Glycemic Improvement with Low-Dose Dulaglutide Is Associated with Leptin and Obestatin Modulation in Type 2 Diabetes Mellitus.

BACKGRUOUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve glycemic control through insulinotropic and anorectic effects. However, the role of adipokines and appetite-related hormones in mediating the glycemic response remains unclear. This study evaluated changes in abdominal fat, food cravings, and circulating adipokines and gut hormones following dulaglutide treatment and identified predictors of glycemic improvement in type 2 diabetes mellitus (T2DM). METHODS: In this 24-week prospective observational study, 82 patients with T2DM and glycosylated hemoglobin (HbA1c) levels ≥7.0% despite standard therapy received dulaglutide 0.75 mg once weekly. Abdominal computed tomography, the General Food Cravings Questionnaire-Trait, and fasting levels of leptin, adiponectin, obestatin, ghrelin, and resistin were assessed at baseline and week 24. Glycemic responders were defined as those with an HbA1c reduction ≥0.5% and/or HbA1c <7.0% at 24 weeks. Multivariable regression analysis was performed to identify the factors associated with glycemic improvement. RESULTS: Among the 67 patients who completed the study, dulaglutide significantly reduced HbA1c, food cravings, leptin, and adiponectin levels. Obestatin levels increased modestly. Responders showed greater improvement in β-cell function and more pronounced reductions in food cravings. In the adjusted models, a decrease in leptin and an increase in obestatin were independently associated with HbA1c reduction, while decreased adiponectin was associated with poorer glycemic outcomes. Changes in body mass index or abdominal fat were not associated with glycemic improvement. CONCLUSION: Dulaglutide improved glycemic control through mechanisms beyond weight reduction. Hormonal changes in leptin, adiponectin, and obestatin may help predict responses to GLP-1 RAs therapy.