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1.
Food Chem ; 409: 135287, 2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-36603475

RESUMO

In this study, Ulva lactuca polysaccharide (ULP) antihyperglycemic effect was assessed by monitoring changes in the gut microbiota of aging diabetic mice. The results showed that ULP alleviated type 2 diabetes by improving insulin tolerance, increasing SOD and CAT activities, and thus lowering blood glucose level. Moreover, ULP regulated the expressions of INSR and AMPK concurrent with inhibition the expression of JNK, JAK, STAT3, p16 and p38 to improve glucose metabolism dysfunction. Interestingly, the abundance of Alloprevotella and Pediococcus change might the key factor for ULP antihyperglycemic effectiveness in aging-related diabetes. These results suggest that ULP can exert a mechanism of blood glucose regulation by improving intestinal diversity composition asides from direct insulin mimetic actions.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Insulinas , Ulva , Camundongos , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Ulva/genética , Ulva/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Glicemia/metabolismo , Polissacarídeos/farmacologia , Hipoglicemiantes/farmacologia , Insulinas/farmacologia
2.
FASEB J ; 37(2): e22772, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36645117

RESUMO

Circadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of glucose and lipid homeostasis. It is, however, unknown if these effects are sex dependent. Here, we subjected male and female C57BL/6J mice to 6-h light phase advancements every 3 days to induce CD and assessed glucose and lipid homeostasis. Within this model, we studied the involvement of gonadal sex hormones by injecting mice with gonadotropin-releasing hormone-antagonist degarelix. We demonstrate that CD has sex-specific effects on glucose homeostasis, as CD elevated fasting insulin levels in male mice while increasing fasting glucose levels in female mice, which appeared to be independent of behavior, food intake, and energy expenditure. Absence of gonadal sex hormones lowered plasma insulin levels in male mice subjected to CD while it delayed glucose clearance in female mice subjected to CD. CD elevated plasma triglyceride (TG) levels and delayed plasma clearance of TG-rich lipoproteins in both sexes, coinciding with reduced TG-derived FA uptake by adipose tissues. Absence of gonadal sex hormones did not notably alter the effects of CD on lipid metabolism. We conclude that CD causes sex-dependent effects on glucose metabolism, as aggravated by male gonadal sex hormones and partly rescued by female gonadal sex hormones. Future studies on CD should consider the inclusion of both sexes, which may eventually contribute to personalized advice for shift workers.


Assuntos
Hormônios Esteroides Gonadais , Insulinas , Camundongos , Masculino , Feminino , Animais , Camundongos Endogâmicos C57BL , Homeostase , Glucose/metabolismo , Ritmo Circadiano , Insulinas/farmacologia
3.
Microvasc Res ; 146: 104468, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36513147

RESUMO

BACKGROUND: Diabetes exacerbates vascular injury by triggering endothelial dysfunction. Endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) both play major roles in endothelial dysfunction. However, effects of hypoglycaemia, the main complication of the insulin therapy to the glycemic control in diabetes, on eNOS activity and iNOS expression, and underlying mechanisms in diabetes remain unknown. Hence, we aimed to determine the effects of hypoglycaemia on eNOS activity and iNOS expression in different arterial beds of diabetic rats. METHODS: Sprague-Dawley rats were subjected to Streptozotocin (STZ) combined with high fat diet (HFD) to induce diabetes and then received insulin injection to attain acute and recurrent hypoglycaemia. Immunoblotting was used to analyse the phosphorylation and O-glycosylation status of eNOS and iNOS level from thoracic aorta and mesenteric artery tissue. Indicators of oxidative stress from plasm were determined, and endothelial-dependent vasodilation was detected via wire myograph system. RESULTS: Hypoglycaemia was associated with a marked increase in eNOS O-GlcNAcylation and decrease in Serine (Ser)-1177 phosphorylation from thoracic aortas and mesenteric arteries. Moreover, hypoglycaemia resulted in elevated phosphorylation of eNOS at Threonine (Thr)-495 site in mesenteric arteries. Besides, changes in these post-translational modifications were associated with increased O-GlcNAc transferase (OGT), decreased phosphorylation of Akt at Ser-473, and increased protein kinase C α subunit (PKCα). iNOS expression was induced in hypoglycaemia. Furthermore, endothelial-dependent vasodilation was impaired under insulin-induced hypoglycaemia, and further in recurrent hypoglycaemia. CONCLUSIONS: Conclusively, these findings strongly indicate that hypoglycaemia-dependent vascular dysfunction in diabetes is mediated through altered eNOS activity and iNOS expression. Therefore, this implies that therapeutic modulation of eNOS activity and iNOS expression in diabetics under intensive glucose control may prevent and treat adverse cardiovascular events.


