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

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

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

Several proteins with NAD+:arginine ADP-ribosyltransferase (ART) activity are expressed in T cells and affect their function. Rat T cells that express the ART designated RT6 are determinants of the expression of autoimmune diabetes. In the mouse, a 35-kDa ecto-ART modulates the proliferation and functional activity of CTL. Here we report on mouse ARTs designated Rt6-1 and Rt6-2 in BALB/c and C57BL/6 mice. mRNAs for Rt6-1 and Rt6-2 were found in spleen, thymus, and intestinal tissue of both strains, but Rt6-1 mRNA in C57BL/6 mice was detected only at low levels. Rt6-1 and Rt6-2 cDNAs from both strains were cloned and sequenced. Predicted amino acid sequences of Rt6-2 were identical in both strains, but there was an in-frame stop codon in the sequence of Rt6-1 in C57BL/6 mice not present in BALB/c mice. Recombinant C57BL/6 Rt6-2 and BALB/c Rt6-1 proteins expressed in COS1 cells exhibited ART activity and were documented to be glycosylphosphatidylinositol-linked membrane proteins. COS-1 cells transfected with a C57BL/6 Rt6-1 cDNA construct expressed a truncated protein consistent in size with that predicted by the presence of the stop codon. This approximately 21-kDa protein appeared not to be glycosylphosphatidylinositol linked to the cell surface and lacked ART activity. C57BL/6 Rt6-1 therefore appears to be a naturally occurring ART knockout. The expression of Rt6-1 and Rt6-2 mRNAs in lymphoid tissues suggests that these ARTs may regulate immune system functions. Expression of Rt6-2 or another redundant ART may compensate for the lack of enzymatically active Rt6-1 in C57BL/6 mice.
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PMID:Expression in BALB/c and C57BL/6 mice of Rt6-1 and Rt6-2 ADP-ribosyltransferases that differ in enzymatic activity: C57BL/6 Rt6-1 is a natural transferase knockout. 930 Jun 95

Four mitochondrial protein kinases have been cloned. These proteins represent a new family of protein kinases, related by sequence to the bacterial protein kinases but by function to the eukaryotic serine protein kinases. Arg288 is required for recognition by BCKDK of the phosphorylation site on the E1alpha subunit of the BCKDH complex. BCKDK inhibits the dehydrogenase activity of the BCKDH complex by introducing a negative charge into the active-site pocket of the E1 component. Protein starvation of rats induces an increase in the amount of BCKDK bound to the BCKDH complex. This causes inactivation of the BCKDH complex and conserves branched-chain amino acids for protein synthesis in the protein-starved state. Expression of the different PDK isoenzymes is tissue specific, and the different PDK isoenzymes are unique with respect to kinetic parameters for ATP and ADP and sensitivity to allosteric effectors (NADH, NAD+, coenzyme A, acetyl-CoA, pyruvate, and dichloroacetate). Preliminary experiments indicate that an increased amount of PDK2 protein partly explains the increase in PDK activity that occurs in rat liver in response to chemically induced diabetes.
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PMID:Mitochondrial alpha-ketoacid dehydrogenase kinases: a new family of protein kinases. 934 45

This morphological study demonstrates a role for endothelial cells in generating reactive oxygen species in early stages of retinopathy in the BBZ/Wor rat, an obese, noninsulin dependent model of diabetes. Hyperglycemia induced pseudohypoxia results in an imbalance in cytosolic NADH/NAD+. In the oxygen-rich environment of the retina, NADH oxidase generates superoxide radical which is dismutated to hydrogen peroxide. Localization of hydrogen peroxide by the cerium NADH oxidase enzyme activity cytochemical localization technique shows a statistically significant increase of peroxide localization in the central retina of diabetic rats as compared to age-matched, nondiabetic controls. Endothelial cell dysfunction, indicated by leakage of endogenous serum albumin, coincided with areas of NADH oxidase activity localization. In diabetic rats there are increased levels of fibronectin in areas of hydrogen peroxide localization. This in vivo, morphological study is the first demonstration of oxidative injury and endothelial cell dysfunction in the retina of a spontaneous, noninsulin dependent model of diabetes.
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PMID:Increased NADH oxidase activity in the retina of the BBZ/Wor diabetic rat. 943 20

Diabetic retinopathy is thought to result from chronic changes in the metabolic pathways of the retina. Hyperglycemia leads to increased intracellular glucose concentrations, alterations in glucose degradation and an increase in lactate/pyruvate ratio. We measured lactate content in retina and other ocular and non-ocular tissues from normal and diabetic rats in the early stages of streptozotocin-induced diabetes. The intracellular redox state was calculated from the cytoplasmic [lactate]/[pyruvate] ratio. Elevated lactate concentration were found in retina and cerebral cortex from diabetic rats. These concentrations led to a significant and progressive decrease in the NAD+/NADH ratio, suggesting that altered glucose metabolism is an initial step of retinopathy. It is thus possible that tissues such as cerebral cortex have mechanisms that prevent the damaging effect of lactate produced by hyperglycemia and/or alterations of the intracellular redox state.
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PMID:Changes in the redox state in the retina and brain during the onset of diabetes in rats. 958 Mar 89

Cyclic ADP-ribose (cADPR) has been shown to be a mediator for intracellular Ca2+ mobilization for insulin secretion by glucose in pancreatic beta cells, and CD38 shows both ADP-ribosyl cyclase to synthesize cADPR from NAD+ and cADPR hydrolase to hydrolyze cADPR to ADP-ribose. We show here that 13.8% of Japanese non-insulin-dependent diabetes (NIDDM) patients examined have autoantibodies against CD38 and that the sera containing anti-CD38 autoantibodies inhibit the ADP-ribosyl cyclase activity of CD38 (P </= 0.05). Insulin secretion from pancreatic islets by glucose is significantly inhibited by the addition of the NIDDM sera with anti-CD38 antibodies (P </= 0.04-0.0001), and the inhibition of insulin secretion is abolished by the addition of recombinant CD38 (P </= 0.02). The increase of cADPR levels in pancreatic islets by glucose was also inhibited by the addition of the sera (P </= 0.05). These results strongly suggest that the presence of anti-CD38 autoantibodies in NIDDM patients can be one of the major causes of impaired glucose-induced insulin secretion in NIDDM.
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PMID:Autoantibodies against CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in noninsulin- dependent diabetes patients. 966 81


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