Human umbilical cord mesenchymal stem cells repair islet structure and function in diabetic rats through metabolic reprogramming

Table 1 Detailed information of 30 key differential metabolites

Metabolite ID	Metabolite name	DM vs control		DM + hUC-MSCs vs DM
		Log2FC	Type	Log2FC	Type
MEDP1339	LPC(18:1/0:0)	-0.327	Down	-0.240	Down
MW0015937	Asclepin	-0.748	Down	-0.621	Down
MW0141637	17-phenyl trinor Prostaglandin F2 cyclopropyl amide	-1.688	Down	-0.950	Down
MW0055257	N-Cyclopropyl-trans-2-cis-6-nonadienamide	-1.118	Down	1.541	Up
MW0006200	MS-PPOH	-0.870	Down	-0.697	Down
MEDTN02450	N-(Cyclopropylmethyl)-7-[3,5-dihydroxy-2-(3-hydroxy-5-phenylpent-1-EN-1-YL)cyclopentyl]hept-5-enamide	-0.916	Down	-2.084	Down
MW0152407	Leu-Leu-Trp	-1.244	Down	1.942	Up
MW0144473	Ala-Arg-His	-0.681	Down	1.264	Up
MW0123754	Doramapimod	-2.032	Down	2.050	Up
MW0054549	LysoPC(22:2(13Z,16Z))	-0.553	Down	0.715	Up
MW0053755	2-[[4-(3,12-dihydroxy-10,13-dimethyl 2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-oxopentyl]amino]acetic acid	-1.625	Down	1.519	Up
MW0014969	6-{[1-(2-{[2-(3,4-dimethoxyphenyl)ethyl]-C-hydroxycarbonimidoyl}eth-1-en-1-yl)-3-methoxy-4-oxocyclohexa-2,5-dien-1-yl]oxy}-3,4,5-trihydroxyoxane-2-carboxylic acid	-0.962	Down	-0.553	Down
MW0128176	(4-{2-[(1R,16Z,24E,26E,28Z)-1,18-dihydroxy-23-(hydroxymethyl)-19,30-dimethoxy-15,17,21,29,35-pentamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0,]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl}-2-methoxycyclohexyl)oxidanesulfonic acid	-4.293	Down	-0.637	Down
MEDN0785	LTB4	-1.503	Down	-0.862	Down
MW0113931	Amygdalin	-1.227	Down	1.407	Up
MW0106148	Chorismic acid	-3.216	Down	2.256	Up
MW0055456	O-Decanoyl-L-carnitine	-1.405	Down	-0.717	Down
MW0012191	12,13-DiHOME	-1.340	Down	-0.627	Down
MW0154243	N-acetyl-N6,N6,O-tridemethylpuromycin-5’-phosphate	-0.731	Down	-0.548	Down
MW0148399	Diacetyl-10-gingerdiol	-1.228	Down	-1.269	Down
MW0157815	Thr-Thr-Gly-Leu-Ile	-0.496	Down	-0.726	Down
MW0149707	Gln-His-Ser-Ser-Leu	0.989	Up	-1.118	Down
MW0123548	Deoxykhivorin	1.904	Up	-0.992	Down
MEDP1343	LPC(0:0/18:3)	0.483	Up	-1.125	Down
MW0152097	L-a-lysophosphatidylserine	0.919	Up	-1.303	Down
MW0151632	Ile-Tyr-Phe-Glu	0.800	Up	-1.079	Down
MW0155794	Pro-Asn-Gln-Met-Ser	0.931	Up	-0.736	Down
MW0114597	HMBOA-Glc	0.684	Up	0.467	Up
ZINC1629864	Gyrophoric acid	0.562	Up	-0.764	Down
FDATN00900	D-Arabinose	1.707	Up	0.582	Up

Control group, n = 8; diabetes mellitus (DM) group, n = 6; DM + human umbilical cord mesenchymal stem cells group, n = 5. FC: Fold change; DM: Diabetes mellitus; hUC-MSCs: Human umbilical cord mesenchymal stem cells.

Table 2 Results of Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis for key differential metabolites

Pathway	Classification level 1	Classification level 2	P value	Enrichment score
PPAR signaling pathway	Organismal systems	Endocrine system	0.0037	268.6667
Choline metabolism in cancer	Human diseases	Cancer: Overview	0.0136	73.2727
Efferocytosis	Cellular processes	Transport and catabolism	0.0258	38.3810
Linoleic acid metabolism	Metabolism	Lipid metabolism	0.0343	28.7857
Phenylalanine, tyrosine and tryptophan biosynthesis	Metabolism	Amino acid metabolism	0.0427	23.0286
Neuroactive ligand-receptor interaction	Environmental information processing	Signaling molecules and interaction	0.0499	19.6585
Glycerophospholipid metabolism	Metabolism	Lipid metabolism	0.0677	14.3929
Folate biosynthesis	Metabolism	Metabolism of cofactors and vitamins	0.0701	13.8966
Ubiquinone and other terpenoid-quinone biosynthesis	Metabolism	Metabolism of cofactors and vitamins	0.0853	11.3521
Arachidonic acid metabolism	Metabolism	Lipid metabolism	0.0945	10.2025

Classification level 1 refers to the first-level classification, and classification level 2 refers to the second-level classification; P value < 0.05 indicates that the enriched pathways are statistically significant. PPAR: Peroxisome proliferator-activated receptor.

Table 3 Results of correlation analysis between key differential metabolites and biochemical indicators in the diabetes mellitus group vs control group

