ABSTRACT
Introducción: La diabetes mellitus (DM) es una enfermedad crónica inflamatoria muy frecuente y por ende una de las emergencias sanitarias mundiales de más rápido crecimiento en las últimas décadas. Hay tres ejes que impactan en la progresión del compromiso renal del paciente diabético. El eje hemodinámico, metabólico e inflamatorio. Resaltamos la importancia del componente inflamatorio como actor protagónico en el desarrollo de la Enfermedad renal diabética (ERD). El manejo del paciente con ERD debe ser holístico, con tres objetivos claros: buen control metabólico, disminuir progresión de la enfermedad renal y disminuir los desenlaces cardiovasculares adversos. Actualmente además de las intervenciones no farmacológicas, el control de los factores de riesgo, el uso de los IECAS/ARA II hay nuevos pilares en el tratamiento de la ERD. Objetivos: El objetivo de esta comunicación es revisar los nuevos pilares en el manejo de la ERD. En la revisión bibliográfica que se hizo, encontramos que hay tres nuevos pilares en el tratamiento. Los inhibidores SGLT-2, los agonistas del receptor GLP-1 y por último finerenona, que es un antagonista selectivo no esteroideo del receptor mineralocorticoide (ARM), no es un antidiabético. Con estas nuevas terapias el manejo actual de estos pacientes ha cambiado considerablemente. Conclusión: Hay nuevos pilares en el tratamiento de la ERD. Los inhibidores SGLT-2, los Agonistas del receptor GLP-1 y el uso de ARM como finerenona, que nos brindan beneficios cardiorenales y que hacen que hoy en día el tratamiento de la ERD tenga un mejor panorama.
Introduction: Diabetes mellitus (DM) is a very common chronic inflammatory disease and finally one of the fastest-growing global health emergencies in recent decades. Three axes impact the progression of renal compromise in diabetic patients. The hemodynamic, metabolic, and inflammatory axis. We highlight the importance of the inflammatory component as a leading actor in developing Diabetic Kidney Disease (DKD). The management of the patient with CKD must be holistic, with three clear objectives: reasonable metabolic control, slowing the progression of kidney disease, and reducing adverse cardiovascular outcomes. Currently, in addition to non-pharmacological interventions, the control of risk factors, and the use of ACE inhibitors/ARA II, there are new pillars in the treatment of CKD. Objectives: The objective of this communication is to review the new pillars in the management of DKD. In the bibliographic review that was carried out, we found that there are three new pillars in the treatment. SGLT-2 inhibitors, GLP-1 receptor agonists, and finally finerenone, which is a selective non-steroidal antagonist of the mineralocorticoid receptor (MRA), not an antidiabetic. With these new therapies, the current management of these patients has changed considerably. Conclusion: There are new pillars in the treatment of DKD. The SGLT-2 inhibitors, the GLP-1 receptor agonists, and the use of MRAs such as finerenone provide us with cardio-renal benefits and which today make the treatment of CKD have a better outlook.
Subject(s)
Diabetes Mellitus , Therapeutics , Kidney DiseasesABSTRACT
Diabetes is a common condition with a dismal prognosis. According to the International Diabetes Federation, 537 million people worldwide have diabetes. Cardiovascular disorders (CVD) are the major cause of death globally. Diabetes mellitus type 2 (T2DM) increases the risk of CVD. Since 2008, the FDA has required all new antihyperglycemic treatments to show no increased CV risk. Years of glucocentric diabetic therapy have left many patients on medicines with no known CV benefit. GLP-1 receptor agonists (GLP-1RAs) are excellent glucose-lowering medicines with little risk of hypoglycaemia, CVD and weight loss. GLP-1RAs may also delay renal disease development. As an adjunct to metformin or ongoing therapy, GLP1RAs or sodium-glucose cotransporter-2 inhibitors are recommended by the American Diabetes Association and the European Association for the Study of Diabetes (EASD). Thus, this review summarises GLP-1RA and their significance in the paradigm shift in diabetes care recommendations from glucocentric to gluco-cardiocentric
ABSTRACT
The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus (T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1, and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM. Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug-drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug-drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.
