Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21.246
Filtrar
1.
Sci Transl Med ; 13(600)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193609

RESUMO

The paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in humans. However, the molecular mechanism of PAX6 in controlling insulin secretion in human beta cells and its pathophysiological role in type 2 diabetes (T2D) remain ambiguous. We investigated the molecular pathway of PAX6 in the regulation of insulin secretion and the potential therapeutic value of PAX6 in T2D by using human pancreatic beta cell line EndoC-ßH1, the db/db mouse model, and primary human pancreatic islets. Through loss- and gain-of-function approaches, we uncovered a mechanism by which PAX6 modulates glucose-stimulated insulin secretion (GSIS) through a cAMP response element-binding protein (CREB)/Munc18-1/2 pathway. Moreover, under diabetic conditions, beta cells and pancreatic islets displayed dampened PAX6/CREB/Munc18-1/2 pathway activity and impaired GSIS, which were reversed by PAX6 replenishment. Adeno-associated virus-mediated PAX6 overexpression in db/db mouse pancreatic beta cells led to a sustained amelioration of glycemic perturbation in vivo but did not affect insulin resistance. Our study highlights the pathophysiological role of PAX6 in T2D-associated beta cell dysfunction in humans and suggests the potential of PAX6 gene transfer in preserving and restoring beta cell function.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Ilhotas Pancreáticas , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Homeostase , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo
2.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206320

RESUMO

Type 2 diabetes (T2D) is a chronic metabolic disease, which could affect the daily life of patients and increase their risk of developing other diseases. Synthetic anti-diabetic drugs usually show severe side effects. In the last few decades, plant-derived drugs have been intensively studied, particularly because of a rapid development of the instruments used in analytical chemistry. We tested the efficacy of Gundelia tournefortii L. (GT) in increasing the translocation of glucose transporter-4 (GLUT4) to the myocyte plasma membrane (PM), as a main strategy to manage T2D. In this study, GT methanol extract was sub-fractionated into 10 samples using flash chromatography. The toxicity of the fractions on L6 muscle cells, stably expressing GLUTmyc, was evaluated using the MTT assay. The efficacy with which GLUT4 was attached to the L6 PM was evaluated at non-toxic concentrations. Fraction 6 was the most effective, as it stimulated GLUT4 translocation in the absence and presence of insulin, 3.5 and 5.2 times (at 250 µg/mL), respectively. Fraction 1 and 3 showed no significant effects on GLUT4 translocation, while other fractions increased GLUT4 translocation up to 2.0 times. Gas chromatography-mass spectrometry of silylated fractions revealed 98 distinct compounds. Among those compounds, 25 were considered anti-diabetic and glucose disposal agents. These findings suggest that GT methanol sub-fractions exert an anti-diabetic effect by modulating GLUT4 translocation in L6 muscle cells, and indicate the potential of GT extracts as novel therapeutic agents for T2D.


Assuntos
Asteraceae/química , Diabetes Mellitus Tipo 2/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Hipoglicemiantes , Células Musculares/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Transportador de Glucose Tipo 4/genética , Hipoglicemiantes/química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Transporte Proteico/efeitos dos fármacos , Ratos
3.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208589

