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1.
Int J Mol Sci ; 22(19)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34639136

RESUMO

BACKGROUND: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. METHODS: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. RESULTS: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). CONCLUSIONS: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.


Assuntos
Trato Gastrointestinal/metabolismo , Hiperglicemia/prevenção & controle , Lecitinas/metabolismo , Período Pós-Prandial , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , alfa-Ciclodextrinas/farmacologia , Animais , Trato Gastrointestinal/efeitos dos fármacos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
2.
Int J Mol Sci ; 22(19)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34639069

RESUMO

The prevalence of type 2 diabetes (T2D) is rapidly increasing across the globe. Fetal exposure to maternal diabetes was correlated with higher prevalence of impaired glucose tolerance and T2D later in life. Previous studies showed aberrant DNA methylation patterns in pancreas of T2D patients. However, the underlying mechanisms remained largely unknown. We utilized human embryonic stem cells (hESC) as the in vitro model for studying the effects of hyperglycemia on DNA methylome and early pancreatic differentiation. Culture in hyperglycemic conditions disturbed the pancreatic lineage potential of hESC, leading to the downregulation of expression of pancreatic markers PDX1, NKX6-1 and NKX6-2 after in vitro differentiation. Genome-wide DNA methylome profiling revealed over 2000 differentially methylated CpG sites in hESC cultured in hyperglycemic condition when compared with those in control glucose condition. Gene ontology analysis also revealed that the hypermethylated genes were enriched in cell fate commitment. Among them, NKX6-2 was validated and its hypermethylation status was maintained upon differentiation into pancreatic progenitor cells. We also established mouse ESC lines at both physiological glucose level (PG-mESC) and conventional hyperglycemia glucose level (HG-mESC). Concordantly, DNA methylome analysis revealed the enrichment of hypermethylated genes related to cell differentiation in HG-mESC, including Nkx6-1. Our results suggested that hyperglycemia dysregulated the epigenome at early fetal development, possibly leading to impaired pancreatic development.


Assuntos
Diferenciação Celular/genética , Metilação de DNA , Células-Tronco Embrionárias/metabolismo , Hiperglicemia/genética , Hiperglicemia/metabolismo , Pâncreas/citologia , Pâncreas/metabolismo , Linhagem Celular , Células Cultivadas , Biologia Computacional/métodos , Diabetes Mellitus Tipo 2 , Células-Tronco Embrionárias/citologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glucose/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo
3.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502120

RESUMO

Diabetes mellitus is a main risk factor for delayed fracture healing and fracture non-unions. Successful fracture healing requires stimuli from different immune cells, known to be affected in diabetics. Especially, application of mononuclear cells has been proposed to promote wound and fracture healing. Thus, aim was to investigate the effect of pre-/diabetic conditions on mononuclear cell functions essential to promote osteoprogenitor cell function. We here show that pre-/diabetic conditions suppress the expression of chemokines, e.g., CCL2 and CCL8 in osteoprogenitor cells. The associated MCP-1 and MCP-2 were significantly reduced in serum of diabetics. Both MCPs chemoattract mononuclear THP-1 cells. Migration of these cells is suppressed under hyperglycemic conditions, proposing that less mononuclear cells invade the site of fracture in diabetics. Further, we show that the composition of cytokines secreted by mononuclear cells strongly differ between diabetics and controls. Similar is seen in THP-1 cells cultured under hyperinsulinemia or hyperglycemia. The altered secretome reduces the positive effect of the THP-1 cell conditioned medium on migration of osteoprogenitor cells. In summary, our data support that factors secreted by mononuclear cells may support fracture healing by promoting migration of osteoprogenitor cells but suggest that this effect might be reduced in diabetics.


