Table 1.

The physiological barriers of oral insulin administration and the mechanisms.

Physiological Barriers	Constitution	Mechanisms to Overcome	References
Destruction by gastric acid	Gastric acid, pH 1.0–2.0	pH responsiveness	[43,44,45,46,47]
Degradation by digestive enzymes	Pepsin, trypsin, chymotrypsin, elastase, and carboxypeptidase	Shielding effect, hydrophobic effect	[48,49,50,51]
Retention by the mucus layer barriers	Water, glycoproteins, proteins, electrolytes and lipids	Charge-reversing, “Mucus-inert” electroneutral surface	[52,53,54,55]
Retardation by intestinal epithelial cell layer	Tight junction, apical endocytosis, degradation of lysosomes, and basolateral to the circulation	Permeation enhancer, increase the active transportation	[31,42,56,57,58]