RESUMO

There is mounting evidence that type 2 diabetes mellitus (T2DM) is related with increased risk for the development of cancer. Apart from shared common risk factors typical for both diseases, diabetes driven factors including hyperinsulinemia, insulin resistance, hyperglycemia and low grade chronic inflammation are of great importance. Recently, vitamin D deficiency was reported to be associated with the pathogenesis of numerous diseases, including T2DM and cancer. However, little is known whether vitamin D deficiency may be responsible for elevated cancer risk development in T2DM patients. Therefore, the aim of the current review is to identify the molecular mechanisms by which vitamin D deficiency may contribute to cancer development in T2DM patients. Vitamin D via alleviation of insulin resistance, hyperglycemia, oxidative stress and inflammation reduces diabetes driven cancer risk factors. Moreover, vitamin D strengthens the DNA repair process, and regulates apoptosis and autophagy of cancer cells as well as signaling pathways involved in tumorigenesis i.e., tumor growth factor ß (TGFß), insulin-like growth factor (IGF) and Wnt-ß-Cathenin. It should also be underlined that many types of cancer cells present alterations in vitamin D metabolism and action as a result of Vitamin D Receptor (VDR) and CYP27B1 expression dysregulation. Although, numerous studies revealed that adequate vitamin D concentration prevents or delays T2DM and cancer development, little is known how the vitamin affects cancer risk among T2DM patients. There is a pressing need for randomized clinical trials to clarify whether vitamin D deficiency may be a factor responsible for increased risk of cancer in T2DM patients, and whether the use of the vitamin by patients with diabetes and cancer may improve cancer prognosis and metabolic control of diabetes.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Neoplasias/etiologia , Deficiência de Vitamina D/complicações , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Redes e Vias Metabólicas , Neoplasias/epidemiologia , Neoplasias/prevenção & controle , Neoplasias/terapia , Prognóstico , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Vitamina D/farmacologia , Deficiência de Vitamina D/metabolismo
4.
Nat Commun ; 12(1): 3385, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099679

RESUMO

Obesity is the key driver of peripheral insulin resistance, one of the key features of type 2 diabetes (T2D). In insulin-resistant individuals, the expansion of beta-cell mass is able to delay or even prevent the onset of overt T2D. Here, we report that beta-arrestin-1 (barr1), an intracellular protein known to regulate signaling through G protein-coupled receptors, is essential for beta-cell replication and function in insulin-resistant mice maintained on an obesogenic diet. Specifically, insulin-resistant beta-cell-specific barr1 knockout mice display marked reductions in beta-cell mass and the rate of beta-cell proliferation, associated with pronounced impairments in glucose homeostasis. Mechanistic studies suggest that the observed metabolic deficits are due to reduced Pdx1 expression levels caused by beta-cell barr1 deficiency. These findings indicate that strategies aimed at enhancing barr1 activity and/or expression in beta-cells may prove useful to restore proper glucose homeostasis in T2D.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/patologia , Obesidade/metabolismo , beta-Arrestina 1/metabolismo , Animais , Glicemia/metabolismo , Proliferação de Células , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Proteínas de Homeodomínio/metabolismo , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/patologia , Transativadores/metabolismo , beta-Arrestina 1/genética
5.
Phytomedicine ; 87: 153582, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34091150

RESUMO

BACKGROUND AND PURPOSE: Diosmetin (Dios), a flavonoid compound with multiple pharmacological activities. However, fewer studies have reported its effects on type 2 diabetic mellitus (T2DM). Here, we address the effect of Dios on glucose metabolism and gut microbiota in KK-Ay diabetic mice. METHOD: Wild type C57BL/6 J mice or diabetic KK-Ay mice were treated with vehicle or Dios for one month. The ELISA kit and fluorescence microscope system were respectively employed to the evaluation of serum biochemical indicators and histopathological changes. Liver RNA-Seq and western blot were used to reveal the key signaling pathway. The effects of Dios on gut microbiota was investigated by the 16S rRNA gene sequencing, as well as the relationship between Dios and C. glu on glucose metabolism was explored with the C. glu transplantation. RESULTS: Dios treatment significantly decreased blood glucose and increased serum insulin concentrations. RNA-Seq analysis found that the underlying action mechanism of Dios on T2DM was via modulating glucose metabolism, which was proved by up-regulating IRS/PI3K/AKT signaling pathway to promote glycogen synthesis and GLUT4 translocation. Besides, Dios treatment reshaped the unbalanced gut microbiota by suppressing the ratio of Firmicutes/Bacteroidetes and markedly increasing the richness of C. glu. Moreover, treatment with C. glu and Dios together could markedly ameliorate glucose metabolism by up-regulating IRS/PI3K/AKT signaling pathway to promote glycogen synthesis and GLUT4 translocation. CONCLUSIONS: Dios treatment remarkably ameliorated glucose metabolism in KK-Ay diabetic mice by the regulation of C. glu via IRS/PI3K/AKT signaling pathway and reshaped the unbalanced gut microbiota. Our study provided evidence for the application of Dios to the treatment of T2DM.


Assuntos
Corynebacterium glutamicum/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Flavonoides/farmacologia , Hipoglicemiantes/farmacologia , Animais , Glicemia/metabolismo , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/genética , Glicogênio/metabolismo , Insulina/sangue , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Ribossômico 16S , Fatores de Transcrição/metabolismo
6.
Nat Commun ; 12(1): 3363, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099651

RESUMO

Impaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL-HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.


Assuntos
Complexos de Coordenação/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Complexos de Coordenação/química , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Irídio/química , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Cicatrização/genética
7.
Adv Food Nutr Res ; 96: 251-310, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1240122

RESUMO

Since the discovery of manifest Zn deficiency in 1961, the increasing number of studies demonstrated the association between altered Zn status and multiple diseases. In this chapter, we provide a review of the most recent advances on the role of Zn in health and disease (2010-20), with a special focus on the role of Zn in neurodegenerative and neurodevelopmental disorders, diabetes and obesity, male and female reproduction, as well as COVID-19. In parallel with the revealed tight association between ASD risk and severity and Zn status, the particular mechanisms linking Zn2+ and ASD pathogenesis like modulation of synaptic plasticity through ProSAP/Shank scaffold, neurotransmitter metabolism, and gut microbiota, have been elucidated. The increasing body of data indicate the potential involvement of Zn2+ metabolism in neurodegeneration. Systemic Zn levels in Alzheimer's and Parkinson's disease were found to be reduced, whereas its sequestration in brain may result in modulation of amyloid ß and α-synuclein processing with subsequent toxic effects. Zn2+ was shown to possess adipotropic effects through the role of zinc transporters, zinc finger proteins, and Zn-α2-glycoprotein in adipose tissue physiology, underlying its particular role in pathogenesis of obesity and diabetes mellitus type 2. Recent findings also contribute to further understanding of the role of Zn2+ in spermatogenesis and sperm functioning, as well as oocyte development and fertilization. Finally, Zn2+ was shown to be the potential adjuvant therapy in management of novel coronavirus infection (COVID-19), underlining the perspectives of zinc in management of old and new threats.


Assuntos
Transtorno do Espectro Autista/metabolismo , COVID-19/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Doenças Neurodegenerativas/metabolismo , Obesidade/metabolismo , Reprodução , Zinco/metabolismo , Doença de Alzheimer/metabolismo , Animais , COVID-19/tratamento farmacológico , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/metabolismo , Estado Nutricional , Doença de Parkinson/metabolismo , Zinco/deficiência , Zinco/uso terapêutico
8.
Clin Interv Aging ; 16: 1185-1191, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34188461

RESUMO

Aim: High glucose (HG)-induced activation of mTOR promotes tau phosphorylation and leads to diabetes-associated dementia. This study aimed to explore the role of metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) in HG-induced neuronal cell injury. Methods: Hippocampus cells were isolated from C57BL/6J mice. After 6 days of culture, the cells were incubated with 5.5 mM glucose in normal medium or 75 mM glucose for 4 days. Cells were transfected with miR-144 mimic, miR-144 inhibitor, siRNA for MALAT1 or corresponding controls. Gene expression was detected by PCR and Western blot analysis. Results: HG increased the levels of MALAT1 and p-tau in hippocampal cells. Knockdown of MALAT1 partially reversed the effects of HG on mTOR activity and p-tau protein levels. MALAT1 functioned as competing endogenous RNA (ceRNA) for miR-144, and pre-treatment with MALAT1 siRNA decreased mTOR activity and p-tau protein level in HG-treated hippocampal cells, which was significantly attenuated by miR-144 mimics. Moreover, miR-144 negatively regulated the expression of mTOR and knockdown of MALAT1 suppressed mTOR, while overexpression of mTOR abrogated protective effects of MALAT1 knockdown in HG-treated hippocampal cells. Conclusion: MALAT1 knockdown prevented HG-induced mTOR activation and inhibited tau phosphorylation. MALAT1 may be a therapy target for diabetes associated dementia.


