Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.596
Filtrar
2.
Diabetes Metab Syndr ; 13(4): 2683-2687, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31405694

RESUMO

AIMS: Simple surrogate indices of insulin sensitivity have been conceived to deal with costly and complicated approaches, such as the hyperinsulinemic-euglycemic clamp; however, their use has not been widespread given their variabilities in different populations. In this paper, we present two simple surrogate indices, one that uses fasting glucose and insulin values and the other based on the values from the oral glucose tolerance test. MATERIALS AND METHODS: The proposed methods integrate easy-to-obtain anthropometric measures. Evolutionary algorithms were used to optimize the proposed methods by maximizing its correlation with the Stumvoll MCR method. RESULTS AND CONCLUSION: When the proposed indices were applied to three study groups (control subjects, metabolic syndrome, marathon runners), a reduction in the intergroup variability of the insulin sensitivity was obtained. Moreover, the proposed index based on the oral glucose tolerance test (OGTT), which considers the glucose metabolism process and the hepatic and peripheral insulin sensitivity, showed stronger correlations with the Stumvoll method and lower intergroup variability than the fasting one.


Assuntos
Biomarcadores/análise , Glicemia/análise , Jejum , Intolerância à Glucose/diagnóstico , Resistência à Insulina , Insulina/sangue , Síndrome Metabólica/fisiopatologia , Adulto , Estudos de Casos e Controles , Seguimentos , Técnica Clamp de Glucose/métodos , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose/métodos , Humanos , Incidência , Masculino , Prognóstico , Venezuela/epidemiologia
3.
Endocr J ; 66(8): 659-662, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31366824

RESUMO

Many researchers pay attention to novel secretory factors, such as adipokines or osteokines, secreted by the tissues that were not formerly recognized as classical endocrine organs. The liver also contributes to the onset of various kinds of pathologies of type 2 diabetes and obesity by producing and releasing secretory proteins "hepatokines." By using the information of gene expression in human livers, we rediscovered selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2) as hepatokines involved in the onset of glucose intolerance. SeP was previously recognized as a selenium transport protein, but we revealed that SeP causes insulin resistance in the muscle and liver. SeP also reduces VEGF signal transduction in vascular endothelial cells, contributing the impaired angiogenesis in diabetes. Importantly, SeP impairs health-promoting effects of exercise training by suppressing reactive oxygen species (ROS)/adenosine monophosphate-dependent protein kinase (AMPK) pathway in the skeletal muscle through its receptor low-density lipoprotein receptor-related protein 1 (LRP1). LECT2, previously-reported as a neutrophil chemotactic protein, promotes skeletal muscle insulin resistance in obesity. Further studies are necessary to develop new diagnostic or therapeutic procedures targeting hepatokines to combat type 2 diabetes or obesity.


Assuntos
Quimiocinas/fisiologia , Diabetes Mellitus Tipo 2/etiologia , Fígado/metabolismo , Obesidade/etiologia , Animais , Quimiocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Exercício/fisiologia , Intolerância à Glucose/complicações , Intolerância à Glucose/metabolismo , Humanos , Resistência à Insulina/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Obesidade/terapia , Selenoproteína P/metabolismo , Selenoproteína P/fisiologia
4.
Life Sci ; 234: 116793, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465735

RESUMO

INTRODUCTION: Environmental factors have a key role in the control of gut microbiota and obesity. TLR2 knockout (TLR2-/-) mice in some housing conditions are protected from diet-induced insulin resistance. However, in our housing conditions these animals are not protected from diet-induced insulin-resistance. AIM: The aim of the present study was to investigate the influence of our animal housing conditions on the gut microbiota, glucose tolerance and insulin sensitivity in TLR2-/- mice. MATERIAL AND METHODS: The microbiota was investigated by metagenomics, associated with hyperinsulinemic euglycemic clamp and GTT associated with insulin signaling through immunoblotting. RESULTS: The results showed that TLR2-/- mice in our housing conditions presented a phenotype of metabolic syndrome characterized by insulin resistance, glucose intolerance and increase in body weight. This phenotype was associated with differences in microbiota in TLR2-/- mice that showed a decrease in the Proteobacteria and Bacteroidetes phyla and an increase in the Firmicutesphylum, associated with and in increase in the Oscillospira and Ruminococcus genera. Furthermore there is also an increase in circulating LPS and subclinical inflammation in TLR2-/-. The molecular mechanism that account for insulin resistance was an activation of TLR4, associated with ER stress and JNK activation. The phenotype and metabolic behavior was reversed by antibiotic treatment and reproduced in WT mice by microbiota transplantation. CONCLUSIONS: Our data show, for the first time, that the intestinal microbiota can induce insulin resistance and obesity in an animal model that is genetically protected from these processes.


