MicroRNAs modulated by DPP-4 Inhibitor and Bedtime NPH Insulin Therapy in Individuals with Type 2 Diabetes

Aritania Sousa Santos¹Silvia Yumi Bando²Maria Lucia Cardillo Correa-Giannella¹Maria Elizabeth Rossi Silva^1*

• ¹Laboratório de Carboidratos e Radioimunoensaio (LIM18), Hospital das Clínicas (HCFMUSP), Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01246-000, Brazil, University of São Paulo, São Paulo, Brazil
• ²Department of Pediatrics -Faculdade de Medicina da Universidade de São Paulo, São Paulo, University of São Paulo, São Paulo, Brazil

Background: MicroRNAs (miRNAs) and their target genes can elucidate mechanisms of drug action and serve as potential therapeutic biomarkers. Methods: To evaluate the effects of bedtime NPH insulin and sitagliptin on serum miRNA expression in individuals with type 2 diabetes (T2D), thirty-two patients with T2D inadequately controlled with metformin and glyburide were randomly assigned to an additional 6-month treatment with either bedtime NPH insulin or sitagliptin. Before and after treatments, fasting as postprandial (60, 120, and 180 minutes) concentrations of glucose, C-peptide, glucagon-like peptide 1 (GLP1), and triglycerides were measured. Fasting HbA1c was also assessed. Expression levels of selected miRNAs were analyzed using quantitative polymerase chain reaction. Results: The sitagliptin and bedtime NPH insulin groups were comparable in age, body mass index, diabetes duration, and baseline metabolic variables. Both treatments led to a similar reduction in HbA1c. Only sitagliptin increased postprandial GLP1 concentrations. Sitagliptin treatment upregulated six miRNAs: miR-24-3p, miR-27a-3p, miR92a-3p, let-7d-5p, miR-30c-5p, and miR-660-5p. NPH insulin upregulated four miRNAs: miR-92a-3p, miR-193b-3p, miR-320a-3p and miR-30c-5p. Both treatments increased miR-92a-3p and miR-30c-5p, particularly at fasting and 60 minutes post-meal. KEGG pathways analysis revealed enrichment in signaling pathways related to insulin action, growth/development, cellular senescence, lipid/atherosclerosis, Th17 cell differentiation, insulin resistance, autophagy, and apoptosis. Sitagliptin and bedtime NPH insulin induced metabolic improvement and distinct modulation of circulating miRNAs, with sitagliptin influencing a broader spectrum of miRNA expression. Conclusion: The upregulated miRNAs are involved in pathways related to insulin signaling, inflammation, and cellular homeostasis and support the hypothesis that sitagliptin exerts pleiotropic effects beyond glycemic control.