Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human intoxication with the rodenticide Vacor [N-3-pyridylmethyl-N'-p-nitrophenyl urea or 1-(4-nitrophenyl)-3-(3-pyridylmethyl) urea] induces acute IDDM. We report here that Vacor specifically inhibits the NADH:ubiquinone reductase activity of complex I in mammalian mitochondria. The activity of other respiratory enzymes of mitochondria is unaffected by Vacor at concentrations that completely inhibit the redox and energetic function of complex I. Vacor inhibition of complex I activity quantitatively correlates with the inhibition of insulin release in insulinoma cells and pancreatic islets and is also consistent with the doses reported in cases of human poisoning. These results indicate that the toxic and diabetogenic action of Vacor primarily derives from the inhibition of mitochondrial respiration of NAD-linked substrates in the high-energy demanding cells of the pancreatic islets. This newly identified mechanism of the pathological effects resulting from Vacor intoxication could constitute a paradigm in which to understand environmental or metabolic causes of IDDM.
Diabetes 1996 Nov
PMID:Inhibition of mitochondrial complex I may account for IDDM induced by intoxication with the rodenticide Vacor. 886 57

The effects of troglitazone and pioglitazone on glucose and fatty acid metabolism were studied in hepatocytes isolated from 24-h-starved rats. These thiazolidinediones inhibited long-chain fatty acid (oleate) oxidation and produced a very oxidized mitochondrial redox state. By contrast, thiazolidinediones did not affect the rate of medium-chain fatty acid (octanoate) oxidation or the activity of mitochondrial carnitine palmitoyltransferase (CPT) I. Thiazolidinediones inhibited selectively triglyceride synthesis but not phospholipid synthesis. The combined inhibition of oleate oxidation and esterification by troglitazone was due to a noncompetitive inhibition of mitochondrial and microsomal long-chain acyl-CoA synthetase (ACS) activities. It was suggested that troglitazone must be metabolized into its sulfo-conjugate derivative in liver cells to inhibit mitochondrial and microsomal ACS activities. Thiazolidinediones inhibited glucose production from lactate/pyruvate or from alanine. Analysis of gluconeogenic metabolite concentrations suggested that troglitazone would inhibit gluconeogenesis at the level of pyruvate carboxylase and glyceraldehyde-3-phosphate dehydrogenase reactions. It was concluded that 1) at a similar concentration, troglitazone was more efficient than pioglitazone to inhibit fatty acid metabolism and gluconeogenesis and 2) the inhibition of gluconeogenesis by troglitazone could be the result of the inhibition of long-chain fatty acid oxidation (decrease in acetyl-CoA, NADH-to-NAD+, and ATP-to-ADP ratios).
Diabetes 1996 Nov
PMID:Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats. 886 61

Cataract remains the major cause of blindness worldwide and a common complication of diabetes. Polyol accumulation in the lens is associated with cataract formation. Here we present evidence for a novel pathway for xylitol production in the lens involving glucuronate metabolism. Xylitol can be produced in rat and bovine lens from glucose, via the enzymes myo-inositol-oxygen oxidoreductase, D-glucuronate reductase, L-gulonate NAD(+)-3-oxidoreductase and L-iditol-NAD(+)-5-oxidoreductase, which have been found in the mammalian lens for the first time. Glucuronate reductase has been purified and was inhibited by thiol quenching reagents. UDP-glucuronyl transferase is also present in mammalian lenses; this enzyme may be an anti-toxic defense mechanism in the lens.
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PMID:Accumulation of xylitol in the mammalian lens is related to glucuronate metabolism. 889 89

ADP-ribosylation of proteins has been observed in numerous animal tissues including chicken heterophils, rat brain, human platelets, and mouse skeletal muscle. ADP-ribosylation in these tissues is thought to modulate critical cellular functions such as muscle cell development, actin polymerization, and cytotoxic T lymphocyte proliferation. Specific substrates of the ADP-ribosyltransferases have been identified; the skeletal muscle transferase ADP-ribosylates integrin alpha 7 whereas the chicken heterophil enzyme modifies the heterophil granule protein p33 and the CTL enzyme ADP-ribosylates the membrane-associated protein p40. Transferase sequence has been determined which should assist in elucidating the role of ADP-ribosylation in cells. There is sequence similarity among the vertebrate transferases and the rodent RT6 alloantigens. The RT6 family of proteins are NAD glycohydrolases that have been shown to possess auto-ADP-ribosyltransferase activity whereas the mouse Rt6-1 is also capable of ADP-ribosylating histone. Absence of RT6+ T cells has been associated with the development of an autoimmune-mediated diabetes in rodents. Humans have an RT6 pseudogene and do not express RT6 proteins. The reversal of ADP-ribosylation is catalyzed by ADP-ribosylarginine hydrolases, which have been purified and cloned from rodent and human tissues. In principle, the transferases and hydrolases could form an intracellular ADP-ribosylation regulatory cycle. In skeletal muscle and lymphocytes, however, the transferases and their substrates are extracellular membrane proteins whereas the hydrolases described thus far are cytoplasmic. In cultured mouse skeletal muscle cells, processing of the ADP-ribosylated integrin alpha 7 was carried out by phosphodiesterases and possibly phosphatases, leaving a residual ribose attached to the (arginine)protein. Several bacterial toxin and eukaryotic mono-ADP-ribosyltransferases, and perhaps other NAD-utilizing enzymes such as the RT6 alloantigens share regions of amino acid sequence similarity, which form, in part, the catalytic site. The catalytic cleft, found in the bacterial toxins that have been studied thus far, contains a critical glutamate and other amino acids that function to position NAD for nucleophilic attack at the N-glycosidic linkage, for either ADP-ribose transfer or NAD hydrolysis. Amino acid differences among the transferases at the active site may be required for accommodating the different ADP-ribose acceptor molecules.
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PMID:Structure and function of eukaryotic mono-ADP-ribosyltransferases. 889 63

