title: Increased perinatal remodelling of the pancreas in somatostatin-deficient mice: potential role of transforming growth factor-beta signalling in regulating beta cell growth in early life.
abstract: Early postnatal life is a critical period for development of the endocrine pancreas, involving remodelling of islet cells and maturation of secretory responses. Factors that regulate these processes are undefined. Somatostatin-secreting delta-cells are abundant in the developing pancreas and, because somatostatin inhibits growth, the hormone may regulate islet expansion in early life. The aim of this study was to investigate effects of somatostatin-deficiency on proliferation, apoptosis and pancreas expansion in the first 3 weeks of life in mice. Pancreases from control or somatostatin-knockout mice were analysed for beta cell, alpha cell and pancreatic volumes by morphometry, proliferation by BrdU incorporation and apoptosis by TUNEL labelling. Signalling pathways associated with proliferation and apoptosis were studied by immunohistochemistry and Western blotting. Knockout mice grew normally in the first 3 weeks of life, but had high circulating insulin that normalised by day 21. Beta cell, alpha cell and pancreatic volumes were decreased in knockout mice, accompanied by reduced proliferation and increased apoptosis in the pancreas. Decreased growth was not due to impaired Akt signalling, as Akt phosphorylation and nuclear cyclin-D2 increased in the knockout pancreas. Levels of TGF-β1, a factor implicated in tissue remodelling, together with SMAD phosphorylation through which TGF-β mediates its effects, were increased in the knockout pancreas. Beta cell expansion was impaired in knockout mice, potentially compensating for increased insulin secretion from islets lacking inhibitory effects of somatostatin, and was associated with increased TGF-β1 levels. TGF-β1 may represent an important regulator of beta cell mass in early life.
authors.affiliation: Division of Diabetes and Nutritional Sciences, King's College London, London, UK.
authors.forename: C C
authors.initials: CC
authors.lastname: Richardson
authors.affiliation: Division of Diabetes and Nutritional Sciences, King's College London, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: To
authors.affiliation: Division of Diabetes and Nutritional Sciences, King's College London, London, UK.
authors.forename: V L
authors.initials: VL
authors.lastname: Foot
authors.affiliation: Division of Diabetes and Nutritional Sciences, King's College London, London, UK.
authors.forename: A C
authors.initials: AC
authors.lastname: Hauge-Evans
authors.affiliation: Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Carmignac
authors.affiliation: Division of Diabetes and Nutritional Sciences, King's College London, London, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Christie
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001835:Body Weight; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D020287:In Situ Nick-End Labeling; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013004:Somatostatin / Q000172:deficiency* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010768:Phosphoserine; D013004:Somatostatin; D051057:Proto-Oncogene Proteins c-akt; D001973:Bromodeoxyuridine