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Increased islet apoptosis in Pdx1+/– mice
James D. Johnson, … , Helena Edlund, Kenneth S. Polonsky
James D. Johnson, … , Helena Edlund, Kenneth S. Polonsky
Published April 15, 2003
Citation Information: J Clin Invest. 2003;111(8):1147-1160. https://doi.org/10.1172/JCI16537.
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Article Metabolism

Increased islet apoptosis in Pdx1+/– mice

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Abstract

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.

Authors

James D. Johnson, Noreen T. Ahmed, Dan S. Luciani, Zhiqiang Han, Hung Tran, Jun Fujita, Stanley Misler, Helena Edlund, Kenneth S. Polonsky

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Figure 1

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Glucose tolerance and secretagogue-induced pancreatic insulin release in...
Glucose tolerance and secretagogue-induced pancreatic insulin release in Pdx1+/– mice. (a) IPGTTs are shown for males (n = 9 Pdx1+/+; n = 8 Pdx1+/–) and females (n = 3 Pdx1+/+; n = 3 Pdx1+/–). (b) Insulin release from perfused pancreata of male Pdx1+/+ (n = 5) and Pdx1+/– (n = 5) mice in response to stepwise increases to 20 mM glucose (black bar) and 20 mM KCl (white bar). (c) Insulin release from perfused pancreata of Pdx1+/+ (n = 3) and Pdx1+/– (n = 3) mice in response to a linear elevation from 2 mM to 26 mM glucose. Insulin secretion in response to 20 mM arginine (arg) was assayed in the continued presence of 26 mM glucose (G) (note the different scale). Data are from mice 8–10 weeks of age.

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