Assuntos
Microbioma Gastrointestinal , Resistência à Insulina , Insulina/metabolismo , Receptor 2 Toll-Like/genética , Animais , Estresse do Retículo Endoplasmático , Deleção de Genes , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/microbiologia , Abrigo para Animais , Resistência à Insulina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 2 Toll-Like/metabolismo
5.
Diabetes Metab Syndr ; 13(2): 1047-1051, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336442

RESUMO

BACKGROUND: The World has seen an emerging trend of diabetes among adolescents and moderately aged people over the last decade. The aim of the study was to identify the risk factors associated with impaired glucose metabolism and the prevalence of impaired glucose metabolism among the adult population of district Srinagar. METHODS: Multi-stage cluster random sampling design was used and from each household, participants were selected using a Kish grid method. Socio-demographic and clinical data were collected. The participants were then subjected to fasting venous blood glucose estimation. RESULTS: Age, waist circumference, hip circumference, weight, and body mass index were all statistically significant between normoglycemic participants and those with impaired glucose metabolism (p < 0.018). On logistic regression, subjects who had a higher BMI were more likely to develop Impaired glucose metabolism (OR = 3.52, OR 95% CI = 1.25-9.87); Moreover, consumption of carbonated drinks, (3-6 times/week OR = 4.40, OR 95% CI = 2.06-9.40; >6 times/week OR = 11.04, OR 95% CI = 0.86-140.66) was found to be a potential risk factor. Participants with a family history of diabetes were more susceptible to develop impaired glucose metabolism (OR = 6.41, OR 95% CI = 3.22-12.78). The risk effect of these factors was even stronger before adjusting for age, sex, family history of diabetes, and BMI in participants. CONCLUSION: Risk factors for impaired glucose metabolism include increasing age, obesity, and higher consumption of carbonated drinks, hypertension, smoking behavior, high-calorie diet intake and positive family history of diabetes.


Assuntos
Biomarcadores/análise , Índice de Massa Corporal , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/etiologia , Obesidade/complicações , Circunferência da Cintura , Adulto , Idoso , Glicemia/análise , Estudos Transversais , Feminino , Seguimentos , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Fatores de Risco , Adulto Jovem
6.
Diabetes Metab Syndr ; 13(3): 1971-1973, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31235123

RESUMO

BACKGROUND: Vitamin D deficiency appears to be lower in diabetic patients. Vitamin D may affect glycemic control & diabetic nephropathy. AIM: To assess vitamin D level in type 2 diabetic patients and its relation to their glycemic control and development of nephropathy compared to healthy controls. DESIGN: and Setting: Case control study including 82 participants (41 cases and 41 controls) from Family Medicine Clinic, Cairo University Hospitals. METHOD: Participants fulfilling the inclusion criteria were allocated into two groups, diabetes and control groups. History was taken, examination was done, and blood sample was withdrawn for analysis of Vitamin D levels and HBA1C. From the diabetic group only, serum creatinine was assessed and urine sample was collected for microalbuminuria. The results were analyzed using SPSS program version 21. RESULTS: Vitamin D level was lower in the diabetic group compared to control (65.5% and 56.1%). Vitamin D level was inversely proportionate to HbA1c levels in the diabetic patients (p value 0.000 & r -0.482), as well as to the A/C ratio (p value 0.01 & r -0.396). CONCLUSION: Vitamin D level appeared to be lower in diabetic patients and is associated with poor glycemic control & microalbuminuria.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Intolerância à Glucose/etiologia , Deficiência de Vitamina D/fisiopatologia , Vitamina D/sangue , Adulto , Glicemia/análise , Estudos de Casos e Controles , Estudos Transversais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Feminino , Seguimentos , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hemoglobina A Glicada/análise , Índice Glicêmico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Deficiência de Vitamina D/sangue , Vitaminas/sangue
7.
Am J Physiol Endocrinol Metab ; 317(2): E362-E373, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237447

