[HTML][HTML] Increased islet apoptosis in Pdx1+/– mice

JD Johnson, NT Ahmed, DS Luciani… - The Journal of …, 2003 - Am Soc Clin Investig
JD Johnson, NT Ahmed, DS Luciani, Z Han, H Tran, J Fujita, S Misler, H Edlund…
The Journal of clinical investigation, 2003Am Soc Clin Investig
Mice with 50% Pdx1, a homeobox gene critical for pancreatic development, had worsening
glucose tolerance with age and reduced insulin release in response to glucose, KCl, and
arginine from the perfused pancreas. Surprisingly, insulin secretion in perifusion or static
incubation experiments in response to glucose and other secretagogues was similar in islets
isolated from Pdx1+/–mice compared with Pdx1+/+ littermate controls. Glucose sensing and
islet Ca2+ responses were also normal. Depolarization-evoked exocytosis and Ca2+ …
Mice with 50% Pdx1, a homeobox gene critical for pancreatic development, had worsening glucose tolerance with age and reduced insulin release in response to glucose, KCl, and arginine from the perfused pancreas. Surprisingly, insulin secretion in perifusion or static incubation experiments in response to glucose and other secretagogues was similar in islets isolated from Pdx1+/– mice compared with Pdx1+/+ littermate controls. Glucose sensing and islet Ca2+ responses were also normal. Depolarization-evoked exocytosis and Ca2+ currents in single Pdx1+/– cells were not different from controls, arguing against a ubiquitous β cell stimulus-secretion coupling defect. However, isolated Pdx1+/– islets and dispersed β cells were significantly more susceptible to apoptosis at basal glucose concentrations than Pdx1+/+ islets. BclXL and Bcl-2 expression were reduced in Pdx1+/– islets. In vivo, increased apoptosis was associated with abnormal islet architecture, positive TUNEL, active caspase-3, and lymphocyte infiltration. Although similar in young mice, both β cell mass and islet number failed to increase with age and were approximately 50% less than controls by one year. These results suggest that an increase in apoptosis, with abnormal regulation of islet number and β cell mass, represents a key mechanism whereby partial PDX1 deficiency leads to an organ-level defect in insulin secretion and diabetes.
The Journal of Clinical Investigation