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)

NAD levels markedly increase upon mitogen stimulation of lymphocytes from young subjects. In contrast, lymphocytes from old subjects do not increase NAD levels upon stimulation. A survey of 35 individuals aged 18-79 years revealed a significant age-dependent decrease in the NAD response to mitogen stimulation. No significant differences were noted in lymphocytes from age-matched individuals with Down's syndrome or diabetes mellitus. On the other hand, cultured skin fibroblasts showed elevated NAD levels with age. However, this effect appears to be due to increased size of the cells since the NAD/protein ratio is unchanged. Skin fibroblasts from patients with progeria exhibit much higher levels of NAD and protein per cell than age-matched controls.
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PMID:Changes in NAD levels in human lymphocytes and fibroblasts during aging and in premature aging syndromes. 622 88

Nicotinamide, a poly(ADP-ribose)synthetase inhibitor, protected NMRI mice against alloxan-induced hyperglycemia when given 10 min before, but not 10 min after, the injection of the drug. Pretreatment in vivo with nicotinamide induced hyperglycemia at the time of alloxan injection, and this could account for the protective action of nicotinamide against alloxan diabetes. Exposure of islets to alloxan (2 mM) in vitro caused a marked inhibition of both glucose-stimulated proinsulin biosynthesis and insulin release, and this was not affected by the action of nicotinamide. Alloxan-impaired islet glucose oxidation was partly restored by nicotinamide. The decreased islet content of NADH plus NAD, which was observed after alloxan treatment, could be prevented by nicotinamide. Glucose-stimulated islet oxygen uptake was abolished after treatment with alloxan, and nicotinamide had no protective effect in this process. Leucine (10 mM) plus glutamine (10 mM), however, were still able to evoke an islet respiratory response after alloxan exposure. Alloxan caused an immediate increase in the islet efflux of radiolabeled nucleotides, which was followed after about 5 min by a further increase. This latter increase of the radio efflux was inhibited by the addition of nicotinamide. The inability of nicotinamide to prevent the alloxan-induced impairment of proinsulin biosynthesis, insulin release, and oxygen uptake, together with the failure of nicotinamide to prevent the development of diabetes when given after alloxan, does not support a current hypothesis that the major cytotoxic effect of alloxan is primarily due to DNA damage. The present data suggest that organelles other than the nuclei, e.g., the mitochondria or the plasma membrane, are the primary sites of B-cell injury by alloxan.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1984 Oct
PMID:Nicotinamide does not protect islet B-cell metabolism against alloxan toxicity. 623 9

We have shown previously that alloxan and streptozotocin, two major diabetogenic agents, cause DNA strand breaks in rat pancreatic islets and stimulate nuclear poly(ADP-ribose) synthetase, thereby depleting intracellular NAD level and inhibiting proinsulin synthesis (Okamoto, H. (1981) Mol. Cell. Biochem. 37, 43-61; Yamamoto, H., Uchigata, Y., and Okamoto, H. (1981) Nature 294, 284-286). In the present study, superoxide dismutase and catalase, scavengers of radical oxygens, were found to protect against islet DNA strand breaks and inhibition of proinsulin synthesis induced by alloxan. The radical scavengers did not affect islet DNA strand breaks or inhibition of proinsulin synthesis induced by streptozotocin. On the other hand, compounds that inhibit islet nuclear poly(ADP-ribose) synthetase were found to protect against alloxan- as well as streptozotocin-induced inhibition of proinsulin synthesis. The poly(ADP-ribose) synthetase inhibitors were ineffective in protection against DNA strand breaks induced by the agents. These results may provide an important clue for elucidating the prevention of insulin-dependent diabetes as well as for understanding the cause of diabetes.
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PMID:Protection by superoxide dismutase, catalase, and poly(ADP-ribose) synthetase inhibitors against alloxan- and streptozotocin-induced islet DNA strand breaks and against the inhibition of proinsulin synthesis. 628 Dec 56

Alloxan and streptozotocin, which produce diabetes mellitus in experimental animals, have been known to inhibit various functions of pancreatic islets including proinsulin synthesis. However, little is known about the mechanisms underlying the action of these agents in pancreatic islets. Our recent in vivo and in vitro study using rats and isolated islets showed that one of the primary targets of the diabetogenic agents is the DNA of pancreatic islets. The first step is the generation of hydroxyl radical by alloxan which attacks DNA to produce strand breaks. In the case of streptozotocin, the alkylating activity of this compound may be causally related to its ability to induce DNA strand breaks. Subsequently, the fragmented DNA activates poly(ADP-ribose) synthetase which depletes cellular NAD. Since NAD is the most abundant of cellular coenzymes and participates in many biological reactions in mammalian cells, the reduction in intracellular NAD to such a nonphysiological level may severely affect islet cell functions including proinsulin synthesis. These results, in turn, raise the possibility that insulin-dependent diabetes may be preventable by inhibiting the occurrence of DNA strand breaks or the poly(ADP-ribose) synthetase. In fact, by poly(ADP-ribose) synthetase inhibitors such as nicotinamide and picolinamide, alloxan- and streptozotocin-induced NAD depletion was completely prevented, and B-cell functions including proinsulin synthesis proceeded normally. However, poly(ADP-ribose) synthetase inhibitors did not prevent the DNA strand breaks at all. Therefore, B-cells may survive with the residual DNA damage within their genome. About one year after the combined administration to rats of alloxan or streptozotocin with poly(ADP-ribose) synthetase inhibitors, diabetes did not develop but islet B-cell tumors were found frequently. This suggests that insulin-dependent diabetes and B-cell tumors are closely related with respect to their developmental processes. In other words, DNA breaks initiate two kinds of pathological state in B-cells, one is degeneratively and the other is oncogenically expressed.
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PMID:DNA strand breaks and poly(ADP-ribose) synthetase activation in pancreatic islets--a new aspect to development of insulin-dependent diabetes and pancreatic B-cell tumors. 631 40

This study examined the effect of an aldose reductase inhibitor (Sorbinil, CP 45634, Pfizer, Sandwich, Kent, United Kingdom) on the metabolite profile of the lens during the first week after induction of diabetes with alloxan. The lens content of sorbitol, fructose, glycerol 3-phosphate, and glucose 6-phosphate was, respectively, 0.33 +/- 0.03, 0.55 +/- 0.05, 0.10 +/- 0.01, and 0.074 +/- 0.006 mumol/g (means +/- SEM) in the control group rising to 12.2 +/- 0.52, 3.20 +/- 0.10, 0.76 +/- 0.10, and 0.200 +/- 0.009 in lenses from alloxan-diabetic rats. Sorbinil treatment (40 mg/kg) decreased the lens content of sorbitol to 0.60 +/- 0.06, fructose to 0.85 +/- 0.08, and glycerol 3-phosphate to 0.36 +/- 0.03 mumol/g; glucose 6-phosphate remained unchanged. Significantly, the lens content of glutathione was decreased to 60% of the normal value in the diabetic group, but was sustained at normal levels with Sorbinil treatment. The ATP content of the lens was not altered by diabetes or Sorbinil treatment at this time interval. Sorbinil has no significant effect on the above metabolites in the normal rat lens. The effect of Sorbinil in restoring normal levels of glutathione and glycerol 3-phosphate may be a potentially important facet of the action of this drug. The interlocking of metabolic pathways by the redox state of NAD+/NADH and NADP+/NADPH, their derangement in diabetes, and the wider effects of Sorbinil on the network of reactions in the lens are discussed.
Diabetes 1983 May
PMID:The effect of an aldose reductase inhibitor (Sorbinil) on the level of metabolites in lenses of diabetic rats. 640 81

Long chain saturated beta-hydroxy fatty acid content and oxidative metabolism were studied in hearts of diabetic mice (C57BL/KsJ db/db) with a progressive cardiomyopathy at intervals of 7, 10, 16, and 26 wk of age. Total beta-hydroxy fatty acid (BHFA) content increases progressively with age in diabetic hearts with a mean value of 143.5 nmol/g dry wt as compared with a mean of 59.6 nmol/g dry wt in control hearts. There was also a redistribution of BHFA in myocardium of diabetic mice when compared with controls, with a relative decrease in beta-hydroxymyristate and an increase of beta-hydroxypalmitate. Oxidative phosphorylation studies using isolated mitochondria from diabetic mice demonstrated depressed state 3 oxidation rates with both palmityl carnitine and pyruvate as substrates. While mitochondrial NADH-oxidase activity was not statistically different from that of controls, there was a significant decrease in mitochondrial total NAD + NADH content in diabetic hearts. In addition, treatment of myocardial tissue with lanthanum demonstrated an abnormal permeability of sarcolemmal, intercalated disc as well as mitochondrial membranes in myocytes of diabetic mice. The data indicate that deficiencies in total NAD + NADH content can account for the depressed state 3 oxidation of palmitylcarnitine and pyruvate in diabetic mice that in turn may explain the abnormal accumulation of BFHA. The latter could play a role in altering the permeability of cardiac cell membranes.
Diabetes 1983 Sep
PMID:Defective oxidative metabolism of heart mitochondria from genetically diabetic mice. 641 61

