The anti-diabetic effects of NAG-1/GDF15 on HFD/STZ-induced mice.
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SUBMITTER: Lertpatipanpong P
PROVIDER: S-EPMC8298384 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background & aimsMetformin is currently the most widely used first-line hypoglycemic agent for diabetes mellitus. Besides glucose-lowering action, there is increasingly interest in the potential anti-inflammatory action of this drug. In the present study, we investigated the actions of metformin on experimental insulitis using STZ-induced diabetic mice.MethodsMice with acute diabetes induced by STZ were administered metformin by gavage. Changes of blood glucose and body weight, and the daily amount of food and water intake were measured. Pancreatic tissues were collected for histologic analyses. Pathological assessment and immunohistochemistry analysis were used to determine the effect of metformin on insulitis. Inflammatory cytokines in the pancreas and insulin levels were measured through ELISA analysis.ResultsMetformin significantly reduced blood glucose levels and improved aberrant water intake behavior in experimental diabetic mice. No significant differences were observed in terms of body weight and food intake behavior in metformin-treated animals. In the STZ-induced model of diabetes, we found the appearance of pronounced insulitis. However, metformin administration reduced the severity of insulitis assessed by blind pathological scoring. In addition, metformin treatment improved insulin levels in experimental diabetic mice. ELISA assay revealed decreased levels of inflammatory response marker IL-1β and TNF-α in the pancreatic tissues following metformin treatment.ConclusionMetformin attenuated insulitis in the STZ-induced mice model of diabetes. This islet-protective effect might be partly correlated with the anti-inflammatory action of metformin.
| S-EPMC5399881 | biostudies-literature
Project description:Background Tianhuang formula (THF) is a Chinese medicine prescription that is patented and clinically approved, and has been shown to improve energy metabolism, but the underlying mechanism remains poorly understood. The purpose of this study is to clarify the potential mechanisms of THF in the treatment of type 2 diabetes mellitus (T2DM). Methods A murine model of T2DM was induced by high-fat diet (HFD) feeding combined with low-dose streptozocin (STZ) injections, and the diabetic mice were treated with THF by gavaging for consecutive 10 weeks. Fasting blood glucose (FBG), serum insulin, blood lipid, mitochondrial Ca2+ (mCa2+) levels and mitochondrial membrane potential (MMP), as well as ATP production were analyzed. The target genes and proteins expression of visceral adipose tissue (Vat) was tested by RT-PCR and western blot, respectively. The underlying mechanism of the regulating energy metabolism effect of THF was further explored in the insulin resistance model of 3T3-L1 adipocytes cultured with dexamethasone (DXM). Results THF restored impaired glucose tolerance and insulin resistance in diabetic mice. Serum levels of lipids were significantly decreased, as well as fasting blood glucose and insulin in THF-treated mice. THF regulated mCa2+ uptake, increased MMP and ATP content in VAT. THF increased the mRNA and protein expression of AMPK, phosphorylated AMPK (p-AMPK), MICU1, sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). THF could increase the mCa2+ level of 3T3-L1 adipocytes and regulate mitochondrial function. The protein expression of AMPK, p-AMPK, mCa2+ uniporter (MCU) and MICU1 decreased upon adding AMPK inhibitor compound C to 3T3-L1 adipocytes and the protein expression of MCU and MICU1 decreased upon adding the MCU inhibitor ruthenium red. Conclusions These results demonstrated that THF ameliorated glucose and lipid metabolism disorders in T2DM mice through the improvement of AMPK/MICU1 pathway-dependent mitochondrial function in adipose tissue. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-023-04009-5. Highlights • AMPK-MCU/MICU1 mediated mCa2+ uptake in adipose tissue played an important role in insulin resistance • THF restored impaired glucose tolerance and insulin resistance in diabetic mice induced by HFD/STZ • THF improved the mitochondrial function of in T2DM mice via AMPK-MICU1 pathway Supplementary Information The online version contains supplementary material available at 10.1186/s12906-023-04009-5.
| S-EPMC10278277 | biostudies-literature
Project description:BackgroundHuang Lian (HL), one of the traditional Chinese medicines (TCMs) that contains multiple active components including berberine (BBR), has been used to treat symptoms associated with diabetes for thousands of years. Compared to the monomer of BBR, HL exerts a better glucose-lowering activity and plays different roles in regulating gut microbiota. However, it remains unclear what role the gut microbiota plays in the anti-diabetic activity of HL.MethodsIn this study, a type 2 diabetes mellitus (T2DM) mouse model was induced with a six-week high-fat diet (HFD) and a one-time injection of streptozotocin (STZ, 75 mg/kg). One group of these mice was administrated HL (50 mg/kg) through oral gavage two weeks after HFD feeding commenced and continued for four weeks; the other mice were given distilled water as disease control. Comprehensive analyses of physiological indices related to glycolipid metabolism, gut microbiota, untargeted metabolome, and hepatic genes expression, function prediction by PICRUSt2 were performed to identify potential mechanism.ResultsWe found that HL, in addition to decreasing body fat accumulation, effectively improved insulin resistance by stimulating the hepatic insulin-mediated signaling pathway. In comparison with the control group, HL treatment constructed a distinct gut microbiota and bile acid (BA) profile. The HL-treated microbiota was dominated by bacteria belonging to Bacteroides and the Clostridium innocuum group, which were associated with BA metabolism. Based on the correlation analysis, the altered BAs were closely correlated with the improvement of T2DM-related markers.ConclusionThese results indicated that the anti-diabetic activity of HL was achieved, at least partly, by regulating the structure of the gut microbiota and the composition of BAs.
| S-EPMC9889990 | biostudies-literature
Project description:BackgroundDiabetes mellitus is a systemic disease mainly caused by the disorder of metabolism, which has become huge threat to human health. Polysaccharides are the main active substance from Inonotus obliquus (I. obliquus) with hypoglycemic effect. This study aims to evaluate the hypoglycemic activity and investigate the molecular mechanism of I. obliquus polysaccharide (IOP) in streptozotocin (STZ)-induced diabetic mice using metabolomics based on UPLC-Q-Exactive-MS method.ResultsThe results showed that the oral administration of IOP in high dose (1.2 g/kg) can significantly reduce the blood glucose with 31% reduction comparing with the diabetic model and relieve dyslipidemia in diabetic mice. By UPLC-Q-Exactive-MS method and multivariate statistical analysis, a total of 15 differential metabolites were identified, including 4 up-regulated and 11 down-regulated biomarkers, of which L-tryptophan, L-leucine, uric acid, 12-HETE, arachidonic acid, PC(20:1(11Z)/14:1(9Z)) and SM(d18:0/24:1(15Z)) were exhibited an important variation, as the potential biomarkers in diabetes. Pathway analysis indicated that phenylalanine, tyrosine and tryptophan biosynthesis and arachidonic acid metabolism were prone to interference in diabetes. Moreover, leucine and proline were reversed and phytosphingosine was further reduced in diabetic mice under the intervention of IOP.ConclusionIOP has predominant hyperglycemic effect on STZ-induced diabetic mice via ameliorating serum profiling.
| S-EPMC8684258 | biostudies-literature
Project description:T2DM patients are believed to have long-term chronic inflammation. We used single cell RNA sequencing (scRNA-seq) to analyze the diversity of immune cell in peripheral blood mononuclear cells （PBMC）from HFD/STZ-induced type 2 diabetic mice
2024-08-15 | GSE274561 | GEO
Project description:Prediabetes (PreD), which is associated with impaired glucose tolerance and fasting blood glucose, is a potential risk factor for type 2 diabetes mellitus (T2D). Growing evidence suggests the role of the gastrointestinal microbiota in both PreD and T2D, which opens the possibility for a novel nutritional approach, based on probiotics, for improving glucose regulation and delaying disease progression of PreD to T2D. In this light, the present study aimed to assess the antidiabetic properties of Pediococcus acidilactici (pA1c) in a murine model of high-fat diet (HFD)-induced T2D. For that purpose, C57BL/6 mice were given HFD enriched with either probiotic (1 × 1010 CFU/day) or placebo for 12 weeks. We determined body weight, fasting blood glucose, glucose tolerance, HOMA-IR and HOMA-β index, C-peptide, GLP-1, leptin, and lipid profile. We also measured hepatic gene expression (G6P, PEPCK, GCK, IL-1β, and IL-6) and examined pancreatic and intestinal histology (% of GLP-1+ cells, % of goblet cells and villus length). We found that pA1c supplementation significantly attenuated body weight gain, mitigated glucose dysregulation by reducing fasting blood glucose levels, glucose tolerance test, leptin levels, and insulin resistance, increased C-peptide and GLP-1 levels, enhanced pancreatic function, and improved intestinal histology. These findings indicate that pA1c improved HFD-induced T2D derived insulin resistance and intestinal histology, as well as protected from body weight increase. Together, our study proposes that pA1c may be a promising new dietary management strategy to improve metabolic disorders in PreD and T2D.
| S-EPMC8839473 | biostudies-literature
Project description:The crucial role of macrophages in the healing of chronic diabetic wounds is widely known, but previous in vitro classification and marker genes of macrophages may not be fully applicable to cells in the microenvironment of chronic wounds. The heterogeneity of macrophages was studied and classified at the single-cell level in a chronic wound model. We performed single-cell sequencing of CD45 + immune cells within the wound edge and obtained 17 clusters of cells, including 4 clusters of macrophages. One of these clusters is a previously undescribed population of macrophages possessing osteoclast gene expression, for which analysis of differential genes revealed possible functions. We also analysed the differences in gene expression between groups of macrophages in the control and diabetic wound groups at different sampling times. We described the differentiation profile of mononuclear macrophages, which has provided an important reference for the study of immune-related mechanisms in diabetic chronic wounds.
