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1.
J Dairy Sci ; 103(11): 10245-10257, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32921457

RESUMO

Pregnancy toxemia is the most frequent metabolic disorder of ewes in late pregnancy. Although propylene glycol (PG) and glycerol (GLY) are common glucogenic supplements for treating pregnancy toxemia in ewes, the relative benefit of these 2 supplements is not entirely clear. Therefore, the objectives of the present study were to determine the changes during 24 h in key blood metabolites and insulin in response to PG or GLY drenching in prolific ewes. To this end, 36 multiparous late-pregnant Afec-Assaf ewes (∼132.4 d pregnant) bearing 2 to 4 fetuses, divided into 2 blocks (18 ewes in each block), with a blood ß-hydroxybutyrate (BHB) concentration of 0.5 to 1.6 mmol/L were included. Ewes were divided into 3 groups (12 ewes each; 6 ewes in each experimental day), according to their BHB levels, expected litter size, body weight, and body condition score, and were drenched with the following: (1) control group (CTL), 55 mL of water; (2) PG, 106 mL of PG (100% PG, 448 calories); or (3) GLY, 108 mL of Koforin 80 (80% GL; 448 calories). Blood samples were taken before drenching and every hour after drenching for 24 h. Plasma concentration of glucose, BHB, nonesterified fatty acids, lactate, glycerol, and insulin were determined. Because there were no effects of treatments after 12 h in the first block, the data were analyzed for 12 h after drenching rather than 24 h. The plasma glucose concentration during the first 5 h after drenching was the highest in the GLY, BHB concentration was the lowest in the PG, and the nonesterified fatty acid levels were lower in the PG compared with the CTL ewes during the first 5 h after drenching. However, glucose concentration was higher in the PG ewes at 9, 11, and 12 h after drenching than in CTL or GLY ewes. The mean lactate concentration in plasma for 12 h was 2.5- and 1.9-fold higher in the PG compared with the CTL and GLY ewes, respectively, and except at 11 h after drenching, it was significantly higher at each time point. The insulin concentration was higher in the GLY than in both other groups at 2 to 5 h after drenching. These results suggest that during the first few hours after drenching the effect of PG was more effective in reducing the BHB concentration, whereas the GLY effect was more effective in enhancing glucose concentration. The increased concentration in lactate following PG treatment suggests that the PG contribution to gluconeogenesis is mediated through its metabolism to lactate. In contrast, the lack of an effect on lactate, and the faster increase in blood glucose in response to GLY suggest that GLY has a more advanced entry point to gluconeogenesis, which influences the immediate response in enhancing the glucose blood concentration.


Assuntos
Ácido 3-Hidroxibutírico/sangue , Glicemia/análise , Glicerol/administração & dosagem , Propilenoglicol/administração & dosagem , Ovinos/sangue , Animais , Suplementos Nutricionais , Ácidos Graxos não Esterificados/sangue , Feminino , Idade Gestacional , Gluconeogênese/efeitos dos fármacos , Glicerol/sangue , Insulina/sangue , Lactação/efeitos dos fármacos , Ácido Láctico/sangue , Pré-Eclâmpsia/prevenção & controle , Pré-Eclâmpsia/veterinária , Gravidez , Doenças dos Ovinos/prevenção & controle
2.
J Med Chem ; 63(18): 10307-10329, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32820629

RESUMO

Liver fructose-1,6-bisphosphatase (FBPase) is a key enzyme in the gluconeogenesis pathway. Inhibiting FBPase activity represents a potential treatment for type 2 diabetes mellitus. A series of novel N-arylsulfonyl-4-arylamino-indole-2-carboxamide derivatives have been disclosed as FBPase inhibitors. Through extensive structure-activity relationship investigations, a promising candidate molecule Cpd118 [sodium (7-chloro-4-((3-methoxyphenyl)amino)-1-methyl-1H-indole-2-carbonyl] [(4-methoxyphenyl)sulfonyl)amide] has been identified with high inhibitory activity against human liver FBPase (IC50, 0.029 ± 0.006 µM) and high selectivity relative to the other six AMP-binding enzymes. Importantly, Cpd118 produced significant glucose-lowering effects on both type 2 diabetic KKAy mice and ZDF rats as demonstrated by substantial reductions in the fasting and postprandial blood glucose levels, as well as the HbA1c level. Furthermore, Cpd118 elicited a favorable pharmacokinetic profile with an oral bioavailability of 99.1%. Moreover, the X-ray crystal structure of the Cpd118-FBPase complex was resolved, which revealed a unique binding mode and provided a structural basis for its high potency and selectivity.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Frutose-Bifosfatase/antagonistas & inibidores , Hipoglicemiantes/uso terapêutico , Indóis/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Sítio Alostérico , Animais , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Frutose-Bifosfatase/química , Frutose-Bifosfatase/metabolismo , Gluconeogênese/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/síntese química , Hipoglicemiantes/metabolismo , Indóis/administração & dosagem , Indóis/síntese química , Indóis/metabolismo , Camundongos , Estrutura Molecular , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
3.
Life Sci ; 258: 118151, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32726661

