Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 63.366
Filtrar
1.
J Int Med Res ; 50(1): 3000605211067316, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34986678

RESUMEN

OBJECTIVE: This meta-analysis evaluated the association between the mean platelet volume (MPV) and polycystic ovary syndrome (PCOS). METHODS: A systematic literature search using PubMed, EMBASE, and Web of Science databases until June 2021 was conducted. Pooled standardized mean differences (SMD) and 95% confidence intervals (CI) were determined using a random effects model. RESULTS: Ten studies involving 866 women with PCOS and 548 age- and body mass index-matched women without PCOS were included. The MPV was significantly increased in women with PCOS compared with non-PCOS women (SMD = 0.43, 95% CI = 0.13-0.72). Subgroup analyses showed that this trend was consistent in cross-sectional studies (SMD = 0.44, 95% CI = 0.03-0.86) and in Turkish women (SMD = 0.46, 95% CI = 0.13-0.79). Meta-regression analysis revealed a marginally positive correlation between the MPV and the homoeostasis model assessment of insulin resistance in women with PCOS. The sensitivity analysis showed that the effect estimate was robust and stable, and publication bias was not evidenced in the pooled analysis. CONCLUSIONS: This meta-analysis revealed that women with PCOS have a significantly increased MPV than women without PCOS, which is probably associated with insulin resistance.INPLASY registration number: INPLASY2021100021.


Asunto(s)
Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Índice de Masa Corporal , Estudios Transversales , Femenino , Humanos , Volúmen Plaquetario Medio
2.
Life Sci ; 289: 120221, 2022 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-34902437

RESUMEN

AIM: Free fatty acid-mediated obesity plays a crucial role in the pathogenesis of Type 2 Diabetes. FFA induced JNK activation acts as a central regulator in causing hepatic insulin resistance. Similarly, Pancreastatin, a chromogranin A peptide, serves as a crucial link between FFA-induced insulin resistance. Therefore, in the present work, we sought to test Pancreastatin inhibitor PSTi8 to ameliorate FFA-induced hepatic insulin resistance in in vitro and in vivo models. MATERIAL AND METHODS: To verify our objective, we exposed hepatocytes (HepG2 cells) with palmitate (0.3 mM) or palmitate + PSTi8 (200 nM). Parallelly mice were fed either HFD or HFD + PSTi8 (1 mg/kg). After 21 days animals were scanned for increased fat mass, along with GTT, ITT and PTT experiment to check glucose, and insulin tolerance. Furthermore, ROS generation and hepatic glycogen content was measured in FFA exposed hepatocytes. Gene expression and protein expression studies were further conducted to delineate the action mechanism of PSTi8. KEY FINDINGS: PSTi8 exposure decreased ROS accumulation, lipid accumulation, and reduced glycogen content in FFA-induced groups. It also enhances glucose uptake and reduces gluconeogenesis to combat the FFA effect. Furthermore, gene expression studies indicate that PSTi8 treatment reduces NADPH oxidase3 (NOX3) expression and inhibits JNK signaling, a predominant source of ROS-induced insulin resistance. SIGNIFICANCE: To summarize, the protective effect of PSTi8 on FFA-induced insulin resistance is mediated via inhibition of JNK signaling, which leads to decreased ROS generation and enhanced insulin sensitivity. Hence PSTi8 could be a therapeutic molecule to prevent western diet-induced insulin resistance.


Asunto(s)
Cromogranina A/antagonistas & inhibidores , Ácidos Grasos/metabolismo , Resistencia a la Insulina , MAP Quinasa Quinasa 4/metabolismo , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Cromogranina A/metabolismo , Células Hep G2 , Humanos , Masculino , Ratones
3.
Life Sci ; 289: 120213, 2022 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-34902439

RESUMEN

BACKGROUND: Regardless of the etiology, any type of DM presents a reduction of insulin-secreting cell mass, so it is important to investigate pathways that induce the increase of this cell mass. AIM: Based on the fact that (1) HNF4α is crucial for ß-cell proliferation, (2) DEX-induced IR promotes ß-cell mass expansion, and (3) the stimulation of ß-cell mass expansion may be an important target for DM therapies, we aimed to investigate whether DEX-induced proliferation of ß pancreatic cells is dependent on HNF4α. METHODS: We used WildType (WT) and Knockout (KO) mice for HNF4-α, treated or not with 100 mg/Kg/day of DEX, for 5 consecutive days. One day after the last injection of DEX the IR was confirmed by ipITT and the mice were euthanized for pancreas removal. RESULTS: In comparison to WT, KO mice presented increased glucose tolerance, lower fasting glucose and increased glucose-stimulates insulin secretion (GSIS). DEX induced IR in both KO and WT mice. In addition, DEX-induced ß-cell mass expansion and an increase in the Ki67 immunostaining were observed only in WT mice, evidencing that IR-induced ß-cell mass expansion is dependent on HNF4α. Also, we observed that DEX-treatment, in an HNF4α-dependent way, promoted an increase in PDX1, PAX4 and NGN3 gene expression. CONCLUSIONS: Our results strongly suggest that DEX-induced IR promotes ß-cell mass expansion through processes of proliferation and neogenesis that depend on the HNF4α activity, pointing to HNF4α as a possible therapeutic target in DM treatment.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Dexametasona/farmacología , Factor Nuclear 4 del Hepatocito/metabolismo , Resistencia a la Insulina , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proliferación Celular/genética , Regulación de la Expresión Génica/efectos de los fármacos , Factor Nuclear 4 del Hepatocito/genética , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/genética , Secreción de Insulina/genética , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Factores de Transcripción Paired Box/biosíntesis , Factores de Transcripción Paired Box/genética , Transactivadores/biosíntesis , Transactivadores/genética
4.
FASEB J ; 36(1): e22088, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34921686

