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2.
Article in Chinese | WPRIM | ID: wpr-772080

ABSTRACT

OBJECTIVE@#To investigate the effect of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on body fat redistribution and muscle mass in overweight/obese patients with type 2 diabetes (T2DM).@*METHODS@#We retrospectively analyzed the data of 76 patients with body mass indexes (BMI)≥24 kg/m, who had an established diagnosis of T2DM in our department between December, 2014 and September, 2015. We divided these patients according to their BMI in overweight group (BMI of 24-27.9 kg/m, =14), obese group (BMI of 28-31.9 kg/m, =35) and severely obese group (BMI≥32 kg/m, =27). All the patients received treatment with GLP-1RAs (Exenatide or Liraglutide) for 3.0 to 29.0 weeks (mean 8.9 weeks), and their blood glucose, HbA1c and serum lipids were analyzed. For each patient, the fat and muscle masses were analyzed using a human body composition analyzer (JAWON-IOI353, Korea) before and after GLP-1RAs treatment.@*RESULTS@#Treatment with GLP-1RAs significantly decreased BMI and visceral adiposity index (VAI) in all the patients in the 3 groups ( < 0.05). The treatment significantly decreased the body weight in the overweight group and obese group by 2.70 kg (0.60-4.95 kg) and 2.65 kg (1.45-6.40 kg), respectively ( < 0.05), and significantly decreased the waist-to-hip ratio (WHR) in the overweight group ( < 0.05). The obese and severely obese patients showed significantly decreased percentage body fat (including both subcutaneous and visceral fat) and increased muscle mass after the treatment ( < 0.05). Compared with those in the overweight group, the percentage body fat and VAI were significantly decreased in the obese group after the treatment ( < 0.05), and the percentage of subcutaneous fat reduced and the muscle ratio increased more obviously in the obese and severely obese patients ( < 0.05).@*CONCLUSIONS@#GLP-1RAs treatment can significantly lower BMI and improve body fat distribution in obese patients with T2DM, especially in patients with a greater BMI.


Subject(s)
Adipose Tissue , Body Mass Index , Diabetes Mellitus, Type 2 , Glucagon-Like Peptide-1 Receptor , Humans , Hypoglycemic Agents , Obesity , Overweight , Retrospective Studies
3.
Article in English | WPRIM | ID: wpr-763717

ABSTRACT

Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.


Subject(s)
Bariatric Surgery , Body Composition , Body Weight , Diabetes Mellitus, Type 2 , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Humans , Muscle, Skeletal , Population Characteristics , Weight Loss
4.
Article in English | WPRIM | ID: wpr-738872

ABSTRACT

The Korean Ministry of Food and Drug Safety has approved three anti-obesity drugs for long-term management in the past decade. In addition, since 2019, bariatric surgery has been financially supported by National Health Insurance Service in Korea. In this review, the mechanisms of action and the clinical implications of the recently approved anti-obesity drugs, lorcaserin, naltrexone/bupropion, and liraglutide are explained. Lorcaserin stimulates proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons and inhibits neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons, which results in the activation of melanocortin 3/4 receptors. Naltrexone/bupropion stimulates POMC neurons through bupropion; this stimulation is augmented by blocking the autoinhibitory mechanism of POMC with naltrexone. The hypophagic effect of liraglutide is mediated through the direct activation of POMC/CART neurons and the indirect suppression of NPY/AgRP neurons through γ-aminobutyric acid-dependent signaling, with adjunctive suppression of the mesolimbic dopamine reward system. In addition to liraglutide, another glucagon-like peptide-1 receptor agonist, semaglutide, is expected to be added to the list of anti-obesity drugs in the near future. In patients with obesity and high cardiovascular risk, lorcaserin was considered neutral and liraglutide was considered favorable, whereas inconclusive results were obtained for naltrexone/bupropion.


Subject(s)
Anti-Obesity Agents , Bariatric Surgery , Bupropion , Dopamine , Glucagon-Like Peptide-1 Receptor , Humans , Korea , Liraglutide , Naltrexone , National Health Programs , Neurons , Neuropeptide Y , Obesity , Pro-Opiomelanocortin , Reward
5.
Acta Physiologica Sinica ; (6): 514-526, 2019.
Article in English | WPRIM | ID: wpr-777160

ABSTRACT

Glucagon-like peptide-1 (GLP-1) expression is shared by both intestinal cells and neurons of brainstem, which plays anorexigenic role on food intake. However, the exact source of physiological GLP-1 influencing food intake and pertinent mechanism of GLP-1 receptor agonists (GLP-1RA) remain unelucidated. In this study, the immediate early gene product c-Fos was chosen as the specific antigen for immunohistochemistry to show the certain areas of central nervous system (CNS) activation by the GLP-1RA. Thirty normal SD rats were randomly assigned to 3 groups, which were single intraperitoneally injected with Liraglutide (200 μg/kg), Exenatide (10 μg/kg) and saline, respectively. After injection, the amount of food intake and acute glycemic variation were assessed for comparison. The results showed that acute pharmacological dosage of GLP-1RA (Liraglutide or Exenatide) could significantly influence food intake. However, glycemic change indicated that the anorexic effect was dissociated with change in blood glucose in normal rats. Moreover, c-Fos was expressed significantly higher in major critical nuclei related to food intake in GLP-1RA groups when compared with the control group, and its expression was also found in spinal cord. The results suggested that acute administration of pharmacological doses of GLP-1 influences CNS via circulation and vagal pathways, especially on the arcuate nucleus (ARC) and the nucleus of solitary tract (NTS), and GLP-1 modulates autonomic nervous activities.


Subject(s)
Animals , Eating , Exenatide , Pharmacology , Glucagon-Like Peptide-1 Receptor , Liraglutide , Pharmacology , Random Allocation , Rats , Rats, Sprague-Dawley
6.
Article in Chinese | WPRIM | ID: wpr-776518

ABSTRACT

OBJECTIVE@#To study the effect of exendin-4(Ex-4) on the differentiation of neural stem cells(NSCs) in adult mouse subventricular zone(SVZ)and its mechanism .@*METHODS@#NSCs in the SVZ were derived from 5-week C57BL/6J mice and the expression of nestin was detected by immunofluorescence. The cell morphology was observed after the cells treatmed with 100 nmol/L Ex-4 for 14 days.The expressions of nestin and glucagon-like peptide-1 receptor (GLP-1R) were detected by immunofluorescence. GLP-1R was knocked down by using shRNA and the study was divided into four groups: control group, Ex-4 group, GLP-1R knockdown group, GLP-1R knockdown + Ex-4 group. After treatment with 100 nmol/L Ex-4 for 14 d, β-tublin III and glial fibrillary acidic protein (GFAP) were labeled by immunofluorescence and then the proportion of β-tublin III positive cells were counted. Western blot was used to detect the activation of cAMP-response element binding protein (CREB) in NSCs. In order to further study the effects of Ex-4 on mitogen-activated protein kinase(MAPK) and phosphatidylinositol 3-hydroxy kinase (PI3K) pathways, the cells were pretreated with MAPK inhibitor U0126 at a concentration of 0.07 μmol/L for 30 min or PI3K inhibitor LY294002 at 50 μmol for 2 h, respectively. The study was divided into six groups: control group, Ex-4 group, U0126 group, U0126 + Ex-4 group, LY294002 group, LY294002 + Ex-4 group. The activation of CREB in each group was detected by Western blot. The experiment was repeated three times independently.@*RESULTS@#NSCs were successfully extracted from SVZ of C57BL/6J mice. Immunofluorescence showed that nestin and GLP-1R were positive in NSCs. Compared with the control group, the proportion of neurons differentiated from Ex-4 group was higher. The percentage of neurons in GLP-1R knockdown + Ex-4 group was basically the same as that in control group (P<0.01). The positive cells of beta-tublin III showed positive activation of GLP-1R and CREB. Western blot showed that CREB was significantly activated in the Ex-4 group, and knockdown of GLP-1R abolished its activation (P<0.01). U0126 did not affect Ex-4-mediated CERB activation, and LY294002 significantly reduced Ex-4-mediated CREB activation (P<0.01).@*CONCLUSION@#Ex-4 promotes the differentiation of NSCs into neurons in SVZ of adult mice through GLP-1R receptor, which may be achieved through PI3K/CREB pathway.