RESUMO

AIMS: Hepatic glucose metabolism involves a variety of catabolic and anabolic pathways, and the dynamic balance of glucose metabolism is regulated in response to environmental and nutritional changes. The molecular mechanism of glucose metabolism in liver is complex and has not been fully elucidated so far. In this study, we hope to elucidate the target and mechanism of cinnamaldehyde (CA) in regulating glucose metabolism. MATERIALS AND METHODS: Molecular image tracing and magnetic capture in combination with an alkynyl-CA probe (Al-CA) was used to show CA covalently binds to α-enolase (ENO1) in both mouse liver and HepG2 cells. Accurate metabolic flow assays subsequently demonstrated that the utilization of glycogenic amino acids and the biosynthesis of tricarboxylic acid (TCA) cycle intermediates were strengthened, which was detected using nontargeted and targeted metabolomics analyses. KEY FINDINGS: Our study shows that CA covalently bonds with ENO1, which affects the stability and activity of ENO1 and changes the dynamic balance of glucose metabolism. The interruption of gluconeogenic reflux by ENO1 enhanced TCA cycle, and eventually led to a decrease in blood glucose and the improvement of mitochondrial efficiency. SIGNIFICANCE: These results provide a detailed description of how CA maintains the dynamic balance of glucose utilization and improves energy metabolism.


Assuntos
Acroleína/análogos & derivados , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática/efeitos dos fármacos , Aromatizantes/farmacologia , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Fosfopiruvato Hidratase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Acroleína/farmacologia , Animais , Ciclo do Ácido Cítrico/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Células Hep G2 , Humanos , Camundongos , Simulação de Acoplamento Molecular
4.
Obesity (Silver Spring) ; 28(7): 1254-1262, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568464

RESUMO

OBJECTIVE: The aim of this study was to determine the effects of empagliflozin on glycerol-derived hepatic gluconeogenesis in adults with obesity without type 2 diabetes mellitus (T2DM) using oral carbon 13 (13 C)-labeled glycerol. METHODS: A randomized, double-blind, placebo-controlled trial was performed in participants with magnetic resonance imaging assessment of body fat and measurement of glycerol-derived 13 C enrichment in plasma glucose by nuclear magnetic resonance spectroscopy following ingestion of [U-13 C3 ]glycerol. Participants were randomized to oral empagliflozin 10 mg once daily or placebo for 3 months. Glycerol-derived 13 C enrichment studies were repeated, and treatment differences in the mean percentage of 13 C glycerol enrichment in glucose were compared using mixed linear models. RESULTS: Thirty-five participants completed the study. Empagliflozin increased glycerol-derived 13 C enrichment between baseline and follow-up by 6.5% (P = 0.005), consistent with less glycerol from visceral adipose tissue (VAT). No difference was found with placebo. Glycerol-derived 13 C enrichment was lower in participants with high VAT compared with low VAT by 12.6% (P = 0.04), but there was no heterogeneity of the treatment effect by baseline VAT. Glycerol-derived 13 C enrichment was inversely correlated with VAT but was not correlated with weight loss. CONCLUSIONS: VAT is associated with endogenous glycerol-derived hepatic gluconeogenesis, and empagliflozin reduces endogenous glycerol gluconeogenesis in adults with obesity without T2DM. These findings suggest a mechanism by which sodium-glucose cotransporter 2 inhibitors may prevent T2DM in obesity.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gluconeogênese/efeitos dos fármacos , Glucosídeos/uso terapêutico , Glicerol/metabolismo , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Feminino , Humanos , Gordura Intra-Abdominal , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Placebos , Perda de Peso/efeitos dos fármacos
5.
Life Sci ; 256: 117922, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32522569

