Glucose regulation of insulin gene expression in pancreatic beta-cells.
Production and secretion of insulin from the beta-cells of the pancreas is very crucial in maintaining normoglycaemia. This is achieved by tight regulation of insulin synthesis and exocytosis from the beta-cells in response to changes in blood glucose levels. The synthesis of insulin is regulated by blood glucose levels at the transcriptional and post-transcriptional levels. Although many transcription factors have been implicated in the regulation of insulin gene transcription, three beta-cell-specific transcriptional regulators, Pdx-1 (pancreatic and duodenal homeobox-1), NeuroD1 (neurogenic differentiation 1) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A), have been demonstrated to play a crucial role in glucose induction of insulin gene transcription and pancreatic beta-cell function. These three transcription factors activate insulin gene expression in a co-ordinated and synergistic manner in response to increasing glucose levels. It has been shown that changes in glucose concentrations modulate the function of these beta-cell transcription factors at multiple levels. These include changes in expression levels, subcellular localization, DNA-binding activity, transactivation capability and interaction with other proteins. Furthermore, all three transcription factors are able to induce insulin gene expression when expressed in non-beta-cells, including liver and intestinal cells. The present review summarizes the recent findings on how glucose modulates the function of the beta-cell transcription factors Pdx-1, NeuroD1 and MafA, and thereby tightly regulates insulin synthesis in accordance with blood glucose levels.
Andrali
Sreenath S
SS
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, 741 South Limestone, Lexington, KY 40536, USA.
Sampley
Megan L
ML
Vanderford
Nathan L
NL
Ozcan
Sabire
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001786:Blood Glucose / Q000502:physiology*; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology*; D051473:Maf Transcription Factors, Large / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D021381:Protein Transport; D015534:Trans-Activators / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D006655:Histone Deacetylases; D018398:Homeodomain Proteins; D007328:Insulin; D051473:Maf Transcription Factors, Large; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; C485159:MAFA protein, human; C084010:pancreatic and duodenal homeobox 1 protein; C093564:Neurogenic differentiation factor 1