HOMA-IR: Homeostasis model assessment of insulin resistance; Insulin level: μIU/mL: G/Ins ratio: G (mg/dL) and Ins (μIU/mL); HOMA-IR: Ins (μIU/mL) × G (mmol/L)/22.5.