Diabetes & Metabolism Journal

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Glucose Toxicity and Pancreatic Beta Cell Dysfunction in Type 2 Diabetes.: Kyu Chang Won, Ji Sung Yoon; Korean Diabetes J. 2008;32(3):175-181. Published online June 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.3.175

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The adverse effects of prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations (i.e. glucose toxicity) is mediated at least in part by glucose oxidation and the subsequent generation of reactive oxygen species (ROS) that can impair insulin gene expression and beta cell function. Multiple biochemical pathways and mechanisms of action for glucose toxicity have been suggested. These include glucose autoxidation, protein kinase C activation, methylglyoxal formation and glycation, hexosamine metabolism, sorbitol formation, and oxidative phosphorylation. There are many potential mechanisms whereby excess glucose metabolites traveling along these pathways might cause beta cell damage. However, all these pathways have in common the formation of reactive oxygen species that, in excess and over time, cause chronic oxidative stress, which in turn causes defective insulin gene expression and insulin secretion as well as increased apoptosis. The intracellular peroxide levels of the pancreatic islets (INS-1 cells, rat islets) by flow cytometry were increased in the high glucose media compared to 5.6 mM glucose media. The insulin, MafA, PDX-1 mRNA levels and glucose stimulated insulin secretion (GSIS) were decreased in high glucose media compared to 5.6 mM glucose media. The HO-1 seems to mediate the protective response of pancreatic islets against the oxidative stress that is due to high glucose conditions. Also, we observed decreased glutathione level, gamma-GCS expression and increased oxidized LDL, malondialdehyde level at leukocytes and mesothelial cells from patients with Korean Type 2 Diabetes (esp, poorly controlled patients). In conclusion, this pathophysiologic sequence sets the scene for considering antioxidant therapy as an adjunct in the management of diabetes, especially type 2 Diabetes.

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Original Articles

Mechanism of 2-Deoxy-D-ribose-induced Damage in Pancreatic beta-cells.: Gwanpyo Koh, Jeong taek Woo, Dae Ho Lee, Seungjoon Oh, Sung Woon Kim, Jin Woo Kim, Young Seol Kim, Deok Bae Park; Korean Diabetes J. 2007;31(2):105-112. Published online March 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.2.105

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Abstract PDF

BACKGROUND
Mechanism for glucose toxicity is known to be an increased oxidative stress produced by multiple pathways. In our previous report, 2-deoxy-d-ribose (dRib) promoted apoptosis by increasing oxidative stress in a pancreatic beta-cell line. We performed this study to investigate the mechanism of dRib-induced damage of beta-cells. METHODS: HIT-T15 cells were cultured in RPMI-1640 medium with 40 mM dRib for 24 hours after pretreatment with various concentrations of a metal chelator (DTPA) and inhibitors of protein glycation (aminoguanidine and pyridoxamine). Cell viability was determined by MTT assay. Apoptosis was analyzed by flow cytometry with annexin V/PI double staining. RESULTS: DTPA, which inhibits the monosaccharide autoxidation, partially reversed dRib-induced cytotoxicity in a dose-dependent manner (P < 0.01). The cytotoxicity was also suppressed dose-dependently by aminoguanidine (AG) and pyridoxamine (PM) (P < 0.05 and P < 0.01, repectively). Flow cytometric analysis showed that pretreatment of DTPA and AG also reversed the dRib-triggered apoptosis in a dose-dependent manner. We assessed the additional protective effects of inhibitors of protein glycation from dRib-induced cytotoxiciy in the presence of a metal chelator. The additions of AG (P < 0.05) and PM (P < 0.01) significantly reduced the cytotoxicity compared with DTPA alone group. CONCLUSION: This results suggest that dRib produce cytotoxicity and apoptosis through the mechanisms of advanced glycation endproducts (AGEs) formation including the monsaccharide autoxidation and protein glycation in pancreatic beta-cell. Thus, dRib could be a surrogate for glucose in the study of glucose toxicity and chronic diabetic complications.

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Isolation of Citrus Peel Flavonoid Bioconversion Microorganism and Inhibitory Effect on the Oxidative Damage in Pancreatic Beta Cells
Chi-Deok Park, Hee-Kyung Jung, Chang-Ho Park, Yoo-Seok Jung, Joo-Heon Hong, Hee-Sun Ko, Dong-Hee Kang, Hyun-Soo Kim
KSBB Journal.2012; 27(1): 67. CrossRef
Kaempferol protects HIT‐T15 pancreatic beta cells from 2‐deoxy‐D‐ribose‐induced oxidative damage
Yun Jung Lee, Kwang Sik Suh, Moon Chan Choi, Suk Chon, Seungjoon Oh, Jeong‐Taek Woo, Sung‐Woon Kim, Jin‐Woo Kim, Young Seol Kim
Phytotherapy Research.2010; 24(3): 419. CrossRef

Glucose Oxidation and Production of Reactive Oxygen Species (ROS) in INS-1 Cells and Rat Islet Cells Exposed to High Glucose.: Ji Sung Yoon, Kyu Chang Won, Hyoung Woo Lee; Korean Diabetes J. 2006;30(4):246-253. Published online July 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.4.246

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Abstract PDF

BACKGROUND
Chronic exposure of pancreatic islets to supraphysiologic concentrations of glucose causes beta cell dysfunction that is a process known as glucose toxicity. It has been reported that hyperglycemia increases the production of reactive oxygen species (ROS) in human islets and that ROS accumulation causes beta cell dysfunction associated with low capacity of intrinsic antioxidant enzymes. Also it has been postulated that this increase in ROS is prevented by an inhibitor of electron transport chain complex. The purpose of this study were to determine whether prolonged exposure of pancreatic islets to supraphysiologic glucose concentrations disrupts the intracellular balance between ROS thereby causing defective insulin secretion and to evaluate the site of hyperglycemia-induced ROS production. METHODS: INS-1 cells & rat islets were incubated in increasing concentrations of glucose and either an inhibitor of complex I & II (TTFA), an uncoupler of oxidative phosphorylation (CCCP), aCCA, etc and also incubated in increasing concentration of glyceraldehyde and N-acetylcystein. Then intracellular peroxide levels by flow cytometric analysis and glucose induced insulin secretion were detected. RESULTS: We observed that incubation with 30 mM glucose increased intracellular peroxide levels but decreased glucose-stimulated insulin secretion (GSIS) (P < 0.05). Exposure to TTFA, CCCP, aCCA did not reduce this increased intracellular peroxide levels, and did not increase GSIS (P < 0.05). 24-h incubation with glyceraldehyde at 5.6 mM glucose increased intracellular peroxide levels and decreased insulin content. CONCLUSION: These observations indicate that there might be other origins in which ROS species are produced besides electron transport chain in mitochondria and glyceraldehyde may be a key molecule to produce ROS, and induce beta cell dysfunction.

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Citations to this article as recorded by

Reactive oxygen species in biological systems: Pathways, associated diseases, and potential inhibitors—A review
Abdur Rauf, Anees Ahmed Khalil, Samir Awadallah, Shahid Ali Khan, Tareq Abu‐Izneid, Muhammad Kamran, Hassan A. Hemeg, Mohammad S. Mubarak, Ahood Khalid, Polrat Wilairatana
Food Science & Nutrition.2023;[Epub] CrossRef
The Protective Effects of Chrysanthemum cornarium L. var. spatiosum Extract on HIT-T15 Pancreatic β-Cells against Alloxan-induced Oxidative Stress
In-Hye Kim, Kang-Jin Cho, Jeong-Sook Ko, Jae-Hyun Kim, Ae-Son Om
The Korean Journal of Food And Nutrition.2012; 25(1): 123. CrossRef

Oxidative Stress of INS-1 Cell, HIT-T15 Cell and Rat Islet Cell as a Mechanism of Glucose Toxicity.: Mi Jung Eun, Kyu Chang Won, Jun Sung Moon, Sun Jung Mun, Ji Eun Lee, Ji Sung Yoon, Kyung Ah Chun, Ihn Ho Cho, Hyoung Woo Lee; Korean Diabetes J. 2005;29(5):393-400. Published online September 1, 2005

