scholarly journals Berberine Slows the Progression of Prediabetes to Diabetes in Zucker Diabetic Fatty Rats by Enhancing Intestinal Secretion of Glucagon-Like Peptide-2 and Improving the Gut Microbiota

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Wang ◽  
Haiyi Liu ◽  
Miaoyan Zheng ◽  
Yanhui Yang ◽  
Huizhu Ren ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Gut Microbiota ◽  
Intestinal Secretion ◽  
High Energy ◽  
Endocrine Function ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tnf Α ◽  
Zdf Rats ◽  
Glucagon Like Peptide

BackgroundBerberine is a plant alkaloid that has multiple beneficial effects against intestine inflammation. In our previous study, we have found that berberine also possesses an antidiabetic effect. However, whether berberine is useful in the prevention of type 2 diabetes mellitus (T2DM) through its effect on intestine endocrine function and gut microbiota is unclear.AimTo investigate the effects of berberine in the prevention of T2DM, as well as its effects on intestine GLP-2 secretion and gut microbiota in ZDF rats.MethodsTwenty Zucker Diabetic Fatty (ZDF) rats were fed a high-energy diet until they exhibited impaired glucose tolerance (IGT). The rats were then divided into two groups to receive berberine (100 mg/kg/d; berberine group) or vehicle (IGT group) by gavage for 3 weeks. Five Zucker Lean (ZL) rats were used as controls. Fasting blood glucose (FBG) was measured, an oral glucose tolerance test was performed, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was calculated. Intestinal expression of TLR-4, NF-κB, TNF-α, mucin, zona occludens-1 (ZO-1) and occludin were assessed (immunohistochemistry). Plasma levels and glutamine-induced intestinal secretion of glucagon-like peptide-1 (GLP-1) and GLP-2 were measured (enzyme-linked immunosorbent assay). The plasma lipopolysaccharide (LPS) level was measured. Fecal DNA extraction, pyrosequencing, and bioinformatics analysis were performed.ResultsAfter 3 weeks of intervention, diabetes developed in all rats in the IGT group, but only 30% of rats in the berberine group. Treatment with berberine was associated with reductions in food intake, FBG level, insulin resistance, and plasma LPS level, as well as increases in fasting plasma GLP-2 level and glutamine-induced intestinal GLP-2 secretion. Berberine could increase the goblet cell number and villi length, and also reverse the suppressed expressions of mucin, occludin, ZO-1 and the upregulated expressions of TLR-4, NF-κB and TNF-α induced in IGT rats (P<0.05). Berberine also improved the structure of the gut microbiota and restored species diversity.ConclusionBerberine may slow the progression of prediabetes to T2DM in ZDF rats by improving GLP-2 secretion, intestinal permeability, and the structure of the gut microbiota.

scholarly journals Elevated Circulating Fetuin-B Levels Are Associated with Insulin Resistance and Reduced by GLP-1RA in Newly Diagnosed PCOS Women

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Mani Mokou ◽  
Shan Yang ◽  
Bin Zhan ◽  
Shan Geng ◽  
Kejia Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Metabolic Diseases ◽  
Polycystic Ovary ◽  
Fasting Blood Glucose ◽  
Resistance Index ◽  
Oral Glucose ◽  
Healthy Women ◽  
Tnf Α

Background. Previous studies have suggested that Fetuin-B seems to be a secreted adipokine related to metabolic diseases. However, the results have been inconsistent. Here, our objective is to investigate the changes in circulating Fetuin-B levels in women with polycystic ovary syndrome (PCOS) and analyze the association of Fetuin-B and insulin resistance (IR). Methods. The current study is comprised of a cross-sectional study and a series of interventional studies. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp (EHC) were engaged to assess glucose tolerance and insulin sensitivity. Serum Fetuin-B levels were determined by ELISA. Results. Serum Fetuin-B and TNF-α levels were markedly increased in women with PCOS compared to healthy women. Circulating Fetuin-B was positively associated with body mass index, waist-to-hip ratio, the percentage of body fat (FAT%), systolic blood pressure, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, 2 h blood glucose after glucose overload, fasting insulin, 2 h insulin after glucose overload, HOMA-insulin resistance index (HOMA-IR), the area under the curve for insulin (AUCi), AUCg, and TNF-α, while negatively associated with M value and follicular stimulating hormone (FSH). During the EHC, Fetuin-B levels were found to be significantly increased in PCOS women. After a glucose challenge, serum Fetuin-B levels in healthy women were significantly increased. Lipid infusion reduced serum Fetuin-B levels in 30 healthy subjects. After six months of glucagon-like peptide-1 receptor agonist (GLP-1RA) intervention, serum Fetuin-B concentrations in PCOS women markedly decreased following ameliorated IR. Conclusion. Our results indicate that Fetuin-B may be a biomarker of IR in individuals with PCOS. This trial is registered with ChiCTR-IIR-16007901.

