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Allen Volchuk - One of the best experts on this subject based on the ideXlab platform.
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action of protein disulfide isomerase on proInsulin exit from endoplasmic reticulum of pancreatic β cells
Journal of Biological Chemistry, 2012Co-Authors: Gautam Rajpal, Ming Liu, Irmgard Schuiki, Allen Volchuk, Peter ArvanAbstract:For Insulin Synthesis, the proInsulin precursor is translated at the endoplasmic reticulum (ER), folds to include its three native disulfide bonds, and is exported to secretory granules for processing and secretion. Protein disulfide isomerase (PDI) has long been assumed to assist proInsulin in this process. Herein we have examined the effect of PDI knockdown (PDI-KD) in β-cells. The data establish that upon PDI-KD, oxidation of proInsulin to form native disulfide bonds is unimpaired and in fact enhanced. This is accompanied by improved proInsulin exit from the ER and increased total Insulin secretion, with no evidence of ER stress. We provide evidence for direct physical interaction between PDI and proInsulin in the ER of pancreatic β-cells, in a manner requiring the catalytic activity of PDI. In β-cells after PDI-KD, enhanced export is selective for proInsulin over other secretory proteins, but the same effect is observed for recombinant proInsulin trafficking upon PDI-KD in heterologous cells. We hypothesize that PDI exhibits unfoldase activity for proInsulin, increasing retention of proInsulin within the ER of pancreatic β-cells.
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grp78 but not protein disulfide isomerase partially reverses hyperglycemia induced inhibition of Insulin Synthesis and secretion in pancreatic β cells
Journal of Biological Chemistry, 2009Co-Authors: Liling Zhang, Allen Volchuk, Elida Lai, Tracy TeodoroAbstract:Abstract Chronic hyperglycemia contributes to pancreatic β-cell dysfunction during the development of type 2 diabetes. Treatment of pancreatic β-cells with prolonged high glucose concentrations has been shown to reduce Insulin promoter activity and Insulin gene expression. Here, we examined the effect of high glucose on endoplasmic reticulum (ER) stress pathway activation and Insulin production in INS-1 832/13 pancreatic β-cells. Treatment of cells with 25 mm glucose for 24-48 h decreased Insulin mRNA and protein levels and reduced the proInsulin translation rate, which was accompanied by enhanced unfolded protein response pathway activation (XBP-1 mRNA splicing and increased phospho-eIF2α, CHOP, and active ATF6 levels). Overexpressing the ER chaperone GRP78 partially rescued high glucose-induced suppression of proInsulin levels and improved glucose-stimulated Insulin secretion with no effect on Insulin 2 mRNA levels. Under these conditions, there was little effect of GRP78 overexpression on ER stress markers. Knockdown of GRP78 expression under basal glucose conditions reduced cellular Insulin levels and glucose-stimulated Insulin secretion. Thus, GRP78 is essential for Insulin bioSynthesis, and enhancing chaperone capacity can improve β-cell function in the presence of prolonged hyperglycemia. In contrast, overexpression of the ER chaperone and oxidoreductase protein-disulfide isomerase (PDI) reduced glucose-stimulated Insulin secretion and induced ER stress resulting from the accumulation of proInsulin in the ER. These results suggest a role for both GRP78 and PDI in Insulin bioSynthesis, although an excess of PDI disrupts normal proInsulin processing.