RESUMEN

Hyperinsulinemia is commonly viewed as a compensatory response to insulin resistance, yet studies have demonstrated that chronically elevated insulin may also drive insulin resistance. The molecular mechanisms underpinning this potentially cyclic process remain poorly defined, especially on a transcriptome-wide level. Transcriptomic meta-analysis in >450 human samples demonstrated that fasting insulin reliably and negatively correlated with INSR mRNA in skeletal muscle. To establish causality and study the direct effects of prolonged exposure to excess insulin in muscle cells, we incubated C2C12 myotubes with elevated insulin for 16 h, followed by 6 h of serum starvation, and established that acute AKT and ERK signaling were attenuated in this model of in vitro hyperinsulinemia. Global RNA-sequencing of cells both before and after nutrient withdrawal highlighted genes in the insulin receptor (INSR) signaling, FOXO signaling, and glucose metabolism pathways indicative of 'hyperinsulinemia' and 'starvation' programs. Consistently, we observed that hyperinsulinemia led to a substantial reduction in Insr gene expression, and subsequently a reduced surface INSR and total INSR protein, both in vitro and in vivo. Bioinformatic modeling combined with RNAi identified SIN3A as a negative regulator of Insr mRNA (and JUND, MAX, and MXI as positive regulators of Irs2 mRNA). Together, our analysis identifies mechanisms which may explain the cyclic processes underlying hyperinsulinemia-induced insulin resistance in muscle, a process directly relevant to the etiology and disease progression of type 2 diabetes.


Asunto(s)
Antígenos CD/biosíntesis , Regulación hacia Abajo , Hiperinsulinismo/metabolismo , Resistencia a la Insulina , Músculo Esquelético/metabolismo , ARN Mensajero/biosíntesis , Receptor de Insulina/biosíntesis , Animales , Antígenos CD/genética , Línea Celular , Humanos , Hiperinsulinismo/genética , Ratones , Ratones Noqueados , ARN Mensajero/genética , RNA-Seq , Receptor de Insulina/genética
5.
FASEB J ; 36(1): e22056, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34939223

RESUMEN

Brown adipose tissue (BAT) transplantation is a promising means of increasing whole-body energy metabolism to ameliorate obesity. However, the changes in BAT following transplantation and the effects of the microenvironment of the recipient site on graft function have yet to be fully characterized. Therefore, we aimed to determine the effects of transplanting BAT from C57BL/6 mice into the dorsal subcutaneous region or deep to the quadriceps femoris muscle of leptin-deficient ob/ob mice. Subcutaneously transplanted BAT lost features of BAT and demonstrated greater inflammatory cell infiltration and more oil cysts 16 weeks following transplantation. By contrast, the sub-muscularly transplanted BAT maintained features of BAT and was more highly vascularized. Interestingly, sub-muscular BAT transplantation led to a significant increase in oxygen consumption and less inflammation in subcutaneous fat, which was associated with long-term reductions in insulin resistance and body mass gain, whereas the subcutaneous transplants failed after 16 weeks. These results demonstrate that the beneficial effects of BAT transplantation depend upon the microenvironment of the recipient site. Skeletal muscle may provide a microenvironment that maintains the inherent features of BAT grafts over a long period of time, which facilitates a reduction in obesity and improvements in glucose homeostasis.


Asunto(s)
Tejido Adiposo Pardo , Microambiente Celular , Resistencia a la Insulina , Músculo Esquelético/metabolismo , Obesidad/metabolismo , Grasa Subcutánea/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/trasplante , Animales , Masculino , Ratones , Ratones Obesos , Obesidad/patología , Obesidad/terapia
6.
Biol Trace Elem Res ; 200(1): 76-83, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33655432

RESUMEN

We aimed to investigate the association between zinc (Zn) supplementation and serum levels of copeptin, high-sensitive C-reactive protein (hs-CRP), glycemic control, anthropometric parameters and renal function in Zn -deficient diabetic hemodialysis patients (DHPs). This randomized, double-blind, placebo-controlled trial (RCT) was conducted on 46 DHPs with Zn-deficiency. The Zn supplement group (n = 21) received a 220-mg/day Zn sulfate capsule (containing 50 mg Zn), and the control group (n = 25) received a placebo capsule (220 mg corn starch), for 8 weeks. Fasting, predialysis blood samples were taken at baseline and after 8 weeks to assess fasting blood glucose (FBG), serum insulin, copeptin, high-sensitive C-reactive protein (hs-CRP), blood urea nitrogen (BUN), creatinine (Cr) concentrations, and homoeostatic model assessment (HOMA-IR) and quantitative insulin-sensitivity check index (QUICKI). Compared to controls, serum copeptin (P < 0.001), hs-CRP (P < 0.001), BUN (P < 0.001), Cr (P < 0.001), Zn (P < 0.001), FBG (P < 0.001) levels, BMI (P < 0.001), and body weight (P < 0.001) were significantly affected following ZnSO4 supplementation for 8 weeks. In contrast, QUICKI (P = 0.57), HOMA-IR (P = 0.60), and serum insulin (P = 0.55) were not affected following Zn supplementation in comparison with patients receiving placebo. Zn sulfate supplementation appears to have favorable effects on serum copeptin and hs-CRP, FBG, and renal function in Zn-deficient DHPs. Iranian Registry of Clinical Trials Identifier: IRCT20190806044461N1.


Asunto(s)
Diabetes Mellitus , Resistencia a la Insulina , Glucemia , Proteína C-Reactiva , Suplementos Dietéticos , Método Doble Ciego , Glicopéptidos , Humanos , Insulina , Irán , Diálisis Renal , Zinc , Sulfato de Zinc
7.
Gene ; 807: 145888, 2022 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-34371096

RESUMEN

BACKGROUND: Gestational diabetes mellitus (GDM) is a glucose intolerance condition encounters for the first time in a fraction of pregnant women. The role of different host inflammatory molecules in GDM etiology has been deciphered. Chemerin is a chemoattractant protein primarily associated with the pathogenesis of type 2 diabetes, obesity, and metabolic syndrome. However, the association of chemerin and its genetic variants with the predisposition of GDM is not clear, and our present study is aimed to address the issue. MATERIALS AND METHODS: A total of 703 Chinese women comprising of GDM (n = 303), glucose tolerant pregnant women (n = 211), and non-pregnant glucose tolerant controls (n = 189) were recruited in the present investigation. GDM was diagnosed according to the World Health Organization recommendation for diagnosis of gestational diabetes during pregnancy. Plasma levels of chemerin were quantified by an Enzyme-linked Immunosorbent Assay (ELISA). Common variants in the chemerin gene (rs4721, rs17173617, rs7806429, and rs17173608) were genotyped by using TaqMan assay. RESULTS: Plasma chemerin level was found higher in subjects with GDM as compared to glucose tolerant pregnant and non-pregnant women. Further, a positive correlation between plasma chemerin and HOMA-IR index suggesting an essential role of chemerin in mediating insulin resistance. Variants of rs4721 and rs17173608 polymorphisms were associated with lower levels of plasma chemerin and low HOMA-IR index. Furthermore, mutants of rs4721 and rs17173608 polymorphisms were associated with protection against the development of GDM in the Chinese cohort. CONCLUSIONS: Plasma chemerin is elevated in GDM patients. Genetic variation in chemerin gene associated with lower plasma levels of chemerin, HOMA-IR index and protects against the development of GDM in Chinese.


Asunto(s)
Quimiocinas/genética , Quimiocinas/metabolismo , Diabetes Gestacional/genética , Adulto , Glucemia/genética , Quimiocinas/sangre , China , Estudios de Cohortes , Diabetes Gestacional/metabolismo , Diabetes Gestacional/fisiopatología , Pruebas Diagnósticas de Rutina/métodos , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Intolerancia a la Glucosa/genética , Humanos , Insulina/metabolismo , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Síndrome Metabólico/genética , Obesidad/genética , Polimorfismo Genético/genética , Embarazo
8.
Phytomedicine ; 95: 153869, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34923235