Subject(s)
Animals , Cell Differentiation , Cells, Cultured , Cyclic AMP Response Element-Binding Protein , Metabolism , Exenatide , Pharmacology , Gene Knockdown Techniques , Glucagon-Like Peptide-1 Receptor , Genetics , Metabolism , Lateral Ventricles , Cell Biology , Mice , Mice, Inbred C57BL , Neural Stem Cells , Cell Biology , Phosphatidylinositol 3-Kinases
7.
Journal of Korean Diabetes ; : 127-135, 2019.
Article in Korean | WPRIM | ID: wpr-761493

ABSTRACT

Diabetes mellitus (DM) is linked to poor outcomes after cardiovascular events and renal complications. Recently, novel antidiabetic agents, such as dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide-1 receptor agonists, are available. Among them, studies on SGLT2 inhibitors show favorable results both for cardiovascular and renal outcomes. SGLT2 inhibitors are well-tolerated with few side effects. Urinary tract infection has not been increased in many studies of SGLT2 inhibitors. The most frequent side-effect associated with SGLT2 inhibitors is mycotic infections in the genital area. Fortunately, these are generally mild in severity and easily treated with antibiotics. Hypoglycemia can occur when an SGLT2 inhibitor is added to sulfonylureas or insulin. Volume depletion and hypotension can be minimized by adjusting diuretics or other antihypertensive agents. Of note, acute kidney injury was observed in a few studies with SGLT2 inhibitors. However, in more recent observational studies, acute kidney injury was less frequently observed in conjunction with SGLT2 inhibitor treatment. An increased incidence of lower extremity amputation and fractures was observed in a large study with canagliflozin but not with other SGLT2 inhibitors. In conclusion, it is critical to understand the benefits and risks associated with use of SGLT2 inhibitors.


Subject(s)
Acute Kidney Injury , Amputation , Anti-Bacterial Agents , Antihypertensive Agents , Canagliflozin , Diabetes Mellitus , Diuretics , Glucagon-Like Peptide-1 Receptor , Hypoglycemia , Hypoglycemic Agents , Hypotension , Incidence , Insulin , Lower Extremity , Risk Assessment , Urinary Tract Infections
8.
Journal of Korean Diabetes ; : 149-156, 2019.
Article in Korean | WPRIM | ID: wpr-761490

ABSTRACT

According to the American Diabetes Association (ADA) and the European Association for the Study of Diabetes guideline for treatment of diabetes, glucagon-like peptide-1 receptor agonist (GLP-1 RA) is recommended in diabetic patients with established atherosclerotic cardiovascular disease. This recommendation is based on the results of recent cardiovascular outcome trials of this kind of medications. GLP-1 RAs have a glucose lowering effect with weight loss and a lower incidence of hypoglycemia, and can improve cardiovascular outcomes such as three-point major cardiovascular events composed of death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke. Also, several GLP-1 RAs have beneficial effects on renal outcomes, mainly due to improvement in macroalbuminuria. In addition, high-dose liraglutide (3 mg/day subcutaneous injection) showed efficacy for reducing body weight. Therefore GLP-1 RA may be effective in patients with established cardiovascular disease, chronic kidney disease, and/or metabolic syndrome.


