Abstract: Ever since its isolation from the 'venom' of Gila monsters, Heloderma suspectum, exendin-4 has received considerable attention for its ability to stimulate insulin secretion and inhibit glucagon secretion in mammals. Exendin-4 is a peptide produced exclusively by the salivary glands of the Gila monster, but its physiologic significance or function is unknown in its native organism. Although exendin-4 is considered a venom component, circulating plasma levels of exendin-4 have been shown to increase in response to feeding. The mechanism controlling its release by the salivary gland was identified by testing Gila Monsters' response to treatments designed to separately test actions associated with feeding and different food types. Exendin-4 levels increased significantly in groups where considerable biting occurred but not in other treatment groups. These results suggest that exendin-4 is released from the salivary glands in response to mechanical stimulation and not the detection of food either by smell, taste, or distention of the gut. Because it has glucose-regulating effects in mammals, exendin-4 may regulate post-prandial plasma glucose and triglycerides or metabolic, digestion, or absorption events. Our results indicate plasma nutrient concentrations in Gila monsters respond relatively slowly to feeding and circulating exendin-4 does not influence plasma glucose and triglyceride concentrations. Metabolic rate, intestinal mucosa thickness, enterocyte size, small intestine nutrient uptake capacity, and aminopeptidase activity were significantly different between unfed and fed animals and over digestion time, but these changes were not associated with circulating exendin-4 concentration. Transport of exendin-4 directly from the salivary gland into the circulation would be unique since the salivary glands are exocrine in nature and not known to have an endocrine function in vertebrates. Gila monsters treated orally with conspecific saliva which contained an exendin-4 concentration of 10mg/ml experienced increased plasma exendin-4 but at a lower level than endogenous increases associated with chewing, suggesting that passive buccal absorption is not likely exendin-4's sole route of transmission into circulation. Salivary gland histology revealed multiple capillaries near venom/saliva secreting cells, suggesting some absorption could occur locally. Further study of exendin-4 in its natural organism is needed to elucidate the functional role of exendin-4 as a venom component and/or a metabolic regulator.