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1.
Rev Med Inst Mex Seguro Soc ; 59(2): 141-150, 2021 Jun 14.
Artigo em Espanhol | MEDLINE | ID: mdl-34232007

RESUMO

Background: Several studies have evaluated the association between a history of type 2 diabetes (T2D) and risk of breast cancer (BC), with controversial results. However, information regarding the population-attributable risk percent (PAR%) remains scarce. Objective: To estimate the association and the PAR% for BC and T2D, lifestyle and gynecologic factors in women in Mexico City. Methods: This case-control study was performed from May-December 2020. Women >40 years of age, from Mexico City, with a confirmed diagnosis for BC were included as cases. Controls were women with a BIRADS 1 or 2 mammography or an ultrasound clear of any BC suggestive findings. Results: A total of 134 cases and 134 controls were included. A higher risk for BC was identified among women who did not perform routine physical activity and those who had a history of hormonal contraceptive use > 5 years. The use of hormone replacement therapy (HRT) was associated with an odds ratio (OR) of 5.0 (p = 0.22) in the first model. After adjustment, HRT was associated with an OR of 2.92 (p=0.492) in the second and an OR of 3.6 (p = 0.753) in the third model. T2D was associated with an OR of 1.04 (p = 0.96) in the first model; an OR of 0.65 (p = 0.65) in the second model and an OR of RMa 0.75(p = 0.79) for the third model. Conclusion: In this case-control study, there was no significant association identified between a T2D diagnosis and BC.


Assuntos
Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , México/epidemiologia , Fatores de Risco
3.
Artigo em Inglês | MEDLINE | ID: mdl-34073854

RESUMO

Few studies have been conducted to classify and predict the influence of nutritional intake on overweight/obesity, dyslipidemia, hypertension and type 2 diabetes mellitus (T2DM) based on deep learning such as deep neural network (DNN). The present study aims to classify and predict associations between nutritional intake and risk of overweight/obesity, dyslipidemia, hypertension and T2DM by developing a DNN model, and to compare a DNN model with the most popular machine learning models such as logistic regression and decision tree. Subjects aged from 40 to 69 years in the 4-7th (from 2007 through 2018) Korea National Health and Nutrition Examination Survey (KNHANES) were included. Diagnostic criteria of dyslipidemia (n = 10,731), hypertension (n = 10,991), T2DM (n = 3889) and overweight/obesity (n = 10,980) were set as dependent variables. Nutritional intakes were set as independent variables. A DNN model comprising one input layer with 7 nodes, three hidden layers with 30 nodes, 12 nodes, 8 nodes in each layer and one output layer with one node were implemented in Python programming language using Keras with tensorflow backend. In DNN, binary cross-entropy loss function for binary classification was used with Adam optimizer. For avoiding overfitting, dropout was applied to each hidden layer. Structural equation modelling (SEM) was also performed to simultaneously estimate multivariate causal association between nutritional intake and overweight/obesity, dyslipidemia, hypertension and T2DM. The DNN model showed the higher prediction accuracy with 0.58654 for dyslipidemia, 0.79958 for hypertension, 0.80896 for T2DM and 0.62496 for overweight/obesity compared with two other machine leaning models with five-folds cross-validation. Prediction accuracy for dyslipidemia, hypertension, T2DM and overweight/obesity were 0.58448, 0.79929, 0.80818 and 0.62486, respectively, when analyzed by a logistic regression, also were 0.52148, 0.66773, 0.71587 and 0.54026, respectively, when analyzed by a decision tree. This study observed a DNN model with three hidden layers with 30 nodes, 12 nodes, 8 nodes in each layer had better prediction accuracy than two conventional machine learning models of a logistic regression and decision tree.