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grp78 but not protein disulfide isomerase partially reverses hyperglycemia induced inhibition of Insulin Synthesis and secretion in pancreatic β cells
Journal of Biological Chemistry, 2009Co-Authors: Liling Zhang, Allen Volchuk, Elida Lai, Tracy TeodoroAbstract:Chronic hyperglycemia contributes to pancreatic beta-cell dysfunction during the development of type 2 diabetes. Treatment of pancreatic beta-cells with prolonged high glucose concentrations has been shown to reduce Insulin promoter activity and Insulin gene expression. Here, we examined the effect of high glucose on endoplasmic reticulum (ER) stress pathway activation and Insulin production in INS-1 832/13 pancreatic beta-cells. Treatment of cells with 25 mm glucose for 24-48 h decreased Insulin mRNA and protein levels and reduced the proInsulin translation rate, which was accompanied by enhanced unfolded protein response pathway activation (XBP-1 mRNA splicing and increased phospho-eIF2alpha, CHOP, and active ATF6 levels). Overexpressing the ER chaperone GRP78 partially rescued high glucose-induced suppression of proInsulin levels and improved glucose-stimulated Insulin secretion with no effect on Insulin 2 mRNA levels. Under these conditions, there was little effect of GRP78 overexpression on ER stress markers. Knockdown of GRP78 expression under basal glucose conditions reduced cellular Insulin levels and glucose-stimulated Insulin secretion. Thus, GRP78 is essential for Insulin bioSynthesis, and enhancing chaperone capacity can improve beta-cell function in the presence of prolonged hyperglycemia. In contrast, overexpression of the ER chaperone and oxidoreductase protein-disulfide isomerase (PDI) reduced glucose-stimulated Insulin secretion and induced ER stress resulting from the accumulation of proInsulin in the ER. These results suggest a role for both GRP78 and PDI in Insulin bioSynthesis, although an excess of PDI disrupts normal proInsulin processing.
Asru K Sinha - One of the best experts on this subject based on the ideXlab platform.
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the control of hyperglycemia by estriol and progesterone in alloxan induced type i diabetes mellitus mice model through hepatic Insulin Synthesis
International journal of biomedical science : IJBS, 2014Co-Authors: Suman Bhattacharya, Sarbashri Bank, Smarajit Maiti, Asru K SinhaAbstract:As much as 20% of the women in menopause are reported to develop type I diabetes mellitus. The cessation of the ovarian syntheses of the female sex hormones is known to cause menopause in women, and the roles of estriol (one of the most abundant estrogens) and progesterone were investigated for hepatic Insulin Synthesis through estriol and progesterone induced Synthesis of nitric oxide in the liver cells. Type 1 Diabetic mellitus mice were prepared by alloxan treatment, Nitric oxide was determined by methemoglobin method. Insulin was determined by enzyme linked immunosorbant assay. Injection of either 3.5 µM estriol or 3.5 nM progesterone to the diabetic mice which cannot synthesize pancreatic Insulin, reduced the blood glucose level from 600 mg/dl to 120 mg/dl and 500 ± 25 mg/dl to 120 ± 6 mg/dl in 6 and 10 h respectively with simultaneous increase of the plasma Insulin from 0 µunits/ml to 40 µunits/ml and 0 µunits/ml to 9.5 µunits/ml in the case of estriol and progesterone respectively with stimulated NO Synthesis. The inhibition of the steroids induced NO Synthesis by using NAME (NG-methyl-l-arginine acetate ester) in the reaction mixture resulted in the inhibition of hepatic Insulin Synthesis. Use of pure NO solution in 0.9% NaCl instead of either estriol or progesterone in the reaction mixture was found to stimulate the hepatic Insulin Synthesis. Both estriol and progesterone might be involved in the prevention of type 1 diabetes mellitus through the hepatic Insulin Synthesis even when the pancreatic Insulin Synthesis was impaired.
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the activation by glucose of liver membrane nitric oxide synthase in the Synthesis and translocation of glucose transporter 4 in the production of Insulin in the mice hepatocytes
PLOS ONE, 2013Co-Authors: Suman Bhattacharya, Rajeshwary Ghosh, Smarajit Maiti, Gausal A Khan, Asru K SinhaAbstract:Introduction Glucose has been reported to have an essential role in the Synthesis and secretion of Insulin in hepatocytes. As the efflux of glucose is facilitated from the liver cells into the circulation, the mechanism of transportation of glucose into the hepatocytes for the Synthesis of Insulin was investigated. Methods Grated liver suspension (GLS) was prepared by grating intact liver from adult mice by using a grater. Nitric oxide (NO) was measured by methemoglobin method. Glucose transporter-4 (Glut-4) was measured by immunoblot technique using Glut-4 antibody. Results Incubation of GLS with different amounts of glucose resulted in the uptake of glucose by the suspension with increased NO Synthesis due to the stimulation of a glucose activated nitric oxide synthase that was present in the liver membrane. The inhibition of glucose induced NO Synthesis resulted in the inhibition of glucose uptake. Glucose at 0.02M that maximally increased NO Synthesis in the hepatocytes led to the translocation and increased Synthesis of Glut-4 by 3.3 fold over the control that was inhibited by the inhibition of NO Synthesis. The glucose induced NO Synthesis was also found to result in the Synthesis of Insulin, in the presence of glucose due to the expression of both proInsulin genes I and II in the liver cells. Conclusion It was concluded that glucose itself facilitated its own transportation in the liver cells both via Glut-4 and by the Synthesis of NO which had an essential role for Insulin Synthesis in the presence of glucose in these cells.
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the role of dermcidin isoform 2 a two faceted atherosclerotic risk factor for coronary artery disease and the effect of acetyl salicylic acid on it
Thrombosis, 2012Co-Authors: Rajeshwary Ghosh, Rabindra Bhattacharya, Uttam K Maji, Asru K SinhaAbstract:Hypertension and diabetes mellitus are considered to be two major atherosclerotic risk factors for coronary artery disease (CAD). A stress-induced protein identified to be dermcidin isoform 2 of Mr. 11 kDa from blood plasma of hypertensive persons when injected (0.1 μM) in rabbits increased the systolic pressure by 77% and diastolic pressure by 45% over the controls within 2 h. Ingestion of acetyl salicylic acid (150 mg/70 kg) by these subjects reduced systolic (130 mm Hg) and diastolic pressures (80 mm Hg) with reduction of plasma dermcidin level to normal ranges (9 nM). The protein was found to be a potent activator of platelet cyclooxygenase and inhibited Insulin Synthesis. Aspirin was found to reduce hypertension by reduction of plasma dermcidin level, neutralized the effect of cyclooxygenase, and restored the pancreatic Insulin Synthesis through NO Synthesis. These results indicated that dermcidin could be a novel atherosclerotic risk factor for its hypertensive and diabetogenic effects.
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doi:10.1155/2012/987932 Clinical Study The Role of Dermcidin Isoform 2: A Two-Faceted Atherosclerotic Risk Factor for Coronary Artery Disease and the Effect of Acetyl Salicylic Acid on It
2011Co-Authors: Rajeshwary Ghosh, Rabindra Bhattacharya, Uttam K Maji, Asru K SinhaAbstract:Copyright © 2012 Rajeshwary Ghosh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hypertension and diabetes mellitus are considered to be two major atherosclerotic risk factors for coronary artery disease (CAD). A stress-induced protein identified to be dermcidin isoform 2 of Mr. 11 kDa from blood plasma of hypertensive persons when injected (0.1 μM) in rabbits increased the systolic pressure by 77 % and diastolic pressure by 45 % over the controls within 2 h. Ingestion of acetyl salicylic acid (150 mg/70 kg) by these subjects reduced systolic (130 mm Hg) and diastolic pressures (80 mm Hg) with reduction of plasma dermcidin level to normal ranges (9 nM). The protein was found to be a potent activator of platelet cyclooxygenase and inhibited Insulin Synthesis. Aspirin was found to reduce hypertension by reduction of plasma dermcidin level, neutralized the effect of cyclooxygenase, and restored the pancreatic Insulin Synthesis through NO Synthesis. These results indicated that dermcidin could be a novel atherosclerotic risk factor for its hypertensive and diabetogenic effects. 1
Rajeshwary Ghosh - One of the best experts on this subject based on the ideXlab platform.
