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The gut plays a crucial role in metabolism by regulating the passage of nutrients, water and microbial-derived substances to the portal circulation. Additionally, it produces incretins, such as glucose-insulinotropic releasing peptide (GIP) and glucagon-like derived peptide 1 (GLP1, encoded by gcg gene) in response to nutrient uptake. We aimed to investigate whether offspring from overweight rats develop anomalies in the barrier function and incretin transcription. We observed pro-inflammatory related changes along with a reduction in Claudin-3 levels resulting in increased gut-permeability in fetuses and offspring from overweight rats. Importantly, we found decreased gip mRNA levels in both fetuses and offspring from overweight rats. Differently, gcg mRNA levels were upregulated in fetuses, downregulated in female offspring and unchanged in male offspring from overweight rats. When cultured with high glucose, intestinal explants showed an increase in gip and gcg mRNA levels in control offspring. In contrast, offspring from overweight rats did not exhibit any response in gip mRNA levels. Additionally, while females showed no response, male offspring from overweight rats did exhibit an upregulation in gcg mRNA levels. Furthermore, female and male offspring from overweight rats showed sex-dependent anomalies when orally challenged with a glucose overload, returning to baseline glucose levels after 120 min. These results open new research questions about the role of the adverse maternal metabolic condition in the programming of impairments in glucose homeostasis, enteroendocrine function and gut barrier function in the offspring from overweight mothers and highlight the importance of a perinatal maternal healthy metabolism.
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Polipeptídeo Inibidor Gástrico , Sobrepeso , Ratos , Masculino , Feminino , Animais , Sobrepeso/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Incretinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Peptídeos/metabolismo , Homeostase , RNA Mensageiro/genéticaRESUMO
This study investigated the neuroprotective effects of exendin-4 (EXE-4), an analog of the glucagon-like peptide 1 receptor (GLP-1R) on memory and on the neuronal populations that constitute the hippocampus of rats submitted to a sporadic dementia of Alzheimer's type (SDAT). Male Wistar rats received streptozotocin (STZ icv, 3 mg/kg diluted in aCFS, 5 µl/ventricle) and were treated for 21 days with EXE-4 (10 µg/kg, ip; saline as the vehicle). Four groups were formed: vehicle, EXE-4, STZ, and STZ + EXE-4. The groups were submitted to Y-Maze (YM), object recognition (ORT), and object displacement tasks (ODT) to assess learning and memory. The brains were used for immunohistochemical and immunofluorescent techniques with antibodies to NeuN, cleaved caspase-3 (CC3), PCNA, doublecortin (DCX), synaptophysin (SYP), and insulin receptor (IR). STZ worsened spatial memory in the YMT, as well as short-term (STM) and long-term (LTM) memories in the ORT and ODT, respectively. EXE-4 protected against memory impairment in STZ animals. STZ reduced mature neuron density (NeuN) and increased cell apoptosis (CC3) in the DG, CA1, and CA3. EXE-4 protected against neuronal death in all regions. EXE-4 increased PCNA+ cells in all regions of the hippocampus, and STZ attenuated this effect. STZ reduced neurogenesis in DG per se as well as synaptogenesis induced by EXE-4. EXE-4 increased immunoreactivity to IR in the CA1. From these findings, EXE-4 showed a beneficial effect on hippocampal pyramidal and granular neurons in the SDAT showing anti-apoptotic properties and promoting cell proliferation. In parallel, EXE-4 preserved the memory of SDAT rats. EXE-4 appears to enhance synapses at CA3 and DG. In conclusion, these data indicate that agonists to GLP-1R have a beneficial effect on hippocampal neurons in AD.
