Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve glycemic control, promote weight loss, reduce insulin requirements, and confer cardiometabolic benefits in type 2 diabetes mellitus (T2DM). This audit evaluated glycemic and metabolic outcomes of GLP-1 RAs in T2DM patients at a single-centre diabetes clinic. Methodology: This audit included T2DM patients who initiated GLP1 RAs between January 2022 and March 2025 at Hospital Sultan Abdul Halim. Primary outcomes were changes in hemoglobin A1c (HbA1c), body weight, and body mass index (BMI) at 3 and 12 months. Secondary outcomes included percentage weight loss, changes in systolic blood pressure (SBP), insulin total daily dose (TDD), low-density lipoprotein (LDL) cholesterol, gastrointestinal adverse effects, and treatment discontinuation. Results: Sixteen patients were included; median age was 58.5 years (interquartile range [IQR] 47.5–65), and 56.3% were female. Median diabetes duration was 15 years (IQR 11.5–20.3). Median HbA1c decreased from 9.7% (IQR 8.6–10.4) at baseline to 8.8% (IQR 7.7–9.1) at 3 months and 7.8% (IQR 7.0–8.5) at 12 months. Body weight decreased from 88.1 kg (IQR 79.5–122.1) at baseline to 85.0 kg (IQR 75.9–113.7) at 3 months and 82.0 kg (IQR 74.8–117.3) at 12 months. BMI decreased from 37.8 kg/m² (IQR 31.7–47.1) to 37.3 kg/m² (IQR 30.7–45.5) at 3 months and 36.0 kg/m² (IQR 30.1–45.6) at 12 months. At 12 months, weight loss was 5.8% (IQR 3.0–8.0), with 56.5% achieving >5% weight reduction. In all, 93.8% achieved >1% HbA1c reduction. Mean SBP decreased by 10 ± 20 mmHg, LDL cholesterol 0.29 mmol/L (IQR -0.77 to 0.07), and insulin TDD 8 units/day (IQR -13 to 10). No gastrointestinal adverse effects reported. Three patients (18.8%) discontinued treatment due to excessive weight loss, treatment plateau, and limited drug availability. Conclusion From our single-centre experience, the observed improvements in glycemic and metabolic outcomes support the benefits of GLP-1 RAs in managing T2DM.
Diabetes Mellitus, Type 2 ; Glucagon-Like Peptide-1 Receptor Agonists ; Clinical Audit

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) induce clinically meaningful weight reduction in patients with type 2 diabetes mellitus (T2DM), but real-world data in Southeast Asian populations are limited. This study evaluated the effectiveness of GLP-1 RAs in achieving clinically significant weight loss in Malaysian patients with obesity and T2DM. Methodology: A retrospective cohort study was conducted among adults with T2DM and obesity attending the Endocrinology Clinic at Hospital Sultan Abdul Aziz Shah between January 2023 and December 2024. Patients receiving GLP-1 RAs (semaglutide or liraglutide) were compared with those on standard care. Anthropometric outcomes were assessed over 6–12 months, with weight loss thresholds of ≥3, ≥5, and ≥10%. Between-group comparisons used Fisher’s exact test, and odds ratios (OR) were calculated. Results: Eighty-five patients were included (GLP-1, n = 47; control, n = 38). The GLP-1 group achieved significantly higher rates of any weight loss (70.0% vs 41.2%; OR = 3.33, p = 0.019) and ≥3% weight loss (42.5% vs 14.7%; OR = 4.29, p = 0.011). Number needed to treat was 3–4 patients. Proportions achieving ≥5 and ≥10% weight loss were higher in the GLP-1 group but did not reach statistical significance. Conclusion GLP-1 RA therapy significantly improves the likelihood of clinically meaningful weight loss in Malaysian patients with obesity and T2DM. These findings support the integration of GLP-1 RAs into routine obesity management strategies in Southeast Asia.
Humans ; Diabetes Mellitus, Type 2 ; Glucagon-Like Peptide-1 Receptor Agonists ; Weight Loss

Introduction: While Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective for weight reduction in type 2 diabetes mellitus (T2DM), interindividual variability exists. Lifestyle factors, particularly baseline physical activity, may modify weight loss outcomes. This study examined whether baseline activity influences GLP-1 RA efficacy in Malaysian patients. Methodology: A retrospective cohort of adults with obesity and T2DM receiving GLP-1 RAs (semaglutide or liraglutide) from January 2023 to December 2024 was analyzed. Baseline physical activity was classified as active or inactive. Primary outcomes were achievement of ≥3 and ≥5% weight loss over 6–12 months. Associations were assessed using Fisher’s exact test and logistic regression. Results: Among GLP-1-treated patients, those reporting baseline physical activity were more likely to achieve ≥3% weight loss and demonstrated trends toward higher, ≥5%, weight loss. Logistic regression suggested baseline activity increased the odds of clinically meaningful weight reduction, though statistical significance was limited by sample size. Conclusion Baseline physical activity may enhance GLP-1 receptor agonist-mediated weight loss in obese patients with T2DM. Integrating lifestyle interventions with pharmacotherapy may optimize treatment outcomes. Larger prospective studies are warranted to confirm these findings.
Humans ; Glucagon-Like Peptide-1 Receptor Agonists ; Exercise ; Weight Loss ; Obesity ; Diabetes Mellitus, Type 2

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

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

GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for treatment of diabetes due to its short half-life (t½, 2-5 min). Exendin-4 is a polypeptide isolated from lizard saliva, which can bind to GLP-1 receptor, produce physiological effects similar to GLP-1, t½ up to 2.5 h, therefore, we developed a long-lasting GLP-1 receptor agonists and GLP-1-exendin-4 fusion IgG4 Fc [GLP-1-exendin-4/ IgG4(Fc)]. We constructed the eukaryotic expression vector of human GLP-1-exendin-4/IgG4(Fc)-pOptiVEC- TOPO by gene recombination technique and expressed the fusion protein human GLP-1-IgG4 (Fc) in CHO/DG44 cells. The fusion protein stimulated the INS-1 cells secretion of insulin, GLP-1, exendin-4 and fusion protein in CD1 mice pharmacokinetic experiments, as well as GLP-1, exendin-4 and fusion protein did anti-diabetic effect on streptozotocin induced mice. Results demonstrated that the GLP-1-exendin-4/IgG4(Fc) positive CHO/DG44 clones were chosen and the media from these positive clones. Western blotting showed that one protein band was found to match well with the predicted relative molecular mass of human GLP-1-exendin-4/IgG4(Fc). Insulin RIA showed that GLP-1-exendin-4/IgG4(Fc) dose-dependently stimulated insulin secretion from INS-1 cells. Pharmacokinetic studies in CD1 mice showed that with intraperitoneal injection (ip), the fusion protein peaked at 30 min in circulation and maintained a plateau for 200 h. Natural biological half-life of exendin-4 was (1.39 ± 0.28) h, GLP-1 in vivo t½ 4 min, indicating that fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1-exendin-4/IgG4(Fc) was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced diabetes in mice, longer duration of the biological activity of the fusion protein. The biological activity was significantly higher than that of GLP-1 and exendin-4. GLP-1-exendin-4/IgG4(Fc) has good anti-diabetic activity. It can be used as a long-acting GLP-1 agonists.
Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Diabetes Mellitus, Experimental ; drug therapy ; Glucagon-Like Peptide 1 ; pharmacology ; Glucagon-Like Peptide-1 Receptor ; agonists ; Half-Life ; Humans ; Hypoglycemic Agents ; pharmacology ; Immunoglobulin G ; pharmacology ; Insulin ; secretion ; Mice ; Peptides ; pharmacology ; Recombinant Fusion Proteins ; pharmacology ; Venoms ; pharmacology

