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)

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

A major obstacle for islet transplantation in insulin-dependent diabetes mellitus is to obtain a sufficient amount of islet tissue. This may partly be overcome if the cell replication in the grafted islet preparation could be stimulated in the recipient. In the present study adult mice were treated for 14 days with daily injections of nicotinamide (500 mg/kg body weight) or saline. Subsequently, the autoradiographic labeling index in the cells of the pancreatic islets were calculated in normal mice and in syngeneic islets transplanted into alloxan-diabetic mice. Treatment with nicotinamide caused a more than three-fold increase in the islet cell labeling index in the endogenous pancreatic islets, and also a 50% increase in the cell replication rates of the transplanted islets. It thus appears that nicotinamide enhances islet cell replication, possibly through an inhibition of poly(ADP-ribose) synthetase activities.
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PMID:Stimulation of cell replication in transplanted pancreatic islets by nicotinamide treatment. 296 53

The effect of chemically-induced diabetes on the hepatic microsomal mixed-function oxidase system and the activation of chemical carcinogens was investigated in animals treated with streptozotocin (STZ). In order to distinguish between the effects of the diabetogenic chemical per se and that of the diabetic state, groups of STZ-treated animals received either nicotinamide simultaneously with STZ to prevent the onset of diabetes, or daily treatment with insulin in order to reverse the effects of diabetes. STZ-treated animals exhibited higher pentoxyresorufin O-dealkylase, ethoxy-resorufin O-deethylase, ethoxycoumarin O-deethylase, aniline p-hydroxylase and NADPH-cytochrome c reductase activities; similarly, increases were seen in cytochrome P-450 and b5 levels. All of these effects were prevented by nicotinamide and, at least partly, antagonised by insulin therapy. Treatment of animals with STZ markedly increased the activation, by liver microsomes in vitro, of Trp-P-1 and Trp-P-2 to mutagens, the effect being totally preventable by nicotinamide and successfully antagonised with insulin therapy. The diabetic animals were similarly more efficient in activating MeIQ but the effect was not preventable by nicotinamide or reversed by insulin. In contrast no changes were seen in the activation of IQ and only a modest increase in the case of MeIQx. It is concluded that diabetes may modulate the metabolic activation of some chemical carcinogens, presumably by changing the ratio of the various cytochrome P-450 isoenzymes.
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PMID:Streptozotocin-induced diabetes modulates the metabolic activation of chemical carcinogens. 297 97

Male rats (200 g) were rendered diabetic with one intraperitoneal injection of alloxan (150 mg/kg) or streptozotocin (60 mg/kg). In hyperglycemic animals within 3 hours after the injection, the binding of EGF to liver membranes decreased by 43-52%; the maximal drop was by 70% and persisted for the 20 days of the experiment. EGF receptors decreased in number with almost no changes in their affinity. Autophosphorylation of the receptors decreased parallel to the ligand binding. In animals that received lower doses and did not develop diabetes and in animals in whom diabetes was prevented by the injections of glucose (before alloxan) or nicotinamide (before streptozotocin) the binding of EGF to liver receptors remained normal. We conclude that the decreased expression of EGF receptors was caused by diabetes and not by the toxic effects of the diabetogenic compounds on the liver.
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PMID:Decreased expression of liver epidermal growth factor receptors in rats with alloxan and streptozotocin diabetes. 301 81

Insulinomas can be induced in experimental animals by the combined administration of diabetogenic agents with polyadenosine diphosphate (polyADP)-ribose synthetase inhibitors. A complementary DNA (cDNA) library that was constructed from streptozocin-nicotinamide-induced rat insulinomas has been found to contain a novel gene encoding a basic protein of 145 amino acids. The gene was expressed in alloxan-nicotinamide-induced insulinomas as well as in streptozocin-nicotinamide-induced insulinomas but not in normal pancreatic islets or in regenerating islets. This indicates that the activation of the gene designated rig, i.e., rat insulinoma gene, may be a general feature of pancreatic beta-cell transformation.
Diabetes 1986 Oct
PMID:Novel gene activated in rat insulinomas. 301 5

This study examines the effect of an aldose reductase inhibitor (sorbinil) on the flux of specifically labeled glucose through alternative pathways of metabolism in the lens of normal and diabetic rats 1 wk after the induction of diabetes with alloxan. In the diabetic rat lens, there was an apparent increase in the flux of glucose through the pentose phosphate pathway (PPP), as measured by the difference in the yields of 14CO2 from [1-14C]glucose and [6-14C]glucose [C1-C6], this value was 0.087 +/- 0.005 and 0.263 +/- 0.034 mumol X g lens-1 X h (mean + SE of 6 values) for control and diabetic rats, respectively; sorbinil treatment decreased the values to 0.065 +/- 0.008 and 0.171 +/- 0.028, respectively. With glucose tritiated on carbon 2 or 3, it has been shown that the flux of glucose through the polyol route is increased, whereas the flux through the glycolytic pathway is decreased in the diabetic rat lens; both are restored toward normal in the sorbinil-treated diabetic group. These results suggest that the dual effects of diabetes in increasing the lens content of glucose and glucose 6-phosphate and the flux of glucose in the polyol pathway will result in an increased utilization of NADPH and production of NADH, factors favoring the flow of glucose through the PPP and restricting the glycolytic route in the diabetic rat lens. The inhibition of aldose reductase by sorbinil tends to normalize the redox state of the nicotinamide nucleotides, reimposing the NADPH limitation on the PPP and increasing the availability of NAD+ for the glycolytic route.
Diabetes 1986 Nov
PMID:Effect of aldose reductase inhibitor (sorbinil) on integration of polyol pathway, pentose phosphate pathway, and glycolytic route in diabetic rat lens. 309 2