RESUMO

Skeletal muscle insulin resistance manifests shortly after high-fat feeding, yet mechanisms are not known. Here we set out to determine whether excess skeletal muscle membrane cholesterol and cytoskeletal derangement known to compromise glucose transporter (GLUT)4 regulation occurs early after high-fat feeding. We fed 6-wk-old male C57BL/6NJ mice either a low-fat (LF, 10% kcal) or a high-fat (HF, 45% kcal) diet for 1 wk. This HF feeding challenge was associated with an increase, albeit slight, in body mass, glucose intolerance, and hyperinsulinemia. Liver analyses did not reveal signs of hepatic insulin resistance; however, skeletal muscle immunoblots of triad-enriched regions containing transverse tubule membrane showed a marked loss of stimulated GLUT4 recruitment. An increase in cholesterol was also found in these fractions from HF-fed mice. These derangements were associated with a marked loss of cortical filamentous actin (F-actin) that is essential for GLUT4 regulation and known to be compromised by increases in membrane cholesterol. Both the withdrawal of the HF diet and two subcutaneous injections of the cholesterol-lowering agent methyl-ß-cyclodextrin at 3 and 6 days during the 1-wk HF feeding intervention completely mitigated cholesterol accumulation, cortical F-actin loss, and GLUT4 dysregulation. Moreover, these beneficial membrane/cytoskeletal changes occurred concomitant with a full restoration of metabolic responses. These results identify skeletal muscle membrane cholesterol accumulation as an early, reversible, feature of insulin resistance and suggest cortical F-actin loss as an early derangement of skeletal muscle insulin resistance.


Assuntos
Membrana Celular/metabolismo , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/etiologia , Resistência à Insulina , Músculo Esquelético/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Colesterol/farmacologia , Dieta Ocidental/efeitos adversos , Gorduras na Dieta/farmacologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hiperinsulinismo/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , beta-Ciclodextrinas/farmacologia , beta-Ciclodextrinas/uso terapêutico
8.
Am J Physiol Endocrinol Metab ; 317(2): E399-E410, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237448

RESUMO

Metabolism alters markedly with advancing gestation, characterized by progressive insulin resistance, dyslipidemia, and raised serum bile acids. The nuclear receptor farnesoid X receptor (FXR) has an integral role in bile acid homeostasis and modulates glucose and lipid metabolism. FXR is known to be functionally suppressed in pregnancy. The FXR agonist, obeticholic acid (OCA), improves insulin sensitivity in patients with type 2 diabetes with nonalcoholic fatty liver disease. We therefore hypothesized that OCA treatment during pregnancy could improve disease severity in a mouse model of gestational diabetes mellitus (GDM). C57BL/6J mice were fed a high-fat diet (HFD; 60% kcal from fat) for 4 wk before and throughout pregnancy to induce GDM. The impact of the diet supplemented with 0.03% OCA throughout pregnancy was studied. Pregnant HFD-fed mice displayed insulin resistance and dyslipidemia. OCA significantly reduced plasma cholesterol concentrations in nonpregnant and pregnant HFD-fed mice (by 22.4%, P < 0.05 and 36.4%, P < 0.001, respectively) and reduced the impact of pregnancy on insulin resistance but did not change glucose tolerance. In nonpregnant HFD-fed mice, OCA ameliorated weight gain, reduced mRNA expression of inflammatory markers in white adipose tissue, and reduced plasma glucagon-like peptide 1 concentrations (by 62.7%, P < 0.01). However, these effects were not evident in pregnant mice. OCA administration can normalize plasma cholesterol levels in a mouse model of GDM. However, the absence of several of the effects of OCA in pregnant mice indicates that the agonistic action of OCA is not sufficient to overcome many metabolic consequences of the pregnancy-associated reduction in FXR activity.


Assuntos
Glicemia/efeitos dos fármacos , Ácido Quenodesoxicólico/análogos & derivados , Diabetes Gestacional/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Animais , Glicemia/metabolismo , Ácido Quenodesoxicólico/uso terapêutico , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/complicações , Dislipidemias/metabolismo , Feminino , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/metabolismo
9.
AIDS Patient Care STDS ; 33(7): 299-307, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31188016

