The development of oral insulin using the eligen technology represents a significant advance in insulin administration which is expected to improve the quality of life of diabetic patients. As clinical studies progress, a great deal of interest has focused on the process by which this technology enables insulin absorption from the intestinal lumen into the bloodstream. The eligen technology employs low molecular weight compounds (termed drug delivery agents or carriers) which interact weakly and non-covalently with insulin, increasing its lipophilicity and thereby its ability to cross the gastrointestinal epithelium. In this study we investigated the mechanism of insulin absorption across caco-2 cell monolayers with one of these drug delivery agents, N-[8-(2-hydroxybenzoyl)amino] caprylate (SNAC). Our results show that SNAC increases insulin permeability approximately ten fold across cell monolayers and does so without affecting mannitol permeability or disrupting cell membranes. Confocal microscopy and immunocytochemistry revealed that insulin is transported transcellularly without detectable alteration of the tight junctions between adjacent cells. SNAC also appears to play some role in protecting insulin from proteolytic degradation, potentially allowing for more intact insulin to be available at the site of absorption.

Background:

SNAC increases the permeability of Caco-2 monolayers to cromolyn without measurable cell damage. SNAC interacts with cromolyn mainly via ring stacking. One major mode of interaction appears to involve the insertion of the aromatic ring of SNAC between cromolyn's rings. Such interaction appears to reduce the hydration of cromolyn and thus optimize its hydrophobicity for oral absorption.

Preoocial copulation in 2-wk.-old male chicks, described behaviorally as free mount, tread, posterior contact, waggle, peck, and seize, was developed through hand-training experience and androgen treatment. Crystalline progesterone was then implanted in various forebrain or midbrain regions. Results indicated that progesterone inhibited copulatory behavior when placed in the periventricular areas of the preoptic-hypothalamic continuum. Progesterone implants in the preoptic lateral forebrain bundle region also suppressed precocial copulation. Forebrain implants of cholesterol did not result in copulatory inhibition. The suppression of copulatory behavior was not accompanied by loss of weight or deficits in general activity or comb growth. These data indicate that brain regions responsible for progesteroneinduced copulatory inhibition are similar in neuroanatornical distribution to those involved in testosterone-induced copulatory activation.

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