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You will be hearing more about INGAP in upcoming newsletters Recent studies have shown that induction of islet neogenesis from adult pancreatic stem cells has the potential for restoring beta cell mass in diabetes. We have previously hypothesized that these stem cells can develop along either a neural or a neuroendocrine path. The factors regulating this development are unknown. We examined the role of INGAP peptide in islet neuroendocrine cell development in vivo. Forty dogs (20 males, 20 females) were randomly divided into 4 groups. Group 1 received daily IM injections of vehicle alone, while the other 3 groups received 0.5, 1.5 or 10 mg/kg injections of INGAP peptide. After 30 days of treatment the animals were sacrificed and pancreatic tissues collected. Analysis was performed with ImagePro software on confocal microscopy images of tissues stained for insulin, the essential islet transdifferentiation transcription factor PDX-1 and the pan-neuroendocrine marker PGP9.5.
The results showed a significant (p<0.001) increase in the percentage of insulin positive cells in animals treated with INGAP peptide (p<0.001, ANOVA, Table 1), with 1.5 mg/kg being the most effective dose, more than doubling controls (Dunnett’s Test, p<0.05). PGP 9.5 was increased, based on stain intensity, in large ducts of treated animals, suggesting development of neuroendocrine cells from ductal elements in response to INGAP. PDX-1 was increased in 1.5mg/kg-treated pancreas especially in isolated cells and duct epithelium.
These results indicate that adult islet stem cells in pancreas of normal dogs are induced to develop along a neuroendocrine pathway in response to INGAP peptide. The expression of PDX-1 and PGP 9.5 in duct cells suggests that INGAP is an initiator of neuroendocrine cell and PDX-1 expression in the path to islet neogenesis. ENDO 2002 [P1-27]
% Insulin Positive Area
Control 0.5mg/kg INGAP 1.5mg/kg INGAP 10mg/kg INGAP
1.2±0.1 1.8±0.2* 2.9±0.2*† 1.5±0.2