SMAD2 disruption in mouse pancreatic beta cells leads to islet hyperplasia and impaired insulin secretion due to the attenuation of ATP-sensitive K+ channel activity.
OBJECTIVE
The TGF-β superfamily of ligands provides important signals for the development of pancreas islets. However, it is not yet known whether the TGF-β family signalling pathway is required for essential islet functions in the adult pancreas.


METHODS
To identify distinct roles for the downstream components of the canonical TGF-β signalling pathway, a Cre-loxP system was used to disrupt SMAD2, an intracellular transducer of TGF-β signals, in pancreatic beta cells (i.e. Smad2β knockout [KO] mice). The activity of ATP-sensitive K(+) channels (KATP channels) was recorded in mutant beta cells using patch-clamp techniques.


RESULTS
The Smad2βKO mice exhibited defective insulin secretion in response to glucose and overt diabetes. Interestingly, disruption of SMAD2 in beta cells was associated with a striking islet hyperplasia and increased pancreatic insulin content, together with defective glucose-responsive insulin secretion. The activity of KATP channels was decreased in mutant beta cells.


CONCLUSIONS
These results suggest that in the adult pancreas, TGF-β signalling through SMAD2 is crucial for not only the determination of beta cell mass but also the maintenance of defining features of mature pancreatic beta cells, and that this involves modulation of KATP channel activity.
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi Ward, Fukuoka, Japan.
Masatoshi
M
Nomura
Hai-Lei
HL
Zhu
Lixiang
L
Wang
Hidetaka
H
Morinaga
Ryoichi
R
Takayanagi
Noriyoshi
N
Teramoto
D000818:Animals; D004594:Electrophysiology; D005260:Female; D006965:Hyperplasia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; D054086:KATP Channels; D051899:Smad2 Protein