Assuntos
Meios de Cultivo Condicionados/metabolismo , Diabetes Mellitus/metabolismo , Consolidação da Fratura , Monócitos/metabolismo , Animais , Biomarcadores , Movimento Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL8/metabolismo , Quimiocinas/metabolismo , Quimiotaxia de Leucócito/imunologia , Humanos , Hiperglicemia/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Sistema de Sinalização das MAP Quinases , Monócitos/imunologia , Osteoblastos/metabolismo , Osteogênese , Células THP-1
4.
Nat Commun ; 12(1): 5296, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489478

RESUMO

The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density lipoprotein receptor-related protein 1 depletion, osteocalcin treatment normalizes hyperglycemia in multiple mouse models. Mechanistically, osteocalcin receptor-G protein-coupled receptor family C group 6 member A and insulin-like-growth-factor-1 receptor are in the same complex with osteocalcin and required for osteocalcin-promoted insulin signaling pathway. Therefore, our results reveal an endocrine/paracrine role of endothelial cells in regulating insulin sensitivity, which may have therapeutic implications in treating diabetes and insulin resistance through manipulating vascular endothelium.


Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Glucose/metabolismo , Hiperglicemia/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Osteocalcina/genética , Animais , Células Endoteliais/patologia , Endotélio Vascular/patologia , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Teste de Tolerância a Glucose , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência , Masculino , Camundongos , Camundongos Knockout , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteocalcina/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
5.
Nutrients ; 13(9)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34578791

RESUMO

Prediabetes is a strong predictor of type 2 diabetes and its associated cardiovascular complications, but few studies explore sexual dimorphism in this context. Here, we aim to determine whether sex influences physiological response to high-fat high-sucrose diet (HFS) and myocardial tolerance to ischemia-reperfusion injury. Male and female Wistar rats were subjected to standard (CTRL) or HFS diet for 5 months. Then, ex-vivo experiments on isolated perfused heart model were performed to evaluate tolerance to ischemia-reperfusion injury. HFS diet induced fasting hyperglycemia and increased body fat percent to a similar level in both sexes. However, glucose intolerance was more pronounced in female HFS. Cholesterol was increased only in female while male displayed higher level of plasmatic leptin. We observed increased heart weight to tibia length ratio only in males, but we showed a similar decrease in tolerance to ischemia-reperfusion injury in female and male HFS compared with respective controls, characterized by impaired cardiac function, energy metabolism and coronary flow during reperfusion. In conclusion, as soon as glucose intolerance and hyperglycemia develop, we observe higher sensitivity of hearts to ischemia-reperfusion injury without difference between males and females.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/efeitos adversos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Animais , Colesterol/sangue , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético , Feminino , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Humanos , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Leptina/sangue , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Estado Pré-Diabético/metabolismo , Ratos , Ratos Wistar , Fatores Sexuais , Ganho de Peso
6.
Nutrients ; 13(9)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34578832

RESUMO

Although fruit juices are a natural source of sugars, there is a controversy whether their sugar content has similar harmful effects as beverages' added-sugars. We aimed to study the role of fruit juice sugars in inducing overweight, hyperglycaemia, glycation and oxidative stress in normal and diabetic animal models. In diabetic Goto-Kakizaki (GK) rats, we compared the effects of four different fruit juices (4-weeks) with sugary solutions having a similar sugar profile and concentration. In vitro, the sugary solutions were more susceptible to AGE formation than fruit juices, also causing higher postprandial glycaemia and lower erythrocytes' antioxidant capacity in vivo (single intake). In GK rats, ad libitum fruit juice consumption (4-weeks) did not change body weight, glycaemia, oxidative stress nor glycation. Consumption of a matched volume of sugary solutions aggravated fasting glycaemia but had a moderate impact on caloric intake and oxidative stress/glycation markers in tissues of diabetic rats. Ad libitum availability of the same sugary solutions impaired energy balance regulation, leading to higher caloric intake than ad libitum fruit juices and controls, as well as weight gain, fasting hyperglycaemia, insulin intolerance and impaired oxidative stress/glycation markers in several tissues. We demonstrated the distinct role of sugars naturally present in fruit juices and added sugars in energy balance regulation, impairing oxidative stress, glycation and glucose metabolism in an animal model of type 2 diabetes.


