Transcriptional regulation of glucose sensors in pancreatic β-cells and liver: an update

Abstract

Pancreatic β-cells and the liver play a key role in glucose homeostasis. After a meal or in a state of hyperglycemia, glucose is transported into the β-cells or hepatocytes where it is metabolized. In the β-cells, glucose is metabolized to increase the ATP:ADP ratio, resulting in the secretion of insulin stored in the vesicle. In the hepatocytes, glucose is metabolized to CO(2), fatty acids or stored as glycogen. In these cells, solute carrier family 2 (SLC2A2) and glucokinase play a key role in sensing and uptaking glucose. Dysfunction of these proteins results in the hyperglycemia which is one of the characteristics of type 2 diabetes mellitus (T2DM). Thus, studies on the molecular mechanisms of their transcriptional regulations are important in understanding pathogenesis and combating T2DM. In this paper, we will review a recent update on the progress of gene regulation of glucose sensors in the liver and β-cells.

Keywords: glucokinase (GCK); glucose sensor; liver; pancreatic β-cell; solute carrier family 2 (SLC2A2); transcription.

Figure 1.

Schematics of transcriptional regulatory elements on the SLC2A2 gene promoter. Abbreviations: HNF1A, HNF1 homeobox A; EP300, E1A binding protein p300; FOXA2, forkhead box A2 (also known as HNF3B); PDX1, pancreatic and duodenal homeobox 1; SP1, Sp1 transcription factor; PAX6, paired box 6; MXD1, MAX dimerization protein 1; EGR1, early growth response 1; MAFA, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A; NEUROD1, neurogenic differentiation 1; PPARA, peroxisome proliferator-activated receptor alpha; PPARG, peroxisome proliferator-activated receptor gamma; FOXO1, forkhead box O1; RXRA, retinoic X receptor alpha; ONECUT1, one cut homeobox 1 (also known as HNF6); NR4A1, nuclear receptor subfamily 4, group A, member 1; SREBF1c, sterol regulatory element binding transcription factor 1c; CEBPA, CCAAT/enhancer binding protein (C/EBP) alpha; CEBPB, CCAAT/enhancer binding protein (C/EBP) beta; HRE, HNF response element; PPRE, PPAR response element; NBRE, nerve growth factor I-B response element; SRE, SREBF response element; C/EBPRE, CEBP response element. +1, transcription start site.

Figure 2.

Schematics of transcriptional regulatory elements on the βGCK gene promoter. Abbreviations: PDX1, pancreatic and duodenal homeobox 1; SP1, Sp1 transcription factor; FOXO1, forkhead box O1; NEUROD1, neurogenic differentiation 1; E47, an immunoglobulin enhancer-binding factor; EP300, E1A binding protein p300; NR0B2, nuclear receptor subfamily 0, group B, member 2 (also known as SHP); PPARG, peroxisome proliferator-activated receptor gamma; RXRA, retinoic X receptor alpha; UPE, upstream promoter element; FRE, FOXO1 response element; PPRE, PPAR response element.

Figure 3.

Schematics of transcriptional regulatory elements on the LGCK gene promoter. Abbreviations: STAT5B, signal transducer and activator of transcription 5B; HNF4A, hepatic nuclear factor 4 alpha; FOXO1, forkhead box O1; ONECUT1, one cut homeobox 1 (also known as HNF6); SREBF1c, sterol regulatory element binding transcription factor 1c; LXRA, liver X receptor alpha (also known as NR1H3); RXRA, retinoid X receptor alpha; NR0B2, nuclear receptor subfamily 0, group B, member 2 (also known as SHP); EP300, E1A binding protein p300; PPARG, peroxisome proliferator-activated receptor gamma; USF2, upstream stimulatory factor 2; HIF1A, hypoxia induced factor 1 alpha subunit; STAT5RE, STAT5B response element; HRE, HNF response element; FRE, FOXO1 response element; SRE, SREBF response element; PPRE, PPAR response element; HIFRE, HIF1A response element; LXRE, LXR response element.