Assuntos
Aprendizado Profundo , Diabetes Mellitus Tipo 2 , Dislipidemias , Hipertensão , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Dislipidemias/epidemiologia , Dislipidemias/etiologia , Ingestão de Alimentos , Humanos , Hipertensão/epidemiologia , Hipertensão/etiologia , Inquéritos Nutricionais , Obesidade/epidemiologia , Sobrepeso/epidemiologia , República da Coreia/epidemiologia
4.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065973

RESUMO

Various types of cells demonstrate ubiquitous rhythmicity registered as simple and complex Ca2+-oscillations, spikes, waves, and triggering phenomena mediated by G-protein and tyrosine kinase coupled receptors. Phospholipase C/IP3-receptors (PLC/IP3R) and endothelial NO-synthase/Ryanodine receptors (NOS/RyR)-dependent Ca2+ signaling systems, organized as multivariate positive feedback generators (PLC-G and NOS-G), underlie this rhythmicity. Loss of rhythmicity at obesity may indicate deregulation of these signaling systems. To issue the impact of cell size, receptors' interplay, and obesity on the regulation of PLC-G and NOS-G, we applied fluorescent microscopy, immunochemical staining, and inhibitory analysis using cultured adipocytes of epididumal white adipose tissue of mice. Acetylcholine, norepinephrine, atrial natriuretic peptide, bradykinin, cholecystokinin, angiotensin II, and insulin evoked complex [Ca2+]i responses in adipocytes, implicating NOS-G or PLC-G. At low sub-threshold concentrations, acetylcholine and norepinephrine or acetylcholine and peptide hormones (in paired combinations) recruited NOS-G, based on G proteins subunits interplay and signaling amplification. Rhythmicity was cell size- dependent and disappeared in hypertrophied cells filled with lipids. Contrary to control cells, adipocytes of obese hyperglycemic and hypertensive mice, growing on glucose, did not accumulate lipids and demonstrated hormonal resistance being non responsive to any hormone applied. Preincubation of preadipocytes with palmitoyl-L-carnitine (100 nM) provided accumulation of lipids, increased expression and clustering of IP3R and RyR proteins, and partially restored hormonal sensitivity and rhythmicity (5-15% vs. 30-80% in control cells), while adipocytes of diabetic mice were not responsive at all. Here, we presented a detailed kinetic model of NOS-G and discussed its control. Collectively, we may suggest that universal mechanisms underlie loss of rhythmicity, Ca2+-signaling systems deregulation, and development of general hormonal resistance to obesity.


Assuntos
Adipócitos Brancos/metabolismo , Sinalização do Cálcio , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Adipócitos Brancos/citologia , Adipócitos Brancos/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Tamanho Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Epididimo , Proteínas de Ligação ao GTP/metabolismo , Masculino , Camundongos , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/induzido quimicamente , Palmitoilcarnitina/farmacologia , Periodicidade , Cultura Primária de Células , Fosfolipases Tipo C/metabolismo
5.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071774

RESUMO

Visceral adipose tissue (VAT) metabolic profiling harbors the potential to disentangle molecular changes underlying obesity-related dysglycemia. In this study, the VAT exometabolome of subjects with obesity and different glycemic statuses are analyzed. The subjects (n = 19) are divided into groups according to body mass index and glycemic status: subjects with obesity and euglycemia (Ob+NGT, n = 5), subjects with obesity and pre-diabetes (Ob+Pre-T2D, n = 5), subjects with obesity and type 2 diabetes under metformin treatment (Ob+T2D, n = 5) and subjects without obesity and with euglycemia (Non-Ob, n = 4), used as controls. VATs are incubated in culture media and extracellular metabolite content is determined by proton nuclear magnetic resonance (1H-NMR). Glucose consumption is not different between the groups. Pyruvate and pyroglutamate consumption are significantly lower in all groups of subjects with obesity compared to Non-Ob, and significantly lower in Ob+Pre-T2D as compared to Ob+NGT. In contrast, isoleucine consumption is significantly higher in all groups of subjects with obesity, particularly in Ob+Pre-T2D, compared to Non-Ob. Acetate production is also significantly lower in Ob+Pre-T2D compared to Non-Ob. In sum, the VAT metabolic fingerprint is associated with pre-diabetes and characterized by higher isoleucine consumption, accompanied by lower acetate production and pyruvate and pyroglutamate consumption. We propose that glucose metabolism follows different fates within the VAT, depending on the individuals' health status.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Gordura Intra-Abdominal/metabolismo , Metaboloma , Metabolômica , Obesidade/metabolismo , Estado Pré-Diabético/metabolismo , Tecido Adiposo/metabolismo , Adulto , Idoso , Biomarcadores , Pesos e Medidas Corporais , Diabetes Mellitus Tipo 2/etiologia , Suscetibilidade a Doenças , Metabolismo Energético , Feminino , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Modelos Biológicos , Adulto Jovem
6.
BMC Public Health ; 21(1): 969, 2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34022833