Glia Maturation Factor-Gamma Negatively Modulates Fatty Acid-Induced Inflammation in Macrophages Via PI3K/AKT Pathway

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1096-1096
Author(s):  
Wulin Aerbajinai ◽  
Kyung Chin ◽  
Jianqiong Zhu ◽  
Griffin P Rodgers
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Enzyme Linked Immunosorbent Assay ◽  
Glia Maturation Factor ◽  
Endogenous Expression ◽  
Maturation Factor ◽  
Tnf Α

Abstract Abstract 1096 The macrophage-mediated inflammatory response plays a critical role in the development of obesity-related tissue inflammation and insulin resistance. Free-fatty acids (FFAs) are well-characterized factors causing production of inflammatory factors and insulin resistance. Glia maturation factor-gamma (GMFG), a member of the ADF/cofilin family of proteins that regulate actin cytoskeleton reorganization, is preferentially expressed in inflammatory cells, but its function in the macrophages immune response remains unclear. In this study, we investigated whether GMFG may affect FFAs-induced inflammatory reaction in macrophages. We show here that silencing of GMFG (80% inhibition of the endogenous expression levels) by transfected with GMFG siRNA significantly enhanced FFAs-induced production of proinflammatory cytokines and chemokines, including TNF-α, IL-6 and IL-8 compared to transfected non-targeting silencing siRNA in human peripheral blood monocytes-derived macrophage (1.2 × 104 ± 224.2 vs. 4.6 × 103 ± 98.4 molecules/ng, P < 0.001; 1.2 × 103 ± 56.1 vs. 2.3 × 102 ± 8.4 molecules/ng, P =0.001; 1.3 × 107 ± 5.8 × 105 vs. 4.9 × 106 ± 2.8 × 105 molecules/ng, P < 0.001) as determined by quantitative real time-PCR and confirmed by enzyme-linked immunosorbent assay (TNF-α: 9.4 × 102 ± 38.6 vs. 5.6 × 102 ± 31.1 ng/mL, P < 0.01; IL-6: 4.5 × 102 ± 31.3 vs. 2.2 × 102 ± 22.7 ng/mL, P < 0.01; IL-8: 2.2 × 103 ± 205.5 vs. 1.3 × 103 ± 113.9 ng/mL, P < 0.01). These increased inflammatory cytokines resulted from an increased activation of NF-κB and the ERK1/2 MAPK signaling pathway (based on increased NF-κB p65 phosphorylation, IκBα loss and enhanced phosphorylation of ERK1/2 in Western blot analysis) and a reduced phosphorylation of the PI3K/Akt/GSK3-β pathway following FFAs stimulation. Overexpression of GFP-GMFG in GMFG-silenced cells abrogated enhanced phosphorylation of NF-κB p65, ERK1/2 MAPK and reduced phosphorylation of Akt and GSK3-β. Furthermore, in cells in which GMFG was knockdown, FFAs induced an increase in the expression of SHIP1, a phosphatase that negatively regulates the PI3K signaling pathway, suggesting increased SHIP1 expression may be responsible for the augmentation of inflammatory cytokines following FFAs stimulation. We also show that silencing of GMFG enhances the oxidized low density lipoprotein (oxLDL) induced expression of TNF-α and IL-6 (2.9 × 104 ± 204.8 vs. 1.3 × 104 ± 153.9 molecules/ng, P < 0.01; 2.5 × 103 ± 31.3 vs. 9.2 × 102 ± 22.7 ng/mL, P < 0.01) in MDM. Taking together with the data that GMFG is constitutively expressed in macrophages and its expression is down-regulated by FFAs stimulation, GMFG might function as a novel negative regulator through participating in the PI3K/Akt signaling pathway, suggesting that macrophage-specific modulation of GMFG may be beneficial in the treatment of FFAs induced inflammation. Disclosures: No relevant conflicts of interest to declare.