RESUMEN

BACKGROUND: Type 2 diabetes mellitus is a complex metabolic disorder associated with obesity, glucose intolerance and insulin resistance. Activation of GALR2 has been proposed as a therapeutic target for the treatment of insulin resistance. The previous studies showed that baicalin could mitigate insulin resistance, but the detailed mechanism of baicalin on insulin resistance has not been fully explored yet. PURPOSE: In the present study, we evaluated whether baicalin mitigated insulin resistance via activation of GALR2 signaling pathway. STUDY DESIGN/METHODS: Baicalin (25 mg/kg/d and 50 mg/kg/d) and/or GALR2 antagonist M871 (10 mg/kg/d) were injected individually or in combinations into obese mice once a day for three weeks, and normal and GALR2 knockdown myotubes were treated with baicalin (100 µM and 400 µM) or metformin (4 mM) in the absence or presence of M871 (800 nM) for 12 h, respectively. The molecular mechanism was explored in skeletal muscle and L6 myotubes. RESULTS: The present findings showed that baicalin mitigated hyperglycemia and insulin resistance and elevated the levels of PGC-1α, GLUT4, p-p38MAPK, p-AKT and p-AS160 in skeletal muscle of obese mice. Strikingly, the baicalin-induced beneficial effects were abolished by GALR2 antagonist M871 in obese mice. In vitro, baicalin dramatically augmented glucose consumption and the activity of PGC1α-GLUT4 axis in myotubes through activation of p38MAPK and AKT pathways. Moreover, baicalin-induced elevations in glucose consumption related genes were abolished by GALR2 antagonist M871 or silencing of GALR2 in myotubes. CONCLUSIONS: The present study for the first time demonstrated that baicalin protected against insulin resistance and metabolic dysfunction mainly through activation of GALR2-GLUT4 signal pathway. Our findings identified that activation of GALR2-GLUT4 signal pathway by baicalin could be a new therapeutic approach to treat insulin resistance and T2DM in clinic.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Animales , Flavonoides/farmacología , Glucosa , Transportador de Glucosa de Tipo 4 , Insulina/metabolismo , Ratones , Músculo Esquelético/metabolismo , Transducción de Señal
9.
Nutrition ; 93: 111439, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34507264

RESUMEN

OBJECTIVES: Species Lactobacillus acidophilus and butyrate producer Clostridium cochlearium have been shown to have potential antiobesity effects. The aim of this study was to show that the combination of C. cochlearium and L. acidophilus (CC-LA) has beneficial effects on body weight control and glucose homeostasis in high-fat diet-induced obese (DIO) mice. METHODS: In this study, thirty-six 6-wk-old male C57BL/6 mice were randomly assigned to three groups of 12 mice each. The experimental group (CC-LA) was administered with CC-LA mixture and fed ad libitum with a high-fat diet. High-fat diet (HF) control and low-fat diet (LF) control groups were treated with the same dose of sterile water as the CC-LA group. RESULTS: After 17 wk of dietary intervention, the CC-LA group showed 17% less body weight gain than the HF group did (P < 0.01). The CC-LA group also showed significantly reduced incremental area under the curve of oral glucose tolerance test and homeostatic model assessment for insulin resistance compared with the HF group. The results from 16S rRNA sequencing analysis of gut microbiota showed that the CC-LA administration led to overall increased α-diversity indices, and a significant microbial separation from the HF group. The ratio of Firmicutes to Bacteroidetes (F/B) was reduced from 3.30 in the HF group to 1.94 in the CC-LA group. The relative abundances of certain obesity-related taxa were also decreased by CC-LA administration. CONCLUSION: The present study provided evidence that the CC-LA combination reduced obesity and improved glucose metabolism in high-fat diet-treated DIO mice, potentially mediated by the modulation of gut microbiota.


Asunto(s)
Microbioma Gastrointestinal , Resistencia a la Insulina , Animales , Clostridium , Dieta Alta en Grasa/efectos adversos , Lactobacillus acidophilus , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , ARN Ribosómico 16S , Aumento de Peso
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 264: 120322, 2022 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-34509062

RESUMEN

IMPORTANCE: One of the consequential and alarming complications of diabetes mellitus is diabetic neuropathy (DN). DN is assured to be caused chiefly by excess sorbitol levels in the body. The harmful consequences of DN alike peripheral nerve damage with extremity ulcers may be dodged with timely detection and treatment. The therapeutic methods for DN are scarce and expensive. Therefore economic and user friendly methodologies to prevent acquiring the disease need proper attention. OBJECTIVE: The present research has been conducted (1) to analyse the levels of sorbitol in diabetic blood samples and compare them with non-diabetic ones and (2) to study the reduction in sorbitol levels upon addition of an important biochemical compounds caffeine in both sample groups. RESEARCH DESIGN, SETTING, PARTICIPANTS AND METHOD: Sorbitol-caffeine interaction analysis of blood samples of 16 patients with type 2 diabetes from KPC Medical College, Kolkata, India was made. The spectroscopic analysis and their interpretations were compared with 16 healthy subjects. MAIN OUTCOMES AND MEASURES: Present work describes that caffeine can be helpful in reducing the sorbitol level in diabetics, so the chances of development and progression of diabetic neuropathy can be controlled with the introduction of caffeine. RESULTS: A total number of 32 blood samples of patients (aged 35-70 years); mean age ranges were 52.06 ± 2.68 and 53.50 ± 2.66 years for non-diabetic and diabetic ones respectively, glucose and sorbitol screening examination were done by enzymatic methodologies where concentrations were assessed by means of either absorption or fluorescence spectroscopy. The calibration range was 18.2-1119.3 mg/dL (Linear regression analysis r2 = 0.996). The sensitivity of this screening program in detecting DN with the healthy adults has been inquired and found efficient. Results of fasting insulin analyses have also been analysed for HOMA-IR (homeostasis model assessment - insulin resistance) and HOMA-B (homeostasis model assessment - pancreatic ß cell function) values. Statistical significance of the results in non-diabetic and diabetic groups were performed and found to be statistically significant. CONCLUSIONS: We have defined the relationship between blood glucose level, insulin level, sorbitol and caffeine in human body and utilized them in the plausible remediation of DN.