RESUMO

BACKGROUND: The objective was to determine whether time spent in different types of sedentary behavior during adolescence are associated with the risk of developing type 2 diabetes in adulthood. METHODS: Participants were 3942 adolescents aged 16 years who were part of the 1970 British Cohort Study. Sedentary behavior was assessed using a questionnaire that asked participants to indicate how much time they spent watching TV and videos, using the computer, reading, and doing homework. Incident cases of type 2 diabetes were determined quadrennially until 46 years of age. The association between adolescent sedentary behaviors and type 2 diabetes was determined using Cox proportional hazards regression that controlled for sex, body mass index, sugary beverage consumption, smoking status, physical activity at baseline, and physical activity in adulthood . RESULTS: There were 91 incident cases of type 2 diabetes with an incidence rate of 9 cases/10,000 person-years. By comparison to those who watched TV and videos for 2 or less hours/day, type 2 diabetes risk was not different in those who watched for 2.1-4.0 h/day (HR = 0.89, 95% CI = 0.54, 1.47) but was increased by 2.06-fold (95% CI = 1.24, 3.43) in those who watched for more than 4 h/day. Time spent using a computer, reading, and doing homework were not significantly associated with type 2 diabetes. CONCLUSION: Spending more than 4 h/day watching television and videos at age 16 was associated with an increased risk of type 2 diabetes. Conversely, using a computer and non-screen based sedentary behaviors were not associated with type 2 diabetes risk.


Assuntos
Comportamento do Adolescente , Diabetes Mellitus Tipo 2 , Adolescente , Adulto , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Humanos , Comportamento Sedentário , Televisão
7.
Diabetes Res Clin Pract ; 176: 108855, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33965448

RESUMO

Having a psychiatric disorder may increase the risk of developing type 2 diabetes[T2D] and this umbrella review aims to determine whether people with a psychiatric disorder have an increased risk of developing T2D and to investigate potential underlying mechanisms. A literature search was performed to identify systematic reviews of longitudinal studies investigating different psychiatric disorders as risk factors for incident T2D in humans (≥18 years). A total of 8612 abstracts were identified, 180 full-text articles were read, and 25 systematic reviews were included. Six categories of psychiatric disorders were identified. Except for eating disorders, all psychiatric disorders were associated with increased risk of incident T2D ranging from RR = 1.18 [95% CI 1.12-1.24] to RR = 1.60 [95% CI 1.37-1.88] for depression; from RR = 1.27 [95% CI 1.19-1.35] to OR = 1.50 [95% CI 1.08-2.10] for use of antidepressant medication; from OR = 1.93 [1.37-2.73] to OR = 1.94 [1.34-2.80] for use of antipsychotic medication; from RR = 1.55 [95% CI 1.21-1.99] to RR = 1.74 [95% CI 1.30-2.34] for insomnia, and finally showed OR = 1.47 [95% CI 1.23-1.75] for anxiety disorders. Plausible underlying mechanisms were discussed, but in most reviews corrections for mechanisms did not explain the association. Notable, only 16% of the systematic reviews had a high methodological quality.