Streptozotocin (STZ) increased the activity of mouse hepatic glutathione (GSH) S-transferases assayed with 1-chloro-2,4-dinitrobenzene. Nicotinamide administered prior to STZ prevented the hyperglycemia indicative of STZ-induced diabetes, but had no effect on the increase in GSH S-transferase activity caused by the drug. Another diabetogenic agent, alloxan, did not alter GSH S-transferase activity. Thus, streptozotocin may be increasing GSH S-transferase activity directly, and not as a result of the diabetic state the drug induces. Two transferases were characterized from mouse liver cytosol. One was a homodimer with a subunit molecular weight of about 28,000 and a pI of about 8.2. The other was also a homodimer with a subunit molecular weight of about 27,500 and a pI of about 9.2. The pI 8.2 GSH S-transferase was induced by STZ, while the pI 9.2 transferase was decreased by the drug. At least one other transferase appeared to be induced by STZ. Two other nitroso compounds, chlorozotocin and diethylnitrosamine, also increased GSH S-transferase activity, suggesting that this effect may be nitroso related.
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PMID:Effect of streptozotocin on the glutathione S-transferases of mouse liver cytosol. 315 1

Multiple low-dose injections of streptozotocin (SZ) induce a gradually developing hyperglycaemia and pancreatic insulitis in certain inbred mouse strains. In the present investigation nicotinamide, which is known to protect against SZ-induced diabetes, was given prior to a single diabetogenic dose of SZ to C57BL/KsJ mice. Nicotinamide protected against SZ-induced hyperglycaemia in the acute phase but 13 of the 18 animals in this group became diabetic during the second week of observation. Nine of these mice had insulitis, seven of which showed overt diabetes. Since nicotinamide increased the serum glucose concentration at the time of the SZ-administration ten minutes later, the possibility that glucose mediated the protective action was evaluated. Glucose-pretreatment, however, was found to potentiate the diabetogenic action of SZ. It is obvious from the present data that another type of diabetes than that induced by a single high dose of SZ can be evoked if the immediate B-cytotoxic effects of SZ are reduced. It may be speculated that islet B-cells of mice given nicotinamide before SZ, for a time retain SZ-induced DNA injuries, which may lead to the expression of neoantigens and an autoimmune reaction.
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PMID:Modulation of streptozotocin-induced insulitis and hyperglycaemia in the mouse. 315 92

Increase in content of glucose in aorta as well as in reducing properties of NAD and NADP coenzymes and alteration in content of cofactor of the sorbitol pathway led to accumulation of sorbitol in streptozotocin-diabetic rats. Administration of nicotinamide into diabetic animals induced an increase in the ratios of NAD+/NADH and NADP+/NADPH, accompanied by a decrease in sorbitol formation occurring in the reaction catalyzed by aldose reductase and stimulation of the sugar oxidation in the reaction catalyzed by sorbitol dehydrogenase. Possible use of nicotinamide for prevention and treatment of vascular lesions in diabetes is discussed.
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PMID:[Nicotinamide coenzyme regulation of the sorbitol pathway of glucose metabolism in the aorta of rats with streptozotocin diabetes]. 315 51

Chlorozotocin (chlorozocin, CLZ), the 2-chloroethyl analogue of streptozocin (STZ), was evaluated in three species of rodents. The drug is currently being used in phase II chemotherapeutic trials in man, and appears to be effective in the treatment of certain tumors. In our studies, hyperglycemia was induced in hamsters as early as 2 days after a single intraperitoneal (i.p.) injection of 30-60 mg/kg and was most striking at 4 days. Greater concentrations of CLZ (greater than or equal to 50 mg/kg) were required to produce hyperglycemia in CD-1 mice. Degranulation and necrosis of beta cells developed in hamsters and mice, whereas alpha and acinar cells of the pancreas revealed no morphologic changes. Hyperglycemia was not induced in rats at any concentration tested; however, animals showed abnormal carbohydrate tolerance after administration of 100 mg/kg CLZ (LD50 dosage). The nature of damage by CLZ to beta cells was investigated both in vivo and in vitro. Pretreatment of hamsters with nicotinamide (500 mg/kg, i.p.) failed to alter the extent of CLZ-induced beta cell injury and associated hyperglycemia, but decreased the amount of beta cell necrosis and hyperglycemia in animals receiving STZ. The nonmetabolizable sugar, 3-O-methylglucose (3-O-MG), and 3-aminobenzamide, an inhibitor of the nuclear enzyme, polyADPribose synthetase, prevented STZ-associated damage to beta cells in islet cell cultures, but only 3-O-MG reduced CLZ-induced toxicity. Thus, in comparison to STZ, CLZ appears to be a diabetogenic agent with different species specificity and alternative mechanisms of cytotoxicity. The glucose moiety of both drugs appears critical in the induction of beta cell damage.
Diabetes 1985 Jun
PMID:Chlorozocin. A diabetogenic analogue of streptozocin with dissimilar mechanisms of action on pancreatic beta cells. 315 9


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