Asunto(s)
Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Resistencia a la Insulina , Glucemia , Cafeína , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Neuropatías Diabéticas/tratamiento farmacológico , Humanos , Insulina , Persona de Mediana Edad
11.
Nutrition ; 93: 111412, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34749061

RESUMEN

OBJECTIVES: Skeletal muscle accounts for 80% of whole body insulin-stimulated glucose uptake, and it plays a key role in preventing and curing obesity and insulin resistance (IR). Vitamin K2 (VK2) plays a beneficial role in improving mitochondrial function through SIRT1 signaling in high-fat diet (HFD)-induced mice and palmitate acid (PA)-treated C2C12 cells. A previous study also found VK2 increases oxidative muscle fibers and decreases glycolytic muscle fibers in obesity-induced mice, however, the underlying molecular mechanism of effect of VK2 on increasing oxidative fibers have not been well established. METHODS: C57BL/6 male mice were induced IR using HFD fed. Animals received HFD for eight weeks, and different doses of VK2 were supplemented by oral gavage for the last eight weeks were randomly and equally divided into seven groups. C2C12 cells were exposed to different doses of PA for 16 h to mimic insulin resistance in vivo. Skeletal muscle types and mitochondrial function evaluated. C2C12 cells were transfected with SIRT1 siRNA. RESULTS: The present study first revealed that VK2 intervention also alleviated plasma non-esterified fatty acid levels that contribute to obesity-induced IR, VK2 administration also could effectively increase the proportion of slow-twitch fibers by improving mitochondrial function via SIRT1 signaling pathway in both HFD-fed mice and PA-exposed cells. However, the benefits of VK2 were abrogated in C2C12 transfected with SIRT1 siRNA in PA-treated C2C12 cells. Thus, SIRT1 is partially required for VK2 improvement the proportion of slow-twitch fiber in PA-treated C2C12 cells. CONCLUSION: Naturally occurring VK2 increases slow-twitch fibers by improving mitochondrial function and decreasing non-esterified fatty acid levels via partially SIRT1/SIRT3 signaling pathway. These data have potential importance for the therapy for a number of muscular and neuromuscular diseases in humans.


Asunto(s)
Resistencia a la Insulina , Sirtuina 3 , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares de Contracción Lenta/metabolismo , Músculo Esquelético/metabolismo , Transducción de Señal , Sirtuina 1/genética , Sirtuina 1/metabolismo , Sirtuina 3/metabolismo , Vitamina K 2
12.
Methods Mol Biol ; 2343: 119-145, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34473318

RESUMEN

The global pandemics of obesity and sedentarism are associated with poor quality of life and increased risks for development of inflammatory chronic diseases, including type 2 diabetes, cardiovascular diseases, and cancer. Physical activity is considered as an antidote to counteract the development of chronic sterile inflammatory diseases. Thus, we review the most promising exercise training protocols for promoting weight loss, improving glucose homeostasis, and reducing inflammation. We discuss the advantages and disadvantages of moderate-intensity continuous aerobic training, high-intensity aerobic training, and combined (aerobic + resistance) training. Our aim with this chapter is to provide evidence and guidance for choosing the most appropriate protocols of exercise training according to the goals of the patient.


Asunto(s)
Diabetes Mellitus Tipo 2 , Ejercicio Físico , Resistencia a la Insulina , Obesidad , Glucemia , Diabetes Mellitus Tipo 2/terapia , Glucosa , Homeostasis , Humanos , Inflamación , Obesidad/terapia , Calidad de Vida
13.
Metabolism ; 126: 154917, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34687727

RESUMEN

INTRODUCTION: Roux-en-Y gastric bypass surgery (RYGB) has been shown to be the gold standard treatment for obesity associated type-2-diabetes (T2D), however many T2D patients do not qualify or are reluctant to proceed with surgery due to its potential risks and permanent changes to GI anatomy. We have previously described a novel oral formulation, LuCI, that provides a transient coating of the proximal bowel and mimics the effects of RYGB. Herein, we aim to investigate the outcome of chronic LuCI administration on weight and glucose homeostasis. METHODS: Sprague-Dawley rats on a high fat diet achieving diet-induced obesity (DIO) received 5 weeks of daily LuCI or normal saline as control (n = 8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At 5 weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, fecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry. RESULTS: At 5 weeks, LuCI animals weighted 8.3% less and had lower fasting glucose levels than Controls (77.6 ±â€¯3.8 mg/dl vs. 99.1 ±â€¯2.7 mg/dl, P < 0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels highlighting the potential to not only improve glucose control but also modify cardiovascular risk. We then investigated whether LuCI's effect on proximal bowel exclusion may play a role in energy balance. Bomb calorimetry analysis suggested that LuCI reduced calorie absorption with no difference in caloric consumption. CONCLUSION: We demonstrated that LuCI recapitulates the physical and hormonal changes seen after RYGB and can ameliorate weight gain and improve insulin sensitivity in a DIO rat model. Since LuCI's effect is transient and without systemic absorption, LuCI has the potential to be a novel therapy for overweight or obese T2D patients.