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Transtornos Mentais/complicações , Fatores de Risco Cardiometabólico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/psicologia , Humanos , Transtornos Mentais/epidemiologia , Metanálise como Assunto , Fatores de Risco , Revisões Sistemáticas como Assunto
8.
Int J Biol Macromol ; 182: 760-771, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33862075

RESUMO

Recent findings suggest that the accumulation of misfolded aggregates of islet amyloid peptide (IAPP) plays an essential role in pancreatic damage and type 2 diabetes (T2D). Pancreastatin (PST), a chromogranin derived peptide, instigates insulin resistance (IR) and promotes T2D. Here, we aimed to investigate whether PST induces IAPP aggregation in the pancreas, liver, and skeletal muscles. Foremost, we unraveled kinetics of fibril formation by ThT kinetic assay, ANS binding, turbidity, and far UV-CD. Subsequently, we checked the microarchitecture of fibril by TEM. Moreover, the PST action on IAPP expression was examined by immunocytochemistry, immunohistochemistry, western blotting, and real-time PCR. The outcome of spectral analysis and TEM demonstrated the fibril formation in the alone IAPP group but not in the alone PST; however, PST with IAPP produced stronger fibril. Moreover, PST was found to stimulate IAPP aggregation and expression more prominently in PANC1 and HepG2 cells, and pancreas and liver tissues than in L6 and skeletal muscle. Subsequently, pancreastatin inhibitor manifested a decline in the extent of the IAPP fibril formation and its expression. To conclude, PST upon combination induces the aggregation of IAPP in the pancreas, liver, and skeletal muscle, which may have the potential to generate IR and cause T2D.


Assuntos
Cromogranina A/farmacologia , Diabetes Mellitus Tipo 2/etiologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Fígado/metabolismo , Pâncreas/metabolismo , Agregação Patológica de Proteínas/metabolismo , Amiloide/metabolismo , Animais , Células Hep G2 , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/genética , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Pâncreas/efeitos dos fármacos , Agregação Patológica de Proteínas/patologia , Dobramento de Proteína
9.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1129733

RESUMO

While there are various kinds of drugs for type 2 diabetes mellitus at present, in this review article, we focus on metformin which is an insulin sensitizer and is often used as a first-choice drug worldwide. Metformin mainly activates adenosine monophosphate-activated protein kinase (AMPK) in the liver which leads to suppression of fatty acid synthesis and gluconeogenesis. Metformin activates AMPK in skeletal muscle as well, which increases translocation of glucose transporter 4 to the cell membrane and thereby increases glucose uptake. Further, metformin suppresses glucagon signaling in the liver by suppressing adenylate cyclase which leads to suppression of gluconeogenesis. In addition, metformin reduces autophagy failure observed in pancreatic ß-cells under diabetic conditions. Furthermore, it is known that metformin alters the gut microbiome and facilitates the transport of glucose from the circulation into excrement. It is also known that metformin reduces food intake and lowers body weight by increasing circulating levels of the peptide hormone growth/differentiation factor 15 (GDF15). Furthermore, much attention has been drawn to the fact that the frequency of various cancers is lower in subjects taking metformin. Metformin suppresses the mechanistic target of rapamycin (mTOR) by activating AMPK in pre-neoplastic cells, which leads to suppression of cell growth and an increase in apoptosis in pre-neoplastic cells. It has been shown recently that metformin consumption potentially influences the mortality in patients with type 2 diabetes mellitus and coronavirus infectious disease (COVID-19). Taken together, metformin is an old drug, but multifaceted mechanisms of action of metformin have been unraveled one after another in its long history.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/farmacologia , Autofagia/efeitos dos fármacos , COVID-19/complicações , COVID-19/mortalidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/mortalidade , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
10.
FASEB J ; 35(5): e21374, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33835493

