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 systems. It has been proposed that endogenous VIP released from VIP-containing nerves is involved in the regulation of the secretory function of the endocrine pancreas. To test this hypothesis in vivo, we produced transgenic mice carrying the human VIP/peptide histidine methionine 27 (PHM-27) gene under the control of Insulin promoter. In immunohistochemical analyses of islets, all the islet beta cells of transgenic mice were intensely stained for both VIP and PHM-27, consistent with the 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 vitro. The blood glucose assays in free-fed mice indicated that the transgene lowered the blood glucose levels of transgenic mice (128 +/- 4 mg/dl) by about 20% below control levels (155 +/- 6 mg/dl). In the glucose tolerance test, at 60 min after glucose administration, the transgenic blood glucose levels (129 +/- 12 mg/dl) were much lower than control levels (175 +/- 13 mg/dl). The transgenic serum Insulin levels at 15 min after glucose administration were 2.5-3.0-fold higher than control levels. The transgene was also effective in ameliorating glucose intolerance of 70% depancreatized mice. These results indicate that VIP and PHM-27 produced from the transgenic beta cells efficiently enhance glucose-induced Insulin secretion from beta cells by an autocrine mechanism. These results also suggest that genetic manipulation of islet beta cells by the human VIP/PHM-27 gene or delivery of VIP to beta cells may ultimately provide a valuable approach to enhancing Insulin secretion in clinical diabetes.