Application of Metabolomics and Traditional Chinese Medicine for Type 2 Diabetes Mellitus Treatment

Figures & data

Table 1 Biomarker Discovery in T2DM

Prediction	Detective Method	Metabolic biomarkers	Ref.
Pre-diabetes	LC-MS	Valine, isoleucine, tryptophan, lysine, arginine, proline	[26]
Pre-diabetes	LC-MS	Hexose, 2-hydroxybutyric/2-hydroxyisobutyric acid, and phenylalanine	[27]
Pre-diabetes	1D 1H NMR, FIA-MS, LC-MS	BCAAs, trimethyl uric acid, trimethylamine N-oxide, lysophosphatidylcholines, β-hydroxybutyrate, phosphatidylcholines, Alanine, acylcarnitine, sphingomyelins, amino acids; Glutamine and SM.C16.1, Lyso.PC.a.C18.0, PC.ae.C34.2, C3. DC. C4.OH,	[28]
Pre-diabetes	GC–MS	Tyrosine, lysine, alanine, valine, proline, phenylalanine, tryptophan, hexadecanoic acid, alpha-ketoglutaric acid, myristic acid, octadecanoic acid, uric acid	[29]
Pre-diabetes and T2DM	LC-MS	Ceramides, saturated sphingomyelins, unsaturated sphingomyelins, hydroxyl-sphingomyelins, and a hexosylceramide	[30]
Pre-diabetes	LC-MS	N2, N2-dimethylguanosine, 7-methylguanine and 3-hydroxytrimethyllysine	[31]
Pre-diabetes	LC-MS	A cluster of saturated sphingomyelins	[32]
Pre-diabetes	1H-NMR	Lipids in HDL subtypes, citrate, glycoprotein acetyls, branched-chain amino acids, VLDL lipids	[33]
Pre-diabetes	LC-MS	Alanine, aspartate, glutamate, isoleucine, leucine, phenylalanine, tyrosine, tryptophan, and valine	[34]
Pre-diabetes	GC-MS and LC-MS	1,5-anhydroglucitol	[35]
Pre-diabetes	HPLC-MRM	TAGs, lyso-phosphatidylinositols, phosphatidylcholines, PUFA-PEps, cholesteryl esters	[36]
Pre-diabetes	CIL-LC-MS	Methionine (Met) sulfoxide, amino acids (Asn, Gln, and His), 2-methyl-3-hydroxy-5-formylpyridine-4-carboxylate, L-2-amino-3-oxobutanoic acid, serotonin, and 4,6-dihydroxyquinoline.	[37]
Pre-diabetes	GC-MS and LC-MS	Lysophosphatidylcholines (muscle), glycodeoxycholic acid (liver)	[38]
Pre-diabetes and diabetes	GC-MS	Maltose, glucose, trehalose, an unknown sugar compound (U15), mannose, fructose, sedoheptulose, and 1,5 anhydroglucitol,	[39]
T2DM	CIL-LC-MS	Amino acids, amino acids metabolites, and dipeptides.	[37]
T2DM	GC-MS and LC-MS	Carnitines (liver), lysophosphatidylcholines (muscle and serum)	[38]
T2DM	LC-MS	Alanine, 3-methyl histidine, glutamic acid, arginine, tryptophan, and ethanolamine sarcosine	[40]
T2DM	1H-NMR and 2D-NMR	61 distinct metabolites	[41]
Pre-diabetes and diabetes	LC-MS	Oxidized glycerophosphatidylcholines	[42]
Obese insulin sensitive (OIS)	LC-MS	Phospholipid metabolites, including choline, glycerophosphoethanolamine, and glycerophosphorylcholine	[43]
T2DM	GC-MS	Tyrosine, alanine, valine, tryptophan, and alpha-ketoglutaric acid	[29]
T2DM	LC-MS	Organophosphate flame retardant (OPFR) diesters	[44]
T2DM	LC-MS	Dimethylguanidino valerate, acisoga, acylcarnitine C10:3, homocitrulline, N2, 1-methyladenosine, N2-dimethylguanosine, hippurate, urobilin, threonine, lysine and tryptophan	[45]
T2DM	LC-MS	Urine 3-hydroxyundecanoyl-carnitine	[46]
Pre-diabetes and T2DM	NMR	Branched-chain, aromatic amino acids, linoleic n-6 fatty acid, triacylglycerol within VLDL particles, and non-esterified cholesterol in large HDL particles	[47]
T2DM	GC-MS	Lysophosphatidylcholine, deoxycholic- and glycodeoxycholic acid, all BCAAs, and their catabolic intermediates	[48]
Pre-diabetes	GC-MS	Lysophosphatidylcholine, ursodeoxycholic- and chenodeoxycholic acid, leucine and its catabolic intermediates (ketoleucine and C5-carnitine)	[48]