RESUMO

We conducted a cross-sectional study of 148 HIV+ on HIV antiretroviral therapy and 149 HIV- adults in Mbarara, Uganda, to estimate the association between HIV infection and homeostasis model assessment of insulin resistance (HOMA-IR) using multivariable regression analysis. In addition, we evaluated whether intestinal fatty acid-binding protein (I-FABP), monocyte activation markers soluble (s)CD14 and sCD163, and proinflammatory cytokine interleukin 6 (IL-6) mediated this association. HOMA-IR was greater among HIV+ than HIV- adults [median (interquartile range): 1.3 (0.7-2.5) vs. 0.9 (0.5-2.4); p = 0.008]. In models adjusted for sociodemographic variables, diet, hypertension, and smoking history, HIV infection was associated with 37% [95% confidence intervals (95% CIs): 5-77] greater HOMA-IR compared with HIV- participants. The magnitude of association was greater when I-FABP was included as a covariate although the additive effect was modest (40% CI: 8-82). By contrast adding sCD14 to the model was associated with greater HOMA-IR (59%; 95% CI: 21-109) among HIV+ participants compared with HIV- participants. Among HIV+ participants, greater CD4 nadir was non-significantly associated with greater HOMA-IR (22%; 95% CI: -2 to 52). Each 5-unit increase in body mass index (BMI; 49% greater HOMA-IR; 95% CI: 18-87) and female sex (71%; 95% CI: 17-150) remained associated in adjusted models. In this study of mainly normal-weight Ugandan adults, HIV infection, female sex, and greater BMI were all associated with greater insulin resistance (IR). This association was strengthened modestly after adjustment for sCD14, suggesting possible distinct immune pathways to IR that are independent of HIV or related to inflammatory changes occurring on HIV treatment.


Assuntos
Biomarcadores/sangue , Proteínas de Ligação a Ácido Graxo , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Adulto , Antirretrovirais/uso terapêutico , Biomarcadores/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Soronegatividade para HIV , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Uganda
10.
Life Sci ; 231: 116574, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207311

RESUMO

AIMS: Electric lighting is beneficial to modern society; however, it is becoming apparent that light at night (LAN) is not without biological consequences. Several studies have reported negative effects of LAN on health and behavior in humans and nonhuman animals. Exposure of non-diabetic mice to dim LAN impairs glucose tolerance, whereas a return to dark nights (LD) reverses this impairment. We predicted that exposure to LAN would exacerbate the metabolic abnormalities in TALLYHO/JngJ (TH) mice, a polygenic model of type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We exposed 7-week old male TH mice to either LD or LAN for 8-10 weeks in two separate experiments. After 8 weeks of light treatment, we conducted intraperitoneal glucose tolerance testing (ipGTT) followed by intraperitoneal insulin tolerance testing (ipITT). In Experiment 1, all mice were returned to LD for 4 weeks, and ipITT was repeated. KEY FINDINGS: The major results of this study are i) LAN exposure for 8 weeks exacerbates glucose intolerance and insulin resistance ii) the effects of LAN on insulin resistance are reversed upon return to LD, iii) LAN exposure results in a greater increase in body weight compared to LD exposure, iv) LAN increases the incidence of mice developing overt T2DM, and v) LAN exposure decreases survival of mice with T2DM. SIGNIFICANCE: In conclusion, LAN exacerbated metabolic abnormalities in a polygenic mouse model of T2DM, and these effects were reversed upon return to dark nights. The applicability of these findings to humans with T2DM needs to be determined.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Iluminação/efeitos adversos , Animais , Barorreflexo , Pressão Sanguínea , Peso Corporal , Ritmo Circadiano/fisiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Frequência Cardíaca , Hemodinâmica , Insulina/sangue , Resistência à Insulina/fisiologia , Luz , Masculino , Camundongos , Norepinefrina , Ganho de Peso
11.
Nat Commun ; 10(1): 2375, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147543

RESUMO

Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins and is involved in many physiological processes. Obesity, as a worldwide healthcare problem, has attracted more and more attention. To investigate the role of adipose HuR, we generate adipose-specific HuR knockout (HuRAKO) mice. As compared with control mice, HuRAKO mice show obesity when induced with a high-fat diet, along with insulin resistance, glucose intolerance, hypercholesterolemia and increased inflammation in adipose tissue. The obesity of HuRAKO mice is attributed to adipocyte hypertrophy in white adipose tissue due to decreased expression of adipose triglyceride lipase (ATGL). HuR positively regulates ATGL expression by promoting the mRNA stability and translation of ATGL. Consistently, the expression of HuR in adipose tissue is reduced in obese humans. This study suggests that adipose HuR may be a critical regulator of ATGL expression and lipolysis and thereby controls obesity and metabolic syndrome.