Assuntos
Diabetes Mellitus Experimental , Hipoglicemia , Insulinas , Doenças Vasculares , Ratos , Animais , Óxido Nítrico Sintase Tipo III/metabolismo , Vasodilatação , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos Sprague-Dawley , Endotélio Vascular/metabolismo , Fosforilação , Insulinas/metabolismo , Insulinas/farmacologia , Insulinas/uso terapêutico , Óxido Nítrico/metabolismo
4.
Life Sci ; 313: 121278, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36521547

RESUMO

Diabetic nephropathy (DN) is a major complication of type 1 diabetes mellitus, and hyperglycemia and hypertension are the main risk factors for the development of DN. N-Acetyl-Cysteine (NAC) has a variety of effects, interfering with the production and scavenging of free radicals and regulating the metabolic activity of tissue cells. However, the efficacy of NAC on DN treatment is unclear. Thus, this study investigated the protective mechanism of NAC combined with insulin on renal injury in dogs with DN. The forty dogs were selected and divided into control group, DM group, INS group, INS + NAC group and NAC group to establish the model for a trial period of 4 months. The results revealed that INS + NAC was effective in reducing and stabilizing blood glucose levels. Biochemical results showed that INS + NAC treatment significantly regulated the stability of UREA, CREA and fructosamine indicators. Meanwhile, histopathology staining showed significant glomerular wrinkling and fibrosis in the DM group, which could be reversed after INS + NAC treatment. In addition, INS + NAC could restore mitochondria homeostasis by upregulating the levels of mitochondrial fission (MFN1, MFN2 and OPA1) and inhibiting of mitochondrial fusion (DRP1, FIS1 and MFF) related indicators. Further studies revealed that INS + NAC regulated the expression levels of renal BNIP3, NIX and FUNDC1 in the DM group, thereby alleviating mitophagy. Collectively, these results suggested that NAC combined with insulin protects DN by regulating the mitochondrial dynamics and FUNDC1-mediated mitophagy.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Insulinas , Animais , Cães , Acetilcisteína/farmacologia , Nefropatias Diabéticas/patologia , Insulinas/farmacologia , Dinâmica Mitocondrial , Proteínas Mitocondriais/metabolismo , Mitofagia
5.
Cell Mol Biol Lett ; 27(1): 110, 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36526973

RESUMO

BACKGROUND: Metabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells. METHODS: A retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage. RESULTS: We found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression. CONCLUSIONS: Our data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.


Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias do Endométrio , Resistência à Insulina , Insulinas , Humanos , Feminino , Espécies Reativas de Oxigênio/metabolismo , Estudos Retrospectivos , Estresse do Retículo Endoplasmático , Apoptose , Ácidos Graxos/farmacologia , Obesidade , Insulinas/farmacologia
6.
Hum Reprod ; 37(12): 2867-2884, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36342870

RESUMO

STUDY QUESTION: Can diet normalization or a calorie-restricted diet for 2 or 4 weeks be used as a preconception care intervention (PCCI) in Western-type diet-induced obese Swiss mice to restore metabolic health and oocyte quality? SUMMARY ANSWER: Metabolic health and oocyte developmental competence was already significantly improved in the calorie-restricted group after 2 weeks, while obese mice that underwent diet normalization showed improved metabolic health after 2 weeks and improved oocyte quality after 4 weeks. WHAT IS KNOWN ALREADY: Maternal obesity is linked with reduced metabolic health and oocyte quality; therefore, infertile obese women are advised to lose weight before conception to increase pregnancy chances. However, as there are no univocal guidelines and the specific impact on oocyte quality is not known, strategically designed studies are needed to provide fundamental insights in the importance of the type and duration of the dietary weight loss strategy for preconception metabolic health and oocyte quality. STUDY DESIGN, SIZE, DURATION: Outbred female Swiss mice were fed a control (CTRL) or high-fat/high-sugar (HF/HS) diet. After 7 weeks, some of the HF mice were put on two different PCCIs, resulting in four treatment groups: (i) only control diet for up to 11 weeks (CTRL_CTRL), (ii) only HF diet for up to 11 weeks (HF_HF), (iii) switch at 7 weeks from an HF to an ad libitum control diet (HF_CTRL) and (iv) switch at 7 weeks from an HF to a 30% calorie-restricted control diet (HF_CR) for 2 or 4 weeks. Metabolic health and oocyte quality were assessed at 2 and 4 weeks after the start of the intervention (n = 8 mice/treatment/time point). PARTICIPANTS/MATERIALS, SETTING, METHODS: Changes in body weight were recorded. To study the impact on metabolic health, serum insulin, glucose, triglycerides, total cholesterol and alanine aminotransferase concentrations were measured, and glucose tolerance and insulin sensitivity were analyzed at PCCI Weeks 2 and 4. The quality of in vivo matured oocytes was evaluated by assessing intracellular lipid droplet content, mitochondrial activity and localization of active mitochondria, mitochondrial ultrastructure, cumulus cell targeted gene expression and oocyte in vitro developmental competence. MAIN RESULTS AND THE ROLE OF CHANCE: Significant negative effects of an HF/HS diet on metabolic health and oocyte quality were confirmed (P < 0.05). HF_CTRL mice already showed restored body weight, serum lipid profile and glucose tolerance, similar to the CTRL_CTRL group after only 2 weeks of PCCI (P < 0.05 compared with HF_HF) while insulin sensitivity was not improved. Oocyte lipid droplet volume was reduced at PCCI Week 2 (P < 0.05 compared with HF_HF), while mitochondrial localization and activity were still aberrant. At PCCI Week 4, oocytes from HF_CTRL mice displayed significantly fewer mitochondrial ultrastructural abnormalities and improved mitochondrial activity (P < 0.05), while lipid content was again elevated. The in vitro developmental capacity of the oocytes was improved but did not reach the levels of the CTRL_CTRL mice. HF_CR mice completely restored cholesterol concentrations and insulin sensitivity already after 2 weeks. Other metabolic health parameters were only restored after 4 weeks of intervention with clear signs of fasting hypoglycemia. Although all mitochondrial parameters in HF_CR oocytes stayed aberrant, oocyte developmental competence in vitro was completely restored already after 2 weeks of intervention. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: In this study, we applied a relevant HF/HS Western-type diet to induce obesity in an outbred mouse model. Nevertheless, physiological differences should be considered when translating these results to the human setting. However, the in-depth study and follow-up of the metabolic health changes together with the strategic implementation of specific PCCI intervals (2 and 4 weeks) related to the duration of the mouse folliculogenesis (3 weeks), should aid in the extrapolation of our findings to the human setting. WIDER IMPLICATIONS OF THE FINDINGS: Our study results with a specific focus on oocyte quality provide important fundamental insights to be considered when developing preconception care guidelines for obese metabolically compromised women wishing to become pregnant. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Flemish Research Fund (FWO-SB grant 1S25020N and FWO project G038619N). The authors declare there are no conflicts of interest.