When isolated rat pancreatic islets are exposed to L-leucine (20 mM), the rate of NH4 production is close to the summed rates of L-[1-14C] leucine decarboxylation and alpha-ketoisocarproate production, whereas the rates of acetoacetate production and L-[U-14C]-leucine oxidation are compatible with conversion of each mole of the amino acid to one mole of acetoacetate and three moles of CO2. ATP content, ATP/ADP ratio, and adenylate charge are maintained at normal values by L-leucine, whereas the NADH/NAD+ ratio (but not the NADPH/NADP+ ratio) is significantly increased. The release of insulin evoked by L-leucine is potentiated by 2-ketoisovalerate, unaffected by L-valine, and inhibited by menadione. L-leucine mimicks the effect of D-glucose on 86Rb+ and 45Ca2+ handling by the islets. However, relative to its rate of oxidation, the insulinotropic effect of L-leucine is less marked than that of D-glucose. This may be due, in part at least, to a decrease in the oxidation of endogenous nutrients. It is concluded that the metabolic, cationic, and secretory effects of L-leucine in isolated islets are not incompatible with the fuel hypothesis for insulin release.
Diabetes 1980 Jun
PMID:The stimulus-secretion coupling of amino acid-induced insulin release: metabolism and cationic effects of leucine. 676 28

Homogenates of isolated pancreatic islets contain 40-70 times as much flavin-linked glycerol-3-phosphate dehydrogenase (EC 1.1.99.5) as homogenates of whole pancreas, liver, heart, or skeletal muscle when the activity is assayed with either iodonitrotetrazolium or with dichloroindophenol as an electron acceptor. Intact mitochondria from islets release 3HOH from [2-3H]glycerol phosphate 7 times faster than do skeletal muscle mitochondria. The activity of the cytosolic, NAD-linked, glycerol phosphate dehydrogenase (EC 1.1.1.8) in pancreatic islets is comparable to that of the mitochondrial dehydrogenase so a glycerol phosphate shuttle is possible in pancreatic islets. Diazoxide, an inhibitor of insulin release in vivo and in vitro, inhibits the islet mitochondrial glycerol phosphate dehydrogenase in all three of the assays mentioned above at concentrations that inhibit insulin release and CO2 formation from glucose by isolated pancreatic islets. Diazoxide does not inhibit the dehydrogenase in mitochondria from skeletal muscle, liver, and heart. A slight inhibition in mitochondria from whole pancreas can be accounted for as inhibition of the islet dehydrogenase because no inhibition is observed in mitochondria from pancreas of rats treated with alloxan, an agent that causes diabetes by destroying pancreatic beta cells. The results of this study are compatible with the hypothesis that the mitochondrial glycerol phosphate dehydrogenase has a key role in stimulus-secretion coupling in the pancreatic beta cell during glucose-induced insulin release.
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PMID:High content of mitochondrial glycerol-3-phosphate dehydrogenase in pancreatic islets and its inhibition by diazoxide. 679 May 37

A new fluorimetric method for the quantification of red blood cell (RBC) sorbitol dehydrogenase is described. It is based on the oxidation of sorbitol to fructose, in presence of NAD+, catalysed by the RBC-sorbitol dehydrogenase. The quantity of NADH formed is then measured in a filter fluorimeter. Comparison with an indirect spectrophotometric assay yielded good correlation; however, the present method offers several advantages: it is more rapid, simple and inexpensive. It should be useful to screen for sorbitol dehydrogenase deficiency in large numbers of individuals, particularly patients with diabetes or cataracts.
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PMID:A fluorimetric method for red blood cell sorbitol dehydrogenase activity. 685 34

The effects of increased cardiac work and availability of pyruvate on the activation of pyruvate dehydrogenase (PDH) was studied in hearts isolated from diabetic rats. Diabetes resulted in complete inactivation of myocardial PDH. At low levels of cardiac work, PDH in hearts perfused with glucose or glucose plus insulin as substrate remained in the inactive form even after 25 min of in vitro perfusion indicating that the factors causing inactivation in the diabetic animal were not easily reversed in vitro. Raising the level of ventricular pressure development from 60 to 180 mmHg caused only a small increase in the percent of active PDH (from 0.3 to 16%). Comparable values in control hearts were 61 and 96% active PDH. Addition of high levels of perfusate pyruvate along with glucose increased the percent active PDH from 0.3 to 45 at 60 mmHg ventricular pressure. Although pyruvate increased active PDH the effect was much less than in normal hearts (85% active under comparable conditions). Increased ventricular pressure development (180 mmHg) in diabetic hearts receiving pyruvate caused a further activation of PDH to 66% but again this effect was much less than occurred in normal hearts (96% active). Inactivation of PDH in hearts from diabetic animals could not be accounted for by high mitochondrial levels of known effectors such as NADH/NAD, acetyl CoA/CoA and ATP/ADP. Increasing cardiac work resulted in decreased mitochondrial levels of NADH, acetyl CoA and ATP, but these changes had little effect on PDH activity. The date indicate that PDH in hearts of diabetic animals is resistant to activation by increased cardiac work and high tissue levels of pyruvate.
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PMID:Effects of increased cardiac work on pyruvate dehydrogenase activity in hearts from diabetic animals. 687 84


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