MiR-425-5p Regulates Glucagon-like Peptide-1 Production and Affects Blood Glucose Levels in High-fat Diet-fed Mice

2021 ◽  
Author(s):  
Lirui Wei ◽  
Xuenan Zhao ◽  
Feng Guo ◽  
Fengjiao Huang ◽  
Yanyan Zhao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Tolerance ◽  
Protein Level ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Tolerance Test ◽  
Control Group ◽  
High Fat ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract BackgroundIn modern society, obesity has become a global problem with resulting in metabolic disorders and poses high risk for type 2 diabetes mellitus (T2DM). The glucagon-like peptide-1 (GLP-1) has been taken as an effective drug for the therapy of T2DM and obesity. In the present study, the regulatory roles and molecular mechanisms of miR-425-5p in GLP-1 secretion in high-fat diet (HFD)-induced diabetic mice were explored. MethodsOral glucose tolerance test and insulin tolerance test were performed to assess glucose metabolism and GLP-1 and LPS levels. Quantitative real time polymerase chain reaction (qRT-PCR) was employed to detect the expression of LPS, GLP-1, GLP-1 receptors, miR-425-5p, phosphatase and tensin homology (PTEN), proglucagon, p65 and β-catenin. Western blot was performed to determine the expression of proglucagon, p65, β-catenin and PTEN. ResultsThe results showed that plasma GLP-1 level was negatively correlated with plasma LPS level in HFD-fed mice, and miR-425-5p expression and LPS level were up-regulated in the ileal fluid compared with control groups. LPS injection boosted miR-425-5p expression in ileum. MiR-425-5p ameliorated glucose intolerance and insulin resistance in HFD-fed mice by increasing GLP-1 secretion. Furthermore, p65 protein level in the cytoplasmic and nuclear in the ileum of HFD-fed mice was increased compared with the control group. MiR-425-5p agomir elevated nuclear β-catenin protein level, but reduced PTEN protein level in HFD-fed mice compared with HFD-fed mice treated with the miR-425-5p antagomir. ConclusionsOur results suggest that miR-425-5p promotes GLP-1 secretion and improves glucose tolerance and insulin resistance in high-fat diet-fed mice.

scholarly journals Effects of IQW and IRW on Inflammation and Gut Microbiota in ETEC-Induced Diarrhea

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Naiyuan Liu ◽  
Lingsi Zhou ◽  
Jun Fang ◽  
Hongmei Jiang ◽  
Gang Liu
Keyword(s):  
Gut Microbiota ◽  
Inflammatory Cytokines ◽  
Shannon Index ◽  
Community Diversity ◽  
Enterotoxigenic Escherichia Coli ◽  
Enzyme Linked Immunosorbent Assay ◽  
Crypt Depth ◽  
Tnf Α ◽  
Group B ◽  
Gut Damage

Background/Aims. Changing gut microbiota is one of the most common causes of host gut inflammation. The active triple peptides, lle-Gln-Trp (IQW) and lle-Arg-Trp (IRW), cause remarkable changes to gut microbiota. The effects of the triple peptides IQW and IRW in gut-damage treatment were explored in this study via an enterotoxigenic Escherichia coli- (ETEC-) induced mouse model. Methods. The mice were randomly distributed into four groups: (a) control (CTRL) group, (b) ETEC group, (c) IQW-ETEC group, and (d) IRW-ETEC group. Villus length and crypt depth were measured after hematoxylin and eosin staining. The inflammatory reaction was analyzed via inflammatory cytokines (i.e., TNF-α, IL-1β, IL-6, and IL-10) using the enzyme-linked immunosorbent assay (ELISA). The microbiota in the colon was sequenced using 16S ribosomal RNA. Results. The villus length decreased, the crypt depth decreased, and the expression of inflammatory cytokines (i.e., TNF-α, IL-1β, IL-6, and IL-10) increased due to ETEC. In the IRW-ETEC and IQW-ETEC groups, the Shannon index decreased ( P < 0.05 ). IQW and IRW increased the abundance of Firmicutes, Proteobacteria, Clostridiales, Lachnospiraceae, and Alloprevotella; contrastingly, it decreased the abundance of Epsilonproteobacteria, Erysipelotrichales, Prevotellaceae, and Flavobacteriaceae compared to the ETEC group (P <0.05). Conclusion. This study ascertained that the addition of IQW and IRW could alleviate jejunal inflammation and increase microbiota community diversity.

scholarly journals Increased Plasma Levels of Nesfatin-1 in Patients with Newly Diagnosed Type 2 Diabetes Mellitus