Assuntos
Doença de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , RNA Longo não Codificante/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Doença de Alzheimer/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Diabetes Mellitus Tipo 2/genética , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , RNA Longo não Codificante/genética , Serina-Treonina Quinases TOR/genética
9.
Adv Food Nutr Res ; 96: 251-310, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34112355

RESUMO

Since the discovery of manifest Zn deficiency in 1961, the increasing number of studies demonstrated the association between altered Zn status and multiple diseases. In this chapter, we provide a review of the most recent advances on the role of Zn in health and disease (2010-20), with a special focus on the role of Zn in neurodegenerative and neurodevelopmental disorders, diabetes and obesity, male and female reproduction, as well as COVID-19. In parallel with the revealed tight association between ASD risk and severity and Zn status, the particular mechanisms linking Zn2+ and ASD pathogenesis like modulation of synaptic plasticity through ProSAP/Shank scaffold, neurotransmitter metabolism, and gut microbiota, have been elucidated. The increasing body of data indicate the potential involvement of Zn2+ metabolism in neurodegeneration. Systemic Zn levels in Alzheimer's and Parkinson's disease were found to be reduced, whereas its sequestration in brain may result in modulation of amyloid ß and α-synuclein processing with subsequent toxic effects. Zn2+ was shown to possess adipotropic effects through the role of zinc transporters, zinc finger proteins, and Zn-α2-glycoprotein in adipose tissue physiology, underlying its particular role in pathogenesis of obesity and diabetes mellitus type 2. Recent findings also contribute to further understanding of the role of Zn2+ in spermatogenesis and sperm functioning, as well as oocyte development and fertilization. Finally, Zn2+ was shown to be the potential adjuvant therapy in management of novel coronavirus infection (COVID-19), underlining the perspectives of zinc in management of old and new threats.


Assuntos
Transtorno do Espectro Autista/metabolismo , COVID-19/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Doenças Neurodegenerativas/metabolismo , Obesidade/metabolismo , Reprodução , Zinco/metabolismo , Doença de Alzheimer/metabolismo , Animais , COVID-19/tratamento farmacológico , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/metabolismo , Estado Nutricional , Doença de Parkinson/metabolismo , Zinco/deficiência , Zinco/uso terapêutico
10.
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
11.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071388

RESUMO

Ageing is a complex process which implies the accumulation of molecular, cellular and organ damage, leading to an increased vulnerability to disease. In Western societies, the increase in the elderly population, which is accompanied by ageing-associated pathologies such as cardiovascular and mental diseases, is becoming an increasing economic and social burden for governments. In order to prevent, treat and determine which subjects are more likely to develop these age-related diseases, predictive biomarkers are required. In this sense, some studies suggest that glycans have a potential role as disease biomarkers, as they modify the functions of proteins and take part in intra- and intercellular biological processes. As the glycome reflects the real-time status of these interactions, its characterisation can provide potential diagnostic and prognostic biomarkers for multifactorial diseases. This review gathers the alterations in protein glycosylation profiles that are associated with ageing and age-related diseases, such as cancer, type 2 diabetes mellitus, metabolic syndrome and several chronic inflammatory diseases. Furthermore, the review includes the available techniques for the determination and characterisation of glycans, such as liquid chromatography, electrophoresis, nuclear magnetic resonance and mass spectrometry.


Assuntos
Envelhecimento/metabolismo , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Síndrome Metabólica/metabolismo , Neoplasias/metabolismo , Polissacarídeos/metabolismo , Cromatografia Líquida/métodos , Glicosilação , Humanos , Espectrometria de Massas/métodos
12.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069914

RESUMO

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Células Secretoras de Insulina/fisiologia , Animais , Apoptose/fisiologia , Células Cultivadas , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Glucose/metabolismo , Humanos , Hiperglicemia/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Transdução de Sinais
13.
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
14.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063817