RESUMO

Inhibition of insulin-degrading enzyme (IDE) is a possible target for treating diabetes. However, it has not yet evolved into a medical intervention, mainly because most developed inhibitors target the zinc in IDE's catalytic site, potentially causing toxicity to other essential metalloproteases. Since IDE is a cellular receptor for the varicella-zoster virus (VZV), we constructed a VZV-based inhibitor. We computationally characterized its interaction site with IDE showing that the peptide specifically binds inside IDE's central cavity, however, not in close proximity to the zinc ion. We confirmed the peptide's effective inhibition on IDE activity in vitro and showed its efficacy in ameliorating insulin-related defects in types 1 and 2 diabetes mouse models. In addition, we suggest that inhibition of IDE may ameliorate the pro-inflammatory profile of CD4+ T-cells toward insulin. Together, we propose a potential role of a designed VZV-derived peptide to serve as a selectively-targeted and as an efficient diabetes therapy.


Assuntos
Diabetes Mellitus Experimental/terapia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Insulina/metabolismo , Insulisina/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , Proteínas do Envelope Viral/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Herpesvirus Humano 3/fisiologia , Insulisina/genética , Insulisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout
11.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916315

RESUMO

Lipids are highly diverse in their composition, properties and distribution in different biological entities. We aim to establish the lipidomes of several insulin-sensitive tissues and to test their plasticity when divergent feeding regimens and lifestyles are imposed. Here, we report a proton nuclear magnetic resonance (1H-NMR) study of lipid abundance across 4 tissues of C57Bl6J male mice that includes the changes in the lipid profile after every lifestyle intervention. Every tissue analysed presented a specific lipid profile irrespective of interventions. Glycerolipids and fatty acids were most abundant in epididymal white adipose tissue (eWAT) followed by liver, whereas sterol lipids and phosphoglycerolipids were highly enriched in hypothalamus, and gastrocnemius had the lowest content in all lipid species compared to the other tissues. Both when subjected to a high-fat diet (HFD) and after a subsequent lifestyle intervention (INT), the lipidome of hypothalamus showed no changes. Gastrocnemius and liver revealed a pattern of increase in content in many lipid species after HFD followed by a regression to basal levels after INT, while eWAT lipidome was affected mainly by the fat composition of the administered diets and not their caloric density. Thus, the present study demonstrates a unique lipidome for each tissue modulated by caloric intake and dietary composition.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Lipidômica , Obesidade/dietoterapia , Obesidade/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Restrição Calórica , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Estilo de Vida Saudável , Hipotálamo/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Obesidade/complicações , Condicionamento Físico Animal
12.
Int J Mol Sci ; 22(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917044

RESUMO

Type-2 diabetes mellitus (T2DM) is a major systemic disease which involves impaired pancreatic function and currently affects half a billion people worldwide. Diet is considered the cornerstone to reduce incidence and prevalence of this disease. Algae contains fiber, polyphenols, ω-3 PUFAs, and bioactive molecules with potential antidiabetic activity. This review delves into the applications of algae and their components in T2DM, as well as to ascertain the mechanism involved (e.g., glucose absorption, lipids metabolism, antioxidant properties, etc.). PubMed, and Google Scholar databases were used. Papers in which whole alga, algal extracts, or their isolated compounds were studied in in vitro conditions, T2DM experimental models, and humans were selected and discussed. This review also focuses on meat matrices or protein concentrate-based products in which different types of alga were included, aimed to modulate carbohydrate digestion and absorption, blood glucose, gastrointestinal neurohormones secretion, glycosylation products, and insulin resistance. As microbiota dysbiosis in T2DM and metabolic alterations in different organs are related, the review also delves on the effects of several bioactive algal compounds on the colon/microbiota-liver-pancreas-brain axis. As the responses to therapeutic diets vary dramatically among individuals due to genetic components, it seems a priority to identify major gene polymorphisms affecting potential positive effects of algal compounds on T2DM treatment.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ingredientes de Alimentos/análise , Alimento Funcional/análise , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Microalgas/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Produtos Biológicos/uso terapêutico , Biomarcadores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Disbiose , Metabolismo Energético/efeitos dos fármacos , Predisposição Genética para Doença , Humanos , Hipoglicemiantes/uso terapêutico , Microalgas/classificação , Microbiota
13.
J Med Chem ; 64(9): 5645-5653, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33914534

RESUMO

Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice.