Subject(s)
Body Weight , Cardiovascular Diseases , Diabetes Mellitus , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Glucose , Humans , Hypoglycemia , Incidence , Kidney Diseases , Liraglutide , Myocardial Infarction , Obesity , Renal Insufficiency, Chronic , Stroke , Weight Loss
9.
Article in Korean | WPRIM | ID: wpr-761472

ABSTRACT

In 2018, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a consensus recommendation on management of hyperglycemia. This consensus report emphasized the need for patient-centered management considering multimorbidity and individual patient preferences and barriers. Patients with type 2 diabetes with established atherosclerotic cardiovascular disease who fail to control blood glucose with the initial glucose-lowering medication are recommended a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist. For patients with chronic kidney disease and heart failure, SGLT2 inhibitors are recommended. In patients who need an injectable medication, GLP-1 receptor agonists are the preferred choice over insulin. In this section, we summarize “Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).”


Subject(s)
Atherosclerosis , Blood Glucose , Cardiovascular Diseases , Comorbidity , Consensus , Diabetes Mellitus , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Heart Failure , Humans , Hyperglycemia , Insulin , Patient Preference , Patient-Centered Care , Renal Insufficiency, Chronic
10.
Article in Korean | WPRIM | ID: wpr-726892

ABSTRACT

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy, which was a change from the previous guideline that recommended them only as a combination therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) have demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RAs may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA.


Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Diabetes Mellitus, Type 2 , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Humans , Hypoglycemia , Hypoglycemic Agents , Insulin , Obesity , Weight Loss
11.
Article in Korean | WPRIM | ID: wpr-726887

ABSTRACT

The management of type 2 diabetes mellitus should comprise healthy lifestyle modifications along with tailored pharmacologic treatment. Traditionally, the American Diabetes Association (ADA)'s Diabetes Management Guidelines have not prioritized specific anti-diabetic drugs over others with regard to cardiovascular disease (CVD) and mortality prevention. Recently, two novel anti-diabetic medications proved to be significantly protective against future CVD and mortality, regardless of the glycemic levels achieved in type 2 diabetic patients with pre-existing CVD. The 2018 ADA Guidelines recommend SGLT2 inhibitor and/or GLP-1 receptor agonist be used for type 2 diabetes patients with atherosclerotic CVD after metformin monotherapy failure. Considering the value of CVD protection in the management of diabetes mellitus, this minor guideline adjustment could have far-reaching implications.


Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Diabetes Mellitus, Type 2 , Glucagon-Like Peptide-1 Receptor , Humans , Life Style , Metformin , Mortality , Sodium-Glucose Transporter 2
12.
Article in English | WPRIM | ID: wpr-728032

ABSTRACT

Dipeptidyl peptidase4 (DPP4) inhibitors such as gemigliptin are anti-diabetic drugs elevating plasma concentration of incretins such as GLP-1. In addition to the DPP4 inhibition, gemigliptin might directly improve the functions of vessels under pathological conditions. To test this hypothesis, we investigated whether the acetylcholine-induced endothelium dependent relaxation (ACh-EDR) of mesenteric arteries (MA) are altered by gemigliptin pretreatment in Spontaneous Hypertensive Rats (SHR) and in Wistar-Kyoto rats (WKY) under hyperglycemia-like conditions (HG; 2 hr incubation with 50 mM glucose). ACh-EDR of WKY was reduced by the HG condition, which was significantly recovered by 1 µM gemigliptin while not by saxagliptin and sitagliptin up to 10 µM. The ACh-EDR of SHR MA was also improved by 1 µM gemigliptin while similar recovery was observed with higher concentration (10 µM) of saxagliptin and sitagliptin. The facilitation of ACh-EDR by gemigliptin in SHR was not observed under pretreatment with NOS inhibitor, L-NAME. In the endotheliumdenuded MA of SHR, sodium nitroprusside induced dose-dependent relaxation was not affected by gemigliptin. The ACh-EDR in WKY was decreased by treatment with 30 µM pyrogallol, a superoxide generator, which was not prevented by gemigliptin. Exendin-4, a GLP-1 analogue, could not enhance the ACh-EDR in SHR MA. The present results of ex vivo study suggest that gemigliptin enhances the NOS-mediated EDR of the HG-treated MA as well as the MA from SHR via GLP-1 receptor independent mechanism.