Assuntos
Peso Corporal , Diabetes Mellitus Experimental/metabolismo , Açúcares da Dieta/administração & dosagem , Ingestão de Energia , Sucos de Frutas e Vegetais , Estresse Oxidativo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Sacarose na Dieta/administração & dosagem , Açúcares da Dieta/efeitos adversos , Jejum , Glucose/metabolismo , Hiperglicemia/metabolismo , Insulina/metabolismo , Masculino , Ratos , Ratos Wistar
7.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502172

RESUMO

Vascular calcification associated with high plasma phosphate (Pi) level is a frequent complication of hyperglycemia, diabetes mellitus, and chronic kidney disease. BGP-15 is an emerging anti-diabetic drug candidate. This study was aimed to explore whether BGP-15 inhibits high Pi-induced calcification of human vascular smooth muscle cells (VSMCs) under normal glucose (NG) and high glucose (HG) conditions. Exposure of VSMCs to Pi resulted in accumulation of extracellular calcium, elevated cellular Pi uptake and intracellular pyruvate dehydrogenase kinase-4 (PDK-4) level, loss of smooth muscle cell markers (ACTA, TAGLN), and enhanced osteochondrogenic gene expression (KLF-5, Msx-2, Sp7, BMP-2). Increased Annexin A2 and decreased matrix Gla protein (MGP) content were found in extracellular vesicles (EVs). The HG condition markedly aggravated Pi-induced VSMC calcification. BGP-15 inhibited Pi uptake and PDK-4 expression that was accompanied by the decreased nuclear translocation of KLF-5, Msx-2, Sp7, retained VSMC markers (ACTA, TAGLN), and decreased BMP-2 in both NG and HG conditions. EVs exhibited increased MGP content and decreased Annexin A2. Importantly, BGP-15 prevented the deposition of calcium in the extracellular matrix. In conclusion, BGP-15 inhibits Pi-induced osteochondrogenic phenotypic switch and mineralization of VSMCs in vitro that make BGP-15 an ideal candidate to attenuate both diabetic and non-diabetic vascular calcification.


Assuntos
Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Oximas/farmacologia , Fosfatos/metabolismo , Piperidinas/farmacologia , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Biomarcadores , Glicemia , Células Cultivadas , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Hiperglicemia/sangue , Osteoblastos/metabolismo , Fosfatos/efeitos adversos , Calcificação Vascular/tratamento farmacológico
8.
Nat Commun ; 12(1): 5616, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556670

RESUMO

Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet ß-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels.


Assuntos
Berberina/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Hiperglicemia/metabolismo , Secreção de Insulina/efeitos dos fármacos , Secretagogos/farmacologia , Adolescente , Adulto , Animais , Linhagem Celular Tumoral , Estudos Cross-Over , Dieta Hiperlipídica/efeitos adversos , Canais de Potássio Éter-A-Go-Go/genética , Células HEK293 , Humanos , Hiperglicemia/etiologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Adulto Jovem
9.
Theranostics ; 11(16): 7829-7843, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335967

RESUMO

Aims/hypothesis: MicroRNAs (miRNAs) are known to contribute to many metabolic diseases, including type 2 diabetes. This study aimed to investigate the roles and molecular mechanisms of miR-185-5p in the regulation of hepatic gluconeogenesis. Methods: MicroRNA high-throughput sequencing was performed to identify differentially expressed miRNAs. High-fat diet-induced obese C57BL/6 mice and db/db mice, a genetic mouse model for diabetes, were used for examining the regulation of hepatic gluconeogenesis. Quantitative reverse transcriptase PCR and Western blotting were performed to measure the expression levels of various genes and proteins. Luciferase reporter assays were used to determine the regulatory roles of miR-185-5p on G6Pase expression. Results: Hepatic miR-185-5p expression was significantly decreased during fasting or insulin resistance. Locked nucleic acid (LNA)-mediated suppression of miR-185-5p increased blood glucose and hepatic gluconeogenesis in healthy mice. In contrast, overexpression of miR-185-5p in db/db mice alleviated blood hyperglycemia and decreased gluconeogenesis. At the molecular level, miR-185-5p directly inhibited G6Pase expression by targeting its 3'-untranslated regions. Furthermore, metformin, an anti-diabetic drug, could upregulate miR-185-5p expression to suppress G6Pase, leading to hepatic gluconeogenesis inhibition. Conclusions/interpretation: Our findings provided a novel insight into the role of miR-185-5p that suppressed hepatic gluconeogenesis and alleviated hyperglycemia by targeting G6Pase. We further identified that the /G6Pase axis mediated the inhibitory effect of metformin on hepatic gluconeogenesis. Thus, miR-185-5p might be a therapeutic target for hepatic glucose overproduction and fasting hyperglycemia.


