TRANSGENIC MICE OVEREXPRESSING HUMAN VASOACTIVE-INTESTINAL-PEPTIDE (VIP) GENE IN PANCREATIC BETA-CELLS - EVIDENCE FOR IMPROVED GLUCOSE-TOLERANCE AND ENHANCED INSULIN-SECRETION BY VIP AND PHM-27 IN-VIVO

Vasoactive intestinal peptide (VIP), a 28-amino acid peptide hormone, plays many physiological roles in the peripheral and central nervous s ystems. It has been proposed that endogenous VIP released from VIP-con taining nerves is involved in the regulation of the secretory function of the endocrine pancreas. To test this hypothesis in vivo, we produc ed transgenic mice carrying the human VIP/peptide histidine methionine 27 (PHM-27) gene under the control of insulin promoter. In immunohist ochemical analyses of islets, all the islet beta cells of transgenic m ice were intensely stained for both VIP and PHM-27, consistent with th e fact that these two peptides are encoded in a single mRNA (Itoh, N., Obata, K., Yanaihara, N., and Okamoto, H. (1983) Nature 304, 547-549) . VIP was efficiently secreted from isolated transgenic islets in vitr o. The blood glucose assays in free-fed mice indicated that the transg ene lowered the blood glucose levels of transgenic mice (128 +/- 4 mg/ dl) by about 20% below control levels (155 +/- 6 mg/dl). In the glucos e tolerance test, at 60 min after glucose administration, the transgen ic blood glucose levels (129 +/- 12 mg/dl) were much lower than contro l levels (175 +/- 13 mg/dl). The transgenic serum insulin levels at 15 min after glucose administration were 2.5-3.0-fold higher than contro l levels. The transgene was also effective in ameliorating glucose int olerance of 70% depancreatized mice. These results indicate that VIP a nd PHM-27 produced from the transgenic beta cells efficiently enhance glucose-induced insulin secretion from beta cells by an autocrine mech anism. These results also suggest that genetic manipulation of islet b eta cells by the human VIP/PHM-27 gene or delivery of VIP to beta cell s may ultimately provide a valuable approach to enhancing insulin secr etion in clinical diabetes.