ABSTRACT
Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t 1/2 > 14 days) compared to t 1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.
ABSTRACT
El ambiente obesogénico promueve la obesidad al facilitar el acceso y consumo de una amplia variedad de alimentos palatables altos en calorías. La activación del receptor de GLP1 (GLP1R) reduce la ingesta de alimentos, enlentece el vaciamiento gástrico y promueve un balance energético negativo a través de su acción en distintos órganos como el músculo esquelético, disminuyendo así el peso corporal. La obesidad inducida por dieta alta en grasa disminuye el efecto anorexigénico de la administración sistémica vía intra-peritoneal de EX4 (agonista de GLP1R). Sin embargo, se desconoce si la exposición a un ambiente obesogénico previo a la manifestación de obesidad disminuye los efectos anorexigénicos de EX4 o un posible efecto de EX4 sobre marcadores de oxidación de ácidos grasos y termogénesis en músculo esquelético. El objetivo de esta investigación fue determinar el efecto a corto plazo de la dieta CAF, un modelo del ambiente obesogénico humano, sobre la capacidad de EX4 de reducir la ingesta y modular la expresión de marcadores proteicos de oxidación de ácidos grasos y termogénesis (CPT1 y UCP2) en músculo de ratones. Nuestros datos muestran que una inyección intraperitoneal de EX4 a ratones C57BL/6J alimentados con dieta CAF o dieta control durante 10 días no altera la ingesta calórica total, peso corporal, o la expresión de proteínas marcadoras de los procesos de beta-oxidación y de termogénesis (CPT1 y UCP2). Estos datos sugieren que protocolos alternativos de administración de EX4 son necesarios para observar los efectos fisiológicos de la activación de GLP1R.
The obesogenic environment promotes obesity by facilitating access to and consumption of a wide variety of palatable, high-calorie foods. Activation of the GLP1 receptor (GLP1R) reduces food intake, slows gastric emptying, and promotes a negative energy balance by acting on organs such as skeletal muscle, thus decreasing body weight. Obesity induced by a high-fat diet decreased the anorexigenic effect of intraperitoneal systemic administration of EX4 (GLP1R agonist). However, it is unknown whether exposure to an obesogenic environment before the manifestation of obesity diminishes the anorexigenic effects of EX4 or a possible effect of EX4 on markers of fatty acid oxidation and thermogenesis in skeletal muscle. This investigation aimed to determine the short-term effect of the CAF diet, a model of the human obesogenic environment, on the ability of EX4 to reduce intake and modulate the expression of protein markers of fatty acid oxidation and thermogenesis (CPT1 and UCP2) in mouse muscle. Our data show that intraperitoneal injection of EX4 to C57BL/6J mice fed CAF diet or control diet for ten days does not alter total caloric intake, body weight, or expression of proteins markers of beta-oxidation and thermogenesis processes (CPT1 and UCP2). These data suggest that alternative EX4 administration protocols are necessary to observe the physiological effects of GLP1R activation.