Assuntos
Inibidores Enzimáticos/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Purinas/química , Administração Oral , Animais , Sítios de Ligação , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Resistência à Insulina , Cinética , Simulação de Dinâmica Molecular , Obesidade/complicações , Obesidade/patologia , Fosforilação/efeitos dos fármacos , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Purinas/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
14.
Artigo em Inglês | MEDLINE | ID: mdl-33888538

RESUMO

INTRODUCTION: Contrasting results have been reported for the association between the variability in body weight and development of diabetes. In the present study, we evaluated the association between the variability in body mass index (BMI) and development of type 2 diabetes in 19 412 Japanese participants without obesity and without body weight gain or loss during the study period. RESEARCH DESIGN AND METHODS: We recorded body weight of the participants consecutively each year in Panasonic Corporation, Osaka, Japan from 2008 to 2014 to evaluate the variability of BMI. The participants with obesity (BMI ≥25 kg/m2) at baseline and body weight gain or loss from 2008 to 2014 (delta BMI ≥±1 kg/m2) were excluded from the study. In total, 416 participants developed type 2 diabetes from 2015 to 2018. We used coefficient of variation (CV) to represent the variability in BMI during 6 years of the study period. RESULTS: Cox regression analyses revealed that the risk of developing type 2 diabetes was higher in the fourth quartile (HR 1.33; 95% CI 1.01 to 1.75) of CV of BMI than that in the first quartile (lowest quartile) of CV of BMI after adjusting for multiple confounding factors. The risk for developing diabetes increased by 11.1% per 1% increase in CV of BMI. CONCLUSIONS: In conclusion, the variability in BMI is a risk factor for the development of diabetes in the Japanese population without obesity and without body weight gain or loss.


Assuntos
Diabetes Mellitus Tipo 2 , Índice de Massa Corporal , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Humanos , Japão/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-33888542

RESUMO

INTRODUCTION: Exposure to malnutrition in early life has been found to significantly elevate type 2 diabetes risk in adulthood. However, the changes in metabolites resulting from malnutrition in early life have not been studied. The aim of this study was to identify metabolites with levels associated with type 2 diabetes resulting from exposure to China's Great Famine (1959-1962). RESEARCH DESIGN AND METHODS: Participants were from SPECT-China 2014 and SPECT-China2 2019, two cross-sectional studies performed at the same site. In total, 2171 subjects participated in SPECT-China and SPECT-China2 simultaneously. The sample size of fetal-exposed (1959-1962) versus non-exposed (1963-1974) individuals was 82 vs 79 in 2014 and 97 vs 94 in 2019. Metabolomic profiling was performed between famine-exposed and non-exposed groups. RESULTS: Among the different famine exposure groups, the fetal-exposed group (1959-1962) had the greatest incidence rate (12.5%), with an OR of 2.11 (95% CI 1.01 to 4.44), compared with the non-exposed group (1963-1974). Moreover, compared with those in the non-exposed group (1963-1974), four metabolites (indole-3-carbinol (I3C), phosphatidylcholine (PC) (22:6(4Z,7Z,10Z,13Z,16Z,19Z)/16:1(9Z)), pyrimidine, and PC(16:1(9Z)/22:5(4Z,7Z,10Z,13Z,16Z))) showed significantly lower relative intensities in the famine and diabetes groups both in 2014 and 2019. Pyrimidine significantly mediated the association of famine exposure with diabetes, and I3C marginally mediated this association. CONCLUSIONS: Famine exposure in the fetal period could increase type 2 diabetes risk in adults, even those in their 60s. I3C and pyrimidine are potential mediators of the effects of famine exposure on diabetes development.


Assuntos
Diabetes Mellitus Tipo 2 , Efeitos Tardios da Exposição Pré-Natal , Adulto , China/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Fome Epidêmica , Feminino , Seguimentos , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia
16.
Nutrients ; 13(4)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920626

RESUMO

In a secondary analysis, we assessed the ability of dietary and physical activity surveys to explain variability in weight loss within a worksite-adapted Diabetes Prevention Program. The program involved 58 overweight/obese female employees (average age = 46 ± 11 years SD; average body mass index = 34.7 ± 7.0 kg/m2 SD) of four long-term care facilities who survey-reported liking and frequency of dietary and physical activity behaviors. Data were analyzed using a latent variable approach, analysis of covariance, and nested regression analysis to predict percent weight change from baseline to intervention end at week 16 (average loss = 3.0%; range-6% gain to 17% loss), and follow-up at week 28 (average loss = 2.0%; range-8% gain to 16% loss). Using baseline responses, restrained eaters (reporting liking but low intakes of high fat/sweets) achieved greater weight loss at 28 weeks than those reporting high liking/high intake (average loss = 3.5 ± 0.9% versus 1.0 ± 0.8% S.E., respectively). Examining the dietary surveys separately, only improvements in liking for a healthy diet were associated significantly with weight loss (predicting 44% of total variance, p < 0.001). By contrasting liking versus intake changes, women reporting concurrent healthier diet liking and healthier intake lost the most weight (average loss = 5.4 ± 1.1% S.E.); those reporting eating healthier but not healthier diet liking (possible misreporting) gained weight (average gain = 0.3 ± 1.4% S.E.). Change in liking and frequency of physical activity were highly correlated but neither predicted weight loss independently. These pilot data support surveying dietary likes/dislikes as a useful measure to capture dietary behaviors associated with weight loss in worksite-based programs. Comparing dietary likes and intake may identify behaviors consistent (appropriate dietary restraint) or inconsistent (misreporting) with weight loss success.


Assuntos
Dieta/psicologia , Comportamento Alimentar/psicologia , Sobrepeso/psicologia , Perda de Peso/fisiologia , Programas de Redução de Peso , Adulto , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Exercício Físico/psicologia , Feminino , Humanos , Análise de Classes Latentes , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/psicologia , Obesidade/terapia , Saúde do Trabalhador , Sobrepeso/complicações , Sobrepeso/terapia , Projetos Piloto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ganho de Peso , Local de Trabalho/psicologia
17.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33804680

RESUMO

Hypofibrinolysis is a key abnormality in diabetes and contributes to the adverse vascular outcome in this population. Plasminogen activator inhibitor (PAI)-1 is an important regulator of the fibrinolytic process and levels of this antifibrinolytic protein are elevated in diabetes and insulin resistant states. This review describes both the physiological and pathological role of PAI-1 in health and disease, focusing on the mechanism of action as well as protein abnormalities in vascular disease with special focus on diabetes. Attempts at inhibiting protein function, using different techniques, are also discussed including direct and indirect interference with production as well as inhibition of protein function. Developing PAI-1 inhibitors represents an alternative approach to managing hypofibrinolysis by targeting the pathological abnormality rather than current practice that relies on profound inhibition of the cellular and/or acellular arms of coagulation, and which can be associated with increased bleeding events. The review offers up-to-date knowledge on the mechanisms of action of PAI-1 together with the role of altering protein function to improve hypofirbinolysis. Developing PAI-1 inhibitors may form for the basis of future new class of antithrombotic agents that reduce vascular complications in diabetes.


Assuntos
Diabetes Mellitus/etiologia , Diabetes Mellitus/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Animais , Antifibrinolíticos/farmacologia , Antifibrinolíticos/uso terapêutico , Biomarcadores , Complicações do Diabetes/sangue , Diabetes Mellitus/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Ativação Enzimática/efeitos dos fármacos , Fibrinólise , Humanos , Terapia de Alvo Molecular , Inibidor 1 de Ativador de Plasminogênio/química , Relação Estrutura-Atividade
18.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916292

RESUMO

Methanolic leaf extracts of four Lauraceae species endemic to Laurisilva forest (Apollonias barbujana, Laurus novocanariensis, Ocotea foetens and Persea indica) were investigated for the first time for their potential to inhibit key enzymes linked to type-2 diabetes (α-amylase, α-glucosidase, aldose reductase) and obesity (pancreatic lipase), and protein glycation. Lauraceae extracts revealed significant inhibitory activities in all assays, altough with different ability between species. In general, P. indica showed the most promissing results. In the protein glycation assay, all analysed extracts displayed a stronger effect than a reference compound: aminoguanidine (AMG). The in vitro anti-diabetic, anti-obesity and anti-glycation activities of analysed extracts showed correlation with their flavonols and flavan-3-ols (in particular, proanthocyanins) contents. These Lauraceae species have the capacity to assist in adjuvant therapy of type-2 diabetes and associated complications, through modulation of the activity of key metabolic enzymes and prevention of advanced glycation end-products (AGEs) formation.


Assuntos
Biomarcadores , Diabetes Mellitus Tipo 2/metabolismo , Glicoproteínas/metabolismo , Hipoglicemiantes/farmacologia , Lauraceae/química , Obesidade/metabolismo , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/química , Animais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/etiologia , Florestas , Glicosilação , Hipoglicemiantes/química , Redes e Vias Metabólicas , Estrutura Molecular , Obesidade/enzimologia , Obesidade/etiologia , Fenóis/química , Extratos Vegetais/química , Ratos
19.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33924206

RESUMO

Pancreatic ß-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for ß-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic ß-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in ß-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced ß-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in ß-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in ß-cells. This inhibitory intervention may be due to an increase of membrane fluidity.


Assuntos
Apoptose , Ácidos Graxos/metabolismo , Células Secretoras de Insulina/metabolismo , Animais , Apoptose/genética , Sobrevivência Celular/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/metabolismo , Humanos , Metabolismo dos Lipídeos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Modelos Biológicos , Transdução de Sinais , Estresse Fisiológico
20.
Top Spinal Cord Inj Rehabil ; 27(1): 36-56, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814882

RESUMO

The population with SCI is at a significant risk for both insulin resistance and type 2 diabetes mellitus (T2DM) secondary to neurogenic obesity. The prevalence of insulin resistance and T2DM in persons with SCI suggests that disorders of carbohydrate metabolism are at epidemic proportions within the population. However, the true frequency of such disorders may be underestimated because biomarkers of insulin resistance and T2DM used from the population without SCI remain nonspecific and may in fact fail to identify true cases that would benefit from intervention. Furthermore, diet and exercise have been used to help mitigate neurogenic obesity, but results on disorders of carbohydrate metabolism remain inconsistent, likely because of the various ways carbohydrate metabolism is assessed. The objective of this article is to review current literature on the prevalence and likely mechanisms driving insulin resistance and T2DM in persons with SCI. This article also explores the various assessments and diagnostic criteria used for insulin resistance and T2DM and briefly discusses the effects of exercise and/or diet to mitigate disorders of carbohydrate metabolism brought on by neurogenic obesity.


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Resistência à Insulina , Obesidade/complicações , Traumatismos da Medula Espinal/complicações , Diabetes Mellitus Tipo 2/terapia , Carboidratos da Dieta/metabolismo , Terapia por Exercício , Humanos , Obesidade/terapia , Traumatismos da Medula Espinal/terapia
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