Formulation & Evaluation of Oral Insulin with Glimepiride for Improved Beta-Cell Function and Glycemic Control

This study engineered a pH-responsive, core shell polymeric nanoparticle platform (w_1/o/w_2) that co-encapsulated recombinant human insulin together with glimepiride, to get around those gastrointestinal delivery hurdles and somehow actively rescue functional pancreatic mass in Type 2 Diabetes Mellitus. It was guided by a statistical box-Behnken design, and the optimized nanocarrier (F3) sort of struck a balance between a well-controlled paracellular-entry diameter of 212.4 nm and high encapsulation efficiencies (>88%) which turned the hydrophobic secretagogue into a much more soluble amorphous state. After that, sequential in vitro dissolution showed excellent enteric protection, keeping premature peptide leakage down to <7% in simulated gastric fluid then, once triggered it released rapidly and relatively synchronized in intestinal conditions. On human Caco-2 monolayers, the protonated chitosan core modulated tight junction proteins in a safe and reversible manner, and this resulted in about a 40-fold increase in insulin transport flux (P_"app" =4.85×〖10〗^(-6) " cm/s" ). Even better, the transepithelial electrical resistance rebounded fully within 4 hours. In vivo, oral administration in diabetic Wistar rats avoided the usual subcutaneous hypoglycemic shock, and it kept stable euglycemia at 92 mg/dL for more than 18 hours. When they dosed daily for 28 days, it corrected metabolic lipid profiles and also lowered HbA1c from 9.4% to 5.6%. Crucially, post-treatment monitoring confirmed a strongly restored biphasic insulin surge, preserved islet structural borders, and marked downregulation of endoplasmic reticulum stress indicators (BiP, CHOP, Caspase-3) through survival preservation transcription factors, PDX-1 along with FoxO1