An oral liraglutide nanomicelle formulation conferring reduced insulin-resistance and long-term hypoglycemic and lipid metabolic benefits.

Type 2 diabetes is a chronic disease characterized by insulin resistance and often worsened by obesity. Effective management involves the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to assist with glycemic control and weight management. However, these drugs must be administered subcutaneously due to their low oral bioavailability. We developed an oral liraglutide (LRG) formulation by electrostatic complexation of GLP-1 RA with bile acid derivatives and nanomicelle (NM) formation, with non-ionic surfactant n-dodecyl-β-d-maltoside (DDM). The optimized formulation, LDD[1:2:4]-NM, had a mean particle size of 75.9 ± 5.60 nm and a permeability 1347 % higher than that of unformulated LRG when tested in Caco-2/HT29-MTX-E12 cell monolayers. In rats, oral bioavailability was 4.63-fold higher than that of unformulated LRG (1.11 ± 0.20 % vs. 5.14 ± 0.63 %). The absorption mechanism included clathrin-mediated endocytosis, macropinocytosis, and an ASBT-mediated pathway. A 12-week oral treatment consisting of a daily dose of 20 mg LDD[1:2:4]-NM/kg significantly reduced glycohemoglobin levels, a marker of diabetic control, and the HOMA-IR index, a marker of insulin resistance. The weight of epididymal and inguinal white adipose tissue and brown adipose tissue (BAT) was also reduced. Moreover, LDD[1:2:4]-NM had a greater impact on BAT activation, pro-inflammatory gene expression, and lipid metabolism than subcutaneous LRG. This study showed that an oral NM formulation can efficiently deliver LRG. Long-term treatment led to improved hyperglycemic effects, insulin resistance, and modulated lipid metabolism. LDD[1:2:4]-NM is thus a promising oral therapeutic option for the management of type 2 diabetes, potentially transforming treatment paradigms based on the availability of a more convenient administration route.