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1.
Int J Mol Sci ; 24(2)2023 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-36674739

RESUMO

Sirolimus (SRL) is widely used as an immunosuppressant to prevent graft rejection, despite the risk of impairing glucose metabolism. Metformin (MET) can reduce the detrimental effects of SRL in many patients, including diabetes and renal transplant recipients. Limited in vivo studies have reported on SRL and MET therapy, particularly in relation to cellular bioenergetics, glucose metabolism, and insulin resistance. Herein, we investigated the efficacy of SRL and MET co-treatment in BALB/c mice over 4 weeks. Balb/c mice (4-6 weeks old) were divided into four groups and injected intraperitoneally (i.p.) with water (control, CTRL), MET (200 µg/g), SRL (5 µg/g), or MET (200 µg/g) +SRL (5 µg/g) over a period of one month. We evaluated the body weight, food consumption rate, random blood glucose (BG), insulin levels, serum biochemistry parameters (ALT, Albumin, BUN, Creatinine), and histomorphology in all groups using standardized techniques and assays. All drug-treated groups showed a statistically significant decrease in weight gain compared to the CTRL group, despite normal food intake. Treatment with SRL caused elevated BG and insulin levels, which were restored with SRL + MET combination. Serum biochemical parameters were within the normal range in all the studied groups. SRL+ MET co-treatment decreased liver cellular respiration and increased cellular ATP levels in the liver. In the pancreas, co-treatment resulted in increased cellular respiration and decreased cellular ATP levels. Liver and pancreatic histology were unchanged in all groups. This study showed that co-treatment of SRL with MET alleviates hyperglycemia induced by SRL without any deleterious effects. These results provide initial insights into the potential use of SRL + MET therapy in various settings.


Assuntos
Hiperglicemia , Insulinas , Metformina , Animais , Camundongos , Sirolimo/farmacologia , Metformina/farmacologia , Camundongos Endogâmicos BALB C , Imunossupressores , Hiperglicemia/tratamento farmacológico , Hiperglicemia/induzido quimicamente , Respiração Celular , Glucose , Trifosfato de Adenosina , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle
2.
Commun Biol ; 6(1): 20, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624306

RESUMO

A high-fat diet can lead to gut microbiota dysbiosis, chronic intestinal inflammation, and metabolic syndrome. Notably, resulting phenotypes, such as glucose and insulin levels, colonic crypt cell proliferation, and macrophage infiltration, exhibit sex differences, and females are less affected. This is, in part, attributed to sex hormones. To investigate if there are sex differences in the microbiota and if estrogenic ligands can attenuate high-fat diet-induced dysbiosis, we used whole-genome shotgun sequencing to characterize the impact of diet, sex, and estrogenic ligands on the microbial composition of the cecal content of mice. We here report clear host sex differences along with remarkably sex-dependent responses to high-fat diet. Females, specifically, exhibited increased abundance of Blautia hansenii, and its levels correlated negatively with insulin levels in both sexes. Estrogen treatment had a modest impact on the microbiota diversity but altered a few important species in males. This included Collinsella aerofaciens F, which we show correlated with colonic macrophage infiltration. In conclusion, male and female mice exhibit clear differences in their cecal microbial composition and in how diet and estrogens impact the composition. Further, specific microbial strains are significantly correlated with metabolic parameters.


Assuntos
Microbioma Gastrointestinal , Insulinas , Feminino , Masculino , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Disbiose , Ligantes , Inflamação/metabolismo , Estrogênios
3.
JAMA Netw Open ; 6(1): e2250375, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36626172