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Tirzepatide is a twincretin recently approved to improve glycemic control in type 2 diabetes mellitus (T2DM). More specifically, tirzepatide is an agonist of both the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide-1 (GLP1) receptors. In recent clinical trials in persons with obesity or overweight with associated conditions, tirzepatide decreased body weight and other cardiorenal risk factors (blood pressure, low-density lipoprotein cholesterol, glycated hemoglobin and albuminuria). Moreover, in a post hoc analysis of the SURPASS-4 randomized clinical trial, tirzepatide decreased albuminuria and total estimated glomerular filtration rate (eGFR) slopes and nearly halved the risk of a pre-specified composite kidney endpoint (eGFR decline ≥40%, renal death, kidney failure or new-onset macroalbuminuria) in participants with T2DM and high cardiovascular risk when compared with insulin glargine. Similar to other kidney-protective drugs, tirzepatide, alone or combined with sodium-glucose co-transporter 2 inhibitors, caused an early dip in eGFR. Moreover, tirzepatide also decreased eGFR slopes in participants with eGFR >60 mL/min/1.73 m2 or with normoalbuminuria. We now review the potential kidney health implications of tirzepatide, addressing its structure and function, relationship to current GLP1 receptor agonists, impact of recent results for the treatment and prevention of kidney disease, and expectations for the future.
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Analogues of glucagon like peptide-1 (GLP-1) and other drugs that increase this peptide half-life are used worldwide in human medicine to treat type 2 diabetes mellitus (DM) and obesity. These molecules can increase insulin release and satiety, interesting effects that could also be useful in the treatment of domestic animals pathologies, however their use in veterinary medicine are still limited. Considering the increasing incidence of DM and obesity in cats and dogs, the aim of this review is to summarize the available information about the physiological and pharmacological actions of GLP-1 in domestic animals and discuss about its potential applications in veterinary medicine. In diabetic dogs, the use of drugs based on GLP-1 actions reduced blood glucose and increased glucose uptake, while in diabetic cats they reduced glycemic variability and exogenous insulin administration. Thus, available evidence indicates that GLP-1 based drugs could become alternatives to DM treatment in domestic animals. Nevertheless, current data do not provide enough elements to recommend these drugs widespread clinical use.
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Background: Diabetes mellitus treatment is based on oral hypoglycemic agents or insulin. Medicinal plants constitute an option, and the leaves of Prosopis ruscifolia (Pr) were shown to be effective in reducing glycemia in hyperglycemic animals. Objective: In this paper, we report the effect of P. rusciofolia (Pr) on insulin and incretin secretion in alloxan-induced hyperglycemic rats. Methodology: The effective dose was selected, and four groups (n=10) of Wistar rats were used. Two groups with normal glycemia received water or Pr (75 mg/Kg, per os, p.o.), and two groups with hyperglycemia induced by alloxan (intraperitoneal, ip), received water or Pr (75 mg/Kg, p.o.) for 2 weeks. Oral glucose tolerance test, and incretin and insulin levels were measured at the end of the experimental period. Results: The results showed that extract promotes better tolerance to oral glucose overload, in addition to a statistically significant (p<0.001) increase in blood levels of incretin and insulin, compared to the hyperglycemic rats. Conclusion: It is concluded that the ethanolic extract of P. ruscifolialeaves has a hypoglycemic effect in hyperglycemic animals by a mechanism that involves the incretin-insulin system
Antecedentes: la diabetes mellitus es una enfermedad metabólica cuyo tratamiento se basa en el uso de agentes hipoglicemiantes orales o insulina. Una opción al tratamiento son las plantas medicinales y en ese sentido, estudios previos en animales con hojas de Prosopis ruscifolia (Pr) han demostrado efecto hipoglicemiante. Objetivo: en este trabajo se reporta el efecto de P. rusciofolia (Pr) en la secreción de insulina e incretina, en ratas hiperglicémicas por aloxano. Metodología: se emplearon cuatro grupos de ratas Wistar (n=10). Dos grupos con glicemia normal que fueron tratadas con agua Pr (75 mg/Kg, per os, p.o.) y dos grupos con hiperglicemia inducida por la inyección intraperitoneal de aloxano recibieron agua Pr (75 mg/Kg, per os, p.o.) durante dos semanas. Se midieron la tolerancia oral a la glucosa, y los niveles de incretina e insulina al final del periodo de experimentación. Resultados: se encontró que el extracto promueve una mayor tolerancia a la sobrecarga de glucosa, y además un incremento significativo (p<0.001) de los niveles de incretina e insulina en sangre, comparados al grupo de ratas hiperglicémicas. Conclusión: se concluye que e l estracto etanólico de las hojas de P. ruscifolia tienen efecto hipoglicemiante en animales hiperglicémicos por un mecanismo que incluye al sistema incretina-insulina
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Animais , Masculino , Feminino , Ratos , Extratos Vegetais/uso terapêutico , Prosopis/química , Incretinas/metabolismo , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Fenômenos Bioquímicos , Ratos Wistar , Aloxano , Hiperglicemia/induzido quimicamenteRESUMO
Diabetic kidney disease is one of the most frequent complications in patients with diabetes mellitus and affects morbidity and mortality. The recent therapies include oral hypoglycemic drugs that, in addition to optimizing glycemic control and reducing the risk of hypoglycemia, may affect the development and progression of diabetic kidney disease; these novel therapies include inhibitors of the enzyme dipeptidyl peptidase 4 (DPP-4), a group of oral hypoglycemic therapeutic agents that act at the level of the incretin system. DPP-4 inhibitors show additional pleiotropic effects in in vitro models, reducing inflammation, fibrosis, and oxidative damage, further suggesting potential kidney protective effects. Although existing trials suggest a possible benefit in the progression of diabetic kidney disease, further studies are needed to demonstrate kidney-specific benefits of DPP-4 inhibitors.