Assuntos
Infertilidade Feminina , Insulinas , Feminino , Camundongos , Humanos , Gravidez , Animais , Técnicas de Maturação in Vitro de Oócitos/métodos , Camundongos Obesos , Restrição Calórica , Cuidado Pré-Concepcional , Oócitos/metabolismo , Infertilidade Feminina/metabolismo , Obesidade/terapia , Obesidade/metabolismo , Colesterol , Glucose , Insulinas/metabolismo , Insulinas/farmacologia , Lipídeos
7.
BMC Complement Med Ther ; 22(1): 270, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229811

RESUMO

BACKGROUND: Cistanche tubulosa is an editable and medicinal traditional Chinese herb and phenylethanoid glycosides are its major components, which have shown various beneficial effects such as anti-tumor, anti-oxidant and neuroprotective activities. However, the anti-obesity effect of C. tubulosa phenylethanoid glycosides (CTPG) and their regulatory effect on gut microbiota are still unclear. In the present study, we investigated its anti-obesity effect and regulatory effect on gut microbiota by 3T3-L1 cell model and obesity mouse model. METHODS: 3T3-L1 adipocytes were used to evaluate CTPG effects on adipogenesis and lipids accumulation. Insulin resistant 3T3-L1 cells were induced and used to measure CTPG effects on glucose consumption and insulin sensitivity. High-fat diet (HFD)-induced C57BL/6 obese mice were used to investigate CTPG effects on fat deposition, glucose and lipid metabolism, insulin resistance and intestinal microorganism. RESULTS: In vitro data showed that CTPG significantly decreased the triglyceride (TG) and non-esterified fatty acid (NEFA) contents of the differentiated 3T3-L1 adipocytes in a concentration-dependent manner without cytotoxicity, and high concentration (100 µg/ml) of CTPG treatment dramatically suppressed the level of monocyte chemoattractant protein-1 (MCP-1) in 3T3-L1 mature adipocytes. Meanwhile, CTPG increased glucose consumption and decreased NEFA level in insulin resistant 3T3-L1 cells. We further found that CTPG protected mice from the development of obesity by inhibiting the expansion of adipose tissue and adipocyte hypertrophy, and improved hepatic steatosis by activating AMPKα to reduce hepatic fat accumulation. CTPG ameliorated HFD-induced hyperinsulinemia, hyperglycemia, inflammation and insulin resistance by activating IRS1/Akt/GLUT4 insulin signaling pathway in white adipose tissue. Moreover, gut microbiota structure and metabolic functions in HFD-induced obese mice was changed by CTPG, especially short chain fatty acids-producing bacteria including Blautia, Roseburia, Butyrivibrio and Bacteriodes were significantly increased by CTPG treatment. CONCLUSIONS: CTPG effectively suppressed adipogenesis and lipid accumulation in 3T3-L1 adipocytes and ameliorated HFD-induced obesity and insulin resistance through activating AMPKα and IRS1/AKT/GLUT4 signaling pathway and regulating the composition and metabolic functions of gut microbiota.


Assuntos
Cistanche , Resistência à Insulina , Insulinas , Células 3T3-L1 , Adipócitos , Adipogenia , Animais , Antioxidantes/farmacologia , Quimiocina CCL2 , Cistanche/metabolismo , Dieta Hiperlipídica , Ácidos Graxos não Esterificados/metabolismo , Ácidos Graxos não Esterificados/farmacologia , Glucose/metabolismo , Glicosídeos/metabolismo , Glicosídeos/farmacologia , Insulinas/metabolismo , Insulinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triglicerídeos/metabolismo
8.
Eur Rev Med Pharmacol Sci ; 26(20): 7522-7532, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36314323

RESUMO

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) still has no accepted pharmacological therapy. Even though monotherapy of L-carnitine or magnesium supplementation exhibits an essential beneficial role in NAFLD treatment, and despite that new NAFLD treatment strategies focus on combination therapies, the combination of L-carnitine with magnesium has not yet been examined in NAFLD patients. We aimed to assess the efficacy of L-carnitine in combination with magnesium in NAFLD patients. PATIENTS AND METHODS: Double-blinded, randomized controlled trial with 22 NAFLD participants who were randomized to either control group receiving placebo for the first 8 weeks and an additional 8 weeks with CIRRHOS product (2 gr L-carnitine and 150 mg magnesium) or treatment group receiving CIRRHOS product for 16 weeks. Weight, serum aspartate aminotransferase (AST), alanine transaminase (ALT) and C-reactive protein (CRP) levels were measured monthly. Lipid profile and serum insulin levels were monitored at baseline and at week 16 of treatment. Shear-wave elastography was used to evaluate liver stiffness (LS). RESULTS: While AST and ALT levels decreased progressively over 16 weeks of treatment in the treatment group, AST and ALT levels of the control group were increased modestly or unaffected. AST and ALT levels of the treatment group decreased by 25% (p=0.9) and 20% (p=0.1) respectively, compared to AST and ALT levels at baseline. However, serum CRP levels, insulin levels, lipid profile and LS were not affected by treatment. CONCLUSIONS: Our findings suggest that L-carnitine with magnesium supplementation could be a potential therapy for NAFLD. However, further studies with a larger population and high-sensitivity diagnostic parameters for early stages of NAFLD are needed to elucidate L-carnitine and magnesium efficacy in NAFLD.