Subject(s)
Animals , Endothelium , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Hyperglycemia , Hypertension , Incretins , Mesenteric Arteries , NG-Nitroarginine Methyl Ester , Nitroprusside , Plasma , Pyrogallol , Rats , Rats, Inbred SHR , Relaxation , Sitagliptin Phosphate , Superoxides , Vasodilation
14.
Article in English | WPRIM | ID: wpr-149585

ABSTRACT

The glucagon-like peptide-1 receptor agonists (GLP-1RAs) were recommended as a monotherapy or combination therapy with oral hypoglycemic agents or basal insulin in the position statement of the Korean Diabetes Association 2017 for pharmacological therapy. Many randomized clinical trials and systematic reviews report that GLP-1RAs have considerable glucose-lowering effect and lead to weight reduction and low risk of hypoglycemia when used as a monotherapy or combination therapy. The cardiovascular safety of GLP-1RAs has been assessed in several randomized clinical trials and systematic reviews. The results of cardiovascular outcome trials of long-acting GLP-1RAs (liraglutide, semaglutide) demonstrated cardiovascular benefits in subjects with type 2 diabetes mellitus and a high risk of cardiovascular disease. The GLP-1RA may be a choice of therapy when weight control and avoidance of hypoglycemia are important, and patients with high risk of cardiovascular disease might also favor choosing GLP-1RA.


Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Humans , Hypoglycemia , Hypoglycemic Agents , Insulin , Weight Loss
15.
Article in English | WPRIM | ID: wpr-226728

ABSTRACT

The prevalence of type 2 diabetes (T2D) is increasing worldwide. Patients with T2D suffer from various diabetes-related complications. Since there are many patients with T2D that cannot be controlled by previously developed drugs, it has been necessary to develop new drugs, one of which is a glucagon-like peptide-1 (GLP-1) based therapy. GLP-1 has been shown to ameliorate diabetes-related conditions by augmenting pancreatic β-cell insulin secretion and having the low risk of causing hypoglycemia. Because of a very short half-life of GLP-1, many researches have been focused on the development of GLP-1 receptor (GLP-1R) agonists with long half-lives such as exenatide and dulaglutide. Now GLP-1R agonists have a variety of dosing-cycle forms to meet the needs of various patients. In this article, we review the physiological features of GLP-1, the effects of GLP-1 on T2D, the features of several GLP-1R agonists, and the therapeutic effect on T2D.


Subject(s)
Diabetes Complications , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Half-Life , Humans , Hypoglycemia , Insulin , Prevalence
16.
Article in English | WPRIM | ID: wpr-194439

ABSTRACT

It is well known that both insulin resistance and decreased insulin secretory capacity are important factors in the pathogenesis of type 2 diabetes mellitus (T2DM). In addition to genetic factors, obesity and lipotoxicity can increase the risk of T2DM. Glucagon-like peptide 1 (GLP-1) receptor agonists are novel antidiabetic drugs with multiple effects. They can stimulate glucose-dependent insulin secretion, inhibit postprandial glucagon release, delay gastric emptying, and induce pancreatic β-cell proliferation. They can also reduce the weight of patients with T2DM and relieve lipotoxicity at the cellular level. Many intracellular targets of GLP-1 have been found, but more remain to be identified. Elucidating these targets could be a basis for developing new potential drugs. My colleagues and I have investigated new targets of GLP-1, with a particular focus on pancreatic β-cell lines and hepatic cell lines. Herein, I summarize the recent work from my laboratory, with profound gratitude for receiving the prestigious 2016 Namgok Award.


Subject(s)
Awards and Prizes , Diabetes Mellitus , Diabetes Mellitus, Type 2 , Gastric Emptying , Glucagon , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Hepatocytes , Humans , Hypoglycemic Agents , Insulin , Insulin Resistance , Obesity
17.
Article in English | WPRIM | ID: wpr-222880

ABSTRACT

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) and obesity is increasing in Korea. Clinical studies in patients with T2DM have shown that combining the glucagon-like peptide-1 receptor agonist exenatide twice daily with basal insulin is an effective glucose-lowering strategy. However, these studies were predominantly conducted in non-Asian populations. METHODS: We conducted a subgroup analysis of data from a multinational, 30-week, randomized, open-label trial to compare the effects of exenatide twice daily (n=10) or three times daily mealtime insulin lispro (n=13) among Korean patients with T2DM inadequately controlled (glycosylated hemoglobin [HbA1c] >7.0%) on metformin plus optimized insulin glargine. RESULTS: Exenatide twice daily and insulin lispro both reduced HbA1c (mean −1.5% and −1.0%, respectively; P<0.01 vs. baseline). Fasting glucose and weight numerically decreased with exenatide twice daily (−0.7 mmol/L and −0.7 kg, respectively) and numerically increased with insulin lispro (0.9 mmol/L and 1.0 kg, respectively). Minor hypoglycemia occurred in four patients receiving exenatide twice daily and three patients receiving insulin lispro. Gastrointestinal adverse events were the most common with exenatide twice daily treatment. CONCLUSION: This analysis found treatment with exenatide twice daily improved glycemic control without weight gain in Korean patients with T2DM unable to achieve glycemic control on metformin plus basal insulin.


Subject(s)
Diabetes Mellitus, Type 2 , Fasting , Glucagon-Like Peptide-1 Receptor , Glucose , Humans , Hypoglycemia , Insulin Glargine , Insulin Lispro , Insulin , Korea , Meals , Metformin , Obesity , Prevalence , Weight Gain
18.
Experimental Neurobiology ; : 227-239, 2017.
Article in English | WPRIM | ID: wpr-22192

ABSTRACT

Glucagon like peptide-1 (GLP-1) stimulates glucose-dependent insulin secretion. Dipeptidyl peptidase-4 (DPP-4) inhibitors, which block inactivation of GLP-1, are currently in clinical use for type 2 diabetes mellitus. Recently, GLP-1 has also been reported to have neuroprotective effects in cases of cerebral ischemia. We therefore investigated the neuroprotective effects of GLP-1 receptor (GLP-1R) agonist, exendin-4 (ex-4), after cerebral ischemia-reperfusion injury. Transient middle cerebral artery occlusion (tMCAO) was induced in rats by intracerebroventricular (i.c.v.) administration of ex-4 or ex9-39. Oxygen-glucose deprivation was also induced in primary neurons, bEnd.3 cells, and BV-2. Ischemia-reperfusion injury reduced expression of GLP-1R. Additionally, higher oxidative stress in SOD2 KO mice decreased expression of GLP-1R. Downregulation of GLP-1R by ischemic injury was 70% restored by GLP-1R agonist, ex-4, which resulted in significant reduction of infarct volume. Levels of intracellular cyclic AMP, a second messenger of GLP-1R, were also increased by 2.7-fold as a result of high GLP-1R expression. Moreover, our results showed that ex-4 attenuated pro-inflammatory cyclooxygenase-2 (COX-2) and prostaglandin E₂ after MCAO. C-Jun NH₂ terminal kinase (JNK) signaling, which stimulates activation of COX-2, was 36% inhibited by i.c.v. injection of ex-4 at 24 h. Islet-brain 1 (IB1), a scaffold regulator of JNK, was 1.7-fold increased by ex-4. GLP-1R activation by ex-4 resulted in reduction of COX-2 through increasing IB1 expression, resulting in anti-inflammatory neuroprotection during stroke. Our study suggests that the anti-inflammatory action of GLP-1 could be used as a new strategy for the treatment of neuroinflammation after stroke accompanied by hyperglycemia.