RESUMO

Importance: Although school-based gardening programs for children have consistently been shown to improve dietary behaviors, no cluster randomized clinical trial (RCT) has evaluated the effects of a school-based gardening intervention on metabolic outcomes. Objective: To evaluate the effects of a school-based gardening, nutrition, and cooking intervention (Texas Sprouts) on changes in metabolic outcomes in elementary schoolchildren. Design, Setting, and Participants: This study was a secondary analysis of a cluster RCT, conducted over 3 years from 2016 to 2019, at low-income elementary schools with majority Hispanic students in the greater Austin, Texas, area. Data were analyzed from January to August 2022. Interventions: Texas Sprouts was 1 school year long (9 months) and consisted of (1) Garden Leadership Committee formation; (2) a 0.25-acre outdoor teaching garden; (3) 18 student gardening, nutrition, and cooking lessons taught by trained educators throughout the school year; and (4) 9 monthly parent lessons. The delayed intervention was implemented the following academic year and received an identical intervention. Main Outcomes and Measures: The following measures were obtained at baseline and postintervention (9 months): demographics via survey; measured height, weight, and body mass index parameters; and glucose, insulin, homeostatic model assessment of insulin resistance, and a lipid panel via an optional fasting blood draw. Results: Sixteen elementary schools were randomly assigned to either Texas Sprouts intervention (8 schools) or to delayed intervention (control, 8 schools). A total of 3302 children (aged 7-12 years) were enrolled in Texas Sprouts, and fasting blood samples were obtained from 1104 children (or 33% of those enrolled) at baseline. The final analytic sample included 695 children (307 boys [44.17%]; mean [SE] age, 9.28 [0.04] years; 480 Hispanic children [69.02%]; 452 [65.03%] eligible for free or reduced lunch) with complete demographic data and baseline and postintervention (9-month) fasting blood draws. Compared with control schools, children from Texas Sprouts schools had a 0.02% reduction in mean hemoglobin A1c (95% CI, 0.03%-0.14%; P = .005) and a 6.40 mg/dL reduction in mean low-density lipoprotein cholesterol (95% CI, 3.82-8.97 mg/dL; P = .048). There were no intervention effects on glucose, insulin, homeostatic model assessment of insulin resistance, or other lipid parameters. Conclusions and Relevance: In this cluster RCT, Texas Sprouts improved glucose control and reduced low-density lipoprotein cholesterol in high-risk youth. These findings suggest that elementary schools should incorporate garden-based interventions as a way to improve metabolic parameters in children. Trial Registration: ClinicalTrials.gov Identifier: NCT02668744.


Assuntos
Resistência à Insulina , Insulinas , Masculino , Criança , Humanos , Adolescente , Jardinagem/educação , Promoção da Saúde , Culinária , Lipoproteínas LDL , Colesterol , Lipídeos
4.
Cells ; 12(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36611986

RESUMO

Feeding is crucial for the growth and survival of animals, including humans, but relatively little is known about how it is regulated. Here, we show that larval feeding in Ostrinia furnacalis is regulated by neuropeptide F (NPF, the homologous peptide of mammalian NPY) via the insulin signalling pathway in the midgut. Furthermore, the genes pi3k and mtor in the insulin pathway positively regulate α-amylase and lipase of the midgut by recruiting the transcription factors c-Myc and PPARγ for binding to the promotors of these two enzymes. Importantly, we find that the feeding behaviour and the digestive system of midgut in O. furnacalis larvae are closely related and interactive in that knocking down α-amylase or lipase induces a reduction in larval feeding, while food-deprived larvae lead to fewer expressions of α-amylase and lipase. Importantly, it is the gut NPF that regulates the α-amylase and lipase, while variations of α-amylase and lipase may feed back to the brain NPF. This current study reveals a molecular feedback mechanism between feeding behaviour and the digestive system that is regulated by the conserved NPF via insulin signalling systems in the midgut of O. furnacalis larvae.


Assuntos
Insulinas , Mariposas , Animais , Humanos , Larva/genética , Lipase , Digestão , alfa-Amilases/genética , Mamíferos
5.
PLoS One ; 18(1): e0280195, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36626404

RESUMO

Aiming to evaluate the effects of increased body energy reserve (BER) in Nellore cows' reproductive efficiency, cows were fed with different nutritional plans to obtain animals with high BER (HBER; Ad libitum diet) and moderate BER (MBER: cows fed 70% of HBER group ingestion). To evaluate the BER, cows were weekly weighted and evaluated for subcutaneous fat thickness and insulin serum concentration along the experimental period. At the end of the experimental period, animals were submitted to estrous synchronization and artificial insemination. Animals were slaughtered approximately 120 h after ovulation induction and the reproductive tracts were collected for embryo recovery and samples collection. Cumulus-oocyte-complexes (COC) and follicular fluid were collected from 3-6 mm in diameter ovarian follicles to perform miRNA analysis of cumulus cells (CC) and extracellular vesicles from follicular fluid (EV FF). As expected, differences were observed among MBER and HBER groups for body weight, fat thickness, and insulin serum concentration. HBER animals showed lower ovulation and embryo recovery rates compared to MBER animals. Different miRNAs were found among CC and EV FF within groups, suggesting that the BER may influence follicular communication. This suggests that small follicles (3-6 mm diameter) are already under BER effects, which may be greater on later stages of follicular development.


Assuntos
Insulinas , MicroRNAs , Feminino , Bovinos , Animais , MicroRNAs/genética , MicroRNAs/farmacologia , Folículo Ovariano , Oócitos , Líquido Folicular , Progesterona
6.
FASEB J ; 37(2): e22772, 2023 Feb.
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
7.
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
8.
Artigo em Inglês | MEDLINE | ID: mdl-36674274

RESUMO

GST (glutathione S-transferases) are capable of influencing glucose homeostasis, probably through regulation of the response to oxidant stress. The aim of our study was to investigate the relationship between GSTP1 gene polymorphism and glycated hemoglobin (HbA1c) levels in type two diabetic (T2D) patients. A total of 307 T2D patients were included. Analysis of the GSTP1 gene polymorphism (rs1695) was conducted using the TaqMan qPCR method endpoint genotyping. HbA1c was determined using a COBAS 6000 autoanalyzer. A univariable linear regression and multivariable linear regression model were used to investigate the association between mean HbA1c level and GSTP1 gene polymorphism, age at T2D diagnosis, T2D duration, therapy with insulin, gender, BMI, smoking status. GSTP1 Val/Val genotype, age at T2D diagnosis, T2D duration and therapy with insulin were statistically significant contributors to HbA1c levels (p < 0.05). Multivariable regression analysis revealed that GSTP1 (Val/Val vs. Ile/Ile) was associated with higher HbA1c even after adjustment for variables that showed a statistically significant relationship with HbA1c in univariable analyses (p = 0.024). The results suggest that GSTP polymorphism may be one of the risk factors for higher HbA1c in T2D patients. Our study is limited by the relatively small sample size, cross-sectional design, and lack of inclusion of other oxidative stress-related genetic variants.


Assuntos
Diabetes Mellitus Tipo 2 , Insulinas , Humanos , Pré-Escolar , Glutationa Transferase/genética , Estudos Transversais , Glutationa S-Transferase pi/genética , Genótipo , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudos de Casos e Controles
9.
Medicina (Kaunas) ; 59(1)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36676776

RESUMO

Background: The association between adrenal insufficiency (AI) and the treatment outcomes of cardiothoracic surgery patients has been little reported. The aims of this study were to investigate the incidence of AI and to compare the post-surgical outcomes of patients with perioperatively treated AI and patients with a normal adrenal response. Methods: A 1.5-year prospective study was conducted in 98 patients scheduled for cardiothoracic surgery. Patients were categorized as either AI or normal-adrenal-response patients. Those with AI were treated with stress doses of glucocorticoid perioperatively. The post-surgical outcomes of patients with AI and of those with a normal adrenaline response were analyzed using multivariable analysis. Results: The overall incidence of AI was 34.7%. There were no statistically significant differences in post-surgical outcomes, including prolonged hospital stay, postoperative infection, prolonged inotropic drug use and relative AI, between the two groups. Only the rate of hyperglycemia requiring insulin infusion was significantly higher in the AI group than in the non-AI group (OR = 14.15, 95% CI = 1.44-138.60, p = 0.02). Conclusions: The proper diagnosis and management of AI can result in surgical outcomes in AI patients comparable to those of normal-adrenal-response patients. Non-life-threatening hyperglycemia requiring insulin infusion was found only in the AI group.