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the activation by glucose of liver membrane nitric oxide synthase in the Synthesis and translocation of glucose transporter 4 in the production of Insulin in the mice hepatocytes
PLOS ONE, 2013Co-Authors: Suman Bhattacharya, Rajeshwary Ghosh, Smarajit Maiti, Gausal A Khan, Asru K SinhaAbstract:Introduction Glucose has been reported to have an essential role in the Synthesis and secretion of Insulin in hepatocytes. As the efflux of glucose is facilitated from the liver cells into the circulation, the mechanism of transportation of glucose into the hepatocytes for the Synthesis of Insulin was investigated. Methods Grated liver suspension (GLS) was prepared by grating intact liver from adult mice by using a grater. Nitric oxide (NO) was measured by methemoglobin method. Glucose transporter-4 (Glut-4) was measured by immunoblot technique using Glut-4 antibody. Results Incubation of GLS with different amounts of glucose resulted in the uptake of glucose by the suspension with increased NO Synthesis due to the stimulation of a glucose activated nitric oxide synthase that was present in the liver membrane. The inhibition of glucose induced NO Synthesis resulted in the inhibition of glucose uptake. Glucose at 0.02M that maximally increased NO Synthesis in the hepatocytes led to the translocation and increased Synthesis of Glut-4 by 3.3 fold over the control that was inhibited by the inhibition of NO Synthesis. The glucose induced NO Synthesis was also found to result in the Synthesis of Insulin, in the presence of glucose due to the expression of both proInsulin genes I and II in the liver cells. Conclusion It was concluded that glucose itself facilitated its own transportation in the liver cells both via Glut-4 and by the Synthesis of NO which had an essential role for Insulin Synthesis in the presence of glucose in these cells.
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the role of dermcidin isoform 2 a two faceted atherosclerotic risk factor for coronary artery disease and the effect of acetyl salicylic acid on it
Thrombosis, 2012Co-Authors: Rajeshwary Ghosh, Rabindra Bhattacharya, Uttam K Maji, Asru K SinhaAbstract:Hypertension and diabetes mellitus are considered to be two major atherosclerotic risk factors for coronary artery disease (CAD). A stress-induced protein identified to be dermcidin isoform 2 of Mr. 11 kDa from blood plasma of hypertensive persons when injected (0.1 μM) in rabbits increased the systolic pressure by 77% and diastolic pressure by 45% over the controls within 2 h. Ingestion of acetyl salicylic acid (150 mg/70 kg) by these subjects reduced systolic (130 mm Hg) and diastolic pressures (80 mm Hg) with reduction of plasma dermcidin level to normal ranges (9 nM). The protein was found to be a potent activator of platelet cyclooxygenase and inhibited Insulin Synthesis. Aspirin was found to reduce hypertension by reduction of plasma dermcidin level, neutralized the effect of cyclooxygenase, and restored the pancreatic Insulin Synthesis through NO Synthesis. These results indicated that dermcidin could be a novel atherosclerotic risk factor for its hypertensive and diabetogenic effects.
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The appearance of dermcidin isoform 2, a novel platelet aggregating agent in the circulation in acute myocardial infarction that inhibits Insulin Synthesis and the restoration by acetyl salicylic acid of its effects
Journal of Thrombosis and Thrombolysis, 2011Co-Authors: Rajeshwary Ghosh, Rabindra Bhattacharya, Soumendra Krishna Karmohapatra, Mau Bhattacharyya, Gorachand Bhattacharya, A. Kumar SinhaAbstract:Hyperglycemia with severe reduction of plasma Insulin level is frequently associated with acute ischemic heart disease. Since Insulin is reported to be an anti thrombotic humoral factor, the mechanism of the impaired Insulin Synthesis was investigated. The plasma from the patients with acute myocardial infarction (AMI) was analyzed by SDS-polyacrylamide gel electrophoresis. Dermcidin isoform 2 (dermcidin) was determined by enzyme linked immunosorbent assay. Insulin Synthesis was determined by in vitro translation of glucose induced Insulin mRNA Synthesis in the pancreatic β cells. Nitric oxide (NO) was determined by methemoglobin method. SDS-polyacrylamide gel electrophoresis of AMI plasma demonstrated the presence of a novel protein band of Mr 11 kDa that was determined to be dermcidin. Addition of 0.1 μM dermcidin inhibited Insulin Synthesis by >65 fold compared to control through the inhibition of NO Synthesis in the pancreatic cells. The oral administration of 150 mg acetyl salicylic acid (aspirin) to the AMI patients increased the plasma Insulin level from 13 (median) to 143 μunits/dl (median) with concomitant decrease of plasma dermcidin level from 112 to 9 nM in these patients within 12 h. It was also found that while the injection of 3.0 ± 0.05 (n = 10) nmol dermcidin with 0.25 ± 0.03 μmol ADP/g body weight caused coronary thrombus in mice, ADP itself at this concentration failed to produce thrombus. These results indicated that dermcidin was a novel platelet aggregating agent, and potentiated the ADP induced thrombosis in the animal model as well as acutely inhibited glucose induced Insulin Synthesis.
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doi:10.1155/2012/987932 Clinical Study The Role of Dermcidin Isoform 2: A Two-Faceted Atherosclerotic Risk Factor for Coronary Artery Disease and the Effect of Acetyl Salicylic Acid on It
2011Co-Authors: Rajeshwary Ghosh, Rabindra Bhattacharya, Uttam K Maji, Asru K SinhaAbstract:Copyright © 2012 Rajeshwary Ghosh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hypertension and diabetes mellitus are considered to be two major atherosclerotic risk factors for coronary artery disease (CAD). A stress-induced protein identified to be dermcidin isoform 2 of Mr. 11 kDa from blood plasma of hypertensive persons when injected (0.1 μM) in rabbits increased the systolic pressure by 77 % and diastolic pressure by 45 % over the controls within 2 h. Ingestion of acetyl salicylic acid (150 mg/70 kg) by these subjects reduced systolic (130 mm Hg) and diastolic pressures (80 mm Hg) with reduction of plasma dermcidin level to normal ranges (9 nM). The protein was found to be a potent activator of platelet cyclooxygenase and inhibited Insulin Synthesis. Aspirin was found to reduce hypertension by reduction of plasma dermcidin level, neutralized the effect of cyclooxygenase, and restored the pancreatic Insulin Synthesis through NO Synthesis. These results indicated that dermcidin could be a novel atherosclerotic risk factor for its hypertensive and diabetogenic effects. 1
Riccardo Perfetti - One of the best experts on this subject based on the ideXlab platform.
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glp 1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells
Diabetes-metabolism Research and Reviews, 2003Co-Authors: Josephine M Egan, Angela Bulotta, Hongxiang Hui, Riccardo PerfettiAbstract:Glucagon-like peptide-1 (GLP-1) is an incretin hormone that, when given exogenously, is capable of normalizing blood glucose in individuals with type 2 diabetes. Until recently most of the research on this compound had been related to its Insulinotropic properties. However, GLP-1 also regulates Insulin Synthesis and proInsulin gene expression, as well as the components of the glucose-sensing machinery. In addition to regulating Insulin release, it is involved in regulating the secretion of at least two other islet hormones--glucagon and somatostatin. Extraislet effects of GLP-1 include a role in the central nervous system stress response, hypothalamic-pituitary function, and the suppression of gastric emptying. Recent studies from our own and other laboratories show that GLP-1 can regulate islet growth and is a differentiation factor of the endocrine pancreas. This leads us to propose that GLP-1 and GLP-1 receptor agonists, in the context of long-term treatment of type 2 diabetes, will have broader biological action on the endocrine pancreas than was earlier anticipated. We propose that GLP-1 is a growth factor for pancreatic endocrine cells and can increase islet cell mass. Here we review those reports that have highlighted its role as a factor for islet cell growth and differentiation.
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glp 1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells
Diabetes-metabolism Research and Reviews, 2003Co-Authors: Josephine M Egan, Angela Bulotta, Hongxiang Hui, Riccardo PerfettiAbstract:Glucagon-like peptide-1 (GLP-1) is an incretin hormone that, when given exogenously, is capable of normalizing blood glucose in individuals with type 2 diabetes. Until recently most of the research on this compound had been related to its Insulinotropic properties. However, GLP-1 also regulates Insulin Synthesis and proInsulin gene expression, as well as the components of the glucose-sensing machinery. In addition to regulating Insulin release, it is involved in regulating the secretion of at least two other islet hormones—glucagon and somatostatin. Extraislet effects of GLP-1 include a role in the central nervous system stress response, hypothalamic-pituitary function, and the suppression of gastric emptying. Recent studies from our own and other laboratories show that GLP-1 can regulate islet growth and is a differentiation factor of the endocrine pancreas. This leads us to propose that GLP-1 and GLP-1 receptor agonists, in the context of long-term treatment of type 2 diabetes, will have broader biological action on the endocrine pancreas than was earlier anticipated. We propose that GLP-1 is a growth factor for pancreatic endocrine cells and can increase islet cell mass. Here we review those reports that have highlighted its role as a factor for islet cell growth and differentiation. Copyright © 2003 John Wiley & Sons, Ltd.
Yonghui Shi - One of the best experts on this subject based on the ideXlab platform.
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effects of dietary oxidized tyrosine products on Insulin secretion via the thyroid hormone t3 regulated trβ1 akt mtor pathway in the pancreas
RSC Advances, 2017Co-Authors: Yinyi Ding, Xiangrong Cheng, Xue Tang, Fangfang Wang, Xingran Kou, Yonghui ShiAbstract:Oxidized tyrosine products (OTPs) have been detected in commercial foods with high protein content. Dityrosine (Dityr) is a typical oxidized tyrosine product. The previous studies in our lab demonstrated that dityrosine administration impaired glucose tolerance and suppressed the bio-function of thyroid hormone T3 of mice. The T3-activated Akt–mTOR signaling pathway plays important roles in Insulin Synthesis in pancreatic β cells. Due to the structural homology between dityrosine and T3, the molecular binding domain for these two compounds in TRβ1 might be the same site. Therefore, the present study investigates the potential impact of dietary OTPs on the pancreatic function. Sprague Dawley (SD) rats were fed a diet containing OTPs for 12 weeks. In addition, a 10 week gavage experiment using C57BL/J mice was performed to explore whether dityrosine was responsible for the injury induced by OTPs. The blood glucose, plasma Insulin levels, and plasma free thyroid hormones (THs) were then measured. After 12 week dietary OTPs or 10 week OTPs/dityrosine gavage, elevated fasting blood glucose and decreased plasma Insulin levels were detected both in rats and mice in the presence of enhanced plasma free THs content, which indicated dysfunction of the pancreatic islets and that the regulation of T3 to Insulin Synthesis was suppressed by OTPs and dityrosine. A cell experiment using mouse MIN-6 cells was performed to explore the mechanism of the diminished T3 bio-function in pancreatic islets induced by dityrosine. Dityrosine incubation attenuated the T3-mediated Insulin Synthesis via an indirect way of regulating the mRNA expression of genes related to Insulin Synthesis and decreasing the protein level of TRβ1. In addition, dityrosine inhibited the Akt phosphorylation activated by T3 in MIN-6 cells. Dityrosine treatment altered the T3-activated translation factors involved in the Akt–mTOR signaling pathway. These findings indicate that decreased Insulin secretion triggered by dietary OTPs may be mediated by suggested T3-stimulated protein Synthesis in pancreatic β cells.
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dityrosine administration induces dysfunction of Insulin secretion accompanied by diminished thyroid hormones t3 function in pancreas of mice
Amino Acids, 2017Co-Authors: Yinyi Ding, Xiangrong Cheng, Yumei Ran, Yonghui ShiAbstract:Oxidized tyrosine products are commonly found in food with high protein content and have been demonstrated to cause damage of liver and kidney in our previous studies. Dityrosine (Dityr) is a typical oxidized tyrosine product. Due to its structural homology with thyroid hormones T3, we assumed that one of the endocrine systems most likely considered in connection with its disruption by Dityr may be the T3 action. T3 plays important roles in Insulin Synthesis, and thyroid hormone resistance (RTH) is associated with the impairment of glucose metabolism. Therefore, this study determined whether Dityr exposure impaired T3 function in pancreas leading to glucose metabolism disruption. After 10-week gavage with Dityr, mice exhibited impaired glucose tolerance and disturbed energy metabolism. The elevated free THs content in plasma, the up-regulation of THs Synthesis-specific genes expressions in thyroid glands, and the increased thyroid follicles histology shapes and areas indicated that Dityr enhanced the THs Synthesis in thyroid glands. In addition, Dityr-induced RTH, which reflected as elevated plasma free THs in the presence of unsuppressed thyroid stimulating hormone. The mRNA downregulation of membrane transporter of T3 (MCT8) and co-activator factors (RXRα, Src-1), together with the decreased protein level of thyroid hormone receptor β1 (TRβ1) in pancreas illustrated that the activation ability of T3 to downstream gene involved in Insulin Synthesis was suppressed by Dityr. In MIN-6 cell experiment, T3 improved glucose-stimulated Insulin secretion by upregulating mRNA levels of Insulin Synthesis-related genes (Ins2, MafA, Pdx1) and T3 action-related genes, as well as increasing protein level of TRβ1. These data suggest that Dityr suppress T3-regulated Insulin Synthesis stimulated by glucose via an indirect way of decreasing sensibility to T3 in pancreas. All these findings indicate that Dityr can disrupt THs function in pancreas leading to glucose metabolism disorder.
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effect of dietary oxidized tyrosine products on Insulin secretion via the oxidative stress induced mitochondria damage in mice pancreas
RSC Advances, 2017Co-Authors: Yinyi Ding, Xiangrong Cheng, Yuhui Yang, Yonghui ShiAbstract:Oxidized tyrosine products (OTPs) have been detected in commercial food and have been demonstrated to induce oxidative damage in vivo. The pancreas plays an important role in glucose metabolism, but its antioxidant capacity is low. The present study investigates the potential impact of dietary OTPs on the pancreatic function. Sprague Dawley (SD) rats (8 rats per group) were fed a diet containing OTPs for 24 weeks, and the blood glucose and plasma Insulin levels were then measured. Elevated fasting blood glucose and decreased plasma Insulin levels indicated dysfunction of the pancreatic islets. The rats fed the OTPs-containing diet also exhibited pancreatic oxidative stress, accompanied by inflammation. Furthermore, the expression of genes involved in the Nrf2/ARE pathway was down-regulated in the OTPs-treated groups. In addition, supplementation with lipoic acid (LA) significantly remitted the OTPs induced oxidative stress of the pancreas, and mitigated the effects of OTPs on the blood glucose and Insulin Synthesis. A gavage experiment was performed to explore whether dityrosine (Dityr), a major component of OTPs, was responsible for the injury induced by OTP. The OTPs, including Dityr, induced mitochondrial defects in cultured mice Insulinoma MIN-6 cells and mice pancreas, as evidenced by less ATP production, loss of mitochondrial membrane potential, mitochondrial DNA (mtDNA) depletion, and alteration of the mRNA levels of genes involved in mitochondrial function. Moreover, the apoptosis of pancreatic islets and MIN-6 cells increased after exposure to OTPs/Dityr. The findings suggest that decreased Insulin secretion triggered by OTPs may be mediated by oxidative stress and mitochondrial damage in pancreatic β cells.