| S-EPMC10030741 | biostudies-literature
Project description:ScopeIn this study, we aim to determine the effects of resveratrol (RSV) on muscle atrophy in streptozocin-induced diabetic mice and to explore mitochondrial quality control (MQC) as a possible mechanism.Methods and resultsThe experimental mice were fed either a control diet or an identical diet containing 0.04% RSV for 8 weeks. Examinations were subsequently carried out, including the effects of RSV on muscle atrophy and muscle function, as well as on the signaling pathways related to protein degradation and MQC processes. The results show that RSV supplementation improves muscle atrophy and muscle function, attenuates the increase in ubiquitin and muscle RING-finger protein-1 (MuRF-1), and simultaneously attenuates LC3-II and cleaved caspase-3 in the skeletal muscle of diabetic mice. Moreover, RSV treatment of diabetic mice results in an increase in mitochondrial biogenesis and inhibition of the activation of mitophagy in skeletal muscle. RSV also protects skeletal muscle against excess mitochondrial fusion and fission in the diabetic mice.ConclusionThe results suggest that RSV ameliorates diabetes-induced skeletal muscle atrophy by modulating MQC.
| S-EPMC6001753 | biostudies-literature
Project description:Background: Diabetic kidney disease is the leading cause of end-stage renal disease. Administration of ACE inhibitors or/and SGLT2 inhibitors show renoprotective effects in diabetic and other kidney diseases. The underlying renoprotective mechanisms of SGLT2 inhibition, especially in combination with ACE inhibition, are incompletely understood. We used longitudinal intravital microscopy to directly elucidate glomerular hemodynamics on a single nephron level in response to the ACE inhibitor enalapril or/and the SGLT2 inhibitor empagliflozin. Methods: Five weeks after the induction of diabetes by streptozotocin, male C57BL/6 mice were treated with enalapril, empagliflozin, enalapril/empagliflozin or placebo for 3 days. To identify hemodynamic regulation mechanisms, longitudinal intravital multiphoton microscopy was employed to measure single nephron glomerular filtration rate (snGFR) and afferent/efferent arteriole width. Results: Diabetic mice presented a significant hyperfiltration. Compared to placebo treatment, snGFR was reduced in response to enalapril, empagliflozin, or enalapril/empagliflozin administration under diabetic conditions. While enalapril treatment caused significant dilation of the efferent arteriole (12.55 ± 1.46 µm vs. control 11.92 ± 1.04 µm, p < 0.05), empagliflozin led to a decreased afferent arteriole diameter (11.19 ± 2.55 µm vs. control 12.35 ± 1.32 µm, p < 0.05) in diabetic mice. Unexpectedly under diabetic conditions, the combined treatment with enalapril/empagliflozin had no effects on both afferent and efferent arteriole diameter change. Conclusion: SGLT2 inhibition, besides ACE inhibition, is an essential hemodynamic regulator of glomerular filtration during diabetes mellitus. Nevertheless, additional mechanisms-independent from hemodynamic regulation-are involved in the nephroprotective effects especially of the combination therapy and should be further explored in future studies.
| S-EPMC9511053 | biostudies-literature
Project description:Nonsteroidal anti-inflammatory drug-activated gene, NAG-1, a transforming growth factor-? member, is involved in tumor progression and development. The association between NAG-1 expression and development and progression of glioma has not been well defined. Glioblastoma cell lines have lower basal expression of NAG-1 than other gliomas and normal astrocytes. Most primary human gliomas have very low levels of NAG-1 expression. NAG-1 basal expression appeared to inversely correlate with tumor grade in glioma. Aberrant promoter hypermethylation is a common mechanism for silencing of tumor suppressor genes in cancer cells. In glioblastoma cell lines, NAG-1 expression was increased by the demethylating agent, 5-aza-2'-deoxycytidine. To investigate whether the NAG-1 gene was silenced by hypermethylation in glioblastoma, we examined DNA methylation status using genomic bisulfite sequencing. The NAG-1 promoter was densely methylated in several glioblastoma cell lines as well as in primary oligodendroglioma tumor samples, which have low basal expression of NAG-1. DNA methylation at two specific sites (-53 and +55 CpG sites) in the NAG-1 promoter was strongly associated with low NAG-1 expression. The methylation of the NAG-1 promoter at the -53 site blocks Egr-1 binding and thereby suppresses Nag-1 induction. Treatment of cells with low basal NAG-1 expression with NAG-1 inducer also did not increase NAG-1. Incubation with a demethylation chemical increased Nag-1 basal expression and subsequent incubation with a NAG-1 inducer increased NAG-1 expression. We concluded from these data that methylation of specific promoter sequences causes transcriptional silencing of the NAG-1 locus in glioma and may ultimately contribute to tumor progression.
| S-EPMC3133861 | biostudies-other