Asunto(s)
Glucemia , Diabetes Mellitus Tipo 2/terapia , Resistencia a la Insulina/fisiología , Intestinos , Obesidad/terapia , Pérdida de Peso/fisiología , Animales , Peso Corporal/fisiología , Diabetes Mellitus Tipo 2/sangre , Dieta Alta en Grasa , Ingestión de Alimentos/fisiología , Derivación Gástrica , Insulina/sangre , Masculino , Obesidad/sangre , Ratas , Ratas Sprague-Dawley
14.
Metabolism ; 126: 154921, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34715116

RESUMEN

BACKGROUND & AIMS: Angiopoietin-like protein 8 (ANGPTL8) is a 198 amino-acid long, novel secreted protein that is mainly expressed in the liver and brown adipose tissues. At present, evidence supporting the involvement of ANGPTL8 in the regulation of glucose metabolism is inconclusive, along with its function in the liver. Previous studies mainly focused on the effect of ANGPTL8 on glucose metabolism in non-diabetic mice, and few relevant studies in diabetic mice exist. Therefore, this study aimed to investigate the role of ANGPTL8 on glucose homeostasis and elucidate the underlying mechanisms in diabetic mice. METHODS: db/db diabetic and high-fat diet/streptozotocin-induced diabetic mice were injected with adenovirus expressing ANGPTL8 through the tail vein. Blood glucose levels were measured and glucose, insulin, and pyruvate tolerance tests were performed. To explore the molecular mechanism by which ANGPTL8 regulates hepatic glucose metabolism and manipulate mouse ANGPTL8 expression levels both in vivo and in vitro based on adenoviral transduction, gain- and loss-of-function strategies were adopted. RESULTS: Adenovirus-mediated overexpression of ANGPTL8 decreased fasting blood glucose levels and improved glucose tolerance and insulin sensitivity in db/db and high-fat diet/streptozotocin-induced diabetic mice. ANGPTL8 knockdown yielded the opposite effects. ANGPTL8 was upregulated in the cAMP/Dex-induced hepatocyte gluconeogenesis model. Moreover, ANGPTL8 overexpression in primary hepatocytes and diabetic mouse livers inhibited the expression of gluconeogenesis-related genes, including PEPCK and G6PC, by activating the AKT signaling pathway and, thereby, reducing glucose production. Therefore, the results demonstrated that ANGPTL8 improved glucose metabolism via inhibition of hepatic gluconeogenesis in diabetic mice. CONCLUSIONS: Current findings highlight a critical role of hepatic ANGPTL8 in glucose homeostasis, suggesting that increased ANGPTL8 expression could be an underlying factor for the inhibition of hepatic gluconeogenesis, which could be targeted for the prevention and treatment of type 2 diabetes.


Asunto(s)
/genética , Diabetes Mellitus Experimental/genética , Gluconeogénesis/genética , Hígado/metabolismo , Transducción de Señal/genética , /metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Dieta Alta en Grasa , Hepatocitos/metabolismo , Resistencia a la Insulina/genética , Masculino , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo
15.
Nutrients ; 13(12)2021 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-34959760

RESUMEN

Hepatokines are liver-derived proteins that may influence metabolic pathways such as insulin sensitivity. Recently, Sparc-related modular calcium-binding protein 1 (SMOC1) was identified as glucose-responsive hepatokine that is dysregulated in the setting of non-alcoholic fatty liver disease (NAFLD). While SMOC1 may influence glucose-insulin homeostasis in rodents, it is unknown if SMOC1 is influenced by NAFLD in humans. It is also unknown if SMOC1 is causally associated with metabolic and disease traits in humans. Therefore, we aimed to determine the effect of NAFLD on SMOC1 gene expression in the liver and aimed to explore the potential causal associations of SMOC1 levels with NAFLD, T2D, and glycemic traits in humans. Using an RNA sequencing dataset from a cohort of 216 patients with NAFLD, we assessed SMOC1 expression levels across the NAFLD spectrum. We performed a series of bidirectional inverse-variance weighted Mendelian randomization (MR) analyses on blood SMOC1 levels using two sources of genome-wide association studies (GWAS) (Fenland study, n = 10,708 and INTERVAL study, n = 3301). We utilized GWAS summary statistics for NAFLD in 8434 cases and 770,180 controls, as well as publicly available GWAS for type 2 diabetes (T2D), body mass index (BMI), waist-to-hip ratio (WHR), fasting blood insulin (FBI), fasting blood glucose (FBG), homeostatic Model Assessment of Insulin Resistance (HOMA-B and HOMA-IR), and hemoglobin A1c (HbA1C). We found that SMOC1 expression showed no significant differences across NAFLD stages. We also identified that the top single-nucleotide polymorphism associated with blood SMOC1 levels, was associated with SMOC1 gene expression in the liver, but not in other tissues. Using MR, we did not find any evidence that genetically predicted NAFLD, T2D, and glycemic traits influenced SMOC1 levels. We also did not find evidence that blood SMOC1 levels were causally associated with T2D, NAFLD, and glycemic traits. In conclusion, the hepatokine SMOC1 does not appear to be modulated by the presence of NAFLD and may not regulate glucose-insulin homeostasis in humans. Results of this study suggest that blood factors regulating metabolism in rodents may not always translate to human biology.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Osteonectina/sangre , Glucemia/metabolismo , Índice de Masa Corporal , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/sangre , Ayuno/sangre , Expresión Génica/fisiología , Estudio de Asociación del Genoma Completo , Hemoglobina A Glucada/metabolismo , Humanos , Insulina/sangre , Resistencia a la Insulina/genética , Hígado/metabolismo , Análisis de la Aleatorización Mendeliana , Enfermedad del Hígado Graso no Alcohólico/sangre , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Relación Cintura-Cadera
16.
Signal Transduct Target Ther ; 6(1): 427, 2021 12 16.
Artículo en Inglés | MEDLINE | ID: mdl-34916489

RESUMEN

Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism. In this study, we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-related diseases, and found new-onset insulin resistance, hyperglycemia, and decreased HDL-C in these patients. Mechanistically, SARS-CoV-2 infection increased the expression of RE1-silencing transcription factor (REST), which modulated the expression of secreted metabolic factors including myeloperoxidase, apelin, and myostatin at the transcriptional level, resulting in the perturbation of glucose and lipid metabolism. Furthermore, several lipids, including (±)5-HETE, (±)12-HETE, propionic acid, and isobutyric acid were identified as the potential biomarkers of COVID-19-induced metabolic dysregulation, especially in insulin resistance. Taken together, our study revealed insulin resistance as the direct cause of hyperglycemia upon COVID-19, and further illustrated the underlying mechanisms, providing potential therapeutic targets for COVID-19-induced metabolic complications.


Asunto(s)
COVID-19/sangre , Hiperglucemia/sangre , Resistencia a la Insulina , Metabolismo de los Lípidos , Lípidos/sangre , SARS-CoV-2/metabolismo , Adulto , Anciano , Biomarcadores/sangre , COVID-19/complicaciones , Femenino , Humanos , Hiperglucemia/etiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
17.
Cells ; 10(12)2021 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-34943849

RESUMEN

In recent years, there has been a large amount of evidence on the role of microRNA (miRNA) in regulating adipose tissue physiology. Indeed, miRNAs control critical steps in adipocyte differentiation, proliferation and browning, as well as lipolysis, lipogenesis and adipokine secretion. Overnutrition leads to a significant change in the adipocyte miRNOME, resulting in adipose tissue dysfunction. Moreover, via secreted mediators, dysfunctional adipocytes may impair the function of other organs and tissues. However, given their potential to control cell and whole-body energy expenditure, miRNAs also represent critical therapeutic targets for treating obesity and related metabolic complications. This review attempts to integrate present concepts on the role miRNAs play in adipose tissue physiology and obesity-related dysfunction and data from pre-clinical and clinical studies on the diagnostic or therapeutic potential of miRNA in obesity and its related complications.


Asunto(s)
Tejido Adiposo/metabolismo , Tejido Adiposo/fisiopatología , MicroARNs/genética , Adipogénesis/genética , Adipoquinas/metabolismo , Regulación de la Expresión Génica , Humanos , Resistencia a la Insulina/genética , MicroARNs/metabolismo
18.
Artículo en Inglés | MEDLINE | ID: mdl-34948750

RESUMEN

The objective of the study was to investigate the effects of different intensity exercise and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure on glucose metabolism in Sprague Dawley (SD) rats, as well as the action of insulin receptor substrate (IRS)/phosphatidylinositol-3-kinases (PI3K)/protein kinase (AKT) signaling pathway in it. Besides that, we explored whether exercise can alleviate the toxicity induced by TCDD. Sixty male SD rats (8 weeks old) were randomly divided into non-exercise group, none-exercise toxic group, moderate-intensity exercise group, moderate-intensity exercise toxic group, high-intensity exercise group, high-intensity exercise toxic group. The toxic groups were intraperitoneally injected with TCDD, which the dose was 6.4 µg/kg· BW for the first week, then 21% of the above week dose for continuous 8 weeks. The 8-week treadmill running of moderate intensity (15 m/min, 60 min/day) and high intensity (26 m/min, 35 min/day) were implemented separately in exercise groups five times a week. After detecting the concentration of fasting serum glucose, insulin and C-peptide, the index of the homeostasis model assessment of insulin resistance (HOMA-IR) and islet ß-cell secretion (HOMA-ß) were calculated. We measured the hepatic mRNA expression levels of IRS2, phosphatidylinositol-3-kinases catalytic subunit alpha (PIK3CA), AKT by real-time PCR. The protein expression of total IRS2 (tIRS2), phosphorylated IRS2 at Ser731 (pSer731), total PIK3CA (tPIK3CA), total Akt (tAkt), phosphorylated Akt at Thr308 (pThr308) in liver were analyzed by western blot. We observed that compared to the non-exercise group, insulin and HOMA-IR index were significantly higher in the none-exercise toxic group (p < 0.05), while glucose, insulin, C-peptide and HOMA-IR index were significantly lower in the moderate-intensity exercise group (p < 0.05). In the high-intensity exercise group, the HOMA-IR index was significantly lower and the gene expression of IRS2 was significantly higher than in the non-exercise group (p < 0.05). Besides that, the HOMA-ß index in the moderate-intensity exercise toxic group was significantly higher compared to the none-exercise toxic group and moderate-intensity exercise group (p < 0.05). The level of IRS2mRNA was significantly lower in the high-intensity exercise toxic group than in the high-intensity exercise group (p < 0.05). Our results demonstrated that 8-week TCDD exposure could induce insulin resistance in rats, while exercise could improve insulin sensitivity in which moderate intensity was more obvious than high intensity exercise. Meanwhile, both intensity exercise could not effectively alleviate the insulin resistance induced by TCDD, but high intensity exercise could promote compensatory insulin secretion to maintain glucose homeostasis. Although the gene expression of IRS2 was changed in high-intensity exercise groups, the mediation role of the hepatic IRS2/PI3K/AKT pathway in the effects of exercise and TCDD exposure on glucose metabolism remains very limited.


Asunto(s)
Resistencia a la Insulina , Dibenzodioxinas Policloradas , Animales , Glucosa , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Hígado/metabolismo , Masculino , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositoles , Dibenzodioxinas Policloradas/toxicidad , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley
19.
Nat Commun ; 12(1): 7256, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34907199

RESUMEN

Several members of the FGF family have been identified as potential regulators of glucose homeostasis. We previously reported that a low threshold of FGF-induced FGF receptor 1c (FGFR1c) dimerization and activity is sufficient to evoke a glucose lowering activity. We therefore reasoned that ligand identity may not matter, and that besides paracrine FGF1 and endocrine FGF21, other cognate paracrine FGFs of FGFR1c might possess such activity. Indeed, via a side-by-side testing of multiple cognate FGFs of FGFR1c in diabetic mice we identified the paracrine FGF4 as a potent anti-hyperglycemic FGF. Importantly, we found that like FGF1, the paracrine FGF4 is also more efficacious than endocrine FGF21 in lowering blood glucose. We show that paracrine FGF4 and FGF1 exert their superior glycemic control by targeting skeletal muscle, which expresses copious FGFR1c but lacks ß-klotho (KLB), an obligatory FGF21 co-receptor. Mechanistically, both FGF4 and FGF1 upregulate GLUT4 cell surface abundance in skeletal muscle in an AMPKα-dependent but insulin-independent manner. Chronic treatment with rFGF4 improves insulin resistance and suppresses adipose macrophage infiltration and inflammation. Notably, unlike FGF1 (a pan-FGFR ligand), FGF4, which has more restricted FGFR1c binding specificity, has no apparent effect on food intake. The potent anti-hyperglycemic and anti-inflammatory properties of FGF4 testify to its promising potential for use in the treatment of T2D and related metabolic disorders.


Asunto(s)
Factor 4 de Crecimiento de Fibroblastos/farmacología , Hipoglucemiantes/farmacología , Músculo Esquelético/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Factor 4 de Crecimiento de Fibroblastos/administración & dosificación , Factor 4 de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/administración & dosificación , Factores de Crecimiento de Fibroblastos/metabolismo , Factores de Crecimiento de Fibroblastos/farmacología , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/metabolismo , Inflamación , Resistencia a la Insulina , Ligandos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Músculo Esquelético/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Comunicación Paracrina , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos
20.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-34948230

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease all over the world due to the obesity pandemic; currently, therapeutic options for NAFLD are scarce, except for diet recommendations and physical activity. NAFLD is characterized by excessive accumulation of fat deposits (>5%) in the liver with subsequent inflammation and fibrosis. Studies in the literature show that insulin resistance (IR) may be considered as the key mechanism in the onset and progression of NAFLD. Recently, using natural products as an alternative approach in the treatment of NAFLD has drawn growing attention among physicians. In this review, the authors present the most recent randomized controlled trials (RCTs) and lines of evidence from animal models about the efficacy of nutraceutics in alleviating NAFLD. Among the most studied substances in the literature, the following molecules were chosen because of their presence in the literature of both clinical and preclinical studies: spirulina, oleuropein, garlic, berberine, resveratrol, curcumin, ginseng, glycyrrhizin, coffee, cocoa powder, epigallocatechin-3-gallate, and bromelain.


Asunto(s)
Productos Biológicos/uso terapéutico , Resistencia a la Insulina , Hígado , Animales , Modelos Animales de Enfermedad , Humanos , Hígado/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Ensayos Clínicos Controlados Aleatorios como Asunto
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...