RESUMO

Soluble epoxide hydrolase (sEH) is abundant in the brain, is upregulated in type 2 diabetes mellitus (DM2), and is possible mediator of ischemic injury via the breakdown of neuroprotective epoxyeicosatrienoic acids (EETs). Prophylactic, pre-ischemic sEH blockade with 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB) reduces stroke-induced infarct in normal and diabetic mice, with larger neuroprotection in DM2. The present study tested whether benefit occurs in normal and DM2 mice if tAUCB is administered after stroke onset. We performed 60 min middle cerebral artery occlusion in young adult male C57BL mice divided into four groups: normal or DM2, with t-AUCB 2 mg/kg or vehicle 30 min before reperfusion. Endpoints were (1) cerebral blood flow (CBF) by laser Doppler, and (2) brain infarct at 24 h. In nondiabetic mice, t-AUCB reduced infarct size by 30% compared to vehicle-treated mice in the cortex (31.4 ± 4 vs. 43.8 ± 3 (SEM)%, respectively) and 26% in the whole hemisphere (26.3 ± 3 vs. 35.2 ± 2%, both p < 0.05). In contrast, in DM2 mice, tAUCB failed to ameliorate either cortical or hemispheric injury. No differences were seen in CBF. We conclude that tAUCB administered after ischemic stroke onset exerts brain protection in nondiabetic but not DM2 mice, that the neuroprotection appears independent of changes in gross CBF, and that DM2-induced hyperglycemia abolishes t-AUCB-mediated neuroprotection after stroke onset.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Acidente Vascular Cerebral/metabolismo , Animais , Benzoatos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/tratamento farmacológico , Ureia/análogos & derivados , Ureia/farmacologia
15.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063911

RESUMO

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer's disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and db/db models) or the novel leptin deficiency (BTBR ob/ob model).


Assuntos
Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Transdução de Sinais/fisiologia , Animais , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos Obesos/metabolismo
16.
Nat Commun ; 12(1): 3340, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099657

RESUMO

Hepatic gluconeogenesis is essential for glucose homeostasis and also a therapeutic target for type 2 diabetes, but its mechanism is incompletely understood. Here, we report that Sam68, an RNA-binding adaptor protein and Src kinase substrate, is a novel regulator of hepatic gluconeogenesis. Both global and hepatic deletions of Sam68 significantly reduce blood glucose levels and the glucagon-induced expression of gluconeogenic genes. Protein, but not mRNA, levels of CRTC2, a crucial transcriptional regulator of gluconeogenesis, are >50% lower in Sam68-deficient hepatocytes than in wild-type hepatocytes. Sam68 interacts with CRTC2 and reduces CRTC2 ubiquitination. However, truncated mutants of Sam68 that lack the C- (Sam68ΔC) or N-terminal (Sam68ΔN) domains fails to bind CRTC2 or to stabilize CRTC2 protein, respectively, and transgenic Sam68ΔN mice recapitulate the blood-glucose and gluconeogenesis profile of Sam68-deficient mice. Hepatic Sam68 expression is also upregulated in patients with diabetes and in two diabetic mouse models, while hepatocyte-specific Sam68 deficiencies alleviate diabetic hyperglycemia and improves insulin sensitivity in mice. Thus, our results identify a role for Sam68 in hepatic gluconeogenesis, and Sam68 may represent a therapeutic target for diabetes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Gluconeogênese/fisiologia , Fígado/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Glicemia/metabolismo , Proteínas de Ligação a DNA , Diabetes Mellitus Tipo 2/metabolismo , Regulação da Expressão Gênica , Glucagon/metabolismo , Gluconeogênese/genética , Glucose/metabolismo , Hepatócitos/metabolismo , Homeostase , Humanos , Hiperglicemia , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genética , Regulação para Cima
17.
Nat Commun ; 12(1): 3350, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099721

RESUMO

Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.


Assuntos
Antígenos CD36/genética , Antígenos CD36/metabolismo , Células Endoteliais/metabolismo , Resistência à Insulina/fisiologia , Obesidade Abdominal/metabolismo , Animais , Antígenos CD , Caderinas , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose/metabolismo , Inflamação , Vasos Linfáticos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fosforilação , Transcriptoma , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
18.
Nat Commun ; 12(1): 3505, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108472

RESUMO

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.


