On the Relentless Pursuit of an Oral Insulin Delivery System: How Far is Too Far?

Abstract As the scientific community celebrates the centenary year of insulin discovery, developing oral insulin delivery systems remains challenging, with disappointing progress. On the contrary, injectable formulations, despite initial setbacks due to poor patient compliance and issues with painful daily injections, have improved considerably—and currently remain the mainstay of insulin therapeutics. Advanced microneedle technology has enabled insulin delivery with minimal nociception in conjunction with automated, user‐friendly delivery platforms. Furthermore, integrating modalities like insulin pumps delivering precise doses based on blood glucose monitoring has emerged. Conversely, oral insulin delivery continues to face arcane challenges, including the denaturation of insulin due to acidic gastric juice, a hostile gut mucus barrier that immobilizes and then removes particulate formulations, and a portal circulation that shunts the residue minuscule (nano)particulate dose from the bloodstream into the liver followed by macrophage activation and hepatobiliary elimination. Unless these barriers are negotiated, breaking the impasse in oral insulin delivery remains elusive. This perspective argues in favor of focusing solely on injectable insulin while deprioritizing, if not fully ceasing, further research toward developing oral insulin formulations to prevent wasting both taxpayers’ money and unethical consumption of animal lives.