Assuntos
Insuficiência Adrenal , Hiperglicemia , Insulinas , Cirurgia Torácica , Humanos , Estudos Prospectivos , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/epidemiologia , Insulinas/uso terapêutico
10.
Mar Drugs ; 21(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36662212

RESUMO

It has been reported that dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential for the preservation of functional ß-cell mass. However, the effect of dietary n-3 PUFA deficiency on pancreatic injury and whether the supplementation of n-3 PUFA could prevent the development of pancreatic injury are still not clear. In the present study, an n-3 PUFA deficiency mouse model was established by feeding them with n-3 PUFA deficiency diets for 30 days. Results showed that n-3 PUFA deficiency aggravated streptozotocin (STZ)-induced pancreas injury by reducing the insulin level by 18.21% and the HOMA ß-cell indices by 31.13% and the area of islet by 52.58% compared with the STZ group. Moreover, pre-intervention with DHA and EPA for 15 days could alleviate STZ-induced pancreas damage by increasing the insulin level by 55.26% and 44.33%, the HOMA ß-cell indices by 118.81% and 157.26% and reversed the area of islet by 196.75% and 205.57% compared to the n-3 Def group, and the effects were significant compared to γ-linolenic acid (GLA) and alpha-linolenic acid (ALA) treatment. The possible underlying mechanisms indicated that EPA and DHA significantly reduced the ration of n-6 PUFA to n-3 PUFA and then inhibited oxidative stress, inflammation and islet ß-cell apoptosis levels in pancreas tissue. The results might provide insights into the prevention and alleviation of pancreas injury by dietary intervention with PUFAs and provide a theoretical basis for their application in functional foods.


Assuntos
Ácidos Graxos Ômega-3 , Insulinas , Camundongos , Animais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Estreptozocina/toxicidade , Ácidos Graxos Insaturados , Ácidos Graxos , Inflamação/tratamento farmacológico , Pâncreas , Suplementos Nutricionais , Apoptose , Estresse Oxidativo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia
11.
Zhongguo Zhen Jiu ; 43(1): 53-9, 2023 Jan 01.
Artigo em Chinês | MEDLINE | ID: mdl-36633240

RESUMO

OBJECTIVE: To observe the hypoglycemic effect of electroacupuncture (EA) at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus (T2DM) as well as its effect on expression of adenosine monophosphate activated protein kinase (AMPK) in liver and pancreas. METHODS: Thirty-six male SD rats were randomly divided into a blank group (6 rats) and a model establishing group (30 rats). The rats in the model establishing group were fed with high-fat diet and treated with intraperitoneal injection of low-dose streptozotocin (STZ) to establish T2DM model. The rats with successful model establishment were randomly divided into a model group, a control group, a metformin group, an EA group and a combination group, 6 rats in each group. The rats in the EA group were treated with EA at "Tianshu" (ST 25), dense-disperse wave, 2 Hz/15 Hz in frequency and 2 mA in current intensity, 20 min each time. The rats in the metformin group were treated with intragastric administration of metformin (190 mg/kg) dissolved in 0.9% sodium chloride solution (2 mL/kg). The rats in the combination group were treated with EA at "Tianshu" (ST 25) and intragastric administration of metformin. The rats in the control group were treated with intragastric administration of 0.9% sodium chloride solution with the same dose. All the treatments were given once a day for 5 weeks. After the intervention, the body mass and random blood glucose were detected; the serum insulin level was detected by ELISA; the expression of AMPK and phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) in liver and pancreas was detected by Western blot method; the expression of protein gene product 9.5 (PGP9.5) was detected by immunofluorescence. RESULTS: ①Compared with the blank group, the body mass in the model group was decreased (P<0.05); compared with the model group, the body mass in the EA group and the combination group was decreased (P<0.05); the body mass in the EA group and the combination group was lower than the metformin group (P<0.05). Compared with the blank group, the random blood glucose in the model group was increased (P<0.01); compared with the model group, the random blood glucose in the metformin group, the EA group and the combination group was decreased (P<0.01). The random blood glucose in the combination group was lower than the metformin group and the EA group (P<0.05). ②Compared with the blank group, the insulin level in the model group was decreased (P<0.05); compared with the model group, the insulin level in the metformin group, the EA group and the combination group was all increased (P<0.05). The insulin level in the combination group was higher than the metformin group and the EA group (P<0.05). ③Compared with the blank group, the protein expression of AMPK and p-AMPK in liver tissue was decreased (P<0.05), and the protein expression of AMPK and p-AMPK in pancreatic tissue was increased (P<0.05) in the model group. Compared with the model group, the protein expression of AMPK and p-AMPK in liver tissue in the metformin group, the EA group and the combination group was increased (P<0.05, P<0.01); the protein expression of AMPK in pancreatic tissue in the metformin group was increased (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was decreased (P<0.05); the protein expression of p-AMPK in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05). The protein expression of AMPK and p-AMPK in liver tissue in the combination group was higher than that in the metformin group and the EA group (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was less than that in the metformin group (P<0.05), and the expression of p-AMPK protein in pancreatic tissue in the combination group was less than that in the metformin group and the EA group (P<0.05). ④Compared with the blank group, the expression of PGP9.5 in pancreatic tissue in the model group was increased (P<0.01); compared with the model group, the expression of PGP9.5 in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05, P<0.01). The expression of PGP9.5 in pancreatic tissue in the EA group was lower than the metformin group and the combination group (P<0.05). CONCLUSION: Electroacupuncture at "Tianshu" (ST 25) could promote the effect of metformin on activating AMPK in liver tissue of T2DM rats, improve the negative effect of metformin on AMPK in pancreatic tissue, and enhance the hypoglycemic effect of metformin. The mechanism may be related to the inhibition of pancreatic intrinsic nervous system.