Assuntos
Tecido Adiposo Branco/metabolismo , Proteína Semelhante a ELAV 1/genética , Intolerância à Glucose/genética , Hipercolesterolemia/genética , Resistência à Insulina/genética , Lipase/genética , Obesidade/genética , Adipócitos/patologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/imunologia , Animais , Crescimento Celular , Dieta Hiperlipídica , Proteína Semelhante a ELAV 1/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Intolerância à Glucose/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Hipertrofia , Inflamação/imunologia , Lipase/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Biossíntese de Proteínas , Estabilidade de RNA/genética , Gordura Subcutânea/metabolismo
12.
Int J Mol Sci ; 20(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100973

RESUMO

It is known that green tea helps prevent obesity and diabetes mellitus. In this study, we aimed to determine whether green tea ameliorates hyperglycemia and the mechanism involved in diabetic rodents. Green tea consumption reduced blood glucose and ameliorated glucose intolerance, which was assessed using an oral glucose tolerance test in both streptozotocin-induced type 1 diabetic rats and type 2 diabetic KK-Ay mice. Green tea also reduced the plasma fructosamine and glycated hemoglobin concentrations in both models. Furthermore, it increased glucose uptake into the skeletal muscle of both model animals, which was accompanied by greater translocation of glucose transporter 4 (GLUT4). Moreover, epigallocatechin gallate (EGCG), the principal catechin in green tea, also ameliorated glucose intolerance in high-fat diet-induced obese and diabetic mice. These results suggest that green tea can ameliorate hyperglycemia in diabetic rodents by stimulating GLUT4-mediated glucose uptake in skeletal muscle, and that EGCG is one of the effective compounds that mediate this effect.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Transportador de Glucose Tipo 4/metabolismo , Hiperglicemia/prevenção & controle , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Extratos Vegetais/farmacologia , Chá/química , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Dieta Hiperlipídica , Frutosamina/sangue , Glucose/metabolismo , Intolerância à Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Teste de Tolerância a Glucose , Hemoglobina A Glicada , Hiperglicemia/metabolismo , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/prevenção & controle , Ratos , Ratos Wistar , Roedores , Estreptozocina/farmacologia
13.
Endocrinology ; 160(7): 1613-1630, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125050

RESUMO

Developmental exposures to phthalates are suspected to contribute to risk of metabolic syndrome. However, findings from human studies are inconsistent, and long-term metabolic impacts of early-life phthalate and phthalate mixture exposures are not fully understood. Furthermore, most animal studies investigating metabolic impacts of developmental phthalate exposures have focused on diethylhexyl phthalate (DEHP), whereas newer phthalates, such as diisononyl phthalate (DINP), are understudied. We used a longitudinal mouse model to evaluate long-term metabolic impacts of perinatal exposures to three individual phthalates, DEHP, DINP, and dibutyl phthalate (DBP), as well as two mixtures (DEHP+DINP and DEHP+DINP+DBP). Phthalates were administered to pregnant and lactating females through phytoestrogen-free chow at the following exposure levels: 25 mg of DEHP/kg of chow, 25 mg of DBP/kg of chow, and 75 mg of DINP/kg of chow. One male and female per litter (n = 9 to 13 per sex per group) were weaned onto control chow and followed until 10 months of age. They underwent metabolic phenotyping at 2 and 8 months, and adipokines were measured in plasma collected at 10 months. Longitudinally, females perinatally exposed to DEHP only had increased body fat percentage and decreased lean mass percentage, whereas females perinatally exposed to DINP only had impaired glucose tolerance. Perinatal phthalate exposures also modified the relationship between body fat percentage and plasma adipokine levels at 10 months in females. Phthalate-exposed males did not exhibit statistically significant differences in the measured longitudinal metabolic outcomes. Surprisingly, perinatal phthalate mixture exposures were statistically significantly associated with few metabolic effects and were not associated with larger effects than single exposures, revealing complexities in metabolic effects of developmental phthalate mixture exposures.


Assuntos
Composição Corporal/efeitos dos fármacos , Dibutilftalato/toxicidade , Dietilexilftalato/toxicidade , Intolerância à Glucose/metabolismo , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Adipocinas/sangue , Animais , Proteínas de Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/metabolismo , Feminino , Lipase/efeitos dos fármacos , Lipase/metabolismo , Masculino , Camundongos , Gravidez
14.
Am J Physiol Endocrinol Metab ; 317(2): E200-E211, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31084499

RESUMO

Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5cont) and spontaneously C5-deficient (C5def, B10.D2-Hc0 H2d H2-T18c/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5def mice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5def mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5def mice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the C5 gene, whole genome sequencing revealed an intronic 31-bp deletion in the Insr gene in the B10.D2-Hc0 H2d H2-T18c/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5cont and C5def mice, indicating an insulin-sensitizing function of C5.


