ABSTRACT
BACKGROUND: Pancreatic islets are not fully developed at birth and it is not clear how they are vascularised and innervated. Nerve Growth Factor (NGF) is required to guide sympathetic neurons that innervate peripheral organs and also in cardiovascular system and ovary angiogenesis. Pancreatic beta cells of a transgenic mouse that over-expressed NGF in attracts sympathetic hyper-innervation towards them. Moreover, we have previously demonstrated that adult beta cells synthesize and secrete NGF; however, we do not know how is NGF secreted during development, nor if it might be trophic for sympathetic innervation and survival in the pancreas.We analyzed sympathetic innervation and vasculature development in rat pancreatic islets at different developmental stages; foetal (F19), early postnatal (P1), weaning period (P20) and adults. We temporarily correlated these events to NGF secretion by islet cells. RESULTS: Sympathetic fibres reached pancreatic islets in the early postnatal period, apparently following blood vessels. The maximal number of sympathetic fibres (TH immunopositive) in the periphery of the islets was observed at P20, and then fibres entered the islets and reached the core where beta cells are mainly located. The number of fibres decreased from that stage to adulthood. At all stages studied, islet cells secreted NGF and also expressed the high affinity receptor TrkA. Foetal and neonatal isolated islet cells secreted more NGF than adults. TrkA receptors were expressed at all stages in pancreatic sympathetic fibres and blood vessels. These last structures were NGF-immunoreactive only at early stages (foetal and P0). CONCLUSION: The results suggest that NGF signalling play an important role in the guidance of blood vessels and sympathetic fibres toward the islets during foetal and neonatal stages and could also preserve innervation at later stages of life.
Subject(s)
Islets of Langerhans/innervation , Sympathetic Nervous System/growth & development , Sympathetic Nervous System/physiology , Animals , Animals, Newborn , Cells, Cultured , Female , Fetus , Fluorescent Antibody Technique , Gene Expression Regulation, Developmental , Glucagon/metabolism , Insulin/metabolism , Islets of Langerhans/embryology , Islets of Langerhans/growth & development , Islets of Langerhans/metabolism , Male , Microscopy, Confocal , Models, Biological , Nerve Growth Factors/metabolism , Pregnancy , Rats , Rats, Wistar , Receptor, trkA/metabolism , Vimentin/metabolismABSTRACT
Neurotrophins (NTs) are important for the survival, differentiation and function of sympathetic and sensorial neurons of central and peripheral nervous system. However, similar functions have been described of NTs in non-neural organs. Nerve Growth factor (NGF) participates in the foliculogenesis and ovulation in the ovary, as well as in the islet morphogenesis and insulin secretion of the pancreatic beta cell. The NTs act by binding to two distinct classes of transmembranal receptors: p75 and Trks. Both receptor types lead to activation of intracellular signaling cascades that end with cell survival or apoptosis. In this review different actions of the NTs in the ovarian and the pancreas are described.
Subject(s)
Nerve Growth Factors/physiology , Ovary/physiology , Pancreas/physiology , Animals , Apoptosis/physiology , Female , Humans , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/metabolism , Male , Mice , Organ Specificity , Ovarian Follicle/physiology , Ovary/growth & development , Ovulation/physiology , Pancreas/growth & development , Rats , Receptors, Nerve Growth Factor/physiology , Signal Transduction/physiologyABSTRACT
CONTEXT: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset and a primary insulin secretion defect. Certain MODY gene sequence variants may be involved in polygenic forms of type 2 diabetes. OBJECTIVE: We assessed the contribution of MODY genes to the etiology of type 2 early-onset diabetes in 23 Mexican families, including five with apparently autosomal dominant inheritance. PATIENTS: Twenty-three unrelated Mexican families with early-onset type 2 diabetes previously screened for the presence of glucokinase mutations, were studied. DESIGN: We screened MODY genes for sequence variants by PCR-SSCP analysis and automated sequencing. We performed a functional analysis of the HNF-1alpha P379H recombinant protein in vitro in both HeLa and RINm5f beta-cell lines. MAIN OUTCOME MEASURES: MODY gene mutation screening and P379H mutant protein transactivation assay. RESULTS: No mutations were detected in the HNF-4alpha, IPF-1, NEUROD1 or HNF-1beta genes in any of the families studied. A new mutation (P379H) of the HNF-1alpha gene was identified in one MODY family. RINm5f and HeLa cell transfection assays revealed decreased transactivation activity of the mutant protein on the human insulin promoter. CONCLUSIONS: All known MODY genes were screened for abnormalities in this cohort of early-onset diabetes families which included 5 MODY pedigrees. We identified a new HNF-1alpha MODY mutation (P379H) and demonstrated that it reduces the transactivation potential of the mutant protein on the human insulin promoter. No other mutation was identified in this cohort indicating that abnormalities in MODY genes are generally not a common cause of early-onset diabetes and this includes MODY families in Mexico.
