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Background Obesity and autoimmune disorders represent a significant comorbidity burden, yet their shared genetic architecture is not fully understood. Elucidating the pleiotropic genetic basis underlying both conditions is crucial for unraveling the mechanisms driving their co-occurrence and advancing therapeutic strategies. Methods We conducted a large-scale cross-trait analysis integrating genome-wide association study (GWAS) summary data for obesity and 17 autoimmune diseases. Genetic correlations were assessed using LD score regression and high-definition likelihood. Cross-trait pleiotropic analysis was performed using Stratified Pleiotropic Locus Mapping (PLACO) to identify shared loci, followed by Bayesian colocalization to confirm shared causal variants. Gene-level and tissue-specific heritability analyses were conducted, and drug targets were prioritized via summary-based Mendelian randomization (SMR). Finally, immune co-localization and bidirectional Mendelian randomization were employed to elucidate immunological mechanisms and causal relationships. Results Our analysis identified eight autoimmune diseases with significant genetic correlations to obesity. We discovered 10,324 pleiotropic SNPs, which mapped to 52 independent risk loci, with nine loci confirmed as shared causal variants by colocalization. Gene-level analysis revealed 133 unique pleiotropic genes, including CLN3, SH2B1, and MMEL1, enriched in pathways of hematopoietic cell differentiation and immune homeostasis. Tissue-specific heritability was most prominent in the spleen, whole blood, and EBV-transformed lymphocytes. Immuno-co-localization implicated six IgD+ CD38- %B cell-related traits as key pathological conduits. Bidirectional Mendelian randomization established a causal role of obesity in hypothyroidism, psoriasis, and multiple sclerosis, while revealing an inverse causal association of type 1 diabetes with obesity risk. Conclusions This study demonstrates a robust shared genetic foundation between obesity and multiple autoimmune diseases, pinpointing specific pleiotropic loci, genes, and immune cell subsets. Our findings provide a mechanistic framework for their comorbidity and highlight potential targets for therapeutic intervention.

A traditional Chinese herbal decoction, Huoxue-Jiangtang decoction (HXJT), has been clinically prescribed to patients with type 2 diabetes mellitus (T2DM) to improve hyperglycemia and hyperlipidemia for many years. However, the potential mechanisms underlying its anti-diabetic effects remain unclear. The aim of this study was to explore the anti-diabetic effects and underlying molecular mechanisms of HXJT in T2DM rats, which were fed with a high-fat diet (HFD) and subsequently induced with streptozotocin (STZ). HPLC-MS analysis was performed to characterize the chemical composition of HXJT and serve as a quality control measure. The T2DM rats were treated with metformin or HXJT for 8 weeks. Treatment with HXJT significantly reduced hyperglycemia and improved insulin resistance in T2DM rats, as revealed by multiple assessments, including fasting blood glucose (FBG), glucose tolerance, fasting insulin levels, homeostasis model assessment of insulin resistance, insulin sensitivity index analysis, and histological examination of pancreas islets. HXJT treatment decreased blood lipid profile, including total cholesterol, low-density lipoprotein cholesterol, and triglycerides, although it did not change the rats' body weight. The Western blot results indicated that HXJT reversed the downregulation of AKT and PI3K and markedly increased glucose transporter type 4 (GLUT4) in skeletal muscles. Moreover, the levels of glycogen synthetase (GS), hexokinase, superoxide dismutase (SOD), glycogen, and muscle glycogen in the HXJT group significantly increased relative to those in untreated T2DM group, while TNF-α levels decreased observably. In conclusion, HXJT improves insulin resistance, enhances insulin sensitivity, and helps preserve glucose homeostasis. The potential molecular mechanisms are related to the activation of PI3K/AKT and GLUT4 in skeletal muscles, either directly or indirectly.