Assuntos
Diabetes Mellitus Tipo 2 , Eletroacupuntura , Insulinas , Metformina , Animais , Masculino , Ratos , Pontos de Acupuntura , Proteínas Quinases Ativadas por AMP/genética , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes , Ratos Sprague-Dawley
12.
J Endocrinol ; 256(2)2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36476407

RESUMO

Vitamin B12 (B12) deficiency is common among individuals with diabetes mellitus, but it is unknown if B12 deficiency contributes to impaired glucose homeostasis in this disorder. Female Sprague-Dawley rats were assigned to a control or B12-deficient diet for 4 weeks. Intraperitoneal glucose tolerance tests were performed after 25 days, and blood and liver samples were collected for metabolic profiling. B12 deficiency resulted in a prediabetic-like phenotype characterised by glucose intolerance, a delayed peak in plasma insulin levels following a glucose challenge and increased ketogenesis. We attributed increased ketogenesis to reduced liver anaplerosis, which limited the availability of the TCA cycle intermediates citrate, succinate and succinyl-CoA. This was associated with increased Mut mRNA levels and citrate synthase activity in the liver. One-carbon metabolite levels were altered in plasma and the liver, which was linked to reduced methylation capacity, altered amino acid levels and elevated Slc7a5 mRNA expression. Plasma folate and biotin levels were reduced, as were the majority of B vitamins in the liver. Changes in these B12-dependent processes and reduced B vitamin amounts likely contributed to deficits in glucose handling. Our findings highlight that B12 deficiency may promote the development of metabolic disorders like diabetes mellitus and emphasise the importance of adequate B12 intake for metabolic health.


Assuntos
Intolerância à Glucose , Insulinas , Deficiência de Vitamina B 12 , Ratos , Animais , Feminino , Ratos Sprague-Dawley , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/metabolismo , Ácido Fólico/metabolismo , Vitaminas , Glucose
13.
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
14.
J Agric Food Chem ; 71(1): 300-310, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36538395

RESUMO

The insulin receptor substrate (IRS), as the core cytoplasmic adapter protein in the insulin/insulin-like signaling (IIS) pathway, is an important mediator of cellular signaling. However, it is still unknown how IRS crosstalk with hormone signaling regulates insect growth, development, and reproduction. In this study, we demonstrated that knockdown of IRS1 significantly inhibited oogenesis, vitellogenesis, and the development of nurse cells and follicular epithelial cells. In addition, qRT-PCR results showed that FOXO transcription factors significantly responded to silencing of the IRS1 gene. However, IRS1 silencing had no significant effect on the expression of juvenile hormone/20-hydroxyecdysone (JH/20E)-signaling genes, JH synthesis, and degradation enzyme-related genes and the JH/20E titers. Our results suggested that the IIS pathway regulated ovarian development and Vg production through FOXO, independent of JH and 20E signaling pathways. This study revealed the reproductive regulation mechanism in Propylea japonica, which provides a theoretical basis for large-scale expansion of P. japonica as an environment-friendly biological control strategy.


