Diabetes Metab J.  2018 Dec;42(6):465-471. 10.4093/dmj.2018.0116.

A Journey to Understand Glucose Homeostasis: Starting from Rat Glucose Transporter Type 2 Promoter Cloning to Hyperglycemia

Affiliations
  • 1Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea. yha111@yuhs.ac

Abstract

My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring.

Keyword

Adipogenesis; Diabetes mellitus, type 2; Glucokinase; Gluconeogenesis; Glucose transporter type 2; Glycolysis; Transcription factors

MeSH Terms

Adipogenesis
Adipose Tissue
Animals
Brain
Clone Cells*
Cloning, Organism*
Diabetes Mellitus, Type 2
Glucokinase
Gluconeogenesis
Glucose Transport Proteins, Facilitative*
Glucose Transporter Type 2*
Glucose*
Glycolysis
Homeostasis*
Humans
Hyperglycemia*
Liver
Promoter Regions, Genetic
Rats*
Transcription Factors
Glucokinase
Glucose
Glucose Transport Proteins, Facilitative
Glucose Transporter Type 2
Transcription Factors

Figure

  • Fig. 1 Schematic summary of the regulation of liver type glucose transporter (glucose transporter type 2 [GLUT2]) and glucokinase (Gck) promoter. During the long journey to understand glucose homeostasis, main interest of my group was how glucose sensors, GLUT2 and glucokinase, are regulated by transcription factors. Tissue-specific study, and disease-specific alteration as well, revealed that many transcriptional factors are interconnected in the regulation of glucose sensor in liver. C/EBP, CCAAT/enhancer binding protein; PPARγ, peroxisome proliferator-activated receptor γ; RXRα, retinoid X receptor α; PPRE, PPARγ response element; SREBP-1c, sterol regulatory element binding protein-1c; SRE, sterol regulatory element; HNF1α, hepatocyte nuclear factor 1 α; HNF, hepatocyte nuclear factor; FOXA2, forkhead box A2; LXRα, liver X-receptor α; SHP, small heterodimer partner; L-GcK, liver glucokinase; TFE3, transcription factor E3; LXRE, liver X-receptor response element.

  • Fig. 2 Role of cyclic AMP-responsive element-binding protein 3 (CREB3)-like 4 (CREB3L4) on the adipogenesis. (A) In preadipocytes, CREB3L4 acts as a negative regulator of adipogenesis by both regulating the stability of CCAAT/enhancer binding protein β (C/EBPβ) protein and increasing GATA binding protein 3 (GATA3) expression. (B) Proposed mechanism of action of CREB3L4 in prostate cancer progression. Adapted from Kim et al. [2426]. IBMX, 3-isobutyl-1-methylxanthine; AR, androgen receptor; IRE1α, inositol requiring enzyme 1α.


Cited by  1 articles

Umbilical Cord-Mesenchymal Stem Cell-Conditioned Medium Improves Insulin Resistance in C2C12 Cell
Kyung-Soo Kim, Yeon Kyung Choi, Mi Jin Kim, Jung Wook Hwang, Kyunghoon Min, Sang Youn Jung, Soo-Kyung Kim, Yong-Soo Choi, Yong-Wook Cho
Diabetes Metab J. 2021;45(2):260-269.    doi: 10.4093/dmj.2019.0191.