Assuntos
Insulinas , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Carnitina/uso terapêutico , Magnésio/uso terapêutico , Magnésio/metabolismo , Projetos Piloto , Hidróxido de Magnésio/metabolismo , Hidróxido de Magnésio/farmacologia , Hidróxido de Magnésio/uso terapêutico , Alanina Transaminase , Aspartato Aminotransferases , Lipídeos , Insulinas/farmacologia , Fígado/metabolismo
9.
Biomol Concepts ; 13(1): 314-321, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36315027

RESUMO

Diabetes is accompanied by inflammation and oxidation. Supplementation of anti-inflammatory and antioxidant compounds can prevent the progression of diabetes. This study aimed to investigate the effects of supplementation of Nannochloropsis oculata microalgae (NOM) on the inflammatory and antioxidant responses in diabetic rats. Sixty male rats were divided into six groups as diabetic and non-diabetic rats receiving 0, 10 and 20 mg/kg of body weight of NOM daily for 21 days. Body weight, the serum concentrations of insulin and glucose and the tissue concentrations of interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), interleukin-6 (IL-6), malondialdehyde (MDA), ferric reducing antioxidant power (FRAP), superoxide dismutase (SOD), glutathione peroxidase (GPx) were assessed. The results showed that induction of diabetes significantly reduced the body weight, the serum concentrations of insulin and the tissue concentrations of SOD, FRAP and GPx while increasing the concentrations of glucose, MDA, IL-1ß, IL-6, NF-κB and TNF-α. Daily oral administration of NOM (10 and 20 mg/kg) significantly maintained the body weight, the serum concentrations of insulin and the tissue concentrations of SOD, FRAP and GPx while preventing the increase in the concentrations of glucose, MDA, IL-1ß and TNF-α. In conclusion, diabetes caused inflammation and oxidation while NOM worked as a natural anti-inflammatory and antioxidant compound.


Assuntos
Diabetes Mellitus , Insulinas , Microalgas , Ratos , Masculino , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Interleucina-6 , NF-kappa B/metabolismo , Estresse Oxidativo , Fator de Necrose Tumoral alfa , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Superóxido Dismutase/metabolismo , Superóxido Dismutase/farmacologia , Superóxido Dismutase/uso terapêutico , Suplementos Nutricionais , Glucose/farmacologia , Glucose/uso terapêutico , Peso Corporal , Insulinas/farmacologia , Insulinas/uso terapêutico
10.
Front Biosci (Landmark Ed) ; 27(9): 278, 2022 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-36224015

RESUMO

BACKGROUND: Impaired glucose regulation (IGR) represents the prediabetic state and is associated with gut microbiota (GM) dysbiosis and chronic inflammation. Tangning Ziyabitusi Tablet (TZT) is a Chinese Uyghur herbal medicine with preventative and therapeutic effects on diabetes, but its hypoglycemic mechanisms are unclear. METHODS: Thirty-six male Wistar rats were divided into the normal diet (ND) and IGR groups. The IGR group was given a high-fat diet (HFD). After the IGR model establishment, the ND group was divided into ND and ND+TZT groups, and the IGR group into IGR and IGR+TZT groups. After 8 weeks of TZT administration, 16S rRNA sequencing and untargeted metabolomics were performed on fecal samples. Mesenteric lymph nodes were also collected, and T lymphocytes separated after rats were sacrificed. Flow cytometry was used to characterize different CD4+ T cell subsets in mesenteric lymph nodes. Finally, we analyzed the correlation between GM and characteristic fecal metabolites. RESULTS: Impaired glucose tolerance and insulin resistance were improved in the IGR+TZT group when compared with the IGR group. Bacterial 16S rRNA sequencing results showed that Sobs and Chao1 indices in the IGR group were significantly decreased, but were increased in the IGR+TZT group. The relative abundance of Bacteroidetes was decreased while the relative abundance of Firmicutes was increased in the IGR group. Adlercreutzia abundance was decreased after TZT administration, while the abundance of Christensenellaceae_R-7_group, norank_f_norank_o_Clostridia_UCG-014, UCG-005, and Eubacterium_nodatum_group was increased in the IGR+TZT group. Lymph node CD4+ T cell proportions in the IGR group were significantly increased, while they were significantly decreased in the IGR+TZT group. Correlation analysis showed that tumor necrosis factor-α, interleukin-6, T helper cells (Th1, Th2, Treg), and insulin had a greater impact on GM community structure. CONCLUSIONS: TZT improved glucose tolerance and ameliorated GM dysbiosis in IGR rats. Additionally, TZT significantly modulated CD4+ T cell subset proportions in rat mesenteric lymph nodes and fecal metabolism. Moreover, correlation analysis showed that key microbiota was closely related to IGR indices. Thus, TZT modulated GM composition and immune functions of the intestinal mucosa. We provide useful information for the investigation of active mechanisms and the clinical application of TZT.


Assuntos
Microbioma Gastrointestinal , Insulinas , Animais , Disbiose/microbiologia , Glucose/farmacologia , Hipoglicemiantes/farmacologia , Insulinas/farmacologia , Insulinas/uso terapêutico , Interleucina-6 , Masculino , RNA Ribossômico 16S/genética , Ratos , Ratos Wistar , Subpopulações de Linfócitos T/metabolismo , Comprimidos/farmacologia , Comprimidos/uso terapêutico , Fator de Necrose Tumoral alfa
11.
Endocrine ; 78(3): 446-457, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36205915

RESUMO

PURPOSE: Sorafenib has been reported to reduce blood glucose levels in diabetic and non-diabetic patients in previous retrospective studies. However, the mechanism of which the hypoglycemic effects of sorafenib is not clearly explored. In this study, we investigated the effect of sorafenib on blood glucose levels in diabetic and normal mice and explored the possible mechanism. METHODS: We established a mouse model of type 2 diabetes by a high-fat diet combined with a low-dose of streptozotocin (STZ), to identify the hypoglycemic effect of sorafenib in different mice. Glucose tolerance, insulin tolerance and pyruvate tolerance tests were done after daily gavage with sorafenib to diabetic and control mice. To explore the molecular mechanism by which sorafenib regulates blood glucose levels, hepatic glucose metabolism signaling was studied by a series of in vivo and in vitro experiments. RESULTS: Sorafenib reduced blood glucose levels in both control and diabetic mice, particularly in the latter. The diabetic mice exhibited improved glucose and insulin tolerance after sorafenib treatment. Further studies showed that the expressions of gluconeogenesis-related enzymes, such as PCK1, G6PC and PCB, were significantly decreased upon sorafenib treatment. Mechanistically, sorafenib downregulates the expression of c-MYC downstream targets PCK1, G6PC and PCB through blocking the ERK/c-MYC signaling pathway, thereby playing its hypoglycemic effect by impairing hepatic glucose metabolism. CONCLUSION: Sorafenib reduces blood glucose levels through downregulating gluconeogenic genes, especially in diabetic mice, suggesting the patients with T2DM when treated with sorafenib need more emphasis in monitoring blood glucose to avoid unnecessary hypoglycemia.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Insulinas , Camundongos , Animais , Glicemia/metabolismo , Glucose/metabolismo , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/farmacologia , Proteínas Proto-Oncogênicas c-myc/uso terapêutico , Transdução de Sinais , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fígado/metabolismo , Insulinas/metabolismo , Insulinas/farmacologia , Insulinas/uso terapêutico , Insulina/metabolismo
12.
Int J Mol Sci ; 23(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36292943

RESUMO

Alcohol abuse is a significant public health problem. While considerable research has shown that alcohol use affects sleep, little is known about the role of sleep deprivation in alcohol toxicity. We investigated sleep as a factor modulating alcohol toxicity using Drosophila melanogaster, a model for studies of sleep, alcohol, and aging. Following 24 h of sleep deprivation using a paradigm that similarly affects males and females and induces rebound sleep, flies were given binge-like alcohol exposures. Sleep deprivation increased mortality, with no sex-dependent differences. Sleep deprivation also abolished functional tolerance measured at 24 h after the initial alcohol exposure, although there was no effect on alcohol absorbance or clearance. We investigated the effect of chronic sleep deprivation using mutants with decreased sleep, insomniac and insulin-like peptide 2, finding increased alcohol mortality. Furthermore, we investigated whether pharmacologically inducing sleep prior to alcohol exposure using the GABAA-receptor agonist 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) mitigated the effects of alcohol toxicity on middle-aged flies, flies with environmentally disrupted circadian clocks, and flies with short sleep. Pharmacologically increasing sleep prior to alcohol exposure decreased alcohol-induced mortality. Thus, sleep prior to binge-like alcohol exposure affects alcohol-induced mortality, even in vulnerable groups such as aging flies and those with circadian dysfunction.


Assuntos
Proteínas de Drosophila , Insulinas , Animais , Masculino , Feminino , Drosophila , Drosophila melanogaster/fisiologia , Privação do Sono/complicações , Sono/fisiologia , Proteínas de Drosophila/genética , Etanol/toxicidade , Insulinas/farmacologia , Ácido gama-Aminobutírico/farmacologia
13.
Cells ; 11(19)2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36230927

RESUMO

Differentiating mesenchymal stromal cells (MSCs) into articular chondrocytes (ACs) for application in clinical cartilage regeneration requires a profound understanding of signaling pathways regulating stem cell chondrogenesis and hypertrophic degeneration. Classifying endochondral signals into drivers of chondrogenic speed versus hypertrophy, we here focused on insulin/insulin-like growth factor 1 (IGF1)-induced phosphoinositide 3-kinase (PI3K)/AKT signaling. Aware of its proliferative function during early but not late MSC chondrogenesis, we aimed to unravel the late pro-chondrogenic versus pro-hypertrophic PI3K/AKT role. PI3K/AKT activity in human MSC and AC chondrogenic 3D cultures was assessed via Western blot detection of phosphorylated AKT. The effects of PI3K inhibition with LY294002 on chondrogenesis and hypertrophy were assessed via histology, qPCR, the quantification of proteoglycans, and alkaline phosphatase activity. Being repressed by ACs, PI3K/AKT activity transiently rose in differentiating MSCs independent of TGFß or endogenous BMP/WNT activity and climaxed around day 21. PI3K/AKT inhibition from day 21 on equally reduced chondrocyte and hypertrophy markers. Proving important for TGFß-induced SMAD2 phosphorylation and SOX9 accumulation, PI3K/AKT activity was here identified as a required stage-dependent driver of chondrogenic speed but not of hypertrophy. Thus, future attempts to improve MSC chondrogenesis will depend on the adequate stimulation and upregulation of PI3K/AKT activity to generate high-quality cartilage from human MSCs.


Assuntos
Insulinas , Células-Tronco Mesenquimais , Fosfatase Alcalina/metabolismo , Cartilagem/metabolismo , Diferenciação Celular , Células Cultivadas , Condrogênese , Humanos , Hipertrofia , Fator de Crescimento Insulin-Like I/metabolismo , Insulinas/metabolismo , Insulinas/farmacologia , Células-Tronco Mesenquimais/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteoglicanas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Crescimento Transformador beta/metabolismo
14.
Clin Nutr ESPEN ; 51: 92-96, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36184253

RESUMO

OBJECTIVES: This study aimed to evaluate the effects of selenium consumption on metabolic profile among infertile females diagnosed with polycystic ovary syndrome (PCOS). MATERIALS AND METHODS: The current randomized, double-blind, placebo-controlled trial was conducted among 40 infertile females with PCOS aged between 18 and 40 years. Patients were randomly allocated to two groups of intervention to receive selenium supplements (200 µg/day) or placebo (starch). Fasting blood samples were taken at baseline and after 8 weeks of intervention. RESULTS: Selenium administration significantly decreased fasting glucose (P = 0.03), homeostasis model assessment for insulin resistance (P = 0.007) and fasting insulin levels (P = 0.006), and elevated quantitative insulin sensitivity check index (P < 0.001). In addition, selenium supplementation significantly reduced malondialdehyde (MDA) levels (P = 0.006). We did not observe any significant effect of selenium supplementation on pregnancy rate, lipid profiles, total antioxidant capacity (TAC) and total glutathione (GSH) levels. CONCLUSIONS: Overall, our study demonstrated that selenium supplementation for 8 weeks in infertile women with polycystic ovary syndrome undergoing IVF had beneficial effects on glycemic control and MDA levels, but did not affect pregnancy rate, lipid profiles, TAC and GSH levels. CLINICAL TRIAL REGISTRATION NUMBER: This trial was registered at www.irct.ir as http://www.irct.ir: IRCT201701025623N100.


Assuntos
Infertilidade Feminina , Insulinas , Síndrome do Ovário Policístico , Selênio , Adolescente , Adulto , Antioxidantes/farmacologia , Biomarcadores , Suplementos Nutricionais , Feminino , Fertilização In Vitro , Glucose , Glutationa , Controle Glicêmico , Humanos , Infertilidade Feminina/tratamento farmacológico , Insulinas/metabolismo , Insulinas/farmacologia , Insulinas/uso terapêutico , Lipoproteínas , Malondialdeído , Estresse Oxidativo , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/tratamento farmacológico , Gravidez , Selênio/uso terapêutico , Amido/metabolismo , Adulto Jovem
15.
Nutr Metab Cardiovasc Dis ; 32(10): 2439-2449, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36096978

RESUMO

BACKGROUND AND AIMS: Betaine supplementation has been shown to enhance hepatic lipid metabolism in obese mice and improve exercise performance in healthy populations. We examined effects of betaine supplementation, alone or in combination with treadmill exercise, on the metabolic consequences of high fat diet (HFD)-induced obesity in mice. METHODS AND RESULTS: Male C57BL/6 J mice were fed chow or HFD. After 15 weeks, HFD mice were split into: HFD, HFD with betaine (1.5% w/v), HFD with treadmill exercise, and HFD with both betaine and exercise (15 m/min for 45min, 6 days/week; n = 12/group) for 10 weeks. Compared to HFD mice, body weight was significantly reduced in exercise and exercise-betaine mice, but not in mice given betaine alone. Similarly, adiposity was reduced by exercise but not by betaine alone. HFD-induced glucose intolerance was slightly improved by exercise, but not with betaine alone. Significantly greater benefits were observed in exercise-betaine mice, compared to exercise alone, such that GTT-outcomes were similar to controls. This was associated with reduced insulin levels during ipGTT, suggesting enhanced insulin sensitivity. Modest benefits were observed in fatty acid metabolism genes in skeletal muscle, whilst limited effects were observed in the liver. HFD-induced increases in hepatic Mpc1 (mitochondrial pyruvate carrier 1) were normalized by all treatments, suggesting potential links to altered glucose metabolism. CONCLUSIONS: Our data show that drinking 1.5% betaine was sufficient to augment metabolic benefits of exercise in obese mice. These processes appear to be facilitated by altered glucose metabolism, with limited effects on hepatic lipid metabolism.


Assuntos
Resistência à Insulina , Insulinas , Animais , Betaína/metabolismo , Betaína/farmacologia , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Glucose , Insulinas/metabolismo , Insulinas/farmacologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/farmacologia , Obesidade/metabolismo
16.
Metabolomics ; 18(10): 75, 2022 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-36125563

RESUMO

INTRODUCTION: The effects of lipopolysaccharides (i.e., endotoxin; LPS) on metabolism are poorly defined in lactating dairy cattle experiencing hyperlipidemia. OBJECTIVES: Our objective was to explore the effects of acute intravenous LPS administration on metabolism in late-lactation Holstein cows experiencing hyperlipidemia induced by intravenous triglyceride infusion and feed restriction. METHODS: Ten non-pregnant lactating Holstein cows (273 ± 35 d in milk) were administered a single bolus of saline (3 mL of saline; n [Formula: see text] 5) or LPS (0.375 [Formula: see text]g of LPS/kg of body weight; n [Formula: see text] 5). Simultaneously, cows were intravenously infused a triglyceride emulsion and feed restricted for 16 h to induce hyperlipidemia in an attempt to model the periparturient period. Blood was sampled at routine intervals. Changes in circulating total fatty acid concentrations and inflammatory parameters were measured. Plasma samples were analyzed using untargeted lipidomics and metabolomics. RESULTS: Endotoxin increased circulating serum amyloid A, LPS-binding protein, and cortisol concentrations. Endotoxin administration decreased plasma lysophosphatidylcholine (LPC) concentrations and increased select plasma ceramide concentrations. These outcomes suggest modulation of the immune response and insulin action. Lipopolysaccharide decreased the ratio of phosphatidylcholine to phosphatidylethanomanine, which potentially indicate a decrease in the hepatic activation of phosphatidylethanolamine N-methyltransferase and triglyceride export. Endotoxin administration also increased plasma concentrations of pyruvic and lactic acids, and decreased plasma citric acid concentrations, which implicate the upregulation of glycolysis and downregulation of the citric acid cycle (i.e., the Warburg effect), potentially in leukocytes. CONCLUSION: Acute intravenous LPS administration decreased circulating LPC concentrations, modified ceramide and glycerophospholipid concentrations, and influenced intermediary metabolism in dairy cows experiencing hyperlipidemia.


Assuntos
Hiperlipidemias , Insulinas , Animais , Bovinos , Ceramidas , Ácido Cítrico , Emulsões/farmacologia , Endotoxinas/farmacologia , Ácidos Graxos , Feminino , Glicerofosfolipídeos , Hidrocortisona/farmacologia , Hiperlipidemias/induzido quimicamente , Insulinas/farmacologia , Lactação , Lipidômica , Lipopolissacarídeos/farmacologia , Lisofosfatidilcolinas/farmacologia , Metaboloma , Metabolômica , Fosfatidilcolinas , Fosfatidiletanolamina N-Metiltransferase/farmacologia , Proteína Amiloide A Sérica , Triglicerídeos
17.
FEBS Open Bio ; 12(12): 2111-2121, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36111501

RESUMO

Insulin secretion is a signal-triggered process that requires membrane fusion between the secretory granules and plasma membrane in pancreatic ß cells. The exocytosis of insulin is mediated by target-soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) on the plasma membrane and vesicle-SNAREs on the vesicles, which assemble into a quaternary trans-SNARE complex to initiate the fusion. Expression of fusion proteins is reduced in the islets of patients with type II diabetes, indicating that SNARE-mediated fusion defect is closely related to insulin-based metabolic diseases. Previous studies have suggested that epigallocatechin gallate (EGCG) has an inhibitory effect on membrane fusion. In the present study, we performed in vitro reconstitution assays to unravel the molecular mechanisms of EGCG in SNARE-mediated insulin secretory vesicle fusion. Our data show that EGCG efficiently inhibits insulin secretory SNARE-mediated membrane fusion. Mechanistic studies indicated that EGCG blocks the formation of the trans-SNARE complex. Furthermore, calcium/synaptotagmin-7-stimulated fusion kinetics were largely reduced by EGCG, confirming that it is a potential regulator of SNARE-dependent insulin secretion. Our findings suggest that the trans-SNARE complex might be a promising target for controlling SNARE-dependent vesicle fusion.


Assuntos
Diabetes Mellitus Tipo 2 , Insulinas , Humanos , Proteínas SNARE , Fusão de Membrana , Insulinas/farmacologia
18.
FASEB J ; 36(10): e22574, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36165227

RESUMO

In this study, the caprine pancreas has been presented as an alternative to the porcine organ for pancreatic xenotransplantation with lesser risk factors. The obtained caprine pancreas underwent a systematic cycle of detergent perfusion for decellularization. It was perfused using anionic (0.5% w/v sodium dodecyl sulfate) as well as non-ionic (0.1% v/v triton X-100, t-octyl phenoxy polyethoxy ethanol) detergents and washed intermittently with 1XPBS supplemented with 0.1% v/v antibiotic and nucleases in a gravitation-driven set-up. After 48 h, a white decellularized pancreas was obtained, and its extracellular matrix (ECM) content was examined for scaffold-like properties. The ECM content was assessed for removal of cellular content, and nuclear material was evaluated with temporal H&E staining. Quantified DNA was found to be present in a negligible amount in the resultant decellularized pancreas tissue (DPT), thus prohibiting it from triggering any immunogenicity. Collagen and fibronectin were confirmed to be preserved upon trichrome and immunohistochemical staining, respectively. SEM and AFM images reveal interconnected collagen fibril networks in the DPT, confirming that collagen was unaffected. sGAG was visualized using Prussian blue staining and quantified with DMMB assay, where DPT has effectively retained this ECM component. Uniaxial tensile analysis revealed that DPT possesses better elasticity than NPT (native pancreatic tissue). Physical parameters like tensile strength, stiffness, biodegradation, and swelling index were retained in the DPT with negligible loss. The cytocompatibility analysis of DPT has shown no cytotoxic effect for up to 72 h on normal insulin-producing cells (MIN-6) and cancerous glioblastoma (LN229) cells in vitro. The scaffold was recellularized using isolated mouse islets, which have established in vitro cell proliferation for up to 9 days. The scaffold received at the end of the decellularization cycle was found to be non-toxic to the cells, retained biological and physical properties of the native ECM, suitable for recellularization, and can be used as a safer and better alternative as a transplantable organ from a xenogeneic source.


Assuntos
Detergentes , Insulinas , Animais , Antibacterianos/farmacologia , Colágeno/metabolismo , DNA/metabolismo , Matriz Extracelular Descelularizada , Detergentes/química , Detergentes/metabolismo , Detergentes/farmacologia , Etanol/farmacologia , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Cabras , Insulinas/análise , Insulinas/metabolismo , Insulinas/farmacologia , Camundongos , Octoxinol/análise , Octoxinol/metabolismo , Octoxinol/farmacologia , Pâncreas , Estudos Prospectivos , Dodecilsulfato de Sódio/análise , Dodecilsulfato de Sódio/metabolismo , Dodecilsulfato de Sódio/farmacologia , Suínos , Engenharia Tecidual/métodos , Tecidos Suporte/química
19.
Andrologia ; 54(11): e14603, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36156807

RESUMO

Insulin plays important role in testicular functions such as germ cell proliferation and steroidogenesis, despite its conventional role as a hypoglycaemic agent. It is also well known that testicular activity is severely get affected by heat stress and heat stress induces testicular pathogenesis. The effect of insulin on heat-induced testicular impairment has not been investigated. Thus, it is hypothesized that insulin might modulate testicular activity in a heat-stressed model. Experimental mice were separated into 4 groups; the first group was the normal control (CN), and the second group was subjected to heat stress (HS) by submerging the lower body part in a thermostatically controlled water bath maintained at 43°C for 15 min. The third and fourth groups were treated with a single dose of intra-testicular insulin (0.6 IU/mice) before and after heat stress. Animal tissue samples were collected after 14 days of heat treatment. Insulin treatment did not improve the sperm parameters; however, both insulin pre and post-treatment improved the markers of spermatogenesis such as Johnsen score, germinal epithelium height and the number of stages VII/VIII. The histoarchitecture of testis also showed amelioration from heat-induced pathogenesis in the insulin-treated groups. Insulin treatment has also increased the proliferation of germ cells (increased PCNA and GCN), survival (Bcl2), and decreased apoptosis (active caspase-3). Furthermore, insulin treatment decreased MDA levels, without pronounced effects on the activities of antioxidant enzymes. Heat stress also decreased the circulating testosterone and oestrogen levels, and insulin treatment significantly increased oestrogen levels only. Although testosterone showed an increasing trend, it was insignificant. The expression of aromatase, AR, ER-α, and ER-ß was down regulated by heat-stress and insulin treatment up regulated these markers. In conclusion, our results showed the amelioration of heat-induced testicular impairment by pre and post-intra-testicular insulin treatments. Insulin-associated improvements in the pre-and post-treatment groups suggested a preventive mechanism of insulin against heat stress in the testis.


Assuntos
Transtornos de Estresse por Calor , Insulinas , Masculino , Camundongos , Animais , Testículo , Sêmen , Espermatogênese , Transtornos de Estresse por Calor/metabolismo , Testosterona/metabolismo , Apoptose , Resposta ao Choque Térmico , Estrogênios/metabolismo , Insulinas/metabolismo , Insulinas/farmacologia
20.
Nutrients ; 14(18)2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36145208

RESUMO

Binge eating is a characteristic symptom observed in obese individuals that is related to dysfunction of dopaminergic neurons (DNs). Intermittent administration of a high-fat diet (HFD) is reported to induce binge-like eating, but the underlying mechanisms remain unclear. We generated dopaminergic neuron specific IKKß deficient mice (KO) to examine the effects of inflammation in DNs on binge-like eating under inflammatory conditions associated with HFD. After administration of HFD for 4 weeks, mice were fasted for 24 h, and then the consumption of HFD was measured for 2 h. We also evaluated that the mRNA expressions of inflammatory cytokines, glial markers, and dopamine signaling-related genes in the ventral tegmental area (VTA) and striatum. Moreover, insulin was administered intraventricularly to assess downstream signaling. The consumption of HFD was significantly reduced, and the phosphorylation of AKT in the VTA was significantly increased in female KO compared to wild-type (WT) mice. Analyses of mRNA expressions revealed that DNs activity and inflammation in the VTA were significantly decreased in female KO mice. Thus, our data suggest that HFD-induced inflammation with glial cell activation in the VTA affects DNs function and causes abnormal eating behaviors accompanied by insulin resistance in the VTA of female mice.


Assuntos
Transtorno da Compulsão Alimentar , Insulinas , Animais , Transtorno da Compulsão Alimentar/metabolismo , Citocinas/metabolismo , Dieta Hiperlipídica , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Feminino , Quinase I-kappa B/metabolismo , Inflamação/metabolismo , Insulinas/metabolismo , Insulinas/farmacologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/metabolismo , Área Tegmentar Ventral/metabolismo
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