Background Heqi San has shown therapeutic potential in the treatment of diabetes. This study aimed to explore the mechanism underlying the effects of Heqi San in treating rats with diabetic atherosclerosis (AS). Methods We established a model of atherosclerosis in diabetic rats and treated them with Heqi San. Body weight, food intake, and water intake were measured every two weeks. Subsequently, we examined the effects of Heqi San on serum biochemical markers, aortic structure, fat accumulation, and serum levels of inflammatory factors. The levels of p-AMPK and AMPK in thoracic aorta tissue were evaluated by western blotting. Mass spectrometry was used to identify differential serum metabolites after Heqi San treatment. Results Intragastric administration of Heqi San enhanced food intake and reduced the excessive water intake caused by diabetic atherosclerosis. Both low and high doses of Heqi San decreased elevated levels of TG, TC, LDL, GLU, and insulin, while increasing HDL levels. Additionally, the AS group showed increased expression of CD68 and CCL-2 in thoracic aorta tissue, along with elevated serum levels of IL-6, IL-1β, and TNF-α. Treatment with Heqi San reduced these inflammatory markers. Heqi San also increased p-AMPK expression in thoracic aorta tissue. Mass spectrometry analysis revealed that the AS group had significantly elevated serum levels of L-NIL, Gln_Cys_Asp, and Geshoidin, whereas high-dose Heqi San treatment decreased the levels of these metabolites. Conclusions Heqi San could alleviate atherosclerosis in diabetic rats, and this effect may be associated with changes in serum metabolites such as L-NIL, Gln_Cys_Asp, and Geshoidin.

Background Heqi San, a traditional Chinese medicine (TCM) has been reported to regulate hormone levels in patients with metabolic disease, suggesting a potential clinical application. In the current study, we aimed to elucidate the effect of Heqi San on rat model of polycystic ovary syndrome (PCOS). Method PCOS model was established in female SD rats. Rats were randomly divided into four groups: the control, untreated PCOS model, Heqi San treated PCOS model (8.1 g/kg) and metformin (MET) treated PCOS model (135 mg/kg) groups. All animals were subcutaneously injected with 6 mg/100 g dehydroepiandrosterone (DHEA) in the neck once a day for 20 consecutive days. The serum hormone levels were measured by ELISA. The ovarian tissues were stained with hematoxylin and eosin (HE) to undergo pathological examination. The expression levels of GLTU4 and PTEN mRNA were examined by real time PCR. The crucial proteins in the PI3K/APT pathway were analyzed by western blotting. Then, the functions of the target genes were analyzed using bioinformatics approaches. Results We found that Heqi San was able to recover the serum hormone levels and improve insulin resistance in PCOS rat model. A morphological lesion of the ovary was also restored with the Heqi San treatment. More importantly, we discovered a correlation between the PI3K/AKT signaling pathway and the beneficial effects of Heqi San, demonstrating that its application could alter the expression levels of p-ERK, p-AKT, p-GSK3β, IRS-1, PTEN and GLTU4, all key factors in the PI3K/APT pathway. Through a bioinformatical analysis, we predicted the related gene function and pathway of the pathological mechanism of PCOS and found miRNAs that are likely to be critical in PCOS occurrence, including rno-miR-144-3p, rno-miR-30c-2-3p, rno-miR-486, rno-miR-3586-3p and rno-miR-146b-5p. Conclusion The beneficial effects of Heqi on PCOS, including alter serum hormone levels, recover ovary morphological lesions and improve insulin resistance, which is mediated through the PI3K/AKT pathway. Graphical abstract The potential role of miRNA-144-3p in PCOS pathogenesis.

The purpose of this study is to investigate miRNAs' effects, targeting the Wnt signaling pathway, on osteogenic differentiation to provide new targets for diabetic osteoporosis treatments. Twelve male rats were divided into a normal rat group (NOR group) and a model rat group (MOD group). Cluster analysis of differentially expressed miRNAs and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. Primary rat bone marrow mesenchymal stem cells (BMSCs) were divided into a high-glucose group and a low-glucose group, and osteogenic differentiation was induced. Alkaline phosphatase (ALP) staining and Alizarin Red staining were used for pathological analysis of the cells. Western blot analysis was used to measure GSK-3 β, β-catenin, p-β-catenin, c-Myc, and CyclinD1 expression. Immunofluorescence (IF) was used to analyze the effect of GSK-3 β inhibitor (CHIR99021) on β-catenin and CyclinD1 expressions levels in BMSCs. A total of 428 differentially expressed miRNAs were found between the NOR and MOD groups. KEGG analysis showed that the target genes were mostly enriched in signaling pathways, including PI3K-Akt, focal adhesion, AGE-RAGE, HIF-1, and Wnt. qPCR verification demonstrated that miR-124-3p exhibited the greatest difference in expression level. In BMSCs, miR-124-3p overexpression could reverse the inhibited expression of BMSC osteogenic markers, including A1p1, Bglap, and Runx2, induced by high glucose. Western blot analysis revealed that the transfection of miR-124-3p mimics could further reverse the upregulated p-β-catenin and GSK-3 β levels and the downregulated c-Myc and CyclinD1 levels induced by high glucose. IF results revealed that BMSCs treated CHIR99021 under high glucose showed the reduced GSK-3 β and increased β-catenin and CyclinD1 expression levels. Our research highlighted miRNAs' important roles in regulating the Wnt pathway and provided new information for the diagnosis and treatment of diabetic osteoporosis.