Assuntos
Diabetes Mellitus Tipo 2/genética , Dislipidemias/genética , Predisposição Genética para Doença/genética , Adulto , Variação Biológica da População , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Exoma/genética , Genótipo , Humanos , Herança Multifatorial , Penetrância , Medição de Risco
19.
Life Sci ; 278: 119586, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33957171

RESUMO

AIMS: The reduction in androgens serum concentration is a physiological condition that accompanies age advancement but can also occur because of prostate cancer and gender affirming treatment or pathological conditions such as functional hypogonadism. However, androgen deficiency is related to a higher risk of developing metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM). Considering that glucagon-like peptide 1 (GLP1) analogs are increasingly used in the treatment of T2DM, we investigated if liraglutide could also attenuate the metabolic changes caused by orchiectomy in rats. MAIN METHODS: Wistar rats were orchiectomized (ORC), and subdivided in four groups: sham saline, sham liraglutide, ORC saline, and ORC liraglutide. After sixty days, metabolic parameters were evaluated in blood, muscle, liver, brown (BAT) and white adipose tissue (WAT) visceral depots. Glucose utilization, oxidation, and conversion to lipids by de novo lipogenesis, and basal and adrenaline-stimulated lipolysis were evaluated in BAT and WAT depots. KEY FINDINGS: Orchiectomy increased triglyceridemia, BAT and rtWAT weight, and lipolysis and reduced glucose utilization. Liraglutide treatment reversed these effects. SIGNIFICANCE: These results indicate that liraglutide improves triglyceridemia and glucose metabolism in WAT depots, which suggests that it may be a promising therapeutic strategy to handle disruptions in energy metabolism caused by androgen deficiency.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Liraglutida/farmacologia , Orquiectomia/efeitos adversos , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Peso Corporal , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipólise , Masculino , Obesidade/metabolismo , Tamanho do Órgão , Oxigênio/metabolismo , Ratos , Ratos Wistar , Triglicerídeos/metabolismo , Ganho de Peso
20.
Clin Nephrol ; 96(2): 96-104, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34042581

RESUMO

AIM: Bone mineral disorders are being increasingly seen among diabetic populations as the frequency of diabetes mellitus (DM) is rising at an alarming rate. Our aim is to examine the relationship between glycemic control and bone turnover markers like osteocalcin (OC), C-terminal carboxy telopeptide (CTX), and bone-specific alkaline phosphatase (ALP) in patients with type 2 diabetes, and the effects of anti-diabetic regimens on these markers. MATERIALS AND METHODS: A total of 80 newly diagnosed type 2 DM patients were enrolled into the study and divided into two groups according to glucose regulation (group 1 HbA1c < 7 and group 2 HbA1c ≥ 7). They were also classified into three groups according to antidiabetic regimen. Physical examination findings, demographic characteristics, and anti-diabetic regimens of the patients were recorded. Hemogram and biochemical parameters were studied after 12 hours of fasting. Serum levels OC and CTX were examined by ELISA method. Bone-specific ALP was examined by Chemiluminesence immuneassay (CLIA) method. Bone densitometry was performed on the 2016 model Stratos DR device of DMS brand, and T scores of the patients were recorded. All parameters were repeated at the 6th month of the study. RESULTS: Serum vitamin D and OC levels of group 1 were higher, while ALP was higher in group 2. However, we failed to determine a significant difference in CTX levels between the groups. OC levels were enhanced only in patients receiving metformin plus vildagliptin therapy. The CTX levels increased in all groups, whereas they decreased in the metformin plus DPP-4 group. CONCLUSION: Better glucose regulation is associated with better bone formation, and among three groups metformin plus vildagliptin therapy has a favorable effect on both bone formation and resorption.


Assuntos
Glicemia/metabolismo , Remodelação Óssea/fisiologia , Colágeno Tipo I/metabolismo , Diabetes Mellitus Tipo 2 , Hipoglicemiantes/uso terapêutico , Peptídeos/metabolismo , Fosfatase Alcalina/metabolismo , Biomarcadores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Controle Glicêmico , Humanos , Osteocalcina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...