RESUMO

To test the hypothesis of STC-1 participation in maintenance of glucose homeostasis in fed and fasting (48 h) rats, we investigated that this hormone may be implicated in the regulation of renal gluconeogenesis pathway from lactate and lactate oxidation in renal cortex and medulla. Our results demonstrate the hSTC-1 role on lactate metabolism in the renal cortex and medulla from fed and fasting rats. hSTC-1 increased the gluconeogenesis activity in fed state in renal cortex, and this increase was induced by raise in Pck1 gene expression. In fasting animals hSTC-1 increase the renal medulla gluconeogenesis activity, but Pck1 gene expression was not alter. The stimulatory effect of hSTC-1 on 14C-lactate oxidation occurred only in the renal cortex from fed rats. These findings show the hSTC-1 contribution to lactate homeostasis and supplies glucose to other tissues. This response may represent a strategy of action of STC-1 in response to fasting stress as postulated by different authors. On the other hand, hSTC-1 acts downstream of adenylcyclase pathway, decreasing the gluconeogenesis activity induced by cAMP intracellular increase or stimulating the phosphodiesterase activity in the renal cortex. However, no hSTC-1 effect on 14C-lactate oxidation was found after increase in the intracellular cAMP. The findings also revealed that the renal cortex and medulla respond differently to hSTC-1, possibly due to the higher level of STC-1 gene expression in inner renal medulla than in renal cortex.


Assuntos
Gluconeogênese/efeitos dos fármacos , Glicoproteínas/metabolismo , Hormônios/metabolismo , Rim/metabolismo , Lactatos/metabolismo , Proteínas Recombinantes/metabolismo , Adenilil Ciclases/metabolismo , Animais , Dióxido de Carbono/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Glicoproteínas/genética , Hormônios/genética , Humanos , Córtex Renal/metabolismo , Medula Renal/metabolismo , Masculino , Oxirredução , Diester Fosfórico Hidrolases/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes/genética , Transdução de Sinais
7.
J Dairy Sci ; 103(8): 7055-7067, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32534927

RESUMO

Our previously published paper demonstrated that fermented ammoniated condensed whey (FACW) supplementation improved feed efficiency and metabolic profile in postpartum dairy cows. The objective of this study was to further explore the effects of FACW supplementation on liver triglyceride content, hepatic gene expression and protein abundance, and plasma biomarkers related to liver function, inflammation, and damage. Individually fed multiparous Holstein cows were blocked by calving date and randomly assigned to postpartum (1 to 45 d in milk, DIM) isonitrogenous treatments: control diet (n = 20) or diet supplemented with FACW (2.9% dry matter of diet as GlucoBoost; Fermented Nutrition, Luxemburg, WI, replacing soybean meal; n = 19). Liver biopsies were performed at 14 and 28 DIM for analysis of mRNA expression, protein abundance, and liver triglyceride content. There was marginal evidence for a reduction in liver triglyceride content at 14 DIM in FACW-supplemented cows compared with the control group. Cows supplemented with FACW had greater mRNA expression of glucose-6-phosphatase at 14 DIM relative to control. Supplementation with FACW increased mRNA expression of pyruvate carboxylase (PC), but did not alter cytosolic phosphoenolpyruvate carboxykinase (PCK1), resulting in a 2.4-fold greater PC:PCK1 ratio for FACW-supplemented cows compared with control. There was no evidence for a FACW effect on mRNA expression of propionyl-CoA carboxylase nor on mRNA expression or protein abundance of lactate dehydrogenase A or B. Cows supplemented with FACW had lower plasma urea nitrogen compared with control. Plasma l-lactate was greater for FACW-supplemented cows compared with control at 2 h before feeding time at 21 DIM. There was no evidence for altered expression of IL1B or IL10, or blood biomarkers related to liver function and damage. Greater glucose-6-phosphatase and PC gene expression, together with greater blood glucose and similar milk lactose output, suggests that FACW increased the supply of glucose precursors, resulting in greater gluconeogenesis between 3 and 14 DIM. Greater hepatic PC:PCK1 ratio, together with previously reported decreased plasma ß-hydroxybutyrate and the marginal evidence for lower liver triglyceride content at 14 DIM, suggests greater hepatic capacity for complete oxidation of fatty acids in FACW-supplemented cows compared with control. Overall, improvements in metabolite profile and feed efficiency observed with postpartum supplementation of FACW may be attributed to increased gluconeogenic and anaplerotic precursors, most likely propionate, due to modulated rumen fermentation.


