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
Aims/hypothesisThe TGF b superfamily of ligands provides important signals for the development of pancreas islets. However, it is not yet known whether the TGF b family signalling pathway is required for essential islet functions in the adult pancreas.MethodsTo identify distinct roles for the downstream components of the canonical TGF b signalling pathway, a Cre loxP system was used to disrupt SMAD2, an intracellular transducer of TGF b signals, in pancreatic beta cells (i.e. Smad2b knockout [KO] mice) The activity of ATP sensitive K+ channels (KATP channels) was recorded in mutant beta cells using patch clamp techniques.ResultsThe Smad2bKO 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/interpretationThese results suggest that in the adult pancreas, TGF b 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.
Diabetologia