Biochemical index	Differential metabolite ID	Correlation coefficient	P value
C-peptide	MW0015937	0.788548168	< 0.001
C-peptide	MW0128176	0.876654109	< 0.001
C-peptide	MW0053755	0.689428985	< 0.01
C-peptide	MW0106148	0.766521683	< 0.01
C-peptide	MW0141637	0.766521683	< 0.01
C-peptide	MEDTN02450	0.674010446	< 0.01
C-peptide	MW0123548	-0.621146881	< 0.05
C-peptide	MW0014969	0.570485965	< 0.05
C-peptide	MW0006200	0.546256832	< 0.05
C-peptide	MW0123754	0.557270074	< 0.05
C-peptide	MW0054549	0.605728342	< 0.05
C-peptide	MW0148399	0.546256832	< 0.05
C-peptide	MW0113931	0.610133639	< 0.05
C-peptide	FDATN00900	-0.640970718	< 0.05
C-peptide	ZINC1629864	-0.557270074	< 0.05
C-peptide	MW0055257	0.539648886	< 0.05
FINS	MW0106148	0.815384615	< 0.001
FINS	MW0006200	0.824175824	< 0.001
FINS	MW0054549	0.920879121	< 0.001
FINS	MW0053755	0.736263736	< 0.01
FINS	MW0123548	-0.736263736	< 0.01
FINS	MW0015937	0.679120879	< 0.01
FINS	MW0014969	0.78021978	< 0.01
FINS	MW0055456	0.696703297	< 0.01
FINS	MW0141637	0.753846154	< 0.01
FINS	MEDP1339	0.608791209	< 0.05
FINS	MW0157815	0.661538462	< 0.05
FINS	MW0154243	0.635164835	< 0.05
FINS	MW0012191	0.657142857	< 0.05
FINS	MEDN0785	0.643956044	< 0.05
FINS	MW0123754	0.657142857	< 0.05
FINS	MW0128176	0.652747253	< 0.05
FINS	FDATN00900	-0.595604396	< 0.05
FINS	ZINC1629864	-0.538461538	< 0.05
FBG	MW0053755	-0.879828407	< 0.001
FBG	FDATN00900	0.793830142	< 0.001
FBG	MW0106148	-0.749728467	< 0.01
FBG	MW0014969	-0.670345453	< 0.01
FBG	MW0006200	-0.685781039	< 0.01
FBG	MW0123754	-0.705626793	< 0.01
FBG	MW0141637	-0.756343718	< 0.01
FBG	MW0054549	-0.725472546	< 0.01
FBG	MW0148399	-0.72767763	< 0.01
FBG	MW0128176	-0.776189472	< 0.01
FBG	MW0113931	-0.679165788	< 0.01
FBG	MW0157815	-0.641679365	< 0.05
FBG	MW0123548	0.606398025	< 0.05
FBG	MW0154243	-0.557886183	< 0.05
FBG	MW0012191	-0.551270932	< 0.05
FBG	MW0015937	-0.624038695	< 0.05
FBG	MEDN0785	-0.546860764	< 0.05
FBG	MW0055456	-0.544655681	< 0.05
FBG	MEDTN02450	-0.599782774	< 0.05
FBG	MW0152407	-0.538040429	< 0.05
FBG	ZINC1629864	0.56229635	< 0.05
FBG	MW0055257	-0.617423444	< 0.05
HOMA-IR	MW0053755	-0.872248812	< 0.001
HOMA-IR	MW0106148	-0.775332277	< 0.01
HOMA-IR	MW0014969	-0.676213094	< 0.01
HOMA-IR	MW0123754	-0.735684604	< 0.01
HOMA-IR	MW0141637	-0.696036931	< 0.01
HOMA-IR	MW0148399	-0.707050173	< 0.01
HOMA-IR	MW0128176	-0.777534926	< 0.01
HOMA-IR	FDATN00900	0.773129629	< 0.01
HOMA-IR	MW0123548	0.535243589	< 0.05
HOMA-IR	MW0154243	-0.660794555	< 0.05
HOMA-IR	MW0114597	0.570485965	< 0.05
HOMA-IR	MW0015937	-0.618944233	< 0.05
HOMA-IR	MW0144473	-0.610133639	< 0.05
HOMA-IR	MW0006200	-0.550662129	< 0.05
HOMA-IR	MW0054549	-0.570485965	< 0.05
HOMA-IR	MW0113931	-0.632160124	< 0.05
HOMA-IR	MW0152407	-0.568283317	< 0.05
HOMA-IR	MW0055257	-0.625552178	< 0.05
GHb	MW0141637	-0.815384615	< 0.001
GHb	MW0054549	-0.806593407	< 0.001
GHb	MW0053755	-0.683516484	< 0.01
GHb	MW0123548	0.793406593	< 0.01
GHb	MW0106148	-0.793406593	< 0.01
GHb	MW0015937	-0.679120879	< 0.01
GHb	MW0014969	-0.775824176	< 0.01
GHb	MW0006200	-0.797802198	< 0.01
GHb	MW0123754	-0.740659341	< 0.01
GHb	MW0128176	-0.758241758	< 0.01
GHb	FDATN00900	0.714285714	< 0.01
GHb	MEDP1339	-0.551648352	< 0.05
GHb	MW0157815	-0.538461538	< 0.05
GHb	MW0154243	-0.665934066	< 0.05
GHb	MW0114597	0.657142857	< 0.05
GHb	MW0012191	-0.604395604	< 0.05
GHb	MEDN0785	-0.648351648	< 0.05
GHb	MW0144473	-0.591208791	< 0.05
GHb	MW0055456	-0.661538462	< 0.05
GHb	MEDTN02450	-0.621978022	< 0.05
GHb	MW0113931	-0.648351648	< 0.05
GHb	MW0055257	-0.657142857	< 0.05
GSP	MW0053755	-0.705494505	< 0.01
GSP	MW0123548	0.714285714	< 0.01
GSP	MW0012191	-0.687912088	< 0.01
GSP	MW0106148	-0.692307692	< 0.01
GSP	MW0015937	-0.789010989	< 0.01
GSP	MW0014969	-0.701098901	< 0.01
GSP	MEDN0785	-0.714285714	< 0.01
GSP	MW0006200	-0.723076923	< 0.01
GSP	MW0055456	-0.723076923	< 0.01
GSP	MW0141637	-0.731868132	< 0.01
GSP	MW0054549	-0.753846154	< 0.01
GSP	MEDTN02450	-0.692307692	< 0.01
GSP	MW0128176	-0.723076923	< 0.01
GSP	MW0152407	-0.701098901	< 0.01
GSP	MEDP1339	-0.556043956	< 0.05
GSP	MW0154243	-0.595604396	< 0.05
GSP	MW0114597	0.556043956	< 0.05
GSP	MW0144473	-0.547252747	< 0.05
GSP	MW0123754	-0.542857143	< 0.05
GSP	FDATN00900	0.591208791	< 0.05
GSP	ZINC1629864	0.569230769	< 0.05

FINS: Fasting insulin; FBG: Fasting blood glucose; HOMA-IR: Homeostasis model assessment of insulin resistance; GHb: Glycosylated hemoglobin; GSP: Glycosylated serum protein.

Table 4 Results of correlation analysis between key differential metabolites and biochemical indicators in the diabetes mellitus + human umbilical cord mesenchymal stem cells group vs diabetes mellitus group

Biochemical index	Differential metabolite ID	Correlation coefficient	P value
C-peptide	MW0152097	-0.874717531	< 0.001
C-peptide	MW0006200	-0.943054838	< 0.001
C-peptide	MW0148399	-0.86560589	< 0.001
C-peptide	MW0149707	-0.797268583	< 0.01
C-peptide	MW0114597	0.76993366	< 0.01
C-peptide	MW0151632	-0.815491865	< 0.01
C-peptide	MW0154243	-0.829159327	< 0.01
C-peptide	MW0155794	-0.829159327	< 0.01
C-peptide	MW0012191	-0.788156942	< 0.01
C-peptide	MW0144473	0.829159327	< 0.01
C-peptide	MEDP1343	-0.742598738	< 0.01
C-peptide	MW0054549	0.76993366	< 0.01
C-peptide	FDATN00900	0.774489481	< 0.01
C-peptide	MW0113931	0.760822019	< 0.01
C-peptide	MW0152407	0.760822019	< 0.01
C-peptide	MW0055257	0.824603506	< 0.01
C-peptide	MEDP1339	-0.619591585	< 0.05
C-peptide	MW0123548	-0.697040533	< 0.05
C-peptide	MW0015937	-0.66970561	< 0.05
C-peptide	MW0014969	-0.66970561	< 0.05
C-peptide	MEDN0785	-0.678817251	< 0.05
C-peptide	MW0055456	-0.683373071	< 0.05
C-peptide	MEDTN02450	-0.706152174	< 0.05
C-peptide	ZINC1629864	-0.605924123	< 0.05
FINS	MW0152097	-0.872727273	< 0.001
FINS	MW0149707	-0.918181818	< 0.001
FINS	MW0154243	-0.945454545	< 0.001
FINS	MW0113931	0.927272727	< 0.001
FINS	MW0151632	-0.781818182	< 0.01
FINS	MW0155794	-0.827272727	< 0.01
FINS	MW0014969	-0.790909091	< 0.01
FINS	MW0054549	0.8	< 0.01
FINS	MW0148399	-0.8	< 0.01
FINS	MW0055257	0.827272727	< 0.01
FINS	MW0144473	0.618181818	< 0.05
FINS	MW0123754	0.681818182	< 0.05
FINS	MW0006200	-0.7	< 0.05
FINS	MW0152407	0.7	< 0.05
FINS	MEDTN02450	-0.681818182	< 0.05
FINS	MW0128176	-0.672727273	< 0.05
FBG	MW0054549	-0.851938429	< 0.001
FBG	MW0152097	0.742598738	< 0.01
FBG	MW0149707	0.76993366	< 0.01
FBG	MW0151632	0.756266199	< 0.01
FBG	MW0154243	0.756266199	< 0.01
FBG	MW0155794	0.738042917	< 0.01
FBG	MW0123754	-0.820047686	< 0.01
FBG	MW0113931	-0.774489481	< 0.01
FBG	MW0128176	0.738042917	< 0.01
FBG	MW0053755	-0.706152174	< 0.05
FBG	MW0123548	0.728931276	< 0.05
