Increased islet apoptosis in Pdx1+/- mice.
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 Ca(2+) responses were also normal. Depolarization-evoked exocytosis and Ca(2+) currents in single Pdx1(+/-) cells were not different from controls, arguing against a ubiquitous beta cell stimulus-secretion coupling defect. However, isolated Pdx1(+/-) islets and dispersed beta cells were significantly more susceptible to apoptosis at basal glucose concentrations than Pdx1(+/+) islets. Bcl(XL) 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 beta 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 beta cell mass, represents a key mechanism whereby partial PDX1 deficiency leads to an organ-level defect in insulin secretion and diabetes.
Johnson
James D
JD
Renal Division, Department of Internal Medicine, Washington University School of Medicine/Barnes-Jewish Hospital, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Ahmed
Noreen T
NT
Luciani
Dan S
DS
Han
Zhiqiang
Z
Tran
Hung
H
Fujita
Jun
J
Misler
Stanley
S
Edlund
Helena
H
Polonsky
Kenneth S
KS
D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D005089:Exocytosis; D005260:Female; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000473:pathology*; D008297:Male; D051379:Mice; D010477:Perfusion; D015534:Trans-Activators / Q000172:deficiency / Q000502:physiology*
D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein