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

• Published in: Diabetologia 2014-01, Vol.57 (1), p.157-166
• Main Authors: Nomura, Masatoshi, Zhu, Hai-Lei, Wang, Lixiang, Morinaga, Hidetaka, Takayanagi, Ryoichi, Teramoto, Noriyoshi
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Electrophysiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Human Physiology; Hyperplasia - metabolism; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Internal Medicine; Islets of Langerhans - metabolism; KATP Channels - genetics; KATP Channels - metabolism; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Knockout; Smad2 Protein - genetics; Smad2 Protein - metabolism
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-3062-2

Aims/hypothesis 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 (K ATP channels) was recorded in mutant beta cells using patch-clamp techniques. Results The Smad2β KO 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 K ATP channels was decreased in mutant beta cells. Conclusions/interpretation 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 K ATP channel activity.