Subject(s)
Animals , Male , Mice , Diet/adverse effects , Exenatide/administration & dosage , Obesity/etiology , Obesity/metabolism , Oxidation-Reduction , Blotting, Western , Muscle, Skeletal/metabolism , Thermogenesis , Fatty Acids/metabolism , Glucagon-Like Peptide-1 Receptor/metabolism , Uncoupling Protein 2 , Irinotecan , Injections, Intraperitoneal , Mice, Inbred C57BLABSTRACT
ObjectiveTo observe the pharmacodynamic effects of Cinnamomi Cortex on the incretin effect in the rat model of diabetes mellites （DM） induced by streptozotocin （STZ） and explore the underlying mechanism from glucagon-like peptide-1 （GLP-1） and dipeptidyl peptidase-4 （DPP-4）. MethodForty SD rats were randomly assigned into blank， model， sitagliptin （0.1 g·kg-1）， and low- and high-dose Cinnamomi Cortex （0.45 and 0.9 g·kg-1， respectively） groups. The DM rat model was established by a high-fat diet combined with intraperitoneal injection of 40 mg·kg-1 STZ in other groups except the blank group. The intervention lasted for 8 weeks. The status， body weight， water intake， food intake， and fasting blood glucose （FBG） of the rats were observed and determined. Hematoxylin-eosin staining was employed to reveal the pathological changes of the pancreas， and immunohistochemistry to detect the expression of glucagon in the pancreas. Biochemical assay was employed to measure the serum levels of lipid metabolism indexes such as total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL）， and high-density lipoprotein （HDL）. Enzyme-linked immunosorbent assay was employed to determine the levels of glycosylated hemoglobin， insulin， glucagon， GLP-1， and glucose-dependent insulinotropic polypeptide （GIP） in rat serum， and Western blot to determine the protein levels of GLP-1 and DPP-4 in the pancreas. ResultAfter 8 weeks of intervention， the model group showed higher body weight， FBG， TC， TG， LDL， glycosylated hemoglobin， glucagon， insulin， and insulin resistance index and lower HDL， GLP-1， and GIP than the blank group （P<0.05， P<0.01）. The Cinnamomi Cortex groups showed lower body weight， FBG， TC， TG， LDL， glycosylated hemoglobin， glucagon， insulin， and insulin resistance index and higher HDL， GLP-1， and GIP than the model group （P<0.05， P<0.01）. The Cinnamomi Cortex groups showed recovered morphology of islet cells and no nucleus aggregation. Compared with the model group， the Cinnamomi Cortex groups showed declined levels of glucagon in the center of islet cells. Compared with the blank group， the model group showed up-regulated protein level of DPP-4 and down-regulated protein level of GLP-1 （P<0.01）. Compared with the model group， the high-dose Cinnamomi Cortex groups showed down-regulated protein level of DPP-4 and up-regulated protein level of GLP-1 （P<0.05）. ConclusionCinnamomi Cortex may reduce blood glucose and improve incretin effect to lower the blood glucose level by regulating DPP-4 and GLP-1 in DM rats.
ABSTRACT
@#Parkinson's disease(PD)is the second common neurodegenerative disease that mostly occurs in middle-aged and elderly people. Currently,Levodopa is the main first-line treatment drug,but the long-term efficacy of patients is not good,and even side effects such as“on-off”phenomenon and orthostatic hypotension occur. Glucagon-like peptide-1receptor agonists(GLP-1RA)and analogues are endogenous peptide hormones that can be released into the blood and enter the central nervous system to exert neuroprotection by crossing the blood-brain barrier. Numerous studies have shown that GLP-1RA can improve movement disorders and restore dopaminergic neuron activity in PD. However,the mechanism of GLP-1RA is not yet fully clear. This paper summarized the mechanism of GLP-1RA and its analogues in improving PD movement disorders and restoring dopaminergic neuron activity,and reviewed the aspects of reducing neuroinflammation,inhibiting oxidative stress,inhibiting apoptosis,regulating mitochondrial morphology,increasing neuronal protrusions,enhancing autophagy,and regulating intestinal flora homeostasis,so as to provide new ideas for research of the mechanisms of PD and development of GLP-1RA-related new drugs.
ABSTRACT
Objective To analyze the onset characteristics of type 2 diabetes mellitus (T2DM) with cognitive impairment in Baotou area, and study the improvement effect of GLP-1 receptor agonists. Methods A total of 320 patients with T2DM admitted between September 2021 and September 2022 were selected and divided into the observation group with T2DM and cognitive dysfunction and the negative control group without cognitive dysfunction according to their cognitive function status , Among the 160 cases in each group; Patients with type 2 diabetes and cognitive impairment were randomly divided into a treatment group and a control group, 80 cases in each group; the control group was treated with conventional treatment, and the treatment group was additionally treated with semaglutide; Logistics multiple regression model was used to analyze T2DM The related risk factors of cognitive impairment in patients were assessed by the Mini-Mental State Examination (MMSE) score to evaluate the cognitive function of the patients. Results Multivariate regression model showed that course of disease, age, vitamin D, HbA1c, LDL-C, BMI, Hcy, Lp-PLA2, TNF-α, IL-6 and folic acid levels were also independent risk factors for cognitive impairment in T2DM patients (P<0.05); There was a significant positive correlation between GLP-1 receptor agonists and cognitive function recovery in T2DM patients with cognitive impairment (P<0.05). Conclusion The onset of T2DM with cognitive impairment in Baotou area is often accompanied by a long course of disease, older age, abnormal levels of vitamin D, HbA1c, LDL-C, BMI, Hcy, Lp-PLA2, TNF-α, IL-6 and folic acid, and GLP -1 receptor agonists have a clear role in improving the cognitive function of patients.
ABSTRACT
ObjectiveTo explore the potential mechanism of Zuogui Jiangtang Tongmai prescription （ZJT） in the treatment of diabetes mellitus complicated with cerebral infarction （DM-CI） in rats based on the short-chain fatty acids （SCFAs）/G protein-coupled receptor 43 （GPR43）/glucagon-like peptide-1 （GLP-1）/GLP-1 receptor （GLP-1R） signaling pathway. MethodSixty SD rats were randomly divided into sham operation group， model group， low- and high-dose ZJT groups （12， 24 g·kg-1）， western medicine group （140 mg·kg-1 pioglitazone metformin tablets + 27 mg·kg-1 enteric-coated aspirin tablets）. Except for the sham operation group， all other groups were fed a high-sugar high-fat diet for 4 weeks and then subjected to intraperitoneal injection of 1% streptozotocin at 35 mg·kg-1 combined with middle cerebral artery occlusion （MCAO） to establish a DM-CI rat model. The corresponding interventions were performed with distilled water， low-dose ZJT， high-dose ZJT， pioglitazone metformin tablets， and enteric-coated aspirin tablets. After surgery， National Institutes of Health Stroke Scale （NIHSS） scoring and triphenyltetrazolium chloride （TTC） staining to measure the rat's cerebral infarct volume were carried out. Random blood glucose levels were measured， and hematoxylin-eosin （HE） staining was used to observe histopathological changes in rat brain tissues. Gas chromatography was employed to detect the content of SCFAs in the cecum contents. Enzyme-linked immunosorbent assay （ELISA） was adopted to measure serum GLP-1 level. Western blot was used to detect the protein expression of GPR43 in rat ileal tissues and GLP-1R in the ischemic brain tissues. ResultCompared with the sham operation group， the model group showed significantly increased NIHSS scores， random blood glucose levels， and cerebral infarct volumes （P<0.01）， and significantly decreased SCFAs content， GLP-1 levels， and GPR43 and GLP-1R protein expression （P<0.01）. Compared with the model group， the high-dose ZJT group and the western medicine group exhibited significantly reduced NIHSS scores， random blood glucose levels， and cerebral infarct volumes （P<0.05， P<0.01）， and significantly increased SCFAs content， GLP-1 levels， and GPR43 and GLP-1R protein expression （P<0.01）. ConclusionZJT can improve glucose metabolism disorder and reduce neurological damage in DM-CI rats， and its mechanism may be related to the increase in SCFAs content and the upregulation of the GPR43/GLP-1/GLP-1R signaling pathway.
ABSTRACT
The glucagon-like peptide-1 receptor agonists (GLP-1RAs) have important beneficial effects on glycemic control and body weight along with their pleiotropic effects on various systems of the body. However, until now these agents were administered via an injection posing a challenge to patient convenience. Oral semaglutide is a first in class oral GLP-1RA co-formulated with an absorption enhancer for the treatment of type 2 diabetes mellitus (T2DM). The clinical efficacy and safety of oral semaglutide has been extensively evaluated in the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) program of clinical trials. This review shall elaborate on the unique diabetes situation in India and why the oral GLP-1RA (semaglutide) will be a game-changer in the Indian setting
ABSTRACT
Introducción: Recientemente se han descubierto nuevos medicamentos para el tratamiento de la diabetes tipo 2, con novedosos mecanismos de acción y menos efectos adversos. Dentro de ellos tenemos los análogos del péptido similar al glucagón tipo 1. Objetivo: Explicar la evidencia existente sobre los efectos del tratamiento con agonistas del receptor del péptido similar al glucagón tipo 1 en las personas con obesidad y diabetes mellitus tipo 2. Material y Métodos: Se realizó una revisión sistemática que incluyó estudios de los efectos de los agonistas del receptor del péptido similar al glucagón tipo1 como tratamiento en personas mayores de 12 años con obesidad y diabetes tipo 2. Se realizó una síntesis narrativa formal de los datos recogidos, no se realizó una síntesis estadístico formal. La calidad de evidencia para cada desenlace se determinó, según la metodología Grading of Recommendations Assessmet, Developmet and Evaluation. Resultados: La evidencia disponible demuestra que los agonistas del receptor del péptido similar al glucagón tipo 1, lograron una mayor disminución del peso corporal (-7,0 por ciento vs -2 por ciento) y de las cifras de hemoglobina glucosilada (HbA1c) (-0,40 por ciento vs -0,10 %) respecto al grupo placebo. Además, de una mayor reducción de la cintura abdominal. Conclusiones: La evidencia analizada muestra que los fármacos del tipo agonistas del receptor del péptido similar al glucagón tipo 1 tienen efectos beneficiosos en el tratamiento de las personas con obesidad y diabetes, disminuyendo el peso corporal y los valores de glucemia(AU)
Introduction: New drugs with novel mechanisms of action and fewer adverse effects have recently been discovered for the treatment of type 2 diabetes. Among them are glucagon-like peptide-1 analogues. Objective: To explain the existing evidence of the effects of treatment with glucagon-like peptide-1 receptor agonists in people with obesity and type 2 diabetes mellitus. Material and Methods: We conducted a systematic review that included studies on the effects of glucagon-like peptide -1 receptor agonists for the treatment of people older than 12 years with obesity and type 2 diabetes. A formal narrative synthesis of the collected data was performed, whereas a formal statistical synthesis was not performed. The quality of evidence for each outcome was determined according to the Grading of Recommendations Assessment, Development and Evaluation method. Results: The available evidence shows that glucagon-like peptide -1 receptor agonists achieved a greater reduction in body weight (-7,0 percent vs -2 percent) and glycosylated hemoglobin (HbA1c) (-0,40 percent vs -0,10 percent) compared to the placebo group. In addition, there was a greater reduction in abdominal waist circumference. Conclusions: The evidence analyzed shows that glucagon-like peptide -1 receptor agonists have beneficial effects in the treatment of people with obesity and diabetes, reducing body weight and glycemia values(AU)
Subject(s)
Humans , Male , Female , Glycated Hemoglobin , Diabetes Mellitus, Type 2 , Reference Drugs , Waist Circumference , Obesity , Methodology as a SubjectABSTRACT
Resumen La prevalencia de diabetes mellitus tipo 2 (DM2) está en aumento, generando un gran impacto tanto a nivel individual como en salud pública. Cerca de la mitad de los pacientes con DM2 sufren un deterioro de la función renal, por esto la nefroprotección resulta de fundamental importancia. El conjunto de evidencia que cambió del enfoque terapéutico glucocéntrico al cardiorrenometabólico en la DM2 motivó la inclu sión en las recomendaciones internacionales de nuevas terapias con beneficios cardiovasculares y renales. Los agonistas del receptor del péptido similar al glucagón tipo 1 (GLP-1) tienen efectos favorables sobre la función renal y sus posibles acciones protectoras son multifactoriales, más allá del control glucémico. Estos beneficios han sido demostrados en los estudios clínicos de eficacia y seguridad, así como también en los estudios de re sultados cardiovasculares y de vida real. En esta revisión narrativa se describen los efectos directos e indirectos de estas moléculas, así como su evidencia en los principales estudios clínicos (LEADER, SUSTAIN 6 y REWIND) y de vida real que demuestran sus efectos beneficiosos sobre la función renal e introduce la expectativa de los resultados futuros de los estudios en curso con objetivos renales.