Streptozotocin, which induces diabetes mellitus in experimental animals, has been reported to be taken up by beta-cells by means of the glucose transporter 2 (GLUT2) and then reduce the cellular level of NAD+, leading to necrosis of the beta-cells. We investigated the effect of insulin pretreatment on the diabetogenic action of streptozotocin (60 mg/kg). Four groups of rats were studied: 1) a group that received streptozotocin (STZ), 2) a group that received insulin pretreatment and streptozotocin (INS + STZ), 3) a group that received insulin (INS), and 4) a control group (CTRL). Insulin treatment reduced the beta-cell immunoreactivity (IR) of insulin and GLUT2, which, thus, was reduced in INS + STZ rats at the time of streptozotocin injection. In STZ rats, plasma insulin concentrations after 3 weeks as well as insulin concentrations in pancreatic tissue samples were significantly lower than those in CTRL rats [plasma, 274.3 +/- 101.9 vs. 1078.8 +/- 254.9 pmol/liter (P < 0.05); tissue, 0.46 +/- 0.02 vs. 117.0 +/- 28.4 nmol/g (P < 0.01)]. INS + STZ rats did not become hyperglycemic, and the plasma and tissue levels of insulin were higher than those in STZ rats [plasma, 538.3 +/- 80.1 vs. 274.3 +/- 101.9 pmol/liter (P = 0.08); tissue, 0.46 +/- 0.02 vs. 37.90 +/- 2.13 nmol/g (P < 0.05)]. The immunohistochemical findings of insulin IR in the pancreatic tissues were in accordance with the results obtained by RIA. We conclude that exogenous insulin suppresses the expression of GLUT2 and insulin in beta-cells, and this may prevent the diabetogenic effect of streptozotocin.
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PMID:Short-term insulin treatment prevents the diabetogenic action of streptozotocin in rats. 897 86

In islet cells isolated from normal outbred Wistar rats, the known high vulnerability of islet cells toward oxygen radicals or nitric oxide can be abolished by inducing a stress response, such as by heat shock. We show here that islet cells from diabetes-prone BB rats are unable to mount such a protective response. Islet cells from diabetes-prone BB rats without recognizable insulitis were heat stressed. Subsequently, cells were exposed to nitric oxide, to oxygen radicals, or to the beta-cell toxin streptozotocin. While prior heat shock substantially increased the survival of toxin-treated Wistar rat islet cells, no protective stress response was noted for islet cells from diabetes-prone BB rats. Islet cells from diabetes-resistant BB rats were protected by heat stress to the same extent as Wistar rats. A survey of four additional major histocompatibility complex (MHC)-disparate rat strains confirmed the existence of a low and high responder type to stress. Parallel analysis of heat shock protein (hsp)70 induction by Western blot showed a low and high hsp70 response phenotype. A high hsp70 response coincided with a protective stress response. The presence (or absence) of a protective stress response correlated with the preservation (or loss) of intracellular NAD+ in toxin-treated islet cells. The lack of a protective stress response in islet cells from diabetes-prone BB rats, but not in diabetes-resistant BB rats, may promote beta-cell lysis and autoantigen release, and hence could be important for initiation or propagation of the disease process.
Diabetes 1997 Feb
PMID:Low stress response enhances vulnerability of islet cells in diabetes-prone BB rats. 900 Jun 99

Diabetes increases the incidence of cardiovascular disease as well as the complications of myocardial infarction. Studies using animal models of diabetes have demonstrated that the metabolic alterations occurring at the myocyte level may contribute to the severity of ischemic injury in diabetic hearts. Of the several mechanisms being investigated to understand the pathogenesis of diabetic complications, the increased metabolism of glucose via the polyol pathway has received considerable attention. Deviant metabolic regulation due to increased flux through aldose reductase in diabetic hearts may influence the ability of the myocardium to withstand ischemia insult. To determine if aldose reductase inhibition improves tolerance to ischemia, hearts from acute type I diabetic and nondiabetic control rats were isolated and retrograde perfused. Each group was exposed to 1 micromol/l zopolrestat, a specific inhibitor of aldose reductase, for 10 min, followed by 20 min of global ischemia and 60 min of reperfusion in the absence of zopolrestat. Zopolrestat reduced sorbitol levels before ischemia in diabetic hearts. The cytosolic redox state (NADH/NAD+), as measured by lactate-to-pyruvate ratios, was significantly lowered under baseline, ischemic, and reperfusion conditions in diabetic hearts perfused with zopolrestat. In these diabetic hearts, ATP was significantly higher in zopolrestat hearts during ischemia, as were phosphocreatine and left ventricular-developed pressure on reperfusion. Zopolrestat provided similar metabolic and functional benefits in nondiabetic hearts. Creatine kinase release was reduced by approximately 50% in both nondiabetic and diabetic hearts treated with zopolrestat. These data indicate that inhibition of aldose reductase activity preserves high-energy phosphates, maintains a lower cytosolic NADH/NAD+ ratio, and markedly protects both diabetic and nondiabetic hearts during ischemia and reperfusion.
Diabetes 1997 Feb
PMID:Aldose reductase inhibition protects diabetic and nondiabetic rat hearts from ischemic injury. 900 Jul 7

Oxidative stress in the course of diabetes mellitus can cause disturbance of lipid membranes of cellular organelles. The study is aimed at the determination of oxidative phosphorylation in mitochondria in rats with experimentally induced acute and chronic insulin-dependent diabetes mellitus (IDDM). IDDM was induced by single dose of streptozotocin (45 mg per kg-1). Insulin Interdep (6 U per kg-1) was administered once a day subcutaneously. The authors investigated glycaemia, cholesterol and triacylglycerol concentrations in the blood and liver. Isolation of mitochondria was succeeded by measurement of oxidative phosphorylation indicators after 8 days (acute IDDM) or after 8 weeks (chronic IDDM) from streptozotocin administration. The authors found out that both acute and chronic IDDM were concommited by hyperglycaemia. The group with acute IDDM yielded an increase in cholesterol and triacyglycerols concentrations in the blood, as well as that of cholesterol in the liver. The group with chronic IDDM yields an increase in cholesterol in the blood. Trialcylglycerols in the liver increased in none of the investigated groups. Liver steatosis did not occur. Indicators of oxidative phosphorylation in the liver mitochondria of rats with acute and with chronic IDDM decreased in contrast to healthy controls from NAD substrates glutamate and pyruvate and also form FAD substrate of succinate. Significant decrease in consumption of oxygen in the 3 state occurred, while in acute IDDM the decrease was more significant than in chronic IDDM. Phosphorylation rate significantly decreased in contrast to controls, but there was no difference between IDDM groups. The investigation results imply that in both acute and chronic IDDM there are decreased effectivity of energetic metabolism in liver mitochondria. (Tab. 5, Ref. 29.).
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PMID:[Bioenergetics of liver mitochondria in rats in experimental insulin-dependent diabetes]. 901 45

The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated with respect to its influence on cellular reducing equivalent homeostasis. The requirement of NADH and NADPH as cofactors in the cellular reduction of alpha-lipoic acid to dihydrolipoate has been reported in various cells and tissues. However, there is no direct evidence describing the influence of such reduction of alpha-lipoate on the levels of cellular reducing equivalents and homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this effect was relatively less and slower compared with that of NADH. A concentration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ and in lactate/pyruvate ratios were observed in alpha-lipoate-treated cells. Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate may have direct implications in diabetes, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic disorders. Under conditions of reductive stress, alpha-lipoate decreases high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms.
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PMID:Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications for diabetes and ischemic injury. 906 43

The effects of L-alanine on hepatic glucose production in diabetic rats and the corresponding controls was investigated. Diabetes was obtained with an injection iv of streptozotocin (STZ) or alloxan. Livers from diabetic and control rats after 24 hours of fasting were perfused in situ and glucose production from L-alanine and several gluconeogenic substrates were measured. Hepatic gluconeogenesis from L-alanine was absent in rats with diabetes induced by STZ or alloxan. STZ-diabetic rats also shown this metabolic change when the period of diabetes was prolonged. It was concluded that this effect may be partly at least, the consequence of an increased NADH/NAD+ ratio in the diabetic rat liver, which indicates that the cytosolic redox potential is favorable to pyruvate conversion to L-lactate but not to glucose. However, considering that glucose production from pyruvate, L-lactate, glycerol and sorbitol was not affected by the diabetic condition, the rate of conversion of L-alanine to pyruvate can contribute to the lack of gluconeogenesis when this amino acid was employed as a substrate.
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PMID:Hepatic glucose production from L-alanine is absent in perfused liver of diabetic rats. 909 Jul 51


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