Assuntos
Besouros , Insulinas , Animais , Vitelogênese/genética , Fatores de Transcrição/genética , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Oogênese/genética , Transdução de Sinais , Hormônios Juvenis/genética , Besouros/metabolismo , Insulinas/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo
15.
Biomacromolecules ; 24(1): 481-488, 2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36512327

RESUMO

Protein aggregation is an obstacle for the development of new biopharmaceuticals, presenting challenges in shipping and storage of vital therapies. Though a variety of materials and methods have been explored, the need remains for a simple material that is biodegradable, nontoxic, and highly efficient at stabilizing protein therapeutics. In this work, we investigated zwitterionic polypeptides prepared using a rapid and scalable polymerization technique and conjugated to a supramolecular macrocycle host, cucurbit[7]uril, for the ability to inhibit aggregation of model protein therapeutics insulin and calcitonin. The polypeptides are based on the natural amino acid methionine, and zwitterion sulfonium modifications were compared to analogous cationic and neutral structures. Each polymer was end-modified with a single cucurbit[7]uril macrocycle to afford supramolecular recognition and binding to terminal aromatic amino acids on proteins. Only conjugates prepared from zwitterionic structures of sufficient chain lengths were efficient inhibitors of insulin aggregation and could also inhibit aggregation of calcitonin. This polypeptide exhibited no cytotoxicity in human cells even at concentrations that were five-fold of the intended therapeutic regime. We explored treatment of the zwitterionic polypeptides with a panel of natural proteases and found steady biodegradation as expected, supporting eventual clearance when used as a protein formulation additive.


Assuntos
Calcitonina , Insulinas , Humanos , Hidrocarbonetos Aromáticos com Pontes/química , Peptídeos/farmacologia
16.
J Pharmacol Exp Ther ; 384(1): 116-122, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36549862

RESUMO

Endothelial dysfunction represents a key mechanism underlying heart failure with preserved ejection fraction (HFpEF), diabetes mellitus (DM), and frailty. However, reliable biomarkers to monitor endothelial dysfunction in these patients are lacking. In this study, we evaluated the expression of a panel of circulating microRNAs (miRs) involved in the regulation of endothelial function in a population of frail older adults with HFpEF and DM treated for 3 months with empagliflozin, metformin, or insulin. We identified a distinctive pattern of miRs that were significantly regulated in HFpEF patients compared to healthy controls and to HFpEF patients treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin. Three miRs were significantly downregulated (miR-126, miR-342-3p, and miR-638) and two were significantly upregulated (miR-21 and miR-92) in HFpEF patients compared to healthy controls. Strikingly, two of these miRs (miR-21 and miR-92) were significantly reduced in HFpEF patients after the 3-month treatment with empagliflozin, whereas no significant differences in the profile of endothelial miRs were detected in patients treated with metformin or insulin. Taken together, our findings demonstrate for the first time that specific circulating miRs involved in the regulation of endothelial function are significantly regulated in frail HFpEF patients with DM and in response to SGLT2 inhibition. SIGNIFICANCE STATEMENT: We have identified a novel microRNA signature functionally involved in the regulation of endothelial function that is significantly regulated in frail patients with HFpEF and diabetes. Moreover, the treatment with the SGLT2 inhibitor empagliflozin caused a modification of some of these microRNAs in a direction that was opposite to what observed in HFpEF patients, indicating a rescue of endothelial function. Our findings are relevant for clinical practice inasmuch as we were able to establish novel biomarkers of disease and response to therapy.


Assuntos
Diabetes Mellitus , Insuficiência Cardíaca , Insulinas , Metformina , MicroRNAs , Doenças Vasculares , Humanos , Idoso , MicroRNAs/genética , Transportador 2 de Glucose-Sódio , Volume Sistólico , Metformina/farmacologia , Metformina/uso terapêutico , Biomarcadores , Insulinas/metabolismo , Insulinas/uso terapêutico
17.
Mol Metab ; 67: 101651, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36481344

RESUMO

OBJECTIVE: Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5'-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis in Ldlr-/- mice. METHODS: Male or female Ldlr-/- mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6Chi monocytes and ex vivo 5-ethynyl-2'-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge. RESULTS: PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and male Ldlr-/- mice, respectively. PPM also decreased IR and hepatic fat and inflammation in male Ldlr-/- mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA- and IsoLG-lysyl adducts in Ldlr-/- mice. In addition, PPM increased the net cholesterol efflux capacity of HDL from Ldlr-/- mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1ß expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6Chi monocytes and proliferation of bone marrow monocytes and HSPC from Ldlr-/- mice. CONCLUSIONS: PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease.


