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

TY - JOUR

T1 - Increased perinatal remodelling of the pancreas in somatostatin-deficient mice

T2 - potential role of transforming growth factor-beta signalling in regulating beta cell growth in early life

AU - Richardson, C C

AU - To, K

AU - Foot, V L

AU - Hauge-Evans, A C

AU - Carmignac, D

AU - Christie, M R

N1 - © Georg Thieme Verlag KG Stuttgart · New York.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Newborn

KW - Apoptosis

KW - Body Weight

KW - Bromodeoxyuridine

KW - Cell Proliferation

KW - Cyclin-Dependent Kinase Inhibitor p21

KW - Cyclin-Dependent Kinase Inhibitor p27

KW - Female

KW - In Situ Nick-End Labeling

KW - Insulin-Secreting Cells

KW - Male

KW - Mice

KW - Phosphorylation

KW - Phosphoserine

KW - Proto-Oncogene Proteins c-akt

KW - Signal Transduction

KW - Smad Proteins

KW - Somatostatin

KW - Transforming Growth Factor beta

U2 - 10.1055/s-0034-1390427

DO - 10.1055/s-0034-1390427

M3 - Article

C2 - 25350519

SN - 0018-5043

VL - 47

SP - 56

EP - 63

JO - Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme

JF - Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme

IS - 1

ER -