Assuntos
Complemento C5/deficiência , Complemento C5/genética , Intolerância à Glucose/genética , /patologia , Adenoviridae/genética , Animais , Complemento C5/fisiologia , Modelos Animais de Doenças , Metabolismo Energético/genética , Metabolismo Energético/imunologia , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Resistência à Insulina/genética , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Transdução de Sinais/genética , Transdução Genética
15.
J Ethnopharmacol ; 240: 111943, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31075382

RESUMO

Ethnopharmacologic relevance: Gyeongshingangjeehwan 18 (GGEx18) is a polyherbal composition derived from Ephedra sinica Stapf (Ephedraceae), Laminaria japonica Aresch (Laminariaceae), and Rheum palmatum L. (Polygonaceae) that is used as an antiobesity drug in Korean clinics. Its constituents are traditionally known to combat obesity, dyslipidemia, and insulin resistance. OBJECTIVE: This study was undertaken to investigate the effects of GGEx18 on glucose metabolism and pancreatic steatosis in obese C57BL/6 J mice fed a high-fat diet (HFD) and to examine the related cellular and molecular mechanisms. MATERIALS AND METHODS: The mice were grouped and fed for 13 weeks as follows: 1) low-fat diet, 2) HFD, or 3) HFD supplemented with GGEx18 (500 mg/kg/day). Various factors affecting insulin sensitivity and pancreatic function were then assessed via blood analysis, histology, immunohistochemistry, and real-time polymerase chain reaction. RESULTS: GGEx18 treatment of obese mice reduced body weight, total fat, and visceral fat mass. GGEx18 inhibited hyperglycemia and hyperinsulinemia and improved glucose and insulin tolerance. GGEx18 also decreased serum leptin levels and concomitantly increased adiponectin levels. Furthermore, GGEx18-treated mice exhibited reduced pancreatic fat accumulation and normalized insulin-secreting ß-cell area. GGEx18 increased pancreatic expression of genes promoting fatty acid ß-oxidation (i.e., MCAD and VLCAD), whereas expression levels of lipogenesis-related genes (i.e., PPARγ, SREBP-1c, and FAS) declined. DISCUSSION AND CONCLUSION: GGEx18 curtailed impaired glucose metabolism and pancreatic steatosis in our mouse model by regulating pancreatic genes that govern lipid metabolism and improving insulin sensitivity. This composition may benefit patients with impaired glucose tolerance, insulin resistance, and pancreatic dysfunction.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Intolerância à Glucose/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Pancreatopatias/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Preparações de Plantas/uso terapêutico , Animais , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Expressão Gênica/efeitos dos fármacos , Intolerância à Glucose/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pancreatopatias/metabolismo , Extratos Vegetais/farmacologia , Preparações de Plantas/farmacologia
16.
Endocr J ; 66(8): 663-675, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142688

RESUMO

Dysregulation of glucagon secretion plays an important role in the pathogenesis of type 2 diabetes (T2DM). However it hasn't been elucidated involvement of glucagon dysregulation in pathophysiology of T2DM. Recently a new glucagon sandwich enzyme-linked immunosorbent assay (ELISA) became available that can measure plasma glucagon level with higher accuracy and simpler procedure than the conventional RIA method. We performed OGTT for adult subjects aged 20-69 years to define normal glucose tolerance (NGT, n = 25), borderline glucose intolerance (defined as pre-diabetes mellitus: preDM, n = 15), or diabetes mellitus (DM, n = 13), and we measured glucagon levels with this new ELISA method at fasting and during OGTT. Plasma glucose, insulin, glucagon and active GLP-1 were also measured. This study took place in diabetes outpatient clinic in Kitasato University Hospital and an affiliated outpatient clinic. PreDM and DM exhibited higher fasting plasma glucagon levels than NGT (34.4 ± 4.6 and 44.1 ± 5.0 vs. 20.6 ± 3.6 pg/mL), and statistical significance was observed between NGT and DM (p < 0.05). There was significant correlation between fasting glucagon level and indexes of insulin sensitivity. During OGTT, glucagon levels were less suppressed in DM and preDM than in NGT, whereas no apparent relationship was observed between glucagon and GLP-1 secretion. Significant positive correlation was observed between glucagon levels during OGTT and fasting TG. In conclusion, subjects with mild T2DM exhibited fasting hyperglucagonemia and insufficient suppression to oral glucose load compared to NGT subjects.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Glucagon/metabolismo , Glucose/farmacologia , Estado Pré-Diabético/metabolismo , Adulto , Idoso , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Glucagon/sangue , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Estado Pré-Diabético/patologia , Índice de Gravidade de Doença , Adulto Jovem
17.
Endocrinology ; 160(6): 1547-1560, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31127273