FBG	MW0144473	-0.615035764	< 0.05
FBG	MW0014969	0.683373071	< 0.05
FBG	MW0006200	0.610479944	< 0.05
FBG	MW0152407	-0.615035764	< 0.05
FBG	MW0148399	0.642370687	< 0.05
FBG	MW0055257	-0.733487097	< 0.05
HOMA-IR	MW0123754	-0.890909091	< 0.001
HOMA-IR	MW0144473	-0.836363636	< 0.01
HOMA-IR	MW0006200	0.772727273	< 0.01
HOMA-IR	MW0055456	0.772727273	< 0.01
HOMA-IR	MW0152407	-0.8	< 0.01
HOMA-IR	MW0128176	0.772727273	< 0.01
HOMA-IR	MW0123548	0.727272727	< 0.05
HOMA-IR	MW0157815	0.690909091	< 0.05
HOMA-IR	MW0151632	0.681818182	< 0.05
HOMA-IR	MW0155794	0.618181818	< 0.05
HOMA-IR	MW0012191	0.745454545	< 0.05
HOMA-IR	MEDN0785	0.7	< 0.05
HOMA-IR	MW0054549	-0.618181818	< 0.05
HOMA-IR	FDATN00900	-0.681818182	< 0.05
HOMA-IR	MW0148399	0.727272727	< 0.05
HOMA-IR	MEDTN02450	0.654545455	< 0.05
HOMA-IR	MW0055257	-0.663636364	< 0.05
GHb	MW0054549	-0.872727273	< 0.001
GHb	MW0055257	-0.936363636	< 0.001
GHb	MW0152097	0.854545455	< 0.01
GHb	MW0149707	0.827272727	< 0.01
GHb	MW0151632	0.781818182	< 0.01
GHb	MW0155794	0.790909091	< 0.01
GHb	MW0144473	-0.809090909	< 0.01
GHb	MW0006200	0.8	< 0.01
GHb	MEDP1339	0.645454545	< 0.05
GHb	MW0053755	-0.663636364	< 0.05
GHb	MW0123548	0.690909091	< 0.05
GHb	MW0154243	0.745454545	< 0.05
GHb	MW0012191	0.663636364	< 0.05
GHb	MW0123754	-0.618181818	< 0.05
GHb	MW0113931	-0.7	< 0.05
GHb	MW0152407	-0.645454545	< 0.05
GHb	MW0148399	0.636363636	< 0.05
GHb	MEDTN02450	0.745454545	< 0.05
GHb	ZINC1629864	0.690909091	< 0.05
GSP	MW0154243	0.872727273	< 0.001
GSP	MW0113931	-0.881818182	< 0.001
GSP	MW0148399	0.936363636	< 0.001
GSP	MW0015937	0.818181818	< 0.01
GSP	MW0006200	0.827272727	< 0.01
GSP	MW0054549	-0.772727273	< 0.01
GSP	MW0152407	-0.818181818	< 0.01
GSP	MW0152097	0.754545455	< 0.05
GSP	MW0149707	0.754545455	< 0.05
GSP	MW0123548	0.627272727	< 0.05
GSP	MW0114597	-0.645454545	< 0.05
GSP	MW0151632	0.727272727	< 0.05
GSP	MW0155794	0.754545455	< 0.05
GSP	MW0012191	0.636363636	< 0.05
GSP	MW0144473	-0.7	< 0.05
GSP	MW0106148	-0.618181818	< 0.05
GSP	MW0014969	0.690909091	< 0.05
GSP	MW0123754	-0.690909091	< 0.05
GSP	MEDTN02450	0.654545455	< 0.05
GSP	MW0055257	-0.754545455	< 0.05

FINS: Fasting insulin; FBG: Fasting blood glucose; HOMA-IR: Homeostasis model assessment of insulin resistance; GHb: Glycosylated hemoglobin; GSP: Glycosylated serum protein.