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OBJECTIVES: To determine the weight, body mass index (BMI), cardiometabolic, and gastrointestinal effects of glucagon-like peptide-1 (GLP-1) receptor agonists in children with obesity. STUDY DESIGN: Web of Science, PubMed/MEDLINE, and Scopus databases from 01/01/1994-01/01/2021 for randomized control trials examining the weight, BMI, cardiometabolic, or gastrointestinal effects of GLP-1 receptor agonists in children and adolescents with obesity. Data were extracted by 2 independent surveyors and a random effects model was applied to meta-analyze generic inverse variance outcomes. Primary outcomes were related to weight and cardiometabolic profile, and secondary outcomes of interest were gastrointestinal-related treatment-emergent adverse events. RESULTS: Nine studies involving 574 participants were identified, of which 3 involved exenatide and 6 involved liraglutide. GLP-1 receptor agonists use caused a modest reduction in body weight (mean difference [MD] -1.50 [-2.50,-0.50] kg, I2 64%), BMI (MD -1.24 [-1.71,-0.77] kg/m2, I2 0%), and BMI z score (MD -0.14 [-0.23,-0.06], I2 43%). Glycemic control was improved in children with proven insulin resistance (glycated hemoglobin A1c MD -1.05 [-1.93,-0.18] %, I2 76%). Although no lipid profile improvements were noted, a modest decrease in systolic blood pressure was detected (MD -2.30 [-4.11,-0.49] mm Hg; I2 0%). Finally, analysis of gastrointestinal-related treatment-emergent adverse events revealed an increased risk of nausea (risk ratio 2.11 [1.44, 3.09]; I2 0%), without significant increases in other gastrointestinal symptoms. CONCLUSIONS: This meta-analysis indicates that GLP-1 receptor agonists are safe and effective in modestly reducing weight, BMI, glycated hemoglobin A1c, and systolic blood pressure in children and adolescents with obesity in a clinical setting, albeit with increased rates of nausea. PROSPERO ID: CRD42020195869.
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Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Obesidade Infantil/tratamento farmacológico , Adolescente , Glicemia , Pressão Sanguínea , Índice de Massa Corporal , Criança , Hemoglobinas Glicadas , Humanos , Obesidade Infantil/metabolismo , Obesidade Infantil/fisiopatologiaRESUMO
ABSTRACT Background: Recently, studies had shown that incretin-based therapies could reduce the levels of pro-inflammatory markers. The data on the effects of incretin-based therapies on serum high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetes (T2DM) were inconsistent. Objective: The objective of the study was to assess the effects of incretin-based therapies on hs-CRP in patients with T2DM by meta-analysis. Methods: We searched PubMed, EMBASE, the Cochrane Collaboration Library, and Web of Science to identify the eligible randomized clinical trials until August 2019. The pooled standard mean differences (SMD) were calculated by random-effects model using STATA 11.0. Results: Twenty-five studies with 28 randomized controlled trials were finally included into the meta-analysis. Meta-analysis revealed a significant reduction in hs-CRP following treatment with incretin-based regimens compared to controls (SMD = −0.452, p < 0.001). Subgroup analysis of different class of incretin-based drugs showed that therapy with both dipeptidyl peptidase 4 inhibitors (DPP-4Is, SMD = −0.338, p = 0.026) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs, SMD = −0.544, p = 0.003) caused significant reductions in hs-CRP. Besides, there was a significant reduction in hs-CRP with an intervention duration more than 24 weeks (SMD = −0.465, p = 0.001), while no significant difference with <24 weeks. Meta-regression analyses showed that better glycemic control and more body mass index (BMI) decline were associated with hs-CRP reduction after incretin-based therapies. Conclusions: This meta-analysis suggests that incretin-based therapies, both GLP-1 RAs and DPP-4Is, can cause a significant reduction in hs-CRP in patients with T2DM, which is related to long intervention duration, better glycemic control, and more BMI decline.