RESUMO

Sirtuin 1 (Sirt1) is an NAD-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, evidence suggests that SIRT1 in neurons plays a role in the central regulation of energy balance and reproduction, but no studies have addressed the contribution of astrocytes. We show here that overexpression of SIRT1 in astrocytes causes markedly increased food intake, body weight gain, and glucose intolerance, but expression of a deacetylase-deficient SIRT1 mutant decreases food intake and body weight and improves glucose tolerance, particularly in female mice. Paradoxically, the effect of these SIRT1 mutants on insulin tolerance was reversed, with overexpression showing greater insulin sensitivity. The mice overexpressing SIRT1 were more active, generated more heat, and had elevated oxygen consumption, possibly in compensation for the increased food intake. The female overexpressing mice were also more sensitive to diet-induced obesity. Reproductively, the mice expressing the deacetylase-deficient SIRT1 mutant had impaired estrous cycles, decreased LH surges, and fewer corpora lutea, indicating decreased ovulation. The GnRH neurons were responsive to kisspeptin stimulation, but hypothalamic expression of Kiss1 was reduced in the mutant mice. Our results showed that SIRT1 signaling in astrocytes can contribute to metabolic and reproductive regulation independent of SIRT1 effects in neurons.


Assuntos
Astrócitos/metabolismo , Ingestão de Alimentos/fisiologia , Ciclo Estral/metabolismo , Intolerância à Glucose/metabolismo , Glucose/metabolismo , Sirtuína 1/metabolismo , Ganho de Peso/fisiologia , Animais , Ciclo Estral/genética , Feminino , Hormônio Foliculoestimulante/sangue , Intolerância à Glucose/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Resistência à Insulina/fisiologia , Leptina/sangue , Hormônio Luteinizante/sangue , Masculino , Camundongos , Neurônios/metabolismo , Sirtuína 1/genética , Testículo/metabolismo
18.
Metabolism ; 97: 40-49, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31129047

RESUMO

BACKGROUND: Metabolic flexibility can be assessed by changes in respiratory exchange ratio (RER) following feeding. Though metabolic flexibility (difference in RER between fasted and fed state) is often impaired in individuals with obesity or type 2 diabetes, the cellular processes contributing to this impairment are unclear. MATERIALS AND METHODS: From several clinical studies we identified the 16 most and 14 least metabolically flexible male and female subjects out of >100 participants based on differences between 24-hour and sleep RER measured in a whole-room indirect calorimeter. Global skeletal muscle gene expression profiles revealed that, in metabolically flexible subjects, transcripts regulated by the RNA binding protein, HuR, are enriched. We generated and characterized mice with a skeletal muscle-specific knockout of the HuR encoding gene, Elavl1 (HuRm-/-). RESULTS: Male, but not female, HuRm-/- mice exhibit metabolic inflexibility, with mild obesity, impaired glucose tolerance, impaired fat oxidation and decreased in vitro palmitate oxidation compared to HuRfl/fl littermates. Expression levels of genes involved in mitochondrial fatty acid oxidation and oxidative phosphorylation are decreased in both mouse and human muscle when HuR is inhibited. CONCLUSIONS: HuR inhibition results in impaired metabolic flexibility and decreased lipid oxidation, suggesting a role for HuR as an important regulator of skeletal muscle metabolism.


Assuntos
Proteína Semelhante a ELAV 1/metabolismo , Músculo Esquelético/metabolismo , Proteínas de Ligação a RNA/metabolismo , Roedores/metabolismo , Adulto , Animais , Diabetes Mellitus Tipo 2/metabolismo , Jejum/metabolismo , Ácidos Graxos/metabolismo , Feminino , Intolerância à Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Obesidade/metabolismo , Oxirredução , Fosforilação Oxidativa , Troca Gasosa Pulmonar/fisiologia
19.
Acta Diabetol ; 56(9): 1061-1071, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31028529

