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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The early stages of insulin-dependent diabetes mellitus are characterized by a selective inability to secrete insulin in response to glucose, coupled to a better response to nonnutrient secretagogues. The deficient glucose response may be a result of the autoimmune process directed toward the beta-cells. Interleukin-1 (IL-1) has been suggested to be one possible mediator of immunological damage of the beta-cells. In the present study we characterized the sensitivity of beta-cells to different secretagogues after human recombinant IL-1 beta (rIL-1 beta) exposure. Furthermore, experiments were performed to clarify the biochemical mechanisms behind the defective insulin response observed in these islets. Rat pancreatic islets were isolated and kept in tissue culture (medium RPMI-1640 plus 10% calf serum) for 5 days. The islets were subsequently exposed to 60 pM human recombinant IL-1 beta during 48 h in the same culture conditions as above and examined immediately after IL-1 exposure. The rIL-1 beta-treated islets showed a marked reduction of glucose-stimulated insulin release. Stimulation with arginine plus different glucose concentrations, and leucine plus glutamine partially counteracted the rIL-1 beta-induced reduction of insulin release. The activities of the glycolytic enzymes hexokinase, glucokinase, and glyceraldehyde 3-phosphate dehydrogenase, were similar in control and IL-1-exposed islets. Treatment with IL-1 also did not impair the activities of NADH+- and NADPH+-dependent glutamate dehydrogenase, glutamate-aspartate transaminase, glutamate-alanine transaminase, citrate synthase, and NAD+-linked isocitrate dehydrogenase. The oxidation of D-[6-14C]glucose and L-[U-14C]leucine were decreased by 50% in IL-1-treated islets. Furthermore, there was a significant decrease in the ratios of [2-14C]pyruvate oxidation/[1-14C]pyruvate decarboxylation and L-[U-14C]leucine oxidation/L-[1-14C]leucine decarboxylation, indicating that IL-1 decreases the proportion of generated acetyl-coenzyme-A residues undergoing oxidation. However, in the presence of IL-1 there was a significant increase in L-[U-14C]glutamate oxidation. These combined observations suggest that exposure to IL-1 induces a preferential decrease in glucose-mediated insulin release and mitochondrial glucose metabolism. This mitochondrial dysfunction seems to reflect an impairment in proximal steps of the Krebs cycle. It is conceivable that the IL-1-induced suppression and shift in islet metabolism can be an explanation for the beta-cell insensitivity to glucose observed in the early phases of human and experimental insulin-dependent diabetes mellitus.
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PMID:Differential sensitivity to beta-cell secretagogues in cultured rat pancreatic islets exposed to human interleukin-1 beta. 266 6

We performed both ex vivo and in vivo fluorometric analyses of pyridine nucleotides (PN) in rabbit and rat lenses. Rabbit lens PN fluorescence (99% NADH) was found to have an excitation maximum at 366 nm and an emission maximum at 462 nm (366:462). The only other fluorescent chromophore in that region of the spectrum has excitation and emission peaks at 328 and 460 nm, respectively. Anaerobic glycolysis in the lens was stimulated by KCN, a known inhibitor of mitochondrial respiration, after which a time-study of fluorescence intensities was performed. Over the course of a 3.5 hr period following treatment with KCN, the PN signal showed a statistically significant increase relative to that in the control lenses (those treated with KCl). while the 328:460 signal (which may be due to some protein involved in energy transfer with the PN) had a significantly greater decrease. We also found that fluorescence intensity of NADH in solution is linearly proportional to physiologic-range concentration. Moreover, there was a close correlation between fluorescence intensity of rat lens PN as measured on a specular microscope-coupled redox fluorometer capable of in vivo use, and the lens PN levels as determined by the analytical cycling assay technique. This fluorometer was then employed to assess the redox state in rats with streptozotocin-induced diabetes. The normalized ratio of PN to flavoproteins (Fp) in the lens epithelium increased from 0.96 +/- 0.12 in the normal state to 1.48 +/- 0.30 2 weeks after diabetes induction. In contrast, the ratio in the diabetic lens treated with an aldose reductase inhibitor, sorbinil, did not increase. The increase in the PN:Fp ratio therefore reflects activation of the polyol pathway and its associated metabolic activities, which results in an increase in the NADH:NAD ratio in the diabetic rat lenses. Our results indicate that the non-invasive, real-time method of redox fluorometry may be useful in the early detection and evaluation of cataracts and other disorders in lens metabolism, long before opacities occur. It can be used to monitor the disease process and evaluate the efficacy of such drugs as aldose reductase inhibitors on a biochemical level.
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PMID:Lens redox fluorometry: pyridine nucleotide fluorescence and analysis of diabetic lens. 279 31

The number of beta-adrenergic receptors in cardiac myocytes isolated from rats made diabetic with streptozocin (STZ) for 10 wk was measured by use of a hydrophilic nonselective antagonist [3H]CGP 12177 and was found to decrease to 59% of the number in control rats (P less than .05), without any change in affinity. Similarly, using [125I]iodocyanopindolol as a ligand, we found a decrease in the beta-adrenergic-receptor number on cardiac plasma membrane isolated from the diabetic rats [29% decrease (P less than .05) at 1 wk, 50% (P less than .01) at 3 wk, and 49% (P less than .01) at 10 wk compared with control rats]. However, the serum triiodothyronine level that had been known to modulate the beta-adrenergic-receptor-adenylate cyclase system was decreased in the 1-wk-diabetic rats but not in the 10-wk-diabetic rats compared with each control group. Furthermore, there was no difference in urinary catecholamine excretion between diabetic and control groups. In the 10-wk-diabetic rats, the response of adenylate cyclase to isoproterenol was significantly defective (56% decrease compared with control rats; P less than .05), although both the basal and the forskolin-stimulated maximum adenylate cyclase activities and a half-maximum concentration of isoproterenol for the stimulation of adenylate cyclase were similar in control and diabetic rats. On the other hand, both cholera toxin-dependent and islet-activating protein-dependent [32P]NAD incorporations into cardiac plasma membrane were markedly increased in the diabetic rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1988 Sep
PMID:Deficiency of cardiac beta-adrenergic receptor in streptozocin-induced diabetic rats. 284 11

Transglutaminase activity in rat islet homogenates was increased after preincubation of the islets at high glucose concentration, and severely decreased after preincubation in the presence of either 1,2-bis(2-chloroethyl)-1-nitrosurea or 2-cyclohexene-1-one. The stimulatory action of glucose was still observed when the islets were preincubated in the absence or extracellular Ca2+. The enzymic activity was decreased by NAD+ or NADP+ but not NADH or NADPH, and inhibited by GSSG more than by GSH. These findings suggest that the glucose-induced activation of transglutaminase may be related to induction of a more reduced redox state with subsequent change in thiol-disulfide balance.
Diabetes Res 1986 Mar
PMID:Glucose-induced activation of transglutaminase in pancreatic islets. 287 59

Isolated mouse liver mitochondria incubated with streptozotocin showed decreased rate and extent of Ca2+ uptake, and, dependent on the concentration of streptozotocin and the addition of alpha-ketoglutarate, glutamate, fluorocitrate or guanosine 5'-triphosphate, the retention of Ca2+ was either increased or decreased. Similar observations were made in liver mitochondria incubated with succinyl-CoA. In mitochondria isolated from the kidneys and islets of mice injected with streptozotocin, with and without additional injections of glucose and/or glucagon, the rate and extent of Ca2+ uptake were reduced and the release of accumulated Ca2+ was stimulated. Electron microscopy and X-ray microanalysis showed dislocation of Ca2+-containing precipitates from the mitochondria to the cytosol, and stereology disclosed increased mitochondrial volume in the B cells of streptozotocin-treated mice. State 3 and state 4 respiration with NAD-linked substrates was inhibited, but succinate oxidation was unaffected, in mitochondria isolated from the kidneys of mice treated with streptozotocin. In the kidneys of streptozotocin-injected mice, the concentration of succinyl-CoA was increased, that of citrate and guanosine 5'-triphosphate was decreased, that of glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-diphosphate was unaffected, and the metabolite concentration ratios suggested increased mitochondrial [NAD+]/[NADH] ratio and decreased cytoplasmic [NAD+]/[NADH] ratio. It is suggested as a new hypothesis that the cytotoxicity and the diabetogenicity of streptozotocin are dependent on inhibited citric acid cycle enzyme activity (primarily that of succinyl-CoA synthetase and citrate synthetase) with altered metabolite concentrations, leading to impairment of the mitochondrial uptake of Ca2+ and the activation of the pyruvate, isocitrate and alpha-ketoglutarate dehydrogenases.
Diabetes Res Clin Pract
PMID:Mitochondrial changes and associated alterations induced in mice by streptozotocin administered in vivo and in vitro. 288 8

The initial step in streptozocin (STZ)-induced beta-cell toxicity has been hypothesized to be the alkylation of specific sites on DNA bases. The enzymatic removal of these lesions results in single-strand breaks that over-activate the nuclear enzyme poly(ADP-ribose) synthetase and critically deplete the cell of NAD. Our studies were performed to quantitatively evaluate the extent of DNA damage in beta-cells and correlate this damage with toxicity. Monolayer cultures of neonatal rat beta-cells were used to determine cytotoxicity and DNA damage after exposure to STZ or the aglycone N-methyl-N-nitrosourea (MNU). Toxicity in beta-cells was determined by correlating morphological alterations observed by phase-contrast microscopy with decrements in immunoreactive insulin release. The extent of DNA damage was determined by alterations in nucleoid density and quantitation of N7-methylguanine formation. Toxicity tests revealed that STZ and MNU were not toxic at equimolar concentrations. Streptozocin was toxic at 10(-3) M, whereas only mild toxicity was observed with MNU at 10(-2) M. Surprisingly, however, at equimolar concentrations the two drugs caused comparable DNA-strand breaks as evidenced by their ability to shift the nucleoid migration ratio in neutral sucrose gradients. Additionally, quantitation of N7-methylguanine formation after exposure to equimolar concentrations of the drugs demonstrated that the two alkylated DNA to the same extent. These findings suggest that factors in addition to the activation of poly(ADP-ribose) synthetase must be responsible for the toxicity seen with STZ, because MNU at a nonlethal concentration is capable of causing comparable DNA damage.
Diabetes 1986 Aug
PMID:Mechanisms of nitrosourea-induced beta-cell damage. Alterations in DNA. 294 32

Protein synthesis and degradation, and redox state were measured in soleus and extensor digitorum longus muscles of rats up to 12 days after injection of streptozotocin. Muscle growth was slower in these animals apparently due to slower protein synthesis throughout the duration of diabetes. Up to day 4 after injection of streptozotocin or withdrawal of insulin from treated, diabetic animals, the muscle ratio of lactate/pyruvate, an indicator of the cytoplasmic NAD+ redox couple, was lower and protein degradation was faster than in control muscles. Thereafter, the ratio of lactate/pyruvate was greater and protein degradation was slower than in size- or age-matched control muscles. Insulin treatment in vitro or in vivo increased lactate/pyruvate and decreased proteolysis. Therefore, in muscles of streptozotocin-diabetic rats, the initial increase and later fall in proteolysis, and the inhibition of proteolysis by insulin, may correlate with opposite changes in NADH/NAD+.
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PMID:Rat muscle protein turnover and redox state in progressive diabetes. 294 34

It has been hypothesized that the critical step in streptozocin (STZ)-induced beta-cell toxicity is the overactivation of the nuclear enzyme poly(ADP-ribose) synthetase resulting from DNA strand breaks. Overactivation of this enzyme leads to a lethal depletion of its substrate, NAD, in the beta-cell. However, recently it has been shown that a lethal concentration of STZ and a nontoxic concentration of its nitrosoamide moiety methylnitrosourea (MNU) damage beta-cell DNA to the same extent and cause comparable amounts of DNA strand breaks. This study was performed to determine whether STZ and MNU activate poly(ADP-ribose) synthetase to the same extent. Monolayer cultures of islet cells from neonatal rats were exposed to concentrations of MNU and STZ of 10(-3) to 10(-2) M. The results show that both chemicals caused comparable activation of the enzyme at all concentrations tested. These data demonstrate that activation of poly(ADP-ribose) synthetase alone is not the critical step in STZ-induced beta-cell toxicity. Based on this finding, it appeared possible that STZ may be selectively sequestered into some critical site in the beta-cell other than the nucleus. Therefore, studies were initiated with 14C-labeled STZ and MNU to determine whether STZ might be distributed in the beta-cell differently than MNU. Total cellular DNA and protein from both RINr (clone 38) and islet cell monolayers were separated on hydroxylapatite columns after exposure to 14C-labeled chemicals. The amount of label incorporated into each fraction was determined by liquid scintillation spectrometry, and the ratio of label incorporated in protein to that in DNA was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1988 Feb
PMID:Mechanisms of nitrosourea-induced beta-cell damage. Activation of poly (ADP-ribose) synthetase and cellular distribution. 296 35

A common mechanism has been proposed for the beta-cell toxins alloxan (ALX) and streptozocin (STZ) involving the formation of single-strand breaks in DNA that lead to the overactivation of the enzyme poly(ADP-ribose) synthetase and the critical depletion of its substrate NAD. If the toxins act via this common mechanism, the poly(ADP-ribose) synthetase inhibitors nicotinamide and thymidine would be expected to affect the formation of DNA single-strand breaks in a similar fashion. To test the effects of these inhibitors, the formation of single-strand breaks in the DNA of insulin-secreting RINr cells was monitored by assessing changes in the supercoiling of nucleoids after exposure to STZ, ALX, or methylnitrosourea (MNU). With the inclusion of nicotinamide or thymidine and STZ or MNU, more single-strand breaks in RINr cell DNA were detected. These results would be expected if nicotinamide and thymidine acted through inhibition of poly(ADP-ribose) synthetase. However, when the inhibitors were used in combination with ALX, fewer single-strand breaks were present. This suggests a reduction in ALX-induced hydroxyl radicals available to interact with DNA. Because nicotinamide has been demonstrated to be a hydroxyl-radical scavenger, the ability of thymidine to scavenge hydroxyl radicals was investigated. Thymidine, like nicotinamide, was found to be a potent scavenger of hydroxyl radicals. Thus, the mechanisms by which nicotinamide and thymidine protect against the toxic effects of STZ or ALX appear different. These findings suggest that the actions of beta-cell toxins are more complex than simply the overactivation of a single enzyme.
Diabetes 1988 Aug
PMID:Mechanisms of nicotinamide and thymidine protection from alloxan and streptozocin toxicity. 296 36

The reduction of oxygen by the ene-diol tautomer of simple monosaccharides produces hydrogen peroxide and alpha-oxoaldehydes. This process, termed monosaccharide autoxidation, occurs at physiological pH and temperature and may contribute to the development of several pathological processes. Enolization of the monosaccharide to an ene-diol tautomer is a prerequisite for the reaction of the monosaccharides with oxygen. The reaction kinetics suggest a two step process: the enolization of the monosaccharide to the ene-diol followed by the reaction of the ene-diol with oxygen. Free-radical reactive intermediates are formed by the reaction of the ene-diol with oxygen: superoxide, semidione, and 1-hydroxyalkyl radicals are formed under physiological conditions (hydroxyl radicals are also detected at high pH). The autoxidation of monosaccharides stimulates the oxidation of oxyhemoglobin in erythrocytes, producing methemoglobin and hydrogen peroxide, and the oxidation of reduced pyridine nucleotides NAD(P)H to the oxidized congener NAD(P)+ and enzymatically inactive nucleotide. This stimulates oxidative metabolism (via the hexose monophosphate shunt) and alpha-oxoaldehyde metabolism (via the glyoxalase system) in erythrocytes in vitro. The oxidative challenge is relatively mild even with very high concentrations (50 mM) of monosaccharide. However, crosslinking of membrane proteins by alpha-oxoaldehydes is enhanced; this effect may exacerbate ageing and decrease the lifetime of erythrocytes in circulation. In vivo, the autoxidation of monosaccharides is expected to be a chronic oxidative process occurring in biological tissue which utilises simple monosaccharides, e.g., in glycolysis and gluconeogenesis. Monosaccharide autoxidation is suggested to be a determinant in the control of cellular mitosis and ageing, providing physiological substrates for the glyoxalase system, and may contribute to the chronic disease processes associated with diabetes mellitus and the smoking of tobacco.
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PMID:Monosaccharide autoxidation in health and disease. 300 96


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