Type 2 diabetes mellitus (T2DM), a complex metabolic disease, has become a major public health issue around the world. Hydroxysafflor yellow A (HSYA) is the major active chemical ingredient of . (safflower), which is widely used in patients with cardiovascular and cerebrovascular diseases in China. The aim of this study was to investigate the anti-diabetic effect and potential mechanism of HSYA on the high-fat diet (HFD) and streptozotocin (STZ-)-induced T2DM rats. T2DM rats were induced by feeding HFD (60% fat) for four weeks followed by intraperitoneal injection of a low dose of streptozocin (35mg/kg). The T2DM rats were treated with HSYA (120mg/kg) or metformin (90mg/kg) for eight weeks. Biochemical analysis, histological analysis and Western blot analysis were conducted after 8 weeks of intervention. The treatment with HSYA evidently reduced fasting-blood glucose and insulin resistance in T2DM rats, indicated by results from fasting-blood glucose, oral glucose tolerance test, fasting insulin levels and histology of pancreas islets. The Western blot results revealed that HSYA reversed the down-regulation of PI3K and AKT in liver. The TUNEL assay analysis of pancreatic tissue showed that HSYA could inhibit the apoptosis of pancreatic β-cells to a certain extent. Moreover, HSYA-treatment increased the levels of glycogen synthase and hepatic glycogen and improved lipid metabolism by reducing the triglyceride, total and low-density lipoprotein cholesterol levels, even though it did not change the rats' body weights. The results of this study suggested that HSYA could promote PI3K/Akt activation and inhibit the apoptosis of pancreatic β-cells directly or indirectly, which might be the underlying mechanisms in HSYA to improve insulin resistance and regulate glycolipid metabolism in T2DM rats.

Background: Baihu Jia Renshen Decoction (BJRD) applied to diabetes mellitus (DM). We explored the metabolic regulatory pathways and mechanisms of BJRD in Type 1 DM (T1DM). Methods: T1DM rat model was established with STZ induction and then continuously treated with insulin and different concentrations of BJRD for 2 weeks. The therapeutic effect of BJRD was evaluated by detecting the levels of fasting blood glucose and insulin in the blood and observing the ultrastructure of pancreatic tissues by transmission electron microscopy and immunofluorescent staining. Metabolomics analysis on rat serum was performed. Results: Compared with the diabetes model (DC) group, the high‐concentration BJRD treatment (BJRD‐H) group reduced fasting blood glucose, increased insulin levels, and increased the quantity of β‐cells in the pancreatic tissues in rats. And rat pancreatic islet β‐cells in the DC group had lost their nuclear membranes, had abnormal mitochondrial morphology, and had significantly reduced secretory granules, whereas rat pancreatic islet β‐cells in the BJRD‐H group had moderately increased secretory granules, and the structure of the nucleus was apparently normal. Moreover, the metabolic profile expression pattern of rats in the BJRD‐H group was closer to that of normal rats, suggesting that a high concentration of BJRD combined with insulin treatment was more effective. And differentially expressed metabolites were predominantly enriched in amino acid metabolism, including amino acids, glycine, serine, and threonine metabolism. Conclusion: BJRD facilitated the therapeutic effect of insulin in T1DM rats and resulted in a significant improvement in their metabolic profiles, expanding the application of traditional Chinese medicine’s alternative therapies in T1DM.