Assuntos
Gluconeogênese/genética , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Gluconeogênese/fisiologia , Glucose/metabolismo , Glucose-6-Fosfatase/metabolismo , Hiperglicemia/metabolismo , Insulina/metabolismo , Resistência à Insulina/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/metabolismo , Obesidade/genética
10.
Nutrients ; 13(7)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34371983

RESUMO

The worldwide prevalence of metabolic diseases such as obesity, metabolic syndrome and type 2 diabetes shows an upward trend in recent decades. A characteristic feature of these diseases is hyperglycemia which can be associated with hyperphagia. Absorption of glucose in the small intestine physiologically contributes to the regulation of blood glucose levels, and hence, appears as a putative target for treatment of hyperglycemia. In fact, recent progress in understanding the molecular and cellular mechanisms of glucose absorption in the gut and its reabsorption in the kidney helped to develop a new strategy of diabetes treatment. Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. The key role of SGLT1 transporter in intestinal glucose absorption in both physiological conditions and in diabetes was clearly established. We conclude that although inhibition of small intestinal glucose absorption represents a valuable target for the treatment of hyperglycemia, it is not always suitable for the treatment of hyperphagia. In fact, independent regulation of glucose absorption and appetite requires a more complex approach for the treatment of metabolic diseases.


Assuntos
Regulação do Apetite , Glucose/metabolismo , Hiperglicemia/metabolismo , Absorção Intestinal/fisiologia , Doenças Metabólicas/metabolismo , Humanos , Hiperglicemia/etiologia , Intestino Delgado/metabolismo , Doenças Metabólicas/complicações , Transportador 1 de Glucose-Sódio/metabolismo
11.
Chem Pharm Bull (Tokyo) ; 69(8): 760-767, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34334519

RESUMO

Daldinins are a novel type of naturally occurring tricyclic heterocycles isolated from Daldinia concentrica. In this study, four daldinin A derivatives with different alkyl side chains were synthesized using the same synthetic protocol. Bioactivity tests first indicated that the daldinin A derivatives showed significant protection for endothelial cells against damage caused by high glucose. The derivative compound with three carbon atoms on the alkyl side exhibited the best effect.


Assuntos
Descoberta de Drogas , Células Endoteliais/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Hiperglicemia/tratamento farmacológico , Ascomicetos/química , Morte Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Hiperglicemia/metabolismo , Estrutura Molecular
12.
Int J Mol Sci ; 22(15)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34360633

RESUMO

Hyperglycemic conditions (HG), at early stages of diabetic nephropathy (DN), cause a decrease in podocyte numbers and an aberration of their function as key cells for glomerular plasma filtration. Klotho protein was shown to overcome some negative effects of hyperglycemia. Klotho is also a coreceptor for fibroblast growth factor receptors (FGFRs), the signaling of which, together with a proper rate of glycolysis in podocytes, is needed for a proper function of the glomerular filtration barrier. Therefore, we measured levels of Klotho in renal tissue, serum, and urine shortly after DN induction. We investigated whether it influences levels of FGFRs, rates of glycolysis in podocytes, and albumin permeability. During hyperglycemia, the level of membrane-bound Klotho in renal tissue decreased, with an increase in the shedding of soluble Klotho, its higher presence in serum, and lower urinary excretion. The addition of Klotho increased FGFR levels, especially FGFR1/FGFR2, after their HG-induced decrease. Klotho also increased levels of glycolytic parameters of podocytes, and decreased podocytic and glomerular albumin permeability in HG. Thus, we found that the decrease in the urinary excretion of Klotho might be an early biomarker of DN and that Klotho administration may have several beneficial effects on renal function in DN.


