Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis.
In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic beta-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 beta-cell hyperplasia but failed to increase their beta-cell insulin content. These results indicate that PDX-1 heterozygosity (approximately 60% of normal protein levels) abrogates the beta-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.
Brissova
Marcela
M
Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, 715 PRB, Dept. of Medicine, Vanderbilt University, Nashville, TN 37232, USA.
Blaha
Michael
M
Spear
Cathi
C
Nicholson
Wendell
W
Radhika
Aramandla
A
Shiota
Masakazu
M
Charron
Maureen J
MJ
Wright
Christopher V E
CV
Powers
Alvin C
AC
D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D020868:Gene Silencing; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006706:Homeostasis; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D018709:Statistics, Nonparametric; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics
D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D018398:Homeodomain Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein