Fibroblast Growth Factors

The fibroblast growth factor (FGF) family of proteins is composed of at least 19 related peptides with actions that include mitogenesis, angiogenesis, and morphogenesis in a variety of fetal, neonatal, and adult tissues. FGF-1 (also called acid FGF) and FGF-2 (also called basic FGF) are present in normal adult human pancreas and are highly expressed in pancreatic tumors (91). FGF-1 has been detected in a-cells and in acinar and ductal epithelial cells, and FGF-2 mRNA has been localized in a- and ß-cells and also in ductal cells (92). Both FGFs strongly increase proliferation in isolated rat islets (92). In addition, FGF-1 is able to increase the insulin content of rat fetal isletlike structures (93). On the other hand, FGF-2 induces pancreatic epithelial cell proliferation during embryonic life (94) and also increases the formation of islet-like cell clusters in culture (93). Interestingly, exogenous FGF-7 (also called keratinocyte growth factor or KGF) is also a potent inducer of islet cell proliferation in vitro (92), although overexpression of this factor in transgenic mice using the human insulin promoter induces the formation of hepatocytes within islets and intraislet duct cell proliferation (95). This suggests that this factor could induce the differentiation of uncommitted stem cells present in the pancreas. Recently, Hart and collaborators have expanded the repertoire of FGFs observed in the islet, demonstrating that the islet also produces FGF-4, FGF-5, and FGF-10 (96).

Fibroblast growth factors effects are mediated by FGF receptors (FGFRs), four high-affinity receptors designated FGFR1 through FGFR4. These receptors are abundant and widespread in the developing pancreas (93,94,96). Hart et al. demonstrated, using dominant negative FGFR1 under the control of the PDX1 promoter (a duct, islet, and exocrine pancreas promoter), that FGFR1, but not FGFR2, is required for normal islet development and function (96). Mice deficient in FGFR1 have a 25% reduction in P-cell mass and also display other P-cell defects, including reduced prohormone con-vertase function and GLUT-2 expression (96). These data provide clear evidence that the FGF family is required for normal attainment of normal P-cell mass in rodents.

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