TY - JOUR
T1 - Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis
AU - Brissova, Marcela
AU - Blaha, Michael
AU - Spear, Cathi
AU - Nicholson, Wendell
AU - Radhika, Aramandla
AU - Shiota, Masakazu
AU - Charron, Maureen J.
AU - Wright, Christopher V.E.
AU - Powers, Alvin C.
PY - 2005/4
Y1 - 2005/4
N2 - In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic β-cell response to the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. Pancreatic duodenal homeodomain-1 (PDX-1), a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet cell mass in mice of four different genotypes: wild-type mice, mice with one PDX-1 allele inactivated (PDX-1 +/-, resulting in impaired insulin secretion), mice with one GLUT4 allele inactivated (GLUT4+/-, resulting in insulin resistance), and mice heterozygous for both PDX-1 and GLUT4 (GLUT4+/-;PDX-1 +/-). The combination of PDX-1 and GLUT4 heterozygosity markedly prolonged glucose clearance. GLUT4+/-;PDX-1+/- mice developed β-cell hyperplasia but failed to increase their β-cell insulin content. These results indicate that PDX-1 heterozygosity (∼60% of normal protein levels) abrogates the β-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.
AB - In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic β-cell response to the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. Pancreatic duodenal homeodomain-1 (PDX-1), a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet cell mass in mice of four different genotypes: wild-type mice, mice with one PDX-1 allele inactivated (PDX-1 +/-, resulting in impaired insulin secretion), mice with one GLUT4 allele inactivated (GLUT4+/-, resulting in insulin resistance), and mice heterozygous for both PDX-1 and GLUT4 (GLUT4+/-;PDX-1 +/-). The combination of PDX-1 and GLUT4 heterozygosity markedly prolonged glucose clearance. GLUT4+/-;PDX-1+/- mice developed β-cell hyperplasia but failed to increase their β-cell insulin content. These results indicate that PDX-1 heterozygosity (∼60% of normal protein levels) abrogates the β-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.
KW - Diabetes
KW - Pancreatic duodenal homeodomain-1
KW - Pancreatic islets
KW - Transcription factors
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U2 - 10.1152/ajpendo.00252.2004
DO - 10.1152/ajpendo.00252.2004
M3 - Article
C2 - 15562255
AN - SCOPUS:15444373040
SN - 0193-1849
VL - 288
SP - E707-E714
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 4 51-4
ER -