2011 ◽  
Vol 120 (02) ◽  
pp. 91-95 ◽  
Author(s):  
Z. Zhang ◽  
L. Li ◽  
M. Yang ◽  
H. Liu ◽  
G. Boden ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Regression Analysis ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Enzyme Linked Immunosorbent Assay ◽  
Newly Diagnosed

AbstractNesfatin-1, which is derived from nucleobindin2 (NUCB2), has been recently identified as a novel satiety regulator. However, its pathophysiological role in humans remains unknown. The aim of the present study was to investigate plasma nesfatin-1 levels and the association between plasma nesfatin-1 levels and various metabolic parameters in humans.74 subjects with newly diagnosed type 2 diabetes mellitus (nT2DM), 73 subjects with impaired glucose tolerance (IGT) and 73 subjects with normal glucose tolerance (NGT) were enrolled in this study. Plasma nesfatin-1 levels were measured by a commercially available enzyme- linked immunosorbent assay.Plasma nesfatin-1 levels were elevated in subjects with both nT2DM and IGT compared to controls (1.91±0.79 and 1.80±0.80 vs. 1.41±0.58 μ g/L, P<0.05 or P<0.01 ). Simple regression analysis showed that in subjects with IGT and nT2DM, plasma nesfatin-1 correlated positively with body mass index (BMI), hemoglobin A1c (HbA1c), fasting blood glucose (FBG), 2 h blood glucose after a glucose load (2hPBG), fasting plasma insulin (FINS) and the homeostasis model assessment of insulin resistance (HOMA-IR). Multivariate logistic regression analysis revealed that plasma nesfatin-1 was significantly associated with IGT and nT2DM, even after controlling for differences in BMI.Plasma nesfatin-1 concentrations were found to be elevated in subjects with both IGT and nT2DM and to be related with several clinical parameters known to be associated with insulin resistance.

Mechanisms of insulin resistance in cystic fibrosis

2001 ◽  
Vol 281 (5) ◽  
pp. E1022-E1028 ◽  
Author(s):  
Dana S. Hardin ◽  
Adrian Leblanc ◽  
Gailen Marshall ◽  
Dan K. Seilheimer
Keyword(s):  
Insulin Resistance ◽  
Cystic Fibrosis ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Clinical Status ◽  
Oral Glucose ◽  
Glut 4 ◽  
Tnf Α ◽  
Glut 4 Translocation

Cystic fibrosis (CF) is associated with a high incidence of diabetes. Studies evaluating causes of CF-related diabetes (CFRD) have consistently documented decreased insulin secretion. In patients with CFRD, insulin sensitivity has been documented to be decreased, but controversy exists in patients with normal or impaired glucose tolerance (IGT). We undertook this study 1) to reexplore insulin sensitivity in patients with IGT and 2) to evaluate potential mechanisms of insulin resistance in CF, including GLUT-4 translocation, elevation of serum cytokines, and free fatty acid (FFA) levels. We recruited nine CF subjects with impaired glucose tolerance (IGTCF) and nine age-, gender-, and body mass index-matched control volunteers. Each underwent a hyperinsulinemic euglycemic clamp (200 mU · m−2 · min−1) to measure insulin sensitivity. A muscle biopsy was obtained at maximal insulin stimulation for measure of GLUT-4 translocation with sucrose gradients. An oral glucose tolerance test and National Institutes of Health (NIH) clinical status scores were measured in all volunteers. We also measured tumor necrosis factor (TNF)-α levels and FFA in all subjects. Additionally, we report the results of TNF-α and FFA in 32 CF patients previously studied by our group. Results were that glucose disposal rate (GDR) was significantly lower in the CFIGT subjects than in controls, indicative of impaired insulin action. GLUT-4 translocation was impaired in CF and correlated with GDR. TNF-α levels were higher in all CF subjects than in controls and correlated with GDR. There was no difference in FFA between CF and control subjects. Modified NIH clinical status scores were inversely correlated with GDR and TNF-α levels. We conclude that IGTCF patients have decreased peripheral insulin sensitivity. Mechanisms include elevation of TNF-α and impaired translocation of GLUT-4.

scholarly journals Intestinal Secretory Factor Released by Macrophages Stimulated with Clostridium difficile Toxin A: Role of Interleukin 1β

1998 ◽  
Vol 66 (10) ◽  
pp. 4910-4916 ◽  
Author(s):  
M. F. G. Rocha ◽  
A. M. Soares ◽  
C. A. Flores ◽  
T. S. Steiner ◽  
D. M. Lyerly ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Receptor Antagonist ◽  
Short Circuit ◽  
Intestinal Secretion ◽  
Interleukin 1Β ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protein Synthesis Inhibitor ◽  
Lipoxygenase Inhibitor ◽  
Toxin A ◽  
Tnf Α

ABSTRACT Clostridium difficile toxin A is associated with enterocolitis in animals and humans. However, the mechanisms of its secretory and damaging effects are not totally understood. In this work, we examined the intestinal secretion of electrolytes and water caused by supernatants from macrophages stimulated with toxin A in rabbit ileal mucosa mounted in Üssing chambers. We also investigated the mechanism by which the intestinal secretory factor (ISF) is released from stimulated macrophages. Supernatants from macrophages stimulated with toxin A caused potent intestinal secretion (change in short-circuit current [ΔIsc], 76 μA · cm−2; P < 0.01). The release of the ISF was pertussis toxin sensitive (reduction, 61%; P < 0.01) and was also reduced (P < 0.05) by a protein synthesis inhibitor (67%), protease inhibitors (57%), a phospholipase A2 inhibitor (54%), a cyclo-oxygenase inhibitor (62%), a dual cyclo- and lipoxygenase inhibitor (48%), a platelet-activating factor (PAF) receptor antagonist (55%), and tumor necrosis factor alpha (TNF-α) synthesis inhibitors (48%). However, this release was not inhibited by a lipo-oxygenase inhibitor. Monoclonal anti-interleukin 1β (IL-1β) but not anti-IL-1α antibody blocked (72%; P < 0.01) the secretory action of the ISF, as did recombinant human IL-1 receptor antagonist (80%;P < 0.01). High levels of IL-1β (3,476 pg/ml) were detected by an enzyme-linked immunosorbent assay in the above supernatants. Furthermore, the addition of IL-1β to the serosal side caused a potent secretory effect (ΔIsc, 80 μA · cm−2; P < 0.01). These results show that macrophages stimulated with toxin A release an ISF capable of provoking intestinal secretion. The regulation of this factor is dependent upon the activation of the G protein. In addition, prostaglandins, PAF, and TNF-α are involved in the release of the ISF. We conclude that IL-1β is probably the ISF released by macrophages in response to toxin A.

scholarly journals d-Allulose Ameliorates Skeletal Muscle Insulin Resistance in High-Fat Diet-Fed Rats

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6310
Author(s):  
Yang Gou ◽  
Bingyang Liu ◽  
Mengyao Cheng ◽  
Takako Yamada ◽  
Tetsuo Iida ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
High Fat Diet ◽  
Wistar Rats ◽  
Tolerance Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Chow Diet ◽  
High Fat ◽  
Glut 4 ◽  
Tnf Α

Background: d-Allulose is a rare sugar with antiobesity and antidiabetic activities. However, its direct effect on insulin sensitivity and the underlying mechanism involved are unknown. Objective: This study aimed to investigate the effect of d-allulose on high-fat diet (HFD)-induced insulin resistance using the hyperinsulinemic–euglycemic (HE)-clamp method and intramuscular signaling analysis. Methods: Wistar rats were randomly divided into three dietary groups: chow diet, HFD with 5% cellulose (HFC), and HFD with 5% d-allulose (HFA). After four weeks of feeding, the insulin tolerance test (ITT), intraperitoneal glucose tolerance test (IPGTT), and HE-clamp study were performed. The levels of plasma leptin, adiponectin, and tumor necrosis factor (TNF)-α were measured using the enzyme-linked immunosorbent assay. We analyzed the levels of cell signaling pathway components in the skeletal muscle using Western blotting. Results: d-allulose alleviated the increase in HFD-induced body weight and visceral fat and reduced the area under the curve as per ITT and IPGTT. d-Allulose increased the glucose infusion rate in the two-step HE-clamp test. Consistently, the insulin-induced phosphorylation of serine 307 in the insulin receptor substrate-1 and Akt and expression of glucose transporter 4 (Glut-4) in the muscle were higher in the HFA group than HFC group. Furthermore, d-allulose decreased plasma TNF-α concentration and insulin-induced phosphorylation of stress-activated protein kinase/Jun N-terminal kinase in the muscle and inhibited adiponectin secretion in HFD-fed rats. Conclusions: d-allulose improved HFD-induced insulin resistance in Wistar rats. The reduction of the proinflammatory cytokine production, amelioration of adiponectin secretion, and increase in insulin signaling and Glut-4 expression in the muscle contributed to this effect.

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