Abstract The prevalence of type 2 diabetes mellitus (DM2) is increasing, generating a great impact both at individual and public health level. Nearly half of the patients with DM2 develop impaired renal function, so nephron-protection is highly important. The robust body of evidence that shifted the therapeutic focus from glycemic to cardio-renal metabolic therapy in DM2 led to the inclusion of new therapies with cardiovascular and renal benefits in international guidelines. Type 1 glucagon (GLP-1) receptor agonists have showed favorable effects on renal function and their potential protective actions are multifactorial, beyond glycemic control. These benefits have been demonstrated in efficacy and safety clini cal studies, as well as in cardiovascular outcomes and real-life studies. This comprehensive review describes the direct and indirect effects of these molecules, as well as evidence obtained from pivotal clinical (LEADER, SUSTAIN 6 and REWIND) and real-life studies demonstrating their beneficial effects on renal function, and also introduces expectations of future results from ongoing studies with renal endpoints.
ABSTRACT
In recent years, obesity has become a global public health problem, and the incidence of obesity among children and adolescents in China has been gradually increasing.Obesity in childhood will affect the development and health of children and may lead to an increased incidence of multiple chronic diseases in adulthood.The current main strategy for weight reduction in obese children is to change their dietary habits and increase physical activity, but it is prone to relapseand has a high failure rate.Obese patients exhibit persistent hunger and lack of satiety.Glucagon-like peptide-1 receptor agonists, which suppress appetite and increase satiety, have successfully treated adult obesity with good results.This article will discuss the feasibility and safety of using glucagon-like peptide-1 receptor agonists for obesity in children and adolescents by reviewing the possible mechanisms of action of glucagon-like peptide-1 receptor agonists for weight reduction and the clinical data of glucagon-like peptide-1 receptor agonists on obesity in children and adolescents.
ABSTRACT
Objective To evaluate cardiovascular benefits in patients with type 2 diabetes mellitus treated with the marketed 11 sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like polypeptide-1 (GLP-1) receptor agonism by Bayesian network meta-analysis system. Methods MEDLINE, Embase and Cochrane Library were searched from the establishment of the database to 18 July 2020. The endpoint of the study was adverse cardiovascular events. The effect measures were hazard ratios (HR) and 95% credible intervals (CI). Results Compared with placebo, empagliflozin, canagliflozin, dapagliflozin, albiglutide, dulaglutide, exenatide, liraglutide, semaglutide reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes with HR and 95% CI ranging between 0.75(0.60-0.95)~0.90(0.82-0.99); The risk of heart failure was reduced by empagliflozin, canagliflozin, dapagliflozin and ertugliflozin, with HR and 95%CI ranging between 0.64(0.49-0.82)~0.74(0.65-0.85); Empagliflozin, canagliflozin, dapagliflozin, exenatide, liraglutide and oral semaglutide reduced the incidence of all-cause mortality with HR and 95%CI ranging between 0.52(0.33-0.84)~0.89(0.80-0.99); Empagliflozin, canagliflozin, liraglutide and oral semaglutide can reduce the risk of cardiovascular death events, with HR and 95% CI ranging between 0.54(0.30-0.95)~0.83(0.71-0.96) . Conclusion The order of the cardiovascular benefits of SGLT-2 inhibitors or GLP-1 receptor agonists in patients with type 2 diabetes mellitus complicated with atherosclerotic cardiovascular disease are canagliflozin (the best), empagliflozin, dulaglutide, liraglutide; for patients with type 2 diabetes and heart failure. The order of the cardiovascular benefits for patients with type 2 diabetes and heart failure are empagliflozin, canagliflozin, ertugliflozin, and dapagliflozin.
ABSTRACT
ObjectiveTo explore the effects of Gegen Qinliantang（GGQL） on the proliferation and apoptosis of intestinal epithelial cells as well as on the expression of cyclic adenosine monophosphate （cAMP）， G protein-coupled receptor 119 （GPR119）， and glucagon-like peptide-1 （GLP-1）， so as to explore its potential hypoglycemic mechanism. MethodTwenty-five Wistar rats were gavaged with GGQL at the dose of 23 g·kg-1 crude drug， twice a day， which meant that 6 mL was administered into each rat per day for preparing the GGQL-containing serum. After seven consecutive times of administration， the intestinal epithelial L （NCI-H716） cells were cultured with different concentrations （1%， 2.5%， 5%， 7.5%， and 10%） of GGQL. The cell proliferation was evaluated using cell counting kit-8 （CCK-8） and the apoptosis by flow cytometry. The GLP-1 and cAMP contents in cell supernatant were determined by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein GLP-1 and GPR119 levels were assayed by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. ResultCompared with the control group， GGQL significantly reduced the proliferation of NCI-H716 cells（P<0.05）. As the GGQL concentration increased， its inhibitory effect became more obvious. GGQL at each concentration significantly promoted the apoptosis of NCI-H716 cells （P<0.05）. Compared with the control group， GGQL significantly up-regulated the expression of cAMP， GLP-1， and GPR119 （P<0.05）. The results showed that the effect of GGQL was positively correlated with its concentration， and 10% GGQL exhibited the best effect. ConclusionGGQL effectively inhibits the proliferation of NCI-H716 cells and promotes their apoptosis， and it may promote the secretion of GLP-1 by up-regulating the expression of cAMP and GPR119.
ABSTRACT
Currently, there is still no effective curative treatment for the development of late-stage liver fibrosis. Here, we have illustrated that TB001, a dual glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) agonist with higher affinity towards GCGR, could retard the progression of liver fibrosis in various rodent models, with remarkable potency, selectivity, extended half-life and low toxicity. Four types of liver fibrosis animal models which were induced by CCl4, α-naphthyl-isothiocyanate (ANIT), bile duct ligation (BDL) and Schistosoma japonicum were used in our study. We found that TB001 treatment dose-dependently significantly attenuated liver injury and collagen accumulation in these animal models. In addition to decreased levels of extracellular matrix (ECM) accumulation during hepatic injury, activation of hepatic stellate cells was also inhibited via suppression of TGF-β expression as well as downstream Smad signaling pathways particularly in CCl4-and S. japonicum-induced liver fibrosis. Moreover, TB001 attenuated liver fibrosis through blocking downstream activation of pro-inflammatory nuclear factor kappa B/NF-kappa-B inhibitor alpha (NFκB/IKBα) pathways as well as c-Jun N-terminal kinase (JNK)-dependent induction of hepatocyte apoptosis. Furthermore, GLP-1R and/or GCGR knock-down results represented GCGR played an important role in ameliorating CCl4-induced hepatic fibrosis. Therefore, TB001 can be used as a promising therapeutic candidate for the treatment of multiple causes of hepatic fibrosis demonstrated by our extensive pre-clinical evaluation of TB001.
ABSTRACT
ABSTRACT Objective: To evaluate the effect of beinaglutide on weight loss and plasma protein patterns of inflammation/obesity relevant cytokines and biomarkers. Materials and methods: This study involved 36 adult patients with a body mass index (BMI) of ≥ 24 kg/m2 and T2DM. Beinaglutide was administered for three months. Changes in body weight, fasting plasma glucose (FPG) level, 2 h postprandial plasma glucose (2h-PG) level, glycosylated hemoglobin (HbA1c) level, BMI and visceral and subcutaneous fat areas were measured at baseline and after three months of treatment. In addition, relevant inflammation/obesity cytokines and biomarkers were measured. Results: After three months, beinaglutide treatment led to significant changes, including in body weight, BMI, FPG level, HbA1c level, visceral and subcutaneous fat areas. In addition, serpin E1, leptin, C-reaction protein (CRP) and tumor necrosis factor-α (TNF-α) also decreased significantly. The plasma protein concentrations of CRP (Log2 transformed) were found to be positively correlated with the percentage of weight loss (R = 0.514 and p-value = 0.021). Conclusion: Beinaglutide treatment resulted in weight loss, plasma glucose control and anti-inflammatory effects in patients with T2DM and overweight/obesity.
Subject(s)
Humans , Adult , Diabetes Mellitus, Type 2/drug therapy , Blood Glucose , Weight Loss , Body Mass Index , China , Overweight/drug therapy , Obesity/drug therapyABSTRACT
IF1 (ATPIF1) is a nuclear DNA-encoded mitochondrial protein whose activity is inhibition of the F
ABSTRACT
Resumen La enfermedad metabólica diabetes mellitus tipo 2 ocasiona alteraciones en la estructura y en la funcionalidad miocárdica por diferentes mecanismos bioquímicos los cuales pueden ocasionar disfunción diastólica y sistólica, por lo cual el uso de los antihiperglicemiantes aparte de su efecto en la reducción de la hiperglicemia y la hemoglobina glicosilada, algunos han demostrado reducción en la mortalidad cardiovascular y de las hospitalizaciones por insuficiencia cardiaca, basado en estudios clínicos sobre este impacto en el miocardio. También se ha evaluado el efecto de estos fármacos por medio del ecocardiograma transtorácico. El objetivo de este articulo es analizar los valores de los parámetros ecocardiográficos sistólicos y diastólicos en pacientes diabéticos tipo 2 o alguna cardiopatía de base como antecedente de infarto al miocardio e insuficiencia cardiaca con el uso de metformina, sulfonilureas, los inhibidores de la dipeptidilpeptidasa 4 (sitagliptina, alogliptina y linagliptina, vildagliptina), los análogos de GLP1 (liraglutide, albiglutide y exenatide).
Abstract Metabolic disease type 2 diabetes mellitus causes alterations in both structure and myocardial functionality by different biochemical mechanisms which can cause diastolic and systolic dysfunction, which is why the use of antihyperglycemic agents apart from its effect in the reduction of hyperglycemia and glycosylated hemoglobin, some groups have shown reduction in cardiovascular mortality and hospitalizations for heart failure this based on clinical studies, by hypothesis, theories and pleiotropic mechanisms on this impact on the myocardium. On the other hand, the effect of these drugs on the myocardium has also been evaluated by transthoracic echocardiography. Therefore, the aim of this article is to analyze the values of systolic and diastolic echocardiographic parameters in type 2 diabetic patients or some underlying heart disease as a history of myocardial infarction and heart failure with the use of metformin, sulfonylureas, inhibitors of the dipeptidylpeptidase 4 (sitagliptin, alogliptin and linagliptin, vildagliptin), GLP1 analogues (liraglutide, albiglutide and exenatide).
Subject(s)
Humans , Echocardiography/drug effects , Diabetes Mellitus , Sodium-Glucose Transporter 2 Inhibitors/analysis , Metformin/analysis , Hyperglycemia/complicationsABSTRACT
Background DPP-4 inhibitors showed analgesic and anti-inflammatory activity in human and animal-studies. DPP-4 inhibitors improved nerve function and thermal nociception in animal models. Aim of the study was to explore analgesic activity of single and multiple doses of teneligliptin 20 mg/day using hot air analgesiometer in healthy human volunteers.Methods: After IEC approval and informed consent, subjects were randomized to receive either teneligliptin 20 mg or placebo in double-blinded manner with standard breakfast. Mean pain threshold and tolerance(sec) using hot air analgesiometer were recorded at baseline and 1 hr, 2 hrs post drug on day 1, for single dose study. Subsequently drugs were administered under supervision daily for 6 days and same procedure repeated on day8 for multiple-dose study. After 2 weeks washout, subjects crossed over in period 2 to receive other formulation and same procedure repeated to determine study parameters. Fasting blood-sugar (FBS) was monitored, ADRs recorded in CRF. Statistical analysis done with SPSS20.0.Results: Twelve-healthy subjects (8 males, 4 females) with mean age 33.08±4.69 years, mean BMI 22.6±1.37kg/m2 participated. Single dose teneligliptin produced significant increase in pain threshold (35.9%) and pain tolerance (25.1%) (p<0.001) at 1hour compared to baseline. With multiple doses, pain threshold increased by 37.1% and pain tolerance by 25.4% (p<0.001) at 1hour compared to baseline. The increase in pain threshold and tolerance values at 1 and 2 hours were similar. There was no significant change in pain threshold(p=0.4135) and tolerance (p=0.4476) at baseline on day1 and day 8. Placebo showed non-significant change in study parameters. Both treatments well tolerated. FBS of volunteers within normal limits during treatment period and no hypoglycemia reported.Conclusions: Results of our study suggest that teneligliptin20mg in healthy subjects demonstrated modest analgesic activity compared to baseline and placebo. Its role in painful diabetic conditions may be further explored.