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). In the brains of patients with AD and PD, insulin signaling is impaired. This finding has motivated new research that showed good effects using drugs that initially had been developed to treat diabetes. Preclinical studies showed good neuroprotective effects applying insulin or long lasting analogues of incretin peptides. In transgenic animal models of AD or PD, analogues of the incretin GLP-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality and reduced the symptoms of the diseases. Amyloid plaque load and synaptic loss as well as cognitive impairment had been prevented in transgenic AD mouse models, and dopaminergic loss of transmission and motor function has been reversed in animal models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results already published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for type 2 diabetes (exendin-4, Byetta) also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients, testing another GLP-1 analogue that is on the market (liraglutide, Victoza). Recently, a third GLP-1 receptor agonist has been brought to the market in Europe (Lixisenatide, Lyxumia), which also shows very promising neuroprotective effects. This review will summarise the range of these protective effects that those drugs have demonstrated. GLP-1 analogues show promise in providing novel treatments that may be protective or even regenerative in AD and PD, something that no current drug does.
Alzheimer Disease ; drug therapy ; Animals ; Diabetes Mellitus, Type 2 ; drug therapy ; Disease Models, Animal ; Glucagon-Like Peptide 1 ; analogs & derivatives ; pharmacology ; Glucagon-Like Peptide-1 Receptor ; Humans ; Liraglutide ; Mice ; Mice, Transgenic ; Neuroprotective Agents ; pharmacology ; Parkinson Disease ; drug therapy ; Peptides ; pharmacology ; Receptors, Glucagon ; agonists ; Venoms ; pharmacology

The aim of this project is to establish a GLP-1 signaling pathway targeted cell model, for screening the new class of GLP-1 receptor agonists as anti-diabetic candidates. Firstly construct a recombined plasmid with multi-copied specific response element (RIP-CRE) regulated by GLP-1 signaling pathway and E-GFP reporter gene. Transient transfect this recombined plasmid into islet cell NIT-1, then detect the responsibility of transfected cell to GLP-1 analogue, Exendin 4. For secondly, use stable transfection and monocloning cell culture to obtain a GLP-1 signaling-specific cell line. It indicates that this cell model can response to Exendin 4, which response can be completely inhibited by GLP-1 receptor antagonist, Exendin 9-39, further showing GLP-1 receptor specific activity with a cAMP-PKA-independently mechanism. Establishment of this novel cell model can be used in high-throughput drug screening of peptides or small molecular GLP-1 analogues.
Animals ; Cell Line ; Cyclic AMP Response Element Modulator ; pharmacology ; Cyclic AMP-Dependent Protein Kinases ; antagonists & inhibitors ; Drug Delivery Systems ; Drug Evaluation, Preclinical ; Genes, Reporter ; Glucagon-Like Peptide-1 Receptor ; Green Fluorescent Proteins ; metabolism ; Hypoglycemic Agents ; agonists ; antagonists & inhibitors ; metabolism ; Islets of Langerhans ; cytology ; drug effects ; metabolism ; Isoquinolines ; pharmacology ; Peptide Fragments ; pharmacology ; Peptides ; antagonists & inhibitors ; pharmacology ; Plasmids ; Rats ; Receptors, Glucagon ; agonists ; antagonists & inhibitors ; genetics ; metabolism ; Recombinant Proteins ; genetics ; metabolism ; Signal Transduction ; Sulfonamides ; pharmacology ; Transfection ; Venoms ; pharmacology

To explore the effect of glucagon-like peptide-1 receptor agonist--Exendin-4 (Ex-4) on murine MIN6 pancreatic beta-cells apoptosis induced by oxidative stress, the morphological changes of cell damage were evaluated by epifluorescence microscopy after staining with AO-EB. The percentage of cell apoptosis was determined by flow cytometric assay after Annexin-V-FITC-PI staining. Nitric oxide level was measured by Griess reagent assay. Inducible nitric oxide synthase (iNOS) protein and NF-kappaBp65 fragment were detected by Western blotting. Ex-4 inhibited the increase of nitrite level and percentage of apoptosis induced by t-BHP in MIN6 cells. Furthermore, Ex-4 partly reduced the expression of iNOS protein and the ratio of NF-kappaBp65 protein in nucleus:cytosol induced by t-BHP. These results suggest that Ex4 protects MIN6 pancreatic kappa-cells from oxidative stress-induced apoptosis via down-regulation of NF-kappaB-iNOS-nitric oxide pathway.
Animals ; Apoptosis ; drug effects ; Down-Regulation ; Glucagon-Like Peptide-1 Receptor ; Hypoglycemic Agents ; pharmacology ; Incretins ; agonists ; Insulin-Secreting Cells ; cytology ; metabolism ; Lizards ; Mice ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type II ; metabolism ; Oxidative Stress ; drug effects ; Peptides ; pharmacology ; Receptors, Glucagon ; agonists ; Signal Transduction ; Transcription Factor RelA ; metabolism ; Venoms ; pharmacology ; tert-Butylhydroperoxide ; pharmacology