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Abstract PDF: BACKGOUND: Chronic hyperglycemia is the proximate cause of many complications of diabetes. The beta cells in type 2 diabetes are also adversely affected by chronic hyperglycemia, with this relentless deterioration in cell function, due to constant exposure to supraphysiologic concentrations of glucose, is termed glucose toxicity; however, the mechanism of glucose toxicity is uncertain. The purpose of this study was to determine whether prolonged exposure of pancreatic islets to supraphysiologic glucose concentration disrupts the intracellular balance between reactive oxygen species(ROS) and antioxidant enzyme; thereby, causing defective insulin secretion. METHODS: HIT-T15 cells were treated with H2O2(20, 50 and 100micrometer) directly added to the culture media, and then intracellular peroxide and insulin mRNA were then measured. The effects of H2O2 on the total peroxide level and insulin secretion were also examined. Isolated pancreatic islet cells from Wistar and 2 beta cell lines (INS-1, HIT-T15) were cultured in either a glucose or ribose (5.6, 11.1, 22.2, 30 and 50mM) containing culture media for 72hours. The intracellular peroxide was measured using flow cytometry and glucose stimulated insulin secretion(GSIS). RESULTS: The intracellular peroxide levels due to H2O2 in HIT-T15 cells were higher with a high concentration of H2O2, and the insulin mRNA in HIT-T15 cells decreased when the cells are treated with a high concentration H2O2. The insulin mRNA of the HIT-T15 cells cultured in a high concentration of ribose was lower than of those cultured in a low concentration of glucose. INS-1, HIT-T15 and rat islet cells, cultured for 72 hours, had progressively greater peroxide levels with higher concentrations of both glucose and ribose. The GSIS in the cells cultured in high concentrations of both glucose and ribose were decreased. CONCLUSION: These results suggest only one potential central mechanism for glucose toxicity in beta cells, this being the formation of excess ROS.

The Effect of cAMP-Elevating Agents on High Glucose-Induced Apoptosis of Isolated Islets of Rat Pancreas.: Gwan Pyo Koh, Kwang Sik Suh, Suk Chon, Seung Joon Oh, Jeong Taek Woo, Sung Woon Kim, Jin Woo Kim, Young Seol Kim, Sun Hee Kwon; Korean Diabetes J. 2004;28(6):490-500. Published online December 1, 2004

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Abstract PDF: BACKGROUND
High glucose-induced apoptosis has been implicated in the loss of beta-cells of the pancreatic islets in animal models of type 2 diabetes. GLP-1 has been shown to reduce apoptosis by the cAMP-dependent mechanism in beta-cells. Other studies have also shown that elevated levels of intracellular cyclic AMP delayed apoptosis in other types of cells. We investigated whether cAMP-elevating agents could suppress the high glucose-induced apoptosis of isolated rat islets. METHODS: Pancreatic islets were isolated from Sprague-Dawley (SD) rats. The expression of phosphodiesterase (PDE) 3 subtypes was investigated by using extracts of freshly isolated islets and analyzing them by RT-PCR. After 2 days of isolation, the islets were cultured in RPMI-1640 media containing 5% FBS with various glucose concentrations (11.1, 16.7 and 27.8 mM), 5x10-6 M forskolin, 2x10-4 M 3-isobutyl-1-methylxanthine (IBMX), 10-5 M cilostazol, and 10-6, 5x10-6 and 10-5 M H-89 for 5 days. The islet apoptosis was measured by a sandwich enzyme-immunoassay using antihistone antibody. RESULTS: Apoptosis was lowest at 11.1 mM glucose concentration, and increased at higher glucose concentrations (1.00 +/- 0.04 A.U. (arbitrary unit) at 11.1 mM, 1.17 +/- 0.12 A.U. at 16.7 mM, and 1.65 +/-0.13 A.U. at 27.8 mM (P <0.05 for 11.1 mM). Both PDE 3A and 3B mRNA were expressed in the islet extracts. In 16.7 and 27.8 mM glucose concentrations, forskolin (P <0.01), IBMX (P <0.05) and cilostazol (P < 0.05) suppressed apoptosis of the islet cells. Protein kinase A (PKA) nhibitor, H-89, did not prevent the inhibition of apoptosis by forskolin. CONCLUSION: These results show that high glucose-induced apoptosis of the cells in rat islet is attenuated by such cAMP-elevating agents as cilostazol. However, cyclic AMP regulation of islet apoptosis may occur via a PKA-independent signaling pathway.

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