Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis

Abstract

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.

Pdx1 ( MODY4 ) regulates pancreatic beta cell susceptibility to ER stress

“…1G). The functional ␤ cell defect observed in HF-fed Pdx1 ϩ/Ϫ mice is consistent with the impaired insulin secretion described in Pdx1 ϩ/Ϫ animals alone or in the context of genetic insulin resistance (4,16,17).…”

“…While the role of Pdx1 in functional islet compensation appears unequivocal in genetic models of insulin resistance, these models provide discrepant results regarding its role in morphological ␤ cell compensation (16,17). To determine whether Pdx1 is required for normal ␤ cell mass expansion in response to HFDinduced insulin resistance, we measured pancreatic ␤ cell mass in Pdx1 ϩ/Ϫ and Pdx1 ϩ/ϩ mice fed HFD or NC for 5 months.…”

“…This hypothesis is supported by studies using genetic mouse models of insulin resistance. In mice doubly heterozygous for the insulin receptor (IR) and insulin receptor substrate 1 (IRS-1), superimposed Pdx1 haploinsufficiency impairs both insulin secretion and compensatory ␤ cell mass expansion, leading to worsened glucose tolerance (16); however, in the insulin resistant Glut4 ϩ/Ϫ model, concurrent Pdx1 heterozygosity leads to hyperglycemia due to defects in insulin secretion with no impairment in ␤ cell mass expansion (17). The basis for the discrepancy regarding the role of Pdx1 in compensatory expansion of ␤ cell mass in these genetic models of insulin resistance has not been elucidated but may involve differences in the sites and severity of insulin resistance.…”

Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

“…Pdx1 is an essential transcription factor for pancreas morphogenesis and postnatally is a key regulator of ␤-cell differentiation, maturation, and survival (31). It is required for the normal adaptive increase in ␤-cell mass and function to insulin resistance (32,33). Distal from Pdx1 is a network of genes that impact diverse aspects of ␤-cell signaling, mass, and function (34) including glucokinase with its well known regulatory effects on glycolysis, insulin secretion, and ␤-cell proliferation (35).…”

“…FoxO1 is well poised to be a master transcriptional regulator over ␤-cell adaptive responses, as its expression and activity are influenced by numerous stimuli such as nutrient overload, growth factors, incretin hormones, and oxidative stress (13,14). Downstream from PPAR␥ is a network of genes that exert important regulatory control over prodifferentiation processes, incretin effects, glucose and mitochondrial fuel metabolism, and ␤-cell compensation to obesity and insulin resistance (13,27,32,33). We have shown that islet PPAR␥ and its target genes are hyperexpressed in nondiabetic insulin-resistant rats (present study and Refs.…”