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Title: Cysteine analogues potentiate glucose-induced insulin release in vitro

Abstract

In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of actionmore » but differences in the affinity to the secretory system.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Univ. of Tuebingen, Germany, F.R.
OSTI Identifier:
6962575
Resource Type:
Journal Article
Resource Relation:
Journal Name: Diabetes; (United States); Journal Volume: 12
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; INSULIN; SECRETION; THIOLS; BIOLOGICAL EFFECTS; CYSTEINE; GLUCOSE; GLUTATHIONE; MEA; PENICILLAMINE; RATS; ALDEHYDES; AMINES; AMINO ACIDS; ANIMALS; CARBOHYDRATES; CARBOXYLIC ACIDS; CHELATING AGENTS; DRUGS; HEXOSES; HORMONES; MAMMALS; MONOSACCHARIDES; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANIC SULFUR COMPOUNDS; PEPTIDE HORMONES; PEPTIDES; POLYPEPTIDES; PROTEINS; RADIOPROTECTIVE SUBSTANCES; RODENTS; SACCHARIDES; VERTEBRATES; 560300* - Chemicals Metabolism & Toxicology

Citation Formats

Ammon, H.P., Hehl, K.H., Enz, G., Setiadi-Ranti, A., and Verspohl, E.J.. Cysteine analogues potentiate glucose-induced insulin release in vitro. United States: N. p., 1986. Web. doi:10.2337/diab.35.12.1390.
Ammon, H.P., Hehl, K.H., Enz, G., Setiadi-Ranti, A., & Verspohl, E.J.. Cysteine analogues potentiate glucose-induced insulin release in vitro. United States. doi:10.2337/diab.35.12.1390.
Ammon, H.P., Hehl, K.H., Enz, G., Setiadi-Ranti, A., and Verspohl, E.J.. 1986. "Cysteine analogues potentiate glucose-induced insulin release in vitro". United States. doi:10.2337/diab.35.12.1390.
@article{osti_6962575,
title = {Cysteine analogues potentiate glucose-induced insulin release in vitro},
author = {Ammon, H.P. and Hehl, K.H. and Enz, G. and Setiadi-Ranti, A. and Verspohl, E.J.},
abstractNote = {In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.},
doi = {10.2337/diab.35.12.1390},
journal = {Diabetes; (United States)},
number = ,
volume = 12,
place = {United States},
year = 1986,
month =
}
  • Purpose: To investigate bystander effects of low-dose-rate (LDR) {sup 125}I seed irradiation on human lung cancer cells in vitro. Methods and Materials: A549 and NCI-H446 cell lines of differing radiosensitivity were directly exposed to LDR {sup 125}I seeds irradiation for 2 or 4 Gy and then cocultured with nonirradiated cells for 24 hours. Induction of micronucleus (MN), {gamma}H2AX foci, and apoptosis were assayed. Results: After 2 and 4 Gy irradiation, micronucleus formation rate (MFR) and apoptotic rate of A549 and NCI-H446 cells were increased, and the MFR and apoptotic rate of NCI-H446 cells was 2.1-2.8 times higher than that ofmore » A549 cells. After coculturing nonirradiated bystander cells with {sup 125}I seed irradiated cells for 24 hours, MFR and the mean number of {gamma}H2AX foci/cells of bystander A549 and NCI-H446 cells were similar and significantly higher than those of control (p <0.05), although they did not increase with irradiation dose. However, the proportion of bystander NCI-H446 cells with MN numbers {>=}3 and {gamma}H2AX foci numbers 15-19 and 20-24 was higher than that of bystander A549 cells. In addition, dimethyl sulfoxide (DMSO) treatment could completely suppress the bystander MN of NCI-H446 cells, but it suppressed only partly the bystander MN of A549 cells, indicating that reactive oxygen species are involved in the bystander response to NCI-H446 cells, but other signaling factors may contribute to the bystander response of A549 cells. Conclusions: Continuous LDR irradiation of {sup 125}I seeds could induce bystander effects, which potentiate the killing action on tumor cells and compensate for the influence of nonuniform distribution of radiation dosage on therapeutic outcomes.« less
  • Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran–iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran–iron (15 mg/kg) for 3 weeks (D0–D20)more » and then (D21) a single sub-lethal intra-peritoneal injection of 6 mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran–iron (125–1000 μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+ 22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. - Highlights: • The effects of iron on cardiomyocytes were opposite to those on cancer cell lines. • In our model, iron overload did not potentiate anthracycline cardiotoxicity. • Chronic oxidative stress induced by iron could mitigate doxorubicin cardiotoxicity. • The role of iron in anthracycline-induced cardiotoxicity should be reconsidered.« less
  • In order to evaluate glucose tolerance following renal transplantation, intravenous glucose tolerance tests (IVGTT), with evaluation of hormonal responses to the intravenous glucose load and percent specific /sup 125/I-insulin binding to peripheral blood monocytes, were studied in eight clinically stable kidney transplant recipients. For comparison purposes, identical studies were done in eight control subjects and seven clinically stable hemodialysis patients. One transplant recipient was glucose intolerant, with fasting hyperglycemia, elevated HbA1C, and abnormal glucose decay constant. Impaired pancreatic insulin release appeared to be the major factor accounting for his glucose intolerance. The seven glucose-tolerant transplant recipients had significantly increased insulinmore » release during IVGTT compared to control subjects, and significant correlations were found among insulin release, glucose decay constant, and fasting blood sugar in those patients. Insulin binding to monocytes was significantly greater in transplant recipients than control subjects due to an increase in insulin binding capacity per cell. A significant correlation was found between percent specific /sup 125/I-insulin binding and steroid dose, expressed as mg/kg body weight/day, in those patients. Thus, chronic steroid administration does not cause glucose intolerance in transplant recipients who manifest steroid-associated increases in pancreatic insulin release and cellular insulin binding capacity.« less
  • L-Histidine, when tested at a 10-mM concentration, caused a rapid and sustained stimulation of insulin release from rat islets exposed to either D-glucose (7.0 or 8.3 mM) or L-leucine (10.0 mM). The stimulation of insulin release could not be ascribed to an increase in oxygen uptake, to the generation of histamine from L-histidine, or to its participation in a transglutaminase-catalyzed reaction. Like other cationic amino acids, however, L-histidine rapidly accumulated in islet cells, increased 86Rb outflow from prelabeled islets perifused in the presence or absence of extracellular Ca2+, and stimulated the entry of Ca2+ into islet cells. Yet, the amountmore » of exogenous L-histidine present in the islet cells with a positively charged side chain was estimated to be below the threshold value required for stimulation of insulin release by fully ionized cationic amino acids, such as L-arginine. Hence, the present findings argue against the view that the insulinotropic action of cationic amino acids is solely attributable to the accumulation of these positively charged molecules inside the islet B cell with subsequent depolarization of the plasma membrane.« less