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ABSTRACT Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.
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Humanos , Resistência à Insulina , Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicemia , Polipeptídeo Inibidor Gástrico/metabolismo , Incretinas , Ácidos Graxos não Esterificados , Secreção de Insulina , Insulina/metabolismoRESUMO
Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and ß-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional ß-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of ß-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Graxos não Esterificados , Polipeptídeo Inibidor Gástrico/metabolismo , Humanos , Incretinas , Insulina/metabolismo , Secreção de InsulinaRESUMO
The objectives of this trial were to evaluate the association between corn processing, glucose-dependent insulinotropic polypeptide (GIP) concentration, and intramuscular (IM) fat deposition. We hypothesized that steers fed whole shelled corn (WSC) would have a greater IM fat deposition than steers fed cracked corn (CC) due to an increase in plasma GIP concentration. Backgrounded, Angus-cross cattle (initial body weight [BW] = 279 ± 9.8 kg) were used in a randomized complete block design in a feedlot setting for an average of 230 d. Cattle were allotted in 12 pens (6 pens per treatment with 8 animals per pen). There were three blocks: heifers (n = 32, initial BW = 265 ± 1.3 kg), small steers (n = 32, initial BW = 262 ± 1.3 kg), and large steers (n = 32, initial BW = 310 ± 1.4 kg). Two pens within each block were randomly assigned to one of the following treatments: 1) CC or 2) WSC. Animal growth performance, carcass characteristics, and plasma hormone and metabolite concentrations were analyzed using the MIXED procedure of SAS, including the fixed effects of treatment, or treatment, time, and their interaction. Pen and block were included as random effects. Carcass yield and quality grade distributions were compared using the GLIMMIX procedure of SAS. including the fixed effects of treatment and time with pen and block as random effects. Linear regression was used to evaluate the association of plasma GIP concentration and IM fat content. Average daily gain (P = 0.57) and final BW (P = 0.34) were similar, regardless of treatment. Cattle fed CC had reduced (P < 0.01) dry matter intake (DMI) when compared with those fed WSC. This lesser DMI resulted in improved gain:feed ratio (P < 0.01) for cattle fed CC compared with cattle fed WSC. There was no effect (P ≤ 0.33) of corn processing on plasma glucose, plasma GIP concentrations, hot carcass weight, dressing percentage, or marbling score. There was a positive linear relationship (P = 0.03) between IM fat concentration and plasma GIP concentration. In conclusion, feeding CC increased gain:feed ratio compared with WSC, but there was no difference in plasma GIP concentration, whereas plasma GIP concentration appears to be related to IM fat deposition.
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BACKGROUND: Osteoporosis has scarcely been prospectively investigated in short-bowel syndrome (SBS). This prospective study was designed to evaluate incretins, adipokines, bone mass, and lipid deposits from marrow adipose tissue (MAT), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver (IHLs). METHODS: The study comprised 2 groups matched by gender, height, and age: the control group (CG) (9 males, 9 females) and the SBS group (SBSG) (6 males, 5 females). The SBSG was evaluated twice in an interval of 1 year (SBSG0 and SBSG1 ). The biochemical evaluation included incretins, leptin, and adiponectin. Dual-energy x-ray absorptiometry and magnetic resonance were, respectively, used to measure BMD and lipid deposits. RESULTS: Bone mineral density (BMD) was lower in the SBSG than in the CG, but there was no difference between SBSG0 and SBSG1 . There was no difference in MAT, SAT, and VAT, but IHL was lower in CG than in SBSG0 and SBSG1 . A negative correlation between MAT and third lumbar vertebrae BMD was found in the CG but not in SBSG0 or SBSG1 . There was a negative association between IHL and bone mass considering all participants (CG and SBSG0 ) (R2 = 0.38; P < .05). CONCLUSION: Appropriate nutrition assistance recovers body composition, reverts the relationship of bone mass and MAT, and mitigates bone loss in SBS. In spite of this, osteoporosis seems to be an early and persistent complication in SBS. Curiously, SBS seems to be a highly vulnerable condition for the development of hepatic steatosis and shows an association between bone mass and IHL.
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Osteoporose , Absorciometria de Fóton , Tecido Adiposo , Densidade Óssea , Feminino , Humanos , Masculino , Osteoporose/etiologia , Estudos ProspectivosRESUMO
INTRODUCTION AND OBJECTIVES: Acute liver injury is a current health problem with few effective treatments. The present study investigated the hepatoprotective and curative potential of the glucagon-like peptide-1 analog liraglutide against carbon tetrachloride (CCl4)-induced hepatotoxicity. MATERIALS AND METHODS: Male Swiss mice were subjected to two protocols. The first protocol (Pretreatment) consisted of intraperitoneal (i.p.) treatment with liraglutide (0.057 and 0.118mgkg-1) or vehicle (distilled water) once daily for 7 days. On days 6 and 7, the animals were challenged with 2% CCl4 (5mgkg-1, i.p.). The second protocol (Late treatment) began with an injection of 5% CCl4 (5mgkg-1, i.p.) and subsequent treatment with liraglutide (0.057mgkg-1) or vehicle (distilled water) for 1 day. In both protocols, 24h after the last administration, blood and bile were collected from anesthetized animals, followed by euthanasia and liver collection. Plasma and bile underwent biochemical analyses, and histological, oxidative stress, and metabolic parameters were evaluated in the liver. RESULTS: Both liraglutide treatment protocols attenuated hepatotoxicity that was induced by CCl4, decreasing plasma levels of hepatic enzymes, stimulating the hepatic antioxidant system, and decreasing centrilobular necrosis, hepatic glycogen, and lipid accumulation. CCl4 tended to reduce bile lipid excretion, but liraglutide did not influence this parameter. CONCLUSIONS: The present results demonstrated the hepatoprotective and therapeutic effects of liraglutide, which may be attributable to a decrease in liver oxidative stress and the preservation of metabolism. Liraglutide may have potential as a complementary therapy for acute liver injury.
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Tetracloreto de Carbono/toxicidade , Incretinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Liraglutida/farmacologia , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Alanina Transaminase/efeitos dos fármacos , Alanina Transaminase/metabolismo , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Aspartato Aminotransferases/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Ácidos e Sais Biliares/metabolismo , Catalase/efeitos dos fármacos , Catalase/metabolismo , Doença Hepática Induzida por Substâncias e Drogas , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Glicogênio/metabolismo , Ácido Láctico/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Ácido Pirúvico/metabolismo , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor (R) agonists are a class of incretin mimetic drugs that have been used for