Subject(s)
Animals , Brain Ischemia , Cyclic AMP , Cyclooxygenase 2 , Diabetes Mellitus, Type 2 , Down-Regulation , Glucagon , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Hyperglycemia , Infarction, Middle Cerebral Artery , Insulin , Mice , Neurons , Neuroprotection , Neuroprotective Agents , Oxidative Stress , Phosphotransferases , Rats , Reperfusion Injury , Second Messenger Systems , Stroke
19.
Medicina (B.Aires) ; 76(3): 173-179, June 2016. ilus, graf, tab
Article in Spanish | LILACS | ID: biblio-841566

ABSTRACT

La diabetes mellitus se asocia con complicaciones vasculares y elevadas tasas de morbimortalidad. La terapia oportuna con insulina y su intensificación cuando es necesaria, representan estrategias apropiadas para evitar o retardar la aparición de dichas complicaciones. Sin embargo, la incidencia de hipoglucemia y las dificultades en la adherencia al tratamiento representan barreras para alcanzar el éxito terapéutico. Las nuevas combinaciones de análogos de insulina constituyen tratamientos que presentarían ventajas farmacocinéticas y farmacodinámicas, logrando beneficios clínicos tales como un mejor control metabólico, la disminución de eventos hipoglucémicos y, por su simplicidad, potencialmente una mayor adherencia al tratamiento.


Diabetes mellitus is associated with vascular complications and high rates of morbidity and mortality. Timely insulin therapy, intensified when necessary, represent appropriate measures to prevent or delay the onset of complications. However, the incidence of hypoglycemia and difficulties in treatment adherence represent barriers to achieve therapeutic success. Premixes analogs and, specially, combinations of insulin analogues are associated with pharmacokinetic and pharmacodynamic advantages, that translate into clinical benefits such as improved metabolic control, decreased hypoglycemic events and, for their simplicity, potentially greater adherence.


Subject(s)
Humans , Diabetes Mellitus, Type 2/drug therapy , Insulins/therapeutic use , Hypoglycemic Agents/therapeutic use , Risk Factors , Treatment Outcome , Diabetes Mellitus, Type 2/prevention & control , Drug Therapy, Combination , Insulins/pharmacokinetics , Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors , Hypoglycemia/chemically induced , Hypoglycemia/prevention & control , Hypoglycemic Agents/pharmacokinetics
20.
Journal of Korean Diabetes ; : 225-232, 2016.
Article in Korean | WPRIM | ID: wpr-726768

ABSTRACT

Since 2008, the Food and Drug Administration has required cardiovascular (CV) safety trials for all anti-diabetic medications available in the USA. Thus, new agents like dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists have been tested in CV safety trials. The results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) were released last year. Of the sodium-glucose cotransporter 2 (SGLT2) inhibitors tested, empagliflozin demonstrated a CV benefit in this trial. Another study of the renal protective effects of empagliflozin was released this year. The mechanisms supporting the cardio- and reno-protective effects of empagliflozin remain controversial. Hemodynamic changes related to SGLT2 inhibitors via natriuresis and osmotic diuresis are one potential mechanism. The Canadian Diabetes Association and European Society of Cardiology recently suggested SGLT2 inhibitors as an optimal anti-diabetic medication for patients with type 2 diabetes with overt CV disease. Further studies elucidating the potential mechanisms of cardio- and reno-protective effects of SGLT2 are needed.


Subject(s)
Cardiology , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Diuresis , Glucagon-Like Peptide-1 Receptor , Hemodynamics , Humans , Natriuresis , Prescriptions , United States Food and Drug Administration
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