Assuntos
Aterosclerose , Resistência à Insulina , Insulinas , Placa Aterosclerótica , Masculino , Feminino , Camundongos , Animais , HDL-Colesterol/uso terapêutico , Piridoxamina , Camundongos Knockout , Aterosclerose/metabolismo , Colesterol/metabolismo , Inflamação/tratamento farmacológico , Insulinas/uso terapêutico , Glucose
18.
Int J Med Inform ; 170: 104960, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36525801

RESUMO

AIM: There is an increasing trend in the use of internet as a search tool for health-related informations. Insulin resistance is one of the most searched subjects online and some of the videos about insulin resistance have been watched by millions of YouTube users. This study aims to determine the quality and reliability of the most popular videos about insulin resistance on YouTube. METHODS: On March 1, 2022, the term "insulin resistance" was searched on YouTube. The videos' popularity was assessed with Video Power Index (VPI). The quality and reliability were assessed with DISCERN score, modified DISCERN score and global quality score (GQS). RESULTS: A total of 100 most popular videos were evaluated after applying the exclusion criteria. Fifty-four percent of the videos were very poor-poor, 35 % moderate, and 11 % good-excellent quality. Although few in number, the videos with relatively higher quality and more reliable had higher numbers of views, likes and comments (p < 0.01). There was a positive correlation between DISCERN score and VPI, duration, view, like, dislike, comment numbers of the videos (p < 0.01). Healthcare providers uploaded 58 % of the videos, while independent users uploaded 42 %. Video like ratio (VLR) at healthcare providers' videos was significantly higher than independent users' videos (p = 0.001). CONCLUSIONS: Despite the high viewing rates of YouTube videos about insulin resistance, the overall quality and reliability were found to be very low. However, when high quality content regarding popular medical topics is produced, more people can be informed correctly.


Assuntos
Insulinas , Mídias Sociais , Humanos , Pessoal de Saúde , Disseminação de Informação , Internet , Reprodutibilidade dos Testes , Resistência à Insulina
19.
Toxicol Lett ; 374: 31-39, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36493961

RESUMO

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphate flame retardant. The primary TDCPP metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), is detectable in the urine of over 90 % of Americans. Epidemiological studies show sex-specific associations between urinary BDCPP levels and metabolic syndrome, which is an established risk factor for type 2 diabetes, heart disease, and stroke. We used a mouse model to determine whether TDCPP exposure disrupts glucose homeostasis. Six-week old male and female C57BL/6J mice were given ad libitum access to diets containing vehicle (0.1 % DMSO) and TDCPP resulting in the following treatment groups: 0 mg/kg/day, 0.02 mg/kg/day, 1 mg/kg/day, or 100 mg/kg/day. After being on the experimental diet for five weeks without interruption, body composition was analyzed, glucose and insulin tolerance tests were performed, and fasting glucose and insulin levels were quantified. TDCPP at 100 mg/kg/day caused male sex-specific adiposity, fasting hyperglycemia, and insulin resistance. TDCPP-induced modulation of nuclear receptor activation was investigated using an in vitro screen to identify potential mechanisms of metabolic disruption. TDCPP activated farnesoid X receptor (FXR) and pregnane X receptor (PXR), and inhibited the androgen receptor (AR). PXR target genes, but not FXR target genes, were upregulated in livers from mice exposed to 100 mg TDCPP/kg/day. Interestingly, PXR target genes were differentially expressed in livers from both males and females. It remains to be determined whether TDCPP-induced metabolic disruption occurs via modulation of nuclear receptor activity. Taken together, these studies build upon the association of TDCPP exposure and metabolic syndrome in humans by identifying sex-specific effects of TDCPP on glucose homeostasis in mice.


Assuntos
Diabetes Mellitus Tipo 2 , Retardadores de Chama , Insulinas , Síndrome Metabólica , Humanos , Masculino , Feminino , Animais , Camundongos , Fosfatos , Camundongos Endogâmicos C57BL , Compostos Organofosforados/metabolismo , Organofosfatos/metabolismo , Receptores Citoplasmáticos e Nucleares , Retardadores de Chama/toxicidade , Retardadores de Chama/metabolismo
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