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. 2024 Aug 22;22(8):377.
doi: 10.3390/md22080377.

Mechanism of Takifugu bimaculatus Skin Peptides in Alleviating Hyperglycemia in Rats with Type 2 Diabetic Mellitus Based on Microbiome and Metabolome Analyses

Min Xu  1   2 , Bei Chen  2 , Kun Qiao  2 , Shuji Liu  2 , Yongchang Su  2 , Shuilin Cai  2 , Zhiyu Liu  2 , Lijun Li  1 , Qingbiao Li  1
Affiliations

Mechanism of Takifugu bimaculatus Skin Peptides in Alleviating Hyperglycemia in Rats with Type 2 Diabetic Mellitus Based on Microbiome and Metabolome Analyses

Min Xu et al. Mar Drugs. .

Abstract

In this study, we aimed to explore the hypoglycemic effects of a hydrolysate on Takifugu bimaculatus skin (TBSH). The effect of the dipeptidyl peptidase-IV (DPP-IV) inhibitory activities from different TBSH fractions was investigated on basic indexes, gut hormones, blood lipid indexes, viscera, and the gut microbiota and its metabolites in rats with type 2 diabetes mellitus (T2DM). The results showed that the <1 kDa peptide fraction from TBSH (TBP) exhibited a more potent DPP-IV inhibitory effect (IC50 = 0.45 ± 0.01 mg/mL). T2DM rats were induced with streptozocin, followed by the administration of TBP. The 200 mg/kg TBP mitigated weight loss, lowered fasting blood glucose levels, and increased insulin secretion by 20.47%, 25.23%, and 34.55%, respectively, rectified irregular hormonal fluctuations, lipid metabolism, and tissue injuries, and effectively remedied gut microbiota imbalance. In conclusion, TBP exerts a hypoglycemic effect in rats with T2DM. This study offers the potential to develop nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus. It will provide information for developing nutritional supplements to treat T2DM and further promote the high-value utilization of processing byproducts from T. bimaculatus.

Keywords: dipeptidyl peptidase-IV; gut microbiota; hypoglycemia; non-targeted metabolome; peptides of Takifugu bimaculatus skin; type 2 diabetes mellitus.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Effects of <1 kDa peptide fraction from Takifugu bimaculatus fish skin hydrolysate (TBP) on body weight and basic indices in rats with T2DM. (A) Experimental protocol; (B) body weight; (C) fasting blood glucose, (D) oral glucose tolerance test, and (E) area under curve, AUC; (F) Fasting blood insulin; (G) glucagon; (H) homeostasis model assessment of insulin resistance, HOMA-IR; (I) glycogen. Results are expressed as the mean ± standard error of the mean (SEM) (n = 6). Different letters represent significant differences (p < 0.05) between groups using one-way analysis of variance (ANOVA) and Duncan’s multiple-range test. The same letters indicate p > 0.05.
Figure 2
Figure 2
Effect of TBP on blood-glucose-related hormones and blood lipid metabolism in rats with T2DM. (A) glucagon-like peptide-1, GLP-1; (B) peptide tyrosine tyrosine, PYY; (C) cholecystokinin, CCK; (D) total cholesterol, TC; (E) triglyceride, TG; (F) low-density lipoprotein cholesterol, LDL-C; (G) high-density lipoprotein cholesterol, HDL-C. Results are expressed as the mean ± standard error of the mean (SEM) (n = 6). Different letters represent significant differences (p < 0.05) between groups using one-way analysis of variance (ANOVA) and Duncan’s multiple-range test. The same letters indicate p > 0.05.
Figure 3
Figure 3
TBP improves the histopathological characteristics of rats with T2DM. (A) Hematoxylin and eosin (H&E) stained images of the pancreas taken with a Leica microscope (200×, scale bar, 100 μm); the black arrows indicate inflammatory cells and red arrows show necrotic islet β cells. (a) NC group, (b) M group, (c) SP group, (d) TBPL group, (e) TBPH group, and (f) the injury scores for the pancreas. (B) Hematoxylin and eosin (H&E) stained images of the liver taken with a Leica microscope (200×, scale bar, 100 μm); the black arrows indicate lipid droplets and yellow arrows show inflammatory liver cells. (a) NC group, (b) M group, (c) SP group, (d) TBPL group, (e) TBPH group, and (f) the injury scores of liver. Results are expressed as the mean ± standard error of the mean (SEM) (n = 6). Different letters represent significant differences (p < 0.05) between groups using one-way analysis of variance (ANOVA) and Duncan’s multiple-range test. The same letters indicate p > 0.05.
Figure 4
Figure 4
Effect of TBPH on the composition of the gut microbiota. (A) Chao1 and Shannon indices and (B) principal coordinate analysis (PCoA). The statistically significant correlation between two variables was tested using the Kruskal-Wallis one-way ANOVA test, * p < 0.05.
Figure 5
Figure 5
Effect of TBH on the gut sample composition. (A) Relative abundance at the phylum level and (B) genus level; (C) LDA, linear discriminant analysis, LDA score > 4; (D) Heatmap of bacterial distribution at the genus level; (E–M) the relative abundance of key bacteria at the phylum and genus level. Results are expressed as the mean ± standard error of the mean (SEM) (n = 6). Different letters represent significant differences (p < 0.05) between groups using one-way analysis of variance (ANOVA) and Duncan’s multiple-range test. The same letters indicate p > 0.05.
Figure 6
Figure 6
Effect of TBH on untargeted metabolomics in gut samples. (A) Score plots of OPLS-DA in the positive modes and (B) negative modes; (C) volcano plot; (D) metabolic pathway enrichment analysis.
Figure 7
Figure 7
Spearman’s correlation heatmap between the gut microbiota, metabolites, and the biochemical parameters. The statistically significant correlation between two variables was tested using the Pearson correlation coefficient, p < 0.05.
See this image and copyright information in PMC

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