Table 2 Treatments for T2DM Evaluated by Metabolomics Approaches

TCM	Sample Sources	Biological Samples	Detection Method	Metabolic Biomarkers	Metabolic Pathways	Ref.
Cicer arietinium L.	T2DM rats	Urine	LC-MS	Acylcarnitines, amino acid-related metabolites, and organic acids	Dicarboxylate and glyoxylate metabolism, vitamin B6 metabolism, tricarboxylic acid cycle, and energy metabolism	[61]
Naoxintong Capsule (NXT)	T2DM rats	Serum	LC-MS	L-carnitine, tyrosine, Tryptophan, Indoleacrylic acid, 11-Dehydrothromboxane B2, 3-Hydroxysebacic acid, etc.	Tyrosine, Phenylalanine, and tryptophan biosynthesis, glycerophospholipid metabolism, arachidonic acid metabolism, tyrosine metabolism, tryptophan metabolism, sphingolipid metabolism, and primary bile acid biosynthesis	[62]
Huanglian Decoction (HLD)	T2DM rats	Urine	LC-MS	Cytosine, L-carnitine, betaine, phenylalanine, glucose, citrate, phenylpyruvate, and hippuric acid	Glyoxylate and dicarboxylate metabolism, phenylalanine metabolism, and tricarboxylic acid (TCA) cycle	[63]
Astragalus Radix (HQ) and Dioscoreae Rhizoma (SY)	T2DM rats	Serum	1H-NMR	Monoamine oxidases B, acetyl-CoA carboxylase 1, carbonic anhydrase 2, and catalase	Aminoacyl-tRNA biosynthesis, Valine, leucine, and isoleucine biosynthesis, Nitrogen metabolism, etc.	[64]
Melastoma dodecandrum Lour. (Melastomataceae)	T2DM rats	Serum	LC-MS	Cholic acid, taurine, nicotinuric acid, hippuric acid, phosphohydroxypyruvic acid, tyrosine, arachidonic acid, PGE2, phenylalanine, glucuronide, carnitine, phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol	Lipid, amino acid, arachidonic acid, taurine, and nicotinic acid metabolism	[65]
Gardenia jasminoides fruits	T2DM rats	Urine	LC-MS	Kynurenic acid, 3-Oxo-4,6-choladienoic acid, Xanthurenic acid, Creatinine, Phenylacetylglycine, etc.	Bile acid biosynthesis, amino acid metabolism, vitamin B metabolism, taurine metabolism, etc.	[66]
Ginseng berry	T2DM rats	Serum	LC-MS	Shikimic acid, 5’ -Methylthioadenosine, 2-Isopropyl-3-oxosuccinate, Liothyronine, Glycocholic Acid, etc.	Bile acid metabolism, arachidonic acid metabolism, glucuronization	[67]
Lycii Cortex (LyC)	(db/db) mouse db/db mice	Serum	LC-MS	Circulating triglycerides, cholesterol, phosphatidylethanolamine, phosphatidylcholines, acylcarnitines	Regulating nuclear transcription factors	[68]
Mulberry (Morus multicaulis) branch bark powder	T2DM mice	Serum	GC-MS	Sugars, fatty, sugar alcohols, amino acids, and organic.	Lipid metabolism, carbohydrate metabolism, energy metabolism, protein metabolism, oxidative stress	[69]
BuZangTongLuo Formula (BZTLF)	T2DM mice	Serum	LC-MS	Geranylfarnesyl diphosphate (GFPP), enterobactin, lasaloid, deferoxamine, vanillic acid, 11-Hydroxyeicosatetraenoate glyceryl ester, cucurbitacin C, and angiotensin IV, koenigicine, 18-Carboxydinor-LTE4 and Ursodeoxycholic acid 3-sulfate	Glutathione metabolism, phosphatidylcholine biosynthesis, and tryptophan metabolism	[70]
The hypoglycemic decoction (HD)	T2DM rats	Urine	LC-MS	L-carnitine, 1-methyladenosine, 1-methylhistamine, 3-indoleacrylic acid, riboflavin, phenylalanine, atrolactic acid, 2-oxoglutarate, citrate, isocitrate, cortisol, and glucose	Glyoxylate metabolism, Tricarboxylic acid cycle, phenylalanine metabolism, and dicarboxylate metabolism	[71]
Huang-Lian-Jie-Du Decoction (HLJDD)	db/db mice	Plasma	LC-MS	D-Galactose, Vigabatrin, D-Glucose, Indoxyl sulfate, LysoPC, Eicosapentaenoic acid, Retinyl acetate, 2-oleoylglycerol, Docosapentaenoic acid	Fatty acid β-oxidation, glycerophospholipid metabolism, glucose metabolism, linoleic acid metabolism, and glutathione metabolism	[72]
Xiaokeyinshui extract combination (XEC)	T2DM mice	Plasma	LC-MS	Carbohydrates, lipids, and amino acids	Fructose and mannose metabolism, galactose metabolism, arachidonic acid metabolism, TCA cycle, glycerolipid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and amino acid metabolism	[73]
Dendrobium officinale stem (DOP)	T2DM rats	Liver	LC-MS	Cholic acid, deoxycholic acid, glycerophospholipids, lysophosphatidylcholine (LPC), and phosphatidylethanolamines	Fatty acid, glycerolipid, glycerophospholipid, ceramide, and bile acids metabolism	[74]
Litchi chinensis Sonn (LSE)	T2DM rats	Serum and urine	LC-MS GC-MS	Carbohydrate, organic acids, amino acids, etc.	Serine, glycine, arginine, threonine, proline, alanine metabolism, etc.	[75]