Assuntos
Bovinos/fisiologia , Suplementos Nutricionais/análise , Leite/metabolismo , Soro do Leite/administração & dosagem , Ácido 3-Hidroxibutírico/sangue , Compostos de Amônio/química , Animais , Dieta/veterinária , Feminino , Fermentação , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Glucose-6-Fosfatase/genética , Lactação/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Nutrientes/metabolismo , Período Pós-Parto/efeitos dos fármacos , Piruvato Carboxilase/genética , Distribuição Aleatória , Rúmen/metabolismo
8.
J Dairy Sci ; 103(6): 5514-5524, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278554

RESUMO

Approximately 15 to 50% of short-chain fatty acids (SCFA) reach the ruminant small intestine. Previous research suggests that activation of small intestinal gluconeogenesis induced by propionate has beneficial effects on energy homeostasis. However, the regulatory effect of propionate on key gluconeogenic genes in enterocytes of the bovine small intestine remains less known. Therefore, the purpose of this study was to establish the long-term cultures of bovine intestinal epithelial cells (BIEC) from bovine jejunum tissue using SV40T (1:200; Santa Cruz, Shanghai, China) and investigate the regulatory effect of propionate on the key gluconeogenic genes in BIEC. Our study showed that long-term BIEC cultures were established by SV40T-induced immortalization. Immortal BIEC were distinguished by the expression of cytokeratin 18, villin, fatty acid binding protein 2, and small intestine peptidase. The mRNA expression of genes involved in the SCFA transporters, monocarboxylate transporter 4, and Na+/H+ exchanger isoforms 1 were significantly elevated with 20 mM SCFA compared with untreated controls. In addition, BIEC exhibited significant uptake of propionate and butyrate from the culture medium. Remarkably, 3 mM propionate induced profound changes in mRNA level of key genes involved in gluconeogenesis, including phosphoenolpyruvate carboxykinase 2, pyruvate carboxylase, fructose-1,6-bisphosphatase 1, and peroxisome proliferator-activated receptor-γ coactivator 1α. Additionally, 3 mM propionate enhanced the expression of PGC1A mRNA at 3, 6, 12, and 24 h of incubation. These findings suggest that propionate controls the mRNA expression of genes involved in key enzymes for gluconeogenesis in the enterocytes of bovines.


Assuntos
Bovinos/fisiologia , Ácidos Graxos Voláteis/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Propionatos/farmacologia , Animais , Bovinos/genética , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/enzimologia , Feminino , Gluconeogênese/genética , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Transportadores de Ácidos Monocarboxílicos/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Piruvato Carboxilase/genética , RNA Mensageiro/genética , Trocador 1 de Sódio-Hidrogênio/genética
9.
Am J Physiol Endocrinol Metab ; 318(5): E779-E790, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32208001

RESUMO

Glucagon's effect on hepatic glucose production (HGP), under hyperglycemic conditions, is time dependent such that after an initial burst of HGP, it slowly wanes. It is not known whether this is also the case under hypoglycemic conditions, where an increase in HGP is essential. This question was addressed using adrenalectomized dogs to avoid the confounding effects of other counterregulatory hormones. During the study, infusions of epinephrine and cortisol were given to maintain basal levels. Somatostatin and insulin (800 µU·kg-1·min-1) were infused to induce hypoglycemia. After 30 min, glucagon was infused at a basal rate (1 ng·kg-1·min-1, baGGN group, n = 5 dogs) or a rate eightfold basal (8 ng·kg-1·min-1, hiGGN group, n = 5 dogs) for 4 h. Glucose was infused to match the arterial glucose levels between groups (≈50 mg/dL). Our data showed that glucagon has a biphasic effect on the liver despite hypoglycemia. Hyperglucagonemia stimulated a rapid, transient peak in HGP (4-fold basal production) over ~60 min, which was followed by a slow reduction in HGP to a rate 1.5-fold basal. During the last 2 h of the experiment, hiGGN stimulated glucose production at a rate fivefold greater than baGGN (2.5 vs. 0.5 mg·kg-1·min-1, respectively), indicating a sustained effect of the hormone. Of note, the hypoglycemia-induced rises in norepinephrine and glycerol were smaller in hiGGN compared with the baGGN group despite identical hypoglycemia. This finding suggests that there is reciprocity between glucagon and the sympathetic nervous system such that when glucagon is increased, the sympathetic nervous response to hypoglycemia is downregulated.