RESUMO

AIMS: To quantify epicardial adipose tissue (EAT) and visceral adipose tissue (VAT) in Chinese adults with impaired glucose regulation (IGR) or diabetes and compare the contributions of EAT and VAT to the occurrence of IGR and diabetes with those of traditional obesity indices. METHODS: Cardiac and abdominopelvic noncontrast computed tomographic images of 668 individuals were used to measure EAT and VAT volume. Multivariable logistic regression and area under the receiver operating characteristic (ROC) curve were used to illustrate the contributions of these tissues. RESULTS: Patients with IGR or diabetes had larger EAT and VAT volumes than did the controls, and the VAT volume was significantly different between the IGR and diabetic groups. In multivariable models, higher EAT or VAT volume was positively associated with the presence of IGR and diabetes. After adjusting further for body mass index (BMI) and waist-to-hip ratio (WHR), a higher EAT volume was still positively associated with IGR (odds ratio (OR) = 1.46; 95% confidence interval (CI), 1.04-2.03), and a higher VAT volume was positively associated with IGR (OR = 1.86; 95% CI, 1.15-3.02) and diabetes (OR = 1.86; 95% CI, 1.16-2.99). The areas under the curve (AUCs) of the association of EAT (AUC = 0.751; 95% CI, 0.712-0.789) and VAT (AUC = 0.752; 95% CI, 0.713-0.792) with dysglycemia (IGR + diabetes) were significantly larger than those of the traditional obesity indices (all P < 0.05). CONCLUSIONS: High EAT or VAT volume is positively associated with IGR and diabetes in Chinese adults. With a given WHR and BMI, such an association still exists to some extent. The correlation may be stronger than those of the traditional obesity indices.


Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus/metabolismo , Intolerância à Glucose/metabolismo , Gordura Intra-Abdominal/metabolismo , Pericárdio , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/patologia , Adulto , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Índice de Massa Corporal , China/epidemiologia , Estudos Transversais/legislação & jurisprudência , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/patologia , Feminino , Intolerância à Glucose/diagnóstico , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/patologia , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/patologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/metabolismo , Obesidade/patologia , Pericárdio/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Relação Cintura-Quadril , Adulto Jovem
20.
Metabolism ; 95: 57-64, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954560

RESUMO

BACKGROUND: South Africa (SA) has the highest global projected increase in diabetes risk. Factors typically associated with insulin resistance and type 2 diabetes risk in Caucasians are not significant correlates in black African populations. Therefore, we aimed to identify circulating metabolite patterns that predict type 2 diabetes development in this high-risk, yet understudied SA population. METHODS: We conducted a prospective cohort study in black SA women with normal glucose tolerance (NGT). Participants were followed for 13 years and developed (i) type 2 diabetes (n = 20, NGT-T2D), (ii) impaired glucose tolerance (IGT) (n = 27, NGT-IGT), or (iii) remained NGT (n = 28, NGT-NGT). Mass-spectrometry based metabolomics and multivariate analyses were used to elucidate metabolite patterns at baseline and at follow-up that were associated with type 2 diabetes development. RESULTS: Metabolites of phospholipid, bile acid and branched-chain amino acid (BCAA) metabolism, differed significantly between the NGT-T2D and NGT-NGT groups. At baseline: the NGT-T2D group had i) a higher lysophosphatidylcholine:lysophosphatidylethanolamine ratio containing linoleic acid (LPC(C18:2):LPE(C18:2)), ii) lower proliferation-related bile acids (ursodeoxycholic- and chenodeoxycholic acid), iii) higher levels of leucine and its catabolic intermediates (ketoleucine and C5-carnitine), compared to the NGT-NGT group. At follow-up: the NGT-T2D group had i) lower LPC(C18:2) levels, ii) higher apoptosis-related bile acids (deoxycholic- and glycodeoxycholic acid), and iii) higher levels of all BCAAs and their catabolic intermediates. CONCLUSIONS: Changes in lysophospholipid metabolism and the bile acid pool occur during the development of type 2 diabetes in black South African women. Further, impaired leucine catabolism precedes valine and isoleucine catabolism in the development of type 2 diabetes. These metabolite patterns can be useful to identify and monitor type 2 diabetes risk >10 years prior to disease onset and provide insight into the pathophysiology of type 2 diabetes in this high risk, but under-studied population.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fosfolipídeos/metabolismo , Adulto , Grupo com Ancestrais do Continente Africano , Apoptose , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Intolerância à Glucose/metabolismo , Humanos , Lisofosfolipídeos/metabolismo , Metabolômica/métodos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , África do Sul/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA