[HTML][HTML] Mafa expression enhances glucose-responsive insulin secretion in neonatal rat beta cells

C Aguayo-Mazzucato, A Koh, I El Khattabi, WC Li… - Diabetologia, 2011 - Springer
C Aguayo-Mazzucato, A Koh, I El Khattabi, WC Li, E Toschi, A Jermendy, K Juhl, K Mao…
Diabetologia, 2011Springer
Aim/hypothesis Neonatal beta cells lack glucose-stimulated insulin secretion and are thus
functionally immature. We hypothesised that this lack of glucose responsiveness results from
a generalised low expression of genes characteristic of mature functional beta cells.
Important glucose-responsive transcription factors, Mafa and Pdx1, regulate genes involved
in insulin synthesis and secretion, and have been implicated in late beta cell development.
The aim of this study was to assess whether Mafa and/or Pdx1 regulates the postnatal …
Aim/hypothesis
Neonatal beta cells lack glucose-stimulated insulin secretion and are thus functionally immature. We hypothesised that this lack of glucose responsiveness results from a generalised low expression of genes characteristic of mature functional beta cells. Important glucose-responsive transcription factors, Mafa and Pdx1, regulate genes involved in insulin synthesis and secretion, and have been implicated in late beta cell development. The aim of this study was to assess whether Mafa and/or Pdx1 regulates the postnatal functional maturation of beta cells.
Methods
By quantitative PCR we evaluated expression of these and other beta cell genes over the first month compared with adult. After infection with adenovirus expressing MAFA, Pdx1 or green fluorescent protein (Gfp), P2 rat islets were evaluated by RT-PCR and insulin secretion with static incubation and reverse haemolytic plaque assay (RHPA).
Results
At P2 most beta cell genes were expressed at about 10% of adult, but by P7 Pdx1 and Neurod1 no longer differ from adult; by contrast, Mafa expression remained significantly lower than adult through P21. Overexpression of Pdx1 increased Mafa, Neurod1, glucokinase (Gck) mRNA and insulin content but failed to enhance glucose responsiveness. Similar overexpression of MAFA resulted in increased Neurod1, Nkx6-1, Gck and Glp1r mRNAs and no change in insulin content but, importantly, acquisition of glucose-responsive insulin secretion. Both the percentage of secreting beta cells and the amount of insulin secreted per beta cell increased, approaching that of adult beta cells.
Conclusions/interpretation
In the process of functional maturation acquiring glucose-responsive insulin secretion, neonatal beta cells undergo a coordinated gene expression programme in which Mafa plays a crucial role.
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