Reference

1. Schuit FC, Huypens P, Heimberg H, Pipeleers DG. Glucose sensing in pancreatic beta-cells: a model for the study of other glucose-regulated cells in gut, pancreas, and hypothalamus. Diabetes. 2001; 50:1–11.
2. Ahn YH, Kim JW, Han GS, Lee BG, Kim YS. Cloning and characterization of rat pancreatic beta-cell/liver type glucose transporter gene: a unique exon/intron organization. Arch Biochem Biophys. 1995; 323:387–396. PMID: 7487103.
3. Kim JW, Ahn YH. CCAAT/enhancer binding protein regulates the promoter activity of the rat GLUT2 glucose transporter gene in liver cells. Biochem J. 1998; 336(Pt 1):83–90. PMID: 9806888.
Article
4. Cha JY, Kim H, Kim KS, Hur MW, Ahn Y. Identification of transacting factors responsible for the tissue-specific expression of human glucose transporter type 2 isoform gene. Cooperative role of hepatocyte nuclear factors 1alpha and 3beta. J Biol Chem. 2000; 275:18358–18365. PMID: 10748140.
5. Cha JY, Kim HS, Kim HI, Im SS, Kim SY, Kim JW, Yeh BI, Ahn YH. Analysis of polymorphism of the GLUT2 promoter in NIDDM patients and its functional consequence to the promoter activity. Ann Clin Lab Sci. 2002; 32:114–122. PMID: 12017192.
6. Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 1994; 331:1188–1193. PMID: 7935656.
Article
7. Kim HI, Kim JW, Kim SH, Cha JY, Kim KS, Ahn YH. Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter. Diabetes. 2000; 49:1517–1524. PMID: 10969836.
Article
8. Kim HI, Cha JY, Kim SY, Kim JW, Roh KJ, Seong JK, Lee NT, Choi KY, Kim KS, Ahn YH. Peroxisomal proliferator-activated receptor-gamma upregulates glucokinase gene expression in beta-cells. Diabetes. 2002; 51:676–685. PMID: 11872666.
9. Kim HI, Ahn YH. Role of peroxisome proliferator-activated receptor-gamma in the glucose-sensing apparatus of liver and beta-cells. Diabetes. 2004; 53(Suppl 1):S60–S65. PMID: 14749267.
10. Kim SY, Kim HI, Park SK, Im SS, Li T, Cheon HG, Ahn YH. Liver glucokinase can be activated by peroxisome proliferator-activated receptor-gamma. Diabetes. 2004; 53(Suppl 1):S66–S70. PMID: 14749268.
11. Kim TH, Kim H, Park JM, Im SS, Bae JS, Kim MY, Yoon HG, Cha JY, Kim KS, Ahn YH. Interrelationship between liver X receptor alpha, sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor gamma, and small heterodimer partner in the transcriptional regulation of glucokinase gene expression in liver. J Biol Chem. 2009; 284:15071–15083. PMID: 19366697.
12. Kim SY, Kim HI, Kim TH, Im SS, Park SK, Lee IK, Kim KS, Ahn YH. SREBP-1c mediates the insulin-dependent hepatic glucokinase expression. J Biol Chem. 2004; 279:30823–30829. PMID: 15123649.
Article
13. Im SS, Kang SY, Kim SY, Kim HI, Kim JW, Kim KS, Ahn YH. Glucose-stimulated upregulation of GLUT2 gene is mediated by sterol response element-binding protein-1c in the hepatocytes. Diabetes. 2005; 54:1684–1691. PMID: 15919789.
Article
14. Im SS, Kwon SK, Kang SY, Kim TH, Kim HI, Hur MW, Kim KS, Ahn YH. Regulation of GLUT4 gene expression by SREBP-1c in adipocytes. Biochem J. 2006; 399:131–139. PMID: 16787385.
Article
15. Nakagawa Y, Shimano H, Yoshikawa T, Ide T, Tamura M, Furusawa M, Yamamoto T, Inoue N, Matsuzaka T, Takahashi A, Hasty AH, Suzuki H, Sone H, Toyoshima H, Yahagi N, Yamada N. TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes. Nat Med. 2006; 12:107–113. PMID: 16327801.
Article
16. Kim MY, Jo SH, Park JM, Kim TH, Im SS, Ahn YH. Adenovirus-mediated overexpression of Tcfe3 ameliorates hyperglycaemia in a mouse model of diabetes by upregulating glucokinase in the liver. Diabetologia. 2013; 56:635–643. PMID: 23269357.
Article
17. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999; 103:1489–1498. PMID: 10359558.
18. Im SS, Kim MY, Kwon SK, Kim TH, Bae JS, Kim H, Kim KS, Oh GT, Ahn YH. Peroxisome proliferator-activated receptor {alpha} is responsible for the up-regulation of hepatic glucose-6-phosphatase gene expression in fasting and db/db mice. J Biol Chem. 2011; 286:1157–1164. PMID: 21081500.
19. Park JM, Kim MY, Kim TH, Min DK, Yang GE, Ahn YH. Prolactin regulatory element-binding (PREB) protein regulates hepatic glucose homeostasis. Biochim Biophys Acta. 2018; 1864(6 Pt A):2097–2107.
Article
20. Niswender KD, Shiota M, Postic C, Cherrington AD, Magnuson MA. Effects of increased glucokinase gene copy number on glucose homeostasis and hepatic glucose metabolism. J Biol Chem. 1997; 272:22570–22575. PMID: 9278411.
Article
21. Park JM, Kim TH, Jo SH, Kim MY, Ahn YH. Acetylation of glucokinase regulatory protein decreases glucose metabolism by suppressing glucokinase activity. Sci Rep. 2015; 5:17395. PMID: 26620281.
Article
22. Park JM, Kim TH, Bae JS, Kim MY, Kim KS, Ahn YH. Role of resveratrol in FOXO1-mediated gluconeogenic gene expression in the liver. Biochem Biophys Res Commun. 2010; 403:329–334. PMID: 21078299.
Article
23. Jo SH, Kim MY, Park JM, Kim TH, Ahn YH. Txnip contributes to impaired glucose tolerance by upregulating the expression of genes involved in hepatic gluconeogenesis in mice. Diabetologia. 2013; 56:2723–2732. PMID: 24037087.
Article
24. Kim TH, Jo SH, Choi H, Park JM, Kim MY, Nojima H, Kim JW, Ahn YH. Identification of Creb3l4 as an essential negative regulator of adipogenesis. Cell Death Dis. 2014; 5:e1527. PMID: 25412305.
Article
25. Kim TH, Park JM, Jo SH, Kim MY, Nojima H, Ahn YH. Effects of low-fat diet and aging on metabolic profiles of Creb3l4 knockout mice. Nutr Diabetes. 2015; 5:e179. PMID: 26302066.
Article
26. Kim TH, Park JM, Kim MY, Ahn YH. The role of CREB3L4 in the proliferation of prostate cancer cells. Sci Rep. 2017; 7:45300. PMID: 28338058.
Article
Full Text Links
  • DMJ
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr