Humans ; Glucagon-Like Peptide-1 Receptor/agonists* ; Diabetic Cardiomyopathies/drug therapy* ; Diabetes Mellitus, Type 2

Obesity is an important risk factor of type 2 diabetes (T2D), which has become an important factor threatening human health. However, no perfect drug choice for obesity exists. Semaglutide is a kind of human glucagon-like peptide-1 (GLP-1) analog that promotes insulin secretion while inhibiting glucagon secretion through a glucose concentration-dependent mechanism. GLP-1 can also delay stomach emptying and suppress appetite to help lose weight. This review summarizes clinical evidence of the semaglutide effect on T2D and obesity and establishes expectations on future clinical trials for obesity treatment.
Diabetes Mellitus, Type 2/drug therapy* ; Glucagon-Like Peptide-1 Receptor/therapeutic use* ; Glucagon-Like Peptides ; Humans ; Hypoglycemic Agents/therapeutic use* ; Motivation ; Obesity/drug therapy*

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.
Adipose Tissue ; Body Mass Index ; Diabetes Mellitus, Type 2 ; Glucagon-Like Peptide-1 Receptor ; Humans ; Hypoglycemic Agents ; Obesity ; Overweight ; Retrospective Studies

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.
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 ; cytology ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells ; cytology ; Phosphatidylinositol 3-Kinases

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.
Animals ; Eating ; drug effects ; Exenatide ; pharmacology ; Glucagon-Like Peptide-1 Receptor ; agonists ; Liraglutide ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley

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).”
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

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.
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

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.
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

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.
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

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.
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