the treatment of type 2 diabetes mellitus and also considered strong candidates for the treatment of obesity. The original prototypical drug in this class is the exenatide, a synthetic peptide with the same structure as the native molecule, exendin-4, found in the saliva of the Gila monster (Heloderma suspectum suspectum lizard). OBJECTIVES: To identify and compare the anti-obesogenic, antidyslipidemic and antidiabetogenic effects of agonism in GLP-1R by exenatide on two distinct models of obesity: induced by hypothalamic injury (MSG) or high-calorie diet (DIO). METHODS: To obtain MSG, neonatal rats were daily subcutaneously injected with 4 g monosodium glutamate/kg, for 10 consecutive days. To obtain DIO, 72-75 days old rats received hyperlipid food and 30% sucrose for drinking up to 142-145 days old. Untreated healthy rats with the same age were used as control. General biometric and metabolic parameters were measured. RESULTS: MSG was characterized by decreased naso-anal length, food and fluid intake, plasma protein and glucose decay rate per minute after insulin administration (KITT), as well as increased Lee index (body mass0.33/naso-anal length), mass of retroperitoneal and periepididymal fat pads, glycemia, triglycerides (TG), LDL and VLDL. Exenatide ameliorated KITT and food and fluid intake, and it also restored glycemia in MSG. DIO was characterized by glucose intolerance, increased body mass, Lee index, fluid intake, mass of retroperitoneal and periepididymal fat pads, glycemia, glycated hemoglobin (HbA1c), TG, VLDL and total cholesterol, as well as decreased food intake and KITT. Exenatide restored glycemia, HbA1c, TG, VLDL, total cholesterol and body mass, and it also ameliorated food and fluid intake, KITT and mass of retroperitoneal fat pad in DIO. CONCLUSIONS: The hypothalamic injury and the high-calorie diet induce dyslipidemia and glycemic dysregulation in addition to obesity in rats. The usual therapeutic dose of exenatide in humans is antidiabetogenic in both these obesity models, but is anti-obesogenic and hypolipidemic only in diet-induced obesity. Agonists of GLP-1R are promising anti-obesogenic and antidyslipidemic drugs in the early stages of the obesity, in which the integrity of the nervous system was unaffected.
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Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Lagartos , Peptídeos/farmacologia , Peçonhas/farmacologia , Animais , Glicemia , Dieta/veterinária , Ingestão de Alimentos/efeitos dos fármacos , Exenatida , Feminino , Hipotálamo/efeitos dos fármacos , Masculino , Obesidade/induzido quimicamente , Ratos Wistar , Saliva/química , Glutamato de Sódio/farmacologiaRESUMO
Accumulating evidence from clinical and experimental studies indicates that the incretin glucagon-like peptide-1 (GLP-1) elicits blood-pressure lowering effects via its diuretic, natriuretic and vasodilatory properties. The present study investigated whether acute infusion of GLP-1 induces diuresis and natriuresis in spontaneously hypertensive rats (SHRs). Additionally, we examined whether GLP-1 influences the vascular reactivity of the renal arteries of normotensive and hypertensive rats and elucidated the underlying mechanisms. We found that the increase in urinary output and urinary sodium excretion in response to systemic infusion of GLP-1 for 30min in SHRs was much less pronounced than in normotensive rats. The diuretic and natriuretic actions of GLP-1 in normotensive rats were accompanied by increases in GFR and RBF and a reduction in RVR through activation of the cAMP signaling pathway. However, no changes in renal hemodynamics were observed in SHRs. Similarly, GLP-1 induced an endothelium-independent relaxation effect in the renal arteries of normotensive rats, whereas the renal vasculature of SHRs was unresponsive to this vasodilator. The absence of a GLP-1-induced renal artery vasodilator effect in SHRs was associated with lower expression of the GLP-1 receptor, blunted GLP-1-induced increases in cAMP production and higher activity and expression of the GLP-1 inactivating enzyme dipeptidyl peptidase IV relative to the renal arteries of normotensive rats. Collectively, these results demonstrate that the renal acute responses to GLP-1 are attenuated in SHRs. Thus, chronic treatment with incretin-based agents may rely upon the upregulation of GLP-1/GLP-1 receptor signaling in the kidneys of hypertensive patients and experimental models.
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Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Hipertensão/fisiopatologia , Natriurese/efeitos dos fármacos , Artéria Renal/efeitos dos fármacos , Animais , AMP Cíclico/metabolismo , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Ratos , Artéria Renal/metabolismo , Artéria Renal/fisiopatologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Isoflavones widely distributed in plants prevent diabetes. This study investigated the in vivo and in vitro effect of 3',4'-dihydroxy-6â³,6â³,6â³',6â³'-tetramethylbis(pyrano[2â³,3â³:5,6::2â³',3â³':7,8]isoflavone (bis-pyrano prenyl isoflavone) on glucose homeostasis in hyperglycemic rats. The ethyl acetate fraction from aerial parts of Polygala molluginifolia that contain isoflavones was assayed on glucose tolerance, on in vitro maltase activity and on protein glycation. The isoflavone bis-pyrano prenyl isolated from this fraction was investigated on glucose homeostasis. The in vivo action of the isoflavone exhibits an anti-hyperglycemic effect by improving glucose tolerance, augmenting the liver glycogen, inhibiting maltase activity, and stimulating glucagon-like peptide-1 (GLP-1) and insulin secretion. The in vitro isoflavone inhibits dipeptidyl peptidase-4 (DPP-4) activity since the glucose tolerance was improved in the presence of the isoflavone as much as sitagliptin, an inhibitor of DPP-4. However, the co-incubation with isoflavone and sitagliptin exhibited an additive anti-hyperglycemic action. The isoflavone increased the GLP-1 faster than the positive hyperglycemic group, which shows that the intestine is a potential target. Thus, to clarify the main site of action in which isoflavone improves glucose balance, the in vitro mechanism of action of this compound was tested in intestine using calcium influx as a trigger for the signal pathways for GLP-1 secretion. The isoflavone stimulates calcium influx in intestine and its mechanism involves voltage-dependent calcium channels, phospholipase C, protein kinase C, and stored calcium contributing for GLP-1 secretion. In conclusion, the isoflavone regulates glycaemia by acting mainly in a serum target, the DPP-4 inhibitor. Furthermore, the long-term effect of isoflavone prevents protein glycation. J. Cell. Biochem. 118: 92-103, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Glicemia/metabolismo , Dipeptidil Peptidase 4/sangue , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hiperglicemia/tratamento farmacológico , Isoflavonas/farmacologia , Polygala/química , Animais , Inibidores da Dipeptidil Peptidase IV/química , Peptídeo 1 Semelhante ao Glucagon/sangue , Hiperglicemia/sangue , Insulina/sangue , Isoflavonas/química , Masculino , Ratos , Ratos Wistar , Fosfato de Sitagliptina/farmacologiaRESUMO
Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue that was recently approved to treat obesity in some countries. Considering that liraglutide effects on brain energy metabolism are little known, we evaluated the effects of liraglutide on the energy metabolism. Animals received a single or daily injection of saline or liraglutide during 7 days (25, 50, 100, or 300 µg/kg i.p.). Twenty-four hours after the single or last injection, the rats were euthanized and the hypothalamus, prefrontal cortex, cerebellum, hippocampus, striatum, and posterior cortex were isolated. Our results demonstrated that a single dose of liraglutide in young rats increased the activity of complexes and inhibited creatine kinase activity. Repeated administrations of liraglutide in young rats reduced the activity of complexes and activated creatine kinase activity. In adult rats, a single dose of liraglutide reduced the activity of complex I and creatine kinase and increased the activity of complexes II and IV. Repeated administrations of liraglutide in adult rats increased the activity of complexes I and IV and reduced the activity of complex II and creatine kinase. We concluded that liraglutide may interfere in energy metabolism, because analysis of different times of administrations, concentrations, and level of brain development leads to divergent results.
Assuntos
Encéfalo/metabolismo , Metabolismo Energético/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Envelhecimento , Animais , Encéfalo/efeitos dos fármacos , Creatina Quinase/metabolismo , Relação Dose-Resposta a Droga , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Humanos , Hipoglicemiantes/administração & dosagem , Liraglutida/administração & dosagem , Masculino , Ratos , Ratos WistarAssuntos
Cirurgia Bariátrica/métodos , Diabetes Mellitus Tipo 1/cirurgia , Nesidioblastose/cirurgia , Adolescente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Derivação Gástrica/métodos , Humanos , Hipoglicemiantes/uso terapêutico , Insulinas/uso terapêutico , Laparoscopia/métodos , Metformina/uso terapêutico , Pancreatectomia/métodos , Resultado do TratamentoRESUMO
Currently, obesity and its associated complications are considered major public health problems worldwide. Because the causes are multifactorial and complex, different treatment methods are used, which include diet and exercise, as well as the use of drugs, although they can have adverse side effects. A new target for the treatment of obesity may be the incretin system, which consists of hormones that seem to contribute to weight loss. In this sense, some studies have shown a relationship between weight loss and drugs related to incretin system, including glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. The objective of this review is to summarize the association between the incretin system and obesity treatment.