Background Baihu Jia Renshen Decoction (BJRD) is used for diabetes mellitus (DM) management in clinics. Objective To elucidate the potential mechanism of BJRD in treating type 1 DM (T1DM). Methods T1DM models were established via intraperitoneal injection of streptozotocin (STZ). Rats were subsequently randomly divided into the normal control (NC), model (MOD), insulin (INS), INS + BJRD-medium dose (MID), and INS + BJRD-high dose (HIGH) groups. The rats’ body weight was measured. Transcriptome sequencing was performed to detect differentially expressed genes (DEGs) in the muscle and adipose tissues. Quantitative real-time polymerase chain reaction was utilized to verify the DEG levels. Results Body weights of MOD, INS, MID, and HIGH groups were significantly reduced as compared to those of NC group. Compared with NC group, MOD group showed significant Hspa1b and Notch3 downregulation and Camkk2 level elevation. Compared with MOD group, INS group showed further downregulation of the Hspa1b level, whereas MID group exhibited an increase. The Camkk2 levels in INS, MID, and HIGH groups were further reduced. The Notch3 levels did not significantly change in INS and MID groups, whereas that of HIGH group increased. Additionally, compared with NC group, MOD group demonstrated upregulation of the Myl1, Mylpf, Acacb, and Pygm levels and downregulation of Fasn level. Compared with MOD group, Myl1, Mylpf, and Pygm levels in INS, MID, and HIGH groups were down-regulated, whereas Fasn and Acacb levels were up-regulated. Conclusion BJRD may influence pancreatic β-cell function, thereby enhancing the function of the skeletal muscle and adipose tissues in a T1DM rat model.

Humans are widely exposed to multiple metals, some of which are suspected to be hepatotoxic, and diabetes mellitus (DM) is a risk factor for chronic liver disease. This cross-sectional study aimed to explore the association of multi-metal exposure and liver function in elderly with diabetes mellitus. We enrolled 1663 subjects aged ≥ 60 years and measured the levels of 22 plasma metals and liver function parameters (total bilirubin (TBIL), alanine transaminase (ALT), and aspartate transaminase (AST). Generalized linear regression model (GLM) and Bayesian kernel machine regression (BKMR) were used to investigate the correlations of multi-metal combined exposure with liver function parameters in the elderly. Multivariate GLM results shown that plasma Fe was positively related with TBIL and plasma Ti and Sr were negatively associated with TBIL in DM elderly. Positive associations were found between Ti-AST and Sn-ALT. In BKMR model, multi-metal combined exposure showed a “ U ” sharp association with TBIL in overall elderly and an inverse association in DM elderly. Further analysis of the BKMR model revealed that Fe, Ti, and Sr combination exposure had interaction effect with TBIL in the overall and non-DM groups; however, no interaction effect was found in the DM elderly group. Our results suggested that combined exposure of plasma Fe, Ti, and Sr was inversely associated with TBIL in elderly with DM. Potential mechanisms of the complex metal effects on liver function in DM elderly deserve further investigation.

HuoxueJiangtang decoction (ZY) is a traditional Chinese medicine for the treatment of diabetes. The protective effect of ZY on renal injury in diabetic nephropathy rats was investigated in this study. Fifty 4-week-old SPF Wistar male rats were selected to construct diabetic nephropathy model rats (DN) group by continuous high-fat feeding for 4 weeks, followed by a tail vein injection of 30 mg/kg streptozotocin for 1 week. The experimental rats were divided into six groups of 10 rats: normal (control), DN, DN + ZY, DN + metformin, DN + metformin + ZY, and DN + metformin + captopril (positive control) groups. Among the groups, 6.25 g/kg ZY, 250 mg/kg metformin, and 17.5 mg/kg captopril were given to the rats by gavage once a day for 16 weeks. Blood glucose, dietary behaviour, biochemical indicators, and gene expression changes were measured in each group. Metformin + ZY treatment significantly lowered blood glucose, water intake, urine total protein, urine albumin, urine volume, serum triglyceride, and serum cholesterol levels in the DN group. The pathological changes of kidney tissue showed that the DN + metformin + ZY group had a protective effect on kidney tissue damage. And ZY and metformin + ZY treatments repaired the expression of genes in the DN group. The ZY and metformin combined treatment showed a clear therapeutic effect on kidney damage in DN. This study provides a potential mechanism for the treatment of diabetic nephropathy with ZY combined with metformin.