Cellular distribution and ontogeny of insulin-like growth factors (IGFs) and IGF binding protein messenger RNAs and peptides in developing rat pancreas

Abstract

To determine the role of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) in the development of the pancreas, and specifically of the islets of Langerhans, we have examined the cellular distribution and developmental changes in the expression of IGFs and IGFBPs in the pancreas of the fetal and neonatal rat between 19·5 days of gestation and postnatal day 28. This represents a period of substantial growth and restructuring of the cell component in islets of this species. IGF-I, IGF-II, and IGFBPs-1 to -6 mRNAs were localized by in situ hybridization, and peptides by immunohistochemistry, in histological sections. IGF-II mRNA was highly expressed in islet cells and some ductal epithelial cells in late fetal and early neonatal life, but was barely detectable by postnatal day 28. IGF-II peptide showed a similar distribution. IGF-I mRNA was barely detected in the fetus or neonate and was localized predominantly in the ductal and acinar tissues after postnatal day 7. IGF-I immunoreactivity was associated with some islet cells in the fetus and neonate, suggesting an endocrine rather than a paracrine source.We performed co-localization studies to assess whether the distribution of IGFs within the pancreas might be due to a sequestration by locally produced IGFBPs. The presence of mRNAs for both IGFBPs-1 and -2 was minimal in the pancreas prior to postnatal day 7, although subsequently IGFBP-1 mRNA was seen in islet cells, while IGFBP-2 mRNA was localized in both islets and acinar tissues. In contrast, both IGFBPs-1 and -2 immunoreactivities were identified in islets from late fetal life, suggesting a circulatory source for these IGFBPs during early pancreatic development. IGFBPs-3 to -5 mRNAs and immunoreactivities were identified within islet cells throughout fetal and neonatal life, with IGFBPs-3 and -5 being mainly associated with the cell-rich islet mantle. The results show a compartmentalization of IGFs within pancreatic tissue, reflecting both paracrine and endocrine sources. The localization and action of IGFs in pancreas likely involves sequestration and distribution by endogenous as well as circulating IGFBPs.

Insulin-like growth factor II in human fetal pancreas and its co-localization with the major islet hormones: comparison with adult pancreas

“…Blocking of endogenous IGF-II with an IGF-II antibody inhibited this protective effect . A decrease in apoptosis in islet cells has also been found in transgenic mice overexpressing IGF-II, giving rise to a marked islet hyperplasia (Petrik et al 1999). Ilieva et al (1999) have recently reported that hamster pancreatic duct epithelium contained IGF-II and that this secretion has an anti-apoptotic effect on B-cells; these results are not in line with ours but raise the question about species dependent differences in IGF-II localization.…”

Maternal undernutrition increases pancreatic IGF-2 and partially suppresses the physiological wave of β-cell apoptosis during the neonatal period

“…It is known that IGFs and their binding proteins (IGFBPs) are expressed by islet cells throughout life (Hill et al 1999). In rats, IGF-2 levels are relatively high in fetal and early neonatal period and then they decline sharply toward adulthood, while IGF-1 levels increase progressively with age (Hogg et al 1994, Petrik et al 1998.…”

“…This effect persists until adulthood ) and can provoke long-lasting consequences related to the plasticity of the endocrine pancreas under situations of increased insulin demand such as aging and pregnancy (Blondeau et al 1999). Accordingly, nutritional insufficiency can alter the timing and amplitude of the ontological events, which trigger the remodeling of endocrine pancreas (Petrik et al 1999).…”

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

“…Evidence for the involvement of the IGF family in beta cell development is abundant and based on physiological studies [7] and genetic mouse models [7][8][9] as follows: (1) IGFs are mitogenic for beta cells [7]; (2) IGFs and their binding proteins are produced in fetal and adult pancreata [10]; (3) IGFs act as cell survival factors by inhibiting beta cell apoptosis [7]; (4) IGF2 overexpression in transgenic mice causes islet hyperplasia [11]; and (5) undernourished fetuses with an increased beta cell mass have locally increased pancreatic Igf1 expression [12].…”