Table 3 Biomarker Discovery in Diabetic Retinopathy

Prediction	Detective Method	Metabolic Biomarkers	Ref.
Proliferative diabetic retinopathy (PDR)	LC-MS	Pyruvate, lactate, proline, allantoin, creatine	[83]
DR	LC-MS	Total DMA, tryptophan, and kynurenine	[84]
PDR	LC-MS	Inosine, hypoxanthine, urate, allantoate	[85]
DR	GC‐MSM, LC‐MSM, and LC‐MSL	2-piperidone and 12-hydroxyeicosatetraenoic acid (12-HETE)	[86]
PDR	LC-MS	Fumaric acid, uridine, acetic acid, and cytidine	[87]
DR	LC-MS	Arginine, citrulline, glutamic γ-semialdehyde, and dehydroxycarnitine	[88]
PDR	LC-MS	Arginine and Carnitine	[88]
DR	1 H-NMR	Lactate, succinate, 2-hydroxybutyrate, asparagine, dimethylamine, histidine, threonine, and glutamine	[89]
DR	GC-MS	Threonic acid, d-2,3-Dihydroxypropanoic acid, l-Lactic acid, isocitric acid, fructose 6-phosphate, l-threonine, ornithine, l-glutamine, pyroglutamic acid, pyruvic acid, and l-alanine	[90]
DR	GC-MS, LC-MS	Plasma glutamine, glutamic acid, and their ratio	[91]
DR	LC-MS	FAS, LPCs, LPC-Os, LPEs, LPE-ps, Cers, CerG1s, etc	[92]

Table 4 Biomarker Discovery in Diabetic Nephropathy

Prediction	Detective Method	Metabolic Biomarkers	Ref.
DN	GC-MS	Serum: benzoic acid, glycerol 1-octadecanoate, fumaric acid, erythrose, L-glutamic acid/pyroglutamic acid, fructose 6-phophate, L-Arabitol, taurine, and L-glutamine. Urine: D-glucose, gluconic acid, L-histidine, L-valine, sucrose, glycine, L-xylonate-2, L-asparagine/L-aspartic acid, and oxalic acid.	[96]
DN	LC-MS	Tyrosine	[97]
DN	LC-MS	Linolelaidic Acid (C18:2N6T), 6-Aminocaproic Acid, Hexadecanoic Acid (C16:0), Trans-4-Hydroxy-L-Proline, L-Dihydroorotic Acid, Azoxystrobin Acid, Linoleic Acid (C18:2N6C), 6-Methylmercaptopurine, Lysopc 20:4, Piperidine, and Cuminaldehyde	[98]
DN	NMR	Glycoprotein acetyls, branched-chain and aromatic amino acids (AAAs), triglycerides (TGs), lipids in very low-density lipoproteins (VLDL), cholesterol, fatty acids, and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1.	[99]
DN	LC-MS	3-methylcrotonyglycine, 3-hydroxyisobutyrate (3-HIBA), citric and aconitic acid	[100]
DN	LC-MS	Pantothenic acid	[101]

Table 5 Biomarker Discovery in Peripheral Neuropathy

Prediction	Detective Method	Metabolic Biomarkers	Ref.
DPN	LC-MS	Glucosamine	[111]
DPN	LC-MS	1-deoxydihydroceramides	[112]
DPN	LC-MS	Sphingosine	[113]
DPN	HNMR	Alanine, histidine, leucine, pyruvate, tyrosine, and valine	[114]

Figure 1 Application of Multi-Omics and microbiome Integration in TCM Treating T2DM. The human microbiome plays a role in the etiology and pathology of T2DM and its complications. Metabolites originating from microorganisms are potentially important compounds that mediate microbiota-host interactions in health and disease. External factors such as TCM and internal factors such as the host genome can influence microbial diversity. Changes in the microbiome later affect the metabolites that they produce. Metagenomics is suitable for determining intestinal microbiota composition, while metabolomics can find functional endpoints. Genomics obtained candidate genes related to transcriptomics, while transcriptomics obtained functional gene clusters related to disease pathogenesis. Proteomics can analyze expressed proteins and protein function in a cellular context. It will be vital to reveal the role of the microbiome in T2DM and the mechanism of traditional Chinese medicine in T2DM treatment by integrating metagenomic data and data generated by host omics in the future.

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