Assuntos
Glucuronidase/metabolismo , Hiperglicemia/metabolismo , Podócitos/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Glicólise , Masculino , Permeabilidade , Ratos Wistar
13.
Int J Mol Sci ; 22(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34445099

RESUMO

Diabetes mellitus (DM) is one of the most common and costly disorders that affect humans around the world. Recently, clinicians and scientists have focused their studies on the effects of glycemic variability (GV), which is especially associated with cardiovascular diseases. In healthy subjects, glycemia is a very stable parameter, while in poorly controlled DM patients, it oscillates greatly throughout the day and between days. Clinically, GV could be measured by different parameters, but there are no guidelines on standardized assessment. Nonetheless, DM patients with high GV experience worse cardiovascular disease outcomes. In vitro and in vivo studies showed that high GV causes several detrimental effects, such as increased oxidative stress, inflammation, and apoptosis linked to endothelial dysfunction. However, the evidence that treating GV is beneficial is still scanty. Clinical trials aiming to improve the diagnostic and prognostic accuracy of GV measurements correlated with cardiovascular outcomes are needed. The present review aims to evaluate the clinical link between high GV and cardiovascular diseases, taking into account the underlined biological mechanisms. A clear view of this challenge may be useful to standardize the clinical evaluation and to better identify treatments and strategies to counteract this DM aspect.


Assuntos
Doenças Cardiovasculares/etiologia , Complicações do Diabetes/complicações , Hiperglicemia/complicações , Animais , Glicemia/metabolismo , Doenças Cardiovasculares/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Humanos , Hiperglicemia/metabolismo , Estresse Oxidativo
14.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360753

RESUMO

Activation of innate immunity and low-grade inflammation contributes to hyperglycemia and an onset of Type 2 Diabetes Mellitus (T2DM). Interleukin-2 (IL-2), leptin, High Mobility Group Box-1 (HMGB-1), and increased glucose concentrations are mediators of these processes also by modulating peripheral blood mononuclear cells (PBMCs) response. The aim of this study was to investigate if HMGB-1 and IL-2 turn on PBMCs and their leptin secretion. In isolated human PBMCs and their subpopulations from healthy individuals and naïve T2DM patients, leptin release, pro-inflammatory response and Toll-like Receptors (TLRs) activation was measured. After treatment with IL-2 and HMGB1, NK (Natural Killer) have the highest amount of leptin secretion, whilst NK-T have the maximal release in basal conditions. TLR4 (TAK242) and/or TLR2 (TLR2-IgA) inhibitors decreased leptin secretion after IL-2 and HMGB1 treatment. A further non-significant increase in leptin secretion was reported in PBMCs of naive T2DM patients in response to IL-2 and HMGB-1 stimulation. Finally, hyperglycemia or hyperinsulinemia might stimulate leptin secretion from PBMCs. The amount of leptin released from PBMCs after the different treatments was enough to stimulate the secretion of IL-1ß from monocytes. Targeting leptin sera levels and secretion from PBMCs could represent a new therapeutic strategy to counteract metabolic diseases such as T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Proteína HMGB1/farmacologia , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Interleucina-2/farmacologia , Leptina/metabolismo , Leucócitos Mononucleares/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/patologia , Hiperinsulinismo/patologia , Leucócitos Mononucleares/patologia
15.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360849

RESUMO

Gestational Diabetes Mellitus (GDM) is a transitory metabolic condition caused by dysregulation triggered by intolerance to carbohydrates, dysfunction of beta-pancreatic and endothelial cells, and insulin resistance during pregnancy. However, this disease includes not only changes related to metabolic distress but also placental immunoendocrine adaptations, resulting in harmful effects to the mother and fetus. In this review, we focus on the placenta as an immuno-endocrine organ that can recognize and respond to the hyperglycemic environment. It synthesizes diverse chemicals that play a role in inflammation, innate defense, endocrine response, oxidative stress, and angiogenesis, all associated with different perinatal outcomes.


Assuntos
Diabetes Gestacional , Células Endoteliais , Feto , Hiperglicemia , Placenta , Diabetes Gestacional/imunologia , Diabetes Gestacional/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Feto/imunologia , Feto/metabolismo , Humanos , Hiperglicemia/imunologia , Hiperglicemia/metabolismo , Placenta/imunologia , Placenta/metabolismo , Placenta/patologia , Gravidez
16.
Nat Commun ; 12(1): 5068, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417460

RESUMO

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.


Assuntos
Acetilglucosamina/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência de Bases , Restrição Calórica , Linhagem Celular , Colforsina/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/metabolismo , Glucagon/metabolismo , Glucocorticoides/metabolismo , Gluconeogênese/efeitos dos fármacos , Glicosilação , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hidrocortisona/metabolismo , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Obesidade/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Ácido Pirúvico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
17.
Nutrients ; 13(8)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34444782

RESUMO

Substrates of semicarbazide-sensitive amine oxidase (SSAO) exert insulin-like actions in adipocytes. One of them, benzylamine (Bza) exhibits antihyperglycemic properties in several rodent models of diabetes. To further study the antidiabetic potential of this naturally occurring amine, a model of severe type 2 diabetes, the obese db-/- mouse, was subjected to oral Bza administration. To this end, db-/- mice and their lean littermates were treated at 4 weeks of age by adding 0.5% Bza in drinking water for seven weeks. Body mass, fat content, blood glucose and urinary glucose output were followed while adipocyte insulin responsiveness and gene expression were checked at the end of supplementation, together with aorta nitrites. Bza supplementation delayed the appearance of hyperglycemia, abolished polydypsia and glycosuria in obese/diabetic mice without any detectable effect in lean control, except for a reduction in food intake observed in both genotypes. The improvement of glucose homeostasis was observed in db-/- mice at the expense of increased fat deposition, especially in the subcutaneous white adipose tissue (SCWAT), without sign of worsened inflammation or insulin responsiveness and with lowered circulating triglycerides and uric acid, while NO bioavailability was increased in aorta. The higher capacity of SSAO in oxidizing Bza in SCWAT, found in the obese mice, was unaltered by Bza supplementation and likely involved in the activation of glucose utilization by adipocytes. We propose that Bza oxidation in tissues, which produces hydrogen peroxide mainly in SCWAT, facilitates insulin-independent glucose utilization. Bza could be considered as a potential agent for dietary supplementation aiming at preventing diabetic complications.


Assuntos
Benzilaminas/administração & dosagem , Benzilaminas/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Suplementos Nutricionais , Obesidade/metabolismo , Adipócitos/metabolismo , Amina Oxidase (contendo Cobre)/metabolismo , Animais , Benzilaminas/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Ingestão de Alimentos , Glucose/metabolismo , Humanos , Peróxido de Hidrogênio , Hiperglicemia/metabolismo , Hipoglicemiantes/metabolismo , Insulina/sangue , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Compostos Fitoquímicos , Receptores para Leptina/genética
18.
Sci Rep ; 11(1): 16362, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381133

RESUMO

This study aimed at comparing the effects of metformin on tubulointerstitial fibrosis (TIF) in different stages of diabetic nephropathy (DN) in vivo and evaluating the mechanism in high glucose (HG)-treated renal tubular epithelial cells (RTECs) in vitro. Sprague-Dawley (SD) rats were used to establish a model of DN, and the changes of biochemical indicators and body weight were measured. The degree of renal fibrosis was quantified using histological analysis, immunohistochemistry, and immunoblot. The underlying relationship between autophagy and DN, and the cellular regulatory mechanism of metformin on epithelial-to-mesenchymal transition (EMT) were investigated. Metformin markedly improved renal function and histological restoration of renal tissues, especially in the early stages of DN, with a significant increase in autophagy and a decrease in the expression of fibrotic biomarkers (fibronectin and collagen I) in renal tissue. Under hyperglycemic conditions, renal tubular epithelial cells inactivated p-AMPK and activated partial EMT. Metformin-induced AMPK significantly ameliorated renal autophagic function, inhibited the partial EMT of RTECs, and attenuated TIF, all of which effectively prevented or delayed the onset of DN. This evidence provides theoretical and experimental basis for the following research on the potential clinical application of metformin in the treatment of diabetic TIF.


Assuntos
Autofagia/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Fibrose/tratamento farmacológico , Túbulos Renais/efeitos dos fármacos , Metformina/farmacologia , Animais , Biomarcadores/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose/metabolismo , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Túbulos Renais/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
19.
Mol Pharmacol ; 100(5): 428-455, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34452975

RESUMO

Vascular pathology is increased in diabetes because of reactive-oxygen-species (ROS)-induced endothelial cell damage. We found that in vitro and in a streptozotocin diabetes model in vivo, metformin at diabetes-therapeutic concentrations (1-50 µM) protects tissue-intact and cultured vascular endothelial cells from hyperglycemia/ROS-induced dysfunction typified by reduced agonist-stimulated endothelium-dependent, nitric oxide-mediated vasorelaxation in response to muscarinic or proteinase-activated-receptor 2 agonists. Metformin not only attenuated hyperglycemia-induced ROS production in aorta-derived endothelial cell cultures but also prevented hyperglycemia-induced endothelial mitochondrial dysfunction (reduced oxygen consumption rate). These endothelium-protective effects of metformin were absent in orphan-nuclear-receptor Nr4a1-null murine aorta tissues in accord with our observing a direct metformin-Nr4a1 interaction. Using in silico modeling of metformin-NR4A1 interactions, Nr4a1-mutagenesis, and a transfected human embryonic kidney 293T cell functional assay for metformin-activated Nr4a1, we identified two Nr4a1 prolines, P505/P549 (mouse sequences corresponding to human P501/P546), as key residues for enabling metformin to affect mitochondrial function. Our data indicate a critical role for Nr4a1 in metformin's endothelial-protective effects observed at micromolar concentrations, which activate AMPKinase but do not affect mitochondrial complex-I or complex-III oxygen consumption rates, as does 0.5 mM metformin. Thus, therapeutic metformin concentrations requiring the expression of Nr4a1 protect the vasculature from hyperglycemia-induced dysfunction in addition to metformin's action to enhance insulin action in patients with diabetes. SIGNIFICANCE STATEMENT: Metformin improves diabetic vasodilator function, having cardioprotective effects beyond glycemic control, but its mechanism to do so is unknown. We found that metformin at therapeutic concentrations (1-50µM) prevents hyperglycemia-induced endothelial dysfunction by attenuating reactive oxygen species-induced damage, whereas high metformin (>250 µM) impairs vascular function. However, metformin's action requires the expression of the orphan nuclear receptor NR4A1/Nur77. Our data reveal a novel mechanism whereby metformin preserves diabetic vascular endothelial function, with implications for developing new metformin-related therapeutic agents.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Endotélio Vascular/metabolismo , Células HEK293 , Humanos , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Estresse Oxidativo/fisiologia , Vasodilatadores/farmacologia
20.
Sci Rep ; 11(1): 16059, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373518

RESUMO

The association between early glycemic change and short-term mortality in non-diabetic patients with acute intracerebral hemorrhage (ICH) is unclear. We retrospectively investigated non-diabetic patients with lobar (n = 262) and non-lobar ICH (n = 370). Each patient had a random serum glucose test on hospital admission and a fasting serum glucose test within the following 48 h. Hyperglycemia was defined as serum glucose ≥ 7.8 mmol/l. Four patterns were determined: no hyperglycemia (reference category), persistent hyperglycemia, delayed hyperglycemia, and decreasing hyperglycemia. Associations with 30-day mortality were estimated using Cox models adjusted for major features of ICH severity. Persistent hyperglycemia was associated with 30-day mortality in both lobar (HR 3.00; 95% CI 1.28-7.02) and non-lobar ICH (HR 4.95; 95% CI 2.20-11.09). In lobar ICH, 30-day mortality was also associated with delayed (HR 4.10; 95% CI 1.77-9.49) and decreasing hyperglycemia (HR 2.01, 95% CI 1.09-3.70). These findings were confirmed in Cox models using glycemic change (fasting minus random serum glucose) as a continuous variable. Our study shows that, in non-diabetic patients with ICH, early persistent hyperglycemia is an independent predictor of short-term mortality regardless of hematoma location. Moreover, in non-diabetic patients with lobar ICH, both a positive and a negative glycemic change are associated with short-term mortality.


Assuntos
Hemorragia Cerebral/mortalidade , Hiperglicemia/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/metabolismo , Hemorragia Cerebral/metabolismo , Feminino , Hematoma/metabolismo , Humanos , Hiperglicemia/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
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