Assuntos
Glucagon/farmacocinética , Gluconeogênese/efeitos dos fármacos , Hipoglicemia/metabolismo , Fígado/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Adrenalectomia , Animais , Cães , Epinefrina/farmacologia , Feminino , Hidrocortisona/farmacologia , Hipoglicemia/induzido quimicamente , Insulina , Fígado/metabolismo , Masculino , Somatostatina , Sistema Nervoso Simpático/metabolismo
10.
Nature ; 579(7798): 279-283, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132708

RESUMO

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment-reversing hepatic steatosis and glucose intolerance-were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.


Assuntos
Glucagon/farmacologia , Gluconeogênese/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Fígado/efeitos dos fármacos , Acetilcoenzima A/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Glucagon/sangue , Receptores de Inositol 1,4,5-Trifosfato/genética , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Lipólise/genética , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Oxirredução/efeitos dos fármacos
11.
Animal ; 14(S1): s144-s154, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32024563

RESUMO

Inflammatory cascades are a critical component of the immune response to infection or tissue damage, involving an array of signals, including water-soluble metabolites, lipid mediators and several classes of proteins. Early investigation of these signaling pathways focused largely on immune cells and acute disease models. However, more recent findings have highlighted critical roles of both immune cells and inflammatory mediators on tissue remodeling and metabolic homeostasis in healthy animals. In dairy cattle, inflammatory signals in various tissues and in circulation change rapidly and dramatically, starting just prior to and at the onset of lactation. Furthermore, several observations in healthy cows point to homeostatic control of inflammatory tone, which we define as a regulatory process to balance immune tolerance with activation to keep downstream effects under control. Recent evidence suggests that peripartum inflammatory changes influence whole-body nutrient flux of dairy cows over the course of days and months. Inflammatory mediators can suppress appetite, even at levels that do not induce acute responses (e.g. fever), thereby decreasing nutrient availability. On the other hand, inhibition of inflammatory signaling with non-steroidal anti-inflammatory drug (NSAID) treatment suppresses hepatic gluconeogenesis, leading to hypoglycemia in some cases. Over the long term, though, peripartum NSAID treatment substantially increases peak and whole-lactation milk synthesis by multiparous cows. Inflammatory regulation of nutrient flux may provide a homeorhetic mechanism to aid cows in adapting to rapid changes in metabolic demand at the onset of lactation, but excessive systemic inflammation has negative effects on metabolic homeostasis through inhibition of appetite and promotion of immune cell activity. Thus, in this review, we provide perspectives on the overlapping regulation of immune responses and metabolism by inflammatory mediators, which may provide a mechanistic underpinning for links between infectious and metabolic diseases in transition dairy cows. Moreover, we point to novel approaches to the management of this challenging phase of the production cycle.


Assuntos
Bovinos/fisiologia , Comportamento Alimentar , Homeostase , Mediadores da Inflamação/metabolismo , Inflamação/veterinária , Transdução de Sinais , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Bovinos/imunologia , Citocinas/metabolismo , Feminino , Gluconeogênese/efeitos dos fármacos , Lactação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Leite/metabolismo , Período Periparto
12.
J Pharmacol Exp Ther ; 373(1): 81-91, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32024803

RESUMO

Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor α (PPARα) agonist that acts on the peripheral control of energy metabolism. However, its therapeutic potential and related mechanisms in hepatic glucose metabolism under type 2 diabetes mellitus (T2DM) are not clear. Here, OEA treatment markedly improved glucose homeostasis in a PPARα-independent manner. OEA efficiently promoted glycogen synthesis and suppressed gluconeogenesis in mouse primary hepatocytes and liver tissue. OEA enhanced hepatic glycogen synthesis and inhibited gluconeogenesis via liver kinase B1 (LKB1)/5' AMP-activated protein kinase (AMPK) signaling pathways. PPARα was not involved in the roles of OEA in the LKB1/AMPK pathways. We found that OEA exerts its antidiabetic effect by increasing glycogenesis and decreasing gluconeogenesis via the LKB1/AMPK pathway. The ability of OEA to control hepatic LKB1/AMPK pathways may serve as a novel therapeutic approach for the treatment of T2DM. SIGNIFICANCE STATEMENT: Oleoylethanolamide (OEA) exerted a potent antihyperglycemic effect in a peroxisome proliferator-activated receptor α-independent manner. OEA played an antihyperglycemic role primarily via regulation of hepatic glycogen synthesis and gluconeogenesis. The main molecular mechanism of OEA in regulating liver glycometabolism is activating the liver kinase B1/5' AMP-activated protein kinase signaling pathways.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Endocanabinoides/farmacologia , Gluconeogênese/fisiologia , Glicogênio/biossíntese , Fígado/metabolismo , Ácidos Oleicos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Endocanabinoides/uso terapêutico , Gluconeogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Knockout , Ácidos Oleicos/uso terapêutico , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
J Endocrinol ; 245(2): 193-205, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32092034

RESUMO

The kidneys release glucose into the systemic circulation through glucose reabsorption and renal gluconeogenesis. Currently, the significance of renal glucose release in pathological conditions has become a subject of interest. We examined the effect of sodium-dependent glucose cotransporter 2 inhibitor (SGLT2i) on renal gluconeogenic enzyme expression in obese rats. Male Wistar rats (180-200 g) were fed either a normal diet (ND, n = 6) or a high-fat diet. At 16 weeks, after confirming the degree of glucose intolerance, high-fat diet-fed rats were randomly subdivided into three groups (n = 6/group): untreated group (HF), treated with dapagliflozin 1 mg/kg/day (HFSG) and treated with metformin 30 mg/kg/day (HFM). The treatment was continued for 4 weeks. We observed that dapagliflozin or metformin mitigated the enhanced expression of renal gluconeogenic enzymes, PEPCK, G6Pase and FBPase, as well as improved glucose tolerance and renal function in obese rats. Dapagliflozin downregulated the elevated expression of gluconeogenic transcription factors p-GSK3ß, p-CREB and coactivator PGC1α in the renal cortical tissue. Metformin reduced the expression levels of renal cortical FOXO1 and CREB. Furthermore, reduced renal insulin signaling was improved and renal oxidative stress was attenuated by either dapagliflozin or metformin treatment in obese rats. We concluded that glucose tolerance was improved by dapagliflozin in obese prediabetic rats by suppressing renal glucose release from not only glucose reabsorption but also renal gluconeogenesis through improving renal cortical insulin signaling and oxidative stress. The efficacy of dapagliflozin in improving renal insulin signaling, oxidative stress and renal function was greater than that of metformin.


Assuntos
Compostos Benzidrílicos/farmacologia , Gluconeogênese/efeitos dos fármacos , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Animais , Dieta Hiperlipídica , Glucose-6-Fosfatase/efeitos dos fármacos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Rim/enzimologia , Masculino , Metformina/farmacologia , Obesidade/etiologia , Fosfoenolpiruvato Carboxiquinase (GTP)/efeitos dos fármacos , Ratos , Ratos Wistar
14.
Toxicol In Vitro ; 65: 104786, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32004540

RESUMO

Dysglycemia is one of the most serious adverse events associated with the clinical use of certain fluoroquinolones. The purpose of this study was to investigate the effects of the representative fluoroquinolones moxifloxacin and gatifloxacin on hepatic gluconeogenesis using primary monkey hepatocytes. Glucose production was induced after the cells were incubated for 4 h with 10 mM sodium lactate and 1 mM sodium pyruvate as gluconeogenic substrates. Under these conditions, moxifloxacin and gatifloxacin dose-dependently suppressed gluconeogenesis at concentrations of 100 µM or higher. Transcriptome analysis of rate-limiting enzymes involved in hepatic gluconeogenesis revealed that moxifloxacin and gatifloxacin at a concentration of 1000 µM did not affect the expression of key gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase, glucose 6-phosphatase, and fructose 1,6-bisphosphatase. Furthermore, metabolome analysis, in vitro glucose production assay using additional gluconeogenic substrates, and fructose 1,6-bisphosphatase assay using the cell extracts showed that fluoroquinolones enzymatically suppressed hepatic gluconeogenesis by inhibiting fructose 1,6-bisphosphatase. These inhibitory effects may involve in the clinically relevant dysglycemia associated with fluoroquinolones in human.


Assuntos
Antibacterianos/farmacologia , Frutose-Bifosfatase/antagonistas & inibidores , Gatifloxacina/farmacologia , Gluconeogênese/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Moxifloxacina/farmacologia , Animais , Células Cultivadas , Frutose-Bifosfatase/genética , Hepatócitos/metabolismo , Macaca fascicularis , Masculino
15.
J Endocrinol ; 245(2): 207-218, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32106090

RESUMO

Steroid 5ß-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.


Assuntos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/farmacologia , Gluconeogênese/efeitos dos fármacos , Fígado/enzimologia , Oxirredutases/efeitos dos fármacos , Adulto , Células Cultivadas , Voluntários Saudáveis , Hepatócitos , Humanos , Masculino
16.
Int J Mol Sci ; 21(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32053943

RESUMO

The phenolic profiles, hypoglycemic activity, and molecular mechanism of the effect on type 2 diabetes mellitus (T2DM) of four highland barley varieties were investigated in the present study. The fundamental phenolics in highland barley were ferulic acid, naringin, and catechin, which mainly existed in bound form. These varieties showed favorable hypoglycemic activity via inhibition of α-glucosidase and α-amylase activities, enhancement of glucose consumption, glycogen accumulation and glycogen synthase 2 (GYS2) activity, and down-regulation of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities. Specifically, ZQ320 variety exhibited the strongest hypoglycemic activity compared to the other varieties. Highland barley phenolics could inhibit gluconeogenesis and motivate glycogen synthesis via down-regulating the gene expression of G6Pase, PEPCK, and glycogen synthase kinase 3ß (GSK3ß), while activating the expression of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3 kinase (PI3K), serine/threonine kinase (Akt), GYS2, and glucose transporter type 4 (GLUT4). Therefore, phenolics from highland barley could be served as suitable candidates for therapeutic agent in T2DM to improve human health.


Assuntos
Hordeum/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Fenóis/química , Fenóis/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
17.
Nutrients ; 12(2)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046170

RESUMO

Dietary intake of fiber-rich food has been reported to contribute to multiple health benefits. The aim of the current study is to investigate the effects of a diet containing the outer bran fraction of rice (OBFR), which is rich in insoluble fiber, on the intestinal environment and metabolite profiles of rats. Fourteen 8-week-old male Sprague-Dawley rats were divided into a control group and an OBFR group. For a period of 21 days, the control group was fed a control diet, while the OBFR group was fed a diet containing 5% OBFR. Metabolomics analysis revealed drastic changes in the cecal metabolites of the rats fed the OBFR diet. Furthermore, in the plasma and liver tissue, the concentrations of metabolites involved in pyruvate metabolism, the pentose phosphate pathway, gluconeogenesis, or valine, leucine, isoleucine degradation were changed. Concordantly, the OBFR diet increased the expression of genes encoding enzymes involved in these metabolic pathways in the livers of the rats. Collectively, these results suggest that the OBFR diet altered the concentrations of metabolites in the cecal contents, plasma, and liver, and the hepatic gene expressions of rats, and that this may have mainly contributed to carbohydrate metabolism in the liver.


Assuntos
Metabolismo dos Carboidratos , Fibras na Dieta/administração & dosagem , Suplementos Nutricionais , Fígado/metabolismo , Oryza , Animais , Metabolismo dos Carboidratos/genética , Fibras na Dieta/farmacologia , Ácidos Graxos Voláteis/metabolismo , Expressão Gênica , Gluconeogênese/efeitos dos fármacos , Leucina/metabolismo , Masculino , Via de Pentose Fosfato/genética , Ácido Pirúvico/metabolismo , Ratos Sprague-Dawley , Valina/metabolismo
18.
J Biol Chem ; 295(10): 3330-3346, 2020 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-31974165

RESUMO

The chronic effects of metformin on liver gluconeogenesis involve repression of the G6pc gene, which is regulated by the carbohydrate-response element-binding protein through raised cellular intermediates of glucose metabolism. In this study we determined the candidate mechanisms by which metformin lowers glucose 6-phosphate (G6P) in mouse and rat hepatocytes challenged with high glucose or gluconeogenic precursors. Cell metformin loads in the therapeutic range lowered cell G6P but not ATP and decreased G6pc mRNA at high glucose. The G6P lowering by metformin was mimicked by a complex 1 inhibitor (rotenone) and an uncoupler (dinitrophenol) and by overexpression of mGPDH, which lowers glycerol 3-phosphate and G6P and also mimics the G6pc repression by metformin. In contrast, direct allosteric activators of AMPK (A-769662, 991, and C-13) had opposite effects from metformin on glycolysis, gluconeogenesis, and cell G6P. The G6P lowering by metformin, which also occurs in hepatocytes from AMPK knockout mice, is best explained by allosteric regulation of phosphofructokinase-1 and/or fructose bisphosphatase-1, as supported by increased metabolism of [3-3H]glucose relative to [2-3H]glucose; by an increase in the lactate m2/m1 isotopolog ratio from [1,2-13C2]glucose; by lowering of glycerol 3-phosphate an allosteric inhibitor of phosphofructokinase-1; and by marked G6P elevation by selective inhibition of phosphofructokinase-1; but not by a more reduced cytoplasmic NADH/NAD redox state. We conclude that therapeutically relevant doses of metformin lower G6P in hepatocytes challenged with high glucose by stimulation of glycolysis by an AMP-activated protein kinase-independent mechanism through changes in allosteric effectors of phosphofructokinase-1 and fructose bisphosphatase-1, including AMP, Pi, and glycerol 3-phosphate.


Assuntos
Glucose-6-Fosfato/metabolismo , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Metformina/farmacologia , Proteínas Quinases Ativadas por AMP/deficiência , Proteínas Quinases Ativadas por AMP/genética , Trifosfato de Adenosina/metabolismo , Animais , Di-Hidroxiacetona/farmacologia , Gluconeogênese/efeitos dos fármacos , Glucose/farmacologia , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Metformina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfofrutoquinase-1/antagonistas & inibidores , Fosfofrutoquinase-1/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Rotenona/farmacologia
19.
Cancer Lett ; 473: 176-185, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31923436

RESUMO

Altered cellular metabolism is a hallmark of cancer. Metabolic rewiring in cancer cells occurs due to the activation of oncogenes, inactivation of tumor suppressor genes, and/or other adaptive changes in cell signaling pathways. Furthermore, altered metabolism is also reported in tumor-corrupted stromal cells as a result of their interaction with cancer cells or due to their adaptation in the dynamic tumor microenvironment. Metabolic alterations are associated with dysregulation of metabolic enzymes and tumor-stromal metabolic crosstalk is vital for the progressive malignant journey of the tumor cells. Therefore, several therapies targeting metabolic enzymes have been evaluated and/or are being investigated in preclinical and clinical studies. In this review, we discuss some important metabolic enzymes that are altered in tumor and/or stromal cells, and focus on their role in supporting tumor growth. Moreover, we also discuss studies carried out in various cancers to target these metabolic abnormalities for therapeutic exploitation.


Assuntos
Carcinogênese/patologia , Inibidores Enzimáticos/farmacologia , Enzimas/metabolismo , Neoplasias/patologia , Células Estromais/enzimologia , Animais , Carcinogênese/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Enzimas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gluconeogênese/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais/patologia , Microambiente Tumoral/fisiologia
20.
Diabetes ; 69(4): 681-688, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31915153

RESUMO

Sodium-glucose cotransport 2 inhibitors (SGLT2i) lower plasma glucose but stimulate endogenous glucose production (EGP). The current study examined the effect of dapagliflozin on EGP while clamping plasma glucose, insulin, and glucagon concentrations at their fasting level. Thirty-eight patients with type 2 diabetes received an 8-h measurement of EGP ([3-3H]-glucose) on three occasions. After a 3-h tracer equilibration, subjects received 1) dapagliflozin 10 mg (n = 26) or placebo (n = 12); 2) repeat EGP measurement with the plasma glucose concentration clamped at the fasting level; and 3) repeat EGP measurement with inhibition of insulin and glucagon secretion with somatostatin infusion and replacement of basal plasma insulin and glucagon concentrations. In study 1, the change in EGP (baseline to last hour of EGP measurement) in subjects receiving dapagliflozin was 22% greater (+0.66 ± 0.11 mg/kg/min, P < 0.05) than in subjects receiving placebo, and it was associated with a significant increase in plasma glucagon and a decrease in the plasma insulin concentration compared with placebo. Under glucose clamp conditions (study 2), the change in plasma insulin and glucagon concentrations was comparable in subjects receiving dapagliflozin and placebo, yet the difference in EGP between dapagliflozin and placebo persisted (+0.71 ± 0.13 mg/kg/min, P < 0.01). Under pancreatic clamp conditions (study 3), dapagliflozin produced an initial large decrease in EGP (8% below placebo), followed by a progressive increase in EGP that was 10.6% greater than placebo during the last hour. Collectively, these results indicate that 1) the changes in plasma insulin and glucagon concentration after SGLT2i administration are secondary to the decrease in plasma glucose concentration, and 2) the dapagliflozin-induced increase in EGP cannot be explained by the increase in plasma glucagon or decrease in plasma insulin or glucose concentrations.


Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucagon/sangue , Gluconeogênese/efeitos dos fármacos , Glucosídeos/farmacologia , Insulina/sangue , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Feminino , Técnica Clamp de Glucose , Glucosídeos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
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