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

In our previous study (Diabetes 44:520-526, 1995), endothelial cells cultured in high glucose condition showed impairment of an oxidant-induced activation of the pentose phosphate pathway (PPP) and a reduced supply of NADPH to the glutathione redox cycle. To gain insight into the mechanisms of this impairment, the protective effect of pyruvate was studied in human umbilical vein endothelial cells cultured in either 5.5 mmol/l glucose (normal glucose [NG] condition) or 33 mmol/l glucose (high glucose [HG] condition). Through pretreatment of cells with 0.2 mmol/l pyruvate for 5-7 days in the HG condition, glucose oxidation through the PPP and total cellular NADPH content in the presence of 0.2 mmol/l H2O2 were increased by 54 (P < 0.05) and 34%, respectively, and glutathione-dependent degradation of H2O2 in HG cells was enhanced by 41% (P < 0.01), when compared with those cells to which pyruvate was not added. The addition of pyruvate significantly reduced the fructose 1,6-bisphosphate (FDP) content and free cytoplasmic NADH/NAD ratio, estimated by increased pyruvate/lactate ratio in NG and HG cells exposed to H2O2. Furthermore, the addition of pyruvate also showed a 46% reduction (P < 0.01) of endothelial cell damage induced by H2O2 in HG cells. These results indicate that abnormalities in PPP activation and glutathione redox cycle activity induced by H2O2 in HG cells are compensated, and that the accentuated reductive stress is improved by an addition of pyruvate. These pyruvate effects are associated with protection against an oxidant-induced endothelial cell injury in the high glucose condition.
Diabetes 1997 Dec
PMID:Pyruvate improves deleterious effects of high glucose on activation of pentose phosphate pathway and glutathione redox cycle in endothelial cells. 939 1

Glucose-stimulated insulin release from pancreatic beta cells involves a complex series of signalling pathways. In many forms of diabetes, lesions in this process cause or aggravate the diabetic phenotype. A common motif in these cascades is the elevation of intracellular Ca2+ both in the cytosolic compartment ([Ca2+]c) and within the mitochondria ([Ca2+]m). These parameters can be effectively monitored using the photoprotein aequorin which can be targeted to subcellular compartments by transfection. It is shown that physiological concentrations of glucose elicit [Ca2+]c oscillations measured with fura-2, which correlate well with oscillatory NAD(P)H fluorescence in the mitochondria. Aequorin measurements of [Ca2+]m, though unable to detect oscillations on a single cell basis, reveal large increases in intraorganellar [Ca2+] in response to glucose, elevated amino acid levels and depolarizing concentrations of KCI. These oscillations, in turn, mirror changes in the insulin secretion profile. Since several of the key mitochondrial dehydrogenases involved in oxidative phosphorylation are exquisitely sensitive to changes in [Ca2+], it is proposed that alterations in [Ca2+]m lead to increased activity of the tricarboxylic acid cycle and subsequent ATP production, thereby facilitating exocytosis of insulin from secretory granules. The involvement of the mitochondria in these processes is examined, as is the putative role of efficient mitochondrial genome transcription and translation in normal and diabetic states.
Diabetes Metab 1998 Feb
PMID:Role of mitochondrial calcium in metabolism-secretion coupling in nutrient-stimulated insulin release. 953 4

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause maturity onset diabetes of the young type 3, a form of type 2 diabetes mellitus. In mice lacking the HNF-1alpha gene, insulin secretion and intracellular calcium ([Ca2+]i) responses were impaired following stimulation with nutrient secretagogues such as glucose and glyceraldehyde but normal with non-nutrient stimuli such as potassium chloride. Patch clamp recordings revealed ATP-sensitive K+ currents (KATP) in beta-cells that were insensitive to suppression by glucose but normally sensitive to ATP. Exposure to mitochondrial substrates suppressed KATP, elevated [Ca2+]i, and corrected the insulin secretion defect. NAD(P)H responses to glucose were substantially reduced, and inhibitors of glycolytic NADH generation reproduced the mutant phenotype in normal islets. Flux of glucose through glycolysis in islets from mutant mice was reduced, as a result of which ATP generation in response to glucose was impaired. We conclude that hepatocyte nuclear factor-1alpha diabetes results from defective beta-cell glycolytic signaling, which is potentially correctable using substrates that bypass the defect.
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PMID:Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice. 973 37

This paper reviews the model of the control of mitochondrial substrate oxidation by Ca2+ ions. The mechanism is the activation by Ca2+ of four mitochondrial dehydrogenases, viz. glycerol 3-phosphate dehydrogenase, the pyruvate dehydrogenase multienzyme complex (PDH), NAD-linked isocitrate dehydrogenase (NAD-IDH) and 2-oxoglutarate dehydrogenase (OGDH). This results in the increase, or near-maintenance, of mitochondrial NADH/NAD ratios in the activated state, depending upon the tissue and the degree of 'downstream' activation by Ca2+, likely at the level of the F1Fo ATPase. Higher values of the redox span of the respiratory chain allow for greatly increased fluxes through oxidative phosphorylation with a minimal drop in protonmotive force and phosphorylation potential. As PDH, NAD-IDH and OGDH are all located within the inner mitochondrial membrane, it is changes in matrix free Ca2+ [Ca2+]m which act as a signal to these activities. In this article, we review recent work in which [Ca2+]m is measured in cells and tissues, using different techniques, with special emphasis on the question of the degree of damping of [Ca2+]m relative to changes in cytosol free Ca2+ in cells with rapid transients in cytosol Ca2+, e.g. cardiac myocytes. Further, we put forward the point of view that the failure of mitochondrial energy transduction to keep pace with cellular energy needs in some forms of heart failure may involve a failure of [Ca2+]m to be raised adequately to allow the activation of the dehydrogenases. We present new data to show that this is so in cardiac myocytes isolated from animals suffering from chronic, streptozocin-induced diabetes. This raises the possibility of therapy based upon partial inhibition of mitochondrial Ca2+ efflux pathways, thereby raising [Ca2+]m at a given, time-average value of cytosol free Ca+2.
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PMID:Role of mitochondrial calcium transport in the control of substrate oxidation. 974 30

Corneal autofluorescence is higher in diabetes mellitus patients with retinopathy than in healthy subjects. In this study, the excitation spectra of corneal autofluorescence of diabetic patients and healthy controls in the range 365 nm-480 nm were compared in an attempt to identify the fluorophores responsible for corneal autofluorescence in health and disease (diabetes). Spectral measurements (from one eye) were recorded from five patients with proliferative diabetic retinopathy and five age-matched healthy controls, using a modified commercial scanning fluorophotometer with a mercury arc or a tungsten halogen lamp as excitation light source in combination with interference filters (excitation wavelengths: 365, 405, 420, 430, 436, 440, 450, 470 and 480 nm; bandwidth: 10 nm). Fluorescence emission was measured in the range 532 nm-630 nm. The sensitivity of the modified fluorophotometer was calibrated by using the excitation spectrum of fluorescein as a reference. The corneal excitation efficiency of the diabetic patients was higher than that of the healthy controls at each wavelength investigated (Mann-Witney test P<0.0005). The ratio between the mean values of both groups was equal for each excitation wavelength (mean ratio 1.9+/-0.12s.d.,P>0. 2), suggesting that the excitation spectra were equal. This indicates that the same fluorophores are responsible for the corneal autofluorescence in both groups. The shapes of the excitation spectra suggest the involvement of flavins, NAD(P)H, and at least one other, as yet unidentified, fluorophore.
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PMID:Autofluorescence of the diabetic and healthy human cornea in vivo at different excitation wavelengths. 998 36

Streptozotocin (STZ), a glucose analogue known to induce diabetes in experimental animals, causes DNA strand breaks and subsequent activation of poly(ADPribose) polymerase (Parp). Because Parp uses NAD as a substrate, extensive DNA damage will result in reduction of cellular NAD level. In fact, STZ induces NAD depletion and cell death in isolated pancreatic islets in vitro. Activation of Parp therefore is thought to play an important role in STZ-induced diabetes. In the present study, we established Parp-deficient (Parp-/-) mice by disrupting Parp exon 1 by using the homologous recombination technique. These mice were used to examine the possible involvement of Parp in STZ-induced beta-cell damage in vivo. The wild-type (Parp+/+) mice showed significant increases in blood glucose concentration from 129 mg/dl to 218, 370, 477, and 452 mg/dl on experimental days 1, 7, 21, and 60, respectively, after a single injection of 180 mg STZ/kg body weight. In contrast, the concentration of blood glucose in Parp-/- mice remained normal up to day 7, slightly increased on day 21, but returned to normal levels on day 60. STZ injection caused extensive necrosis in the islets of Parp+/+ mice on day 1, with subsequent progressive islet atrophy and loss of functional beta cells from day 7. In contrast, the extent of islet beta-cell death and dysfunction was markedly less in Parp-/- mice. Our findings clearly implicate Parp activation in islet beta-cell damage and glucose intolerance induced by STZ in vivo.
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PMID:Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes. 1005 36

Glucose-induced insulin secretion depends on an acceleration of glucose metabolism, requires a rise in the cytoplasmic free Ca2+ concentration ([Ca2+]i), and is modulated by activation of protein kinases in beta-cells. Normal mouse islets were used to determine whether oscillations of these three signals are able and necessary to trigger oscillations of insulin secretion. The approach was to minimize or abolish spontaneous oscillations and to compare the impact of forced oscillations of each signal on insulin secretion. In a control medium, repetitive increases in the glucose concentration triggered oscillations in metabolism [NAD(P)H fluorescence], [Ca2+]i (fura-PE3 method), and insulin secretion. In the presence of diazoxide, metabolic oscillations persisted, but [Ca2+]i and insulin oscillations were abolished. When the islets were depolarized with high K+ with or without diazoxide, [Ca2+]i was elevated, and insulin secretion was stimulated. Forced metabolic oscillations transiently decreased or did not affect [Ca2+]i and potentiated insulin secretion with oscillations of small amplitude. These oscillations of secretion followed metabolic oscillations only when [Ca2+]i did not change. When [Ca2+]i fluctuated, these changes prevailed over those of metabolism for timing secretion. Repetitive depolarizations with high K+ in the presence of stable glucose (10 mmol/l) induced synchronous pulses of [Ca2+]i and insulin secretion with only small oscillations of metabolism. Continuous stimulation of protein kinase A (PKA) and protein kinase C (PKC) did not dissociate the [Ca2+]i and insulin pulses from the high K+ pulses. However, the amplitude of the insulin pulses was consistently increased, whereas that of the [Ca2+]i pulses was either increased (PKA) or decreased (PKC). In conclusion, metabolic oscillations can induce oscillations of insulin secretion independently of but with a lesser effectiveness than [Ca2+]i oscillations. Although oscillations in metabolism may cyclically influence secretion through an ATP-sensitive K+ channel (K+-ATP channel)-independent pathway, their regulatory effects are characterized by a hysteresis that makes them unlikely drivers of fast oscillations, unless they also involve [Ca2+]i changes through the K+-ATP channel-dependent pathway.
Diabetes 1999 Dec
PMID:Oscillations of insulin secretion can be triggered by imposed oscillations of cytoplasmic Ca2+ or metabolism in normal mouse islets. 1058 Apr 26

Type 2 diabetes mellitus is one of the most common chronic metabolic diseases in man. Due to long-term complications of the disease, severely decreasing the quality of life of diabetic patients, early interventions to obviate the risk of complications are of major importance. Therefore, diabetic animal models are of major importance in research for interventional treatment of type 2 diabetes. In this work we investigated the possible alterations in mitochondrial energetic metabolism of Goto-Kakizaki (GK) rats during the progression of the disease, since glucose metabolism is closely related to intracellular ATP content. For that reason, respiratory indexes (state 4, state 3, RCR and ADP/O) were evaluated either in the presence of NAD- or FAD-linked substrates (glutamate + malate and succinate, respectively) in mitochondrial preparations of GK and control rats with 8, 12, 26 and 52 weeks of age. Until the age of 1 year (52 weeks) we found no impairment of mitochondrial respiratory indexes both in the presence of glutamate + malate and succinate. In conclusion, this study indicates that GK rat is a good model for studying the initial events of diabetes, since it presents no impairment of liver mitochondrial functions during the first year of life, contrasting clearly with pharmacological induced diabetes.
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PMID:Age-related alterations in liver mitochondrial bioenergetics of diabetic Goto-Kakizaki rats. 1066 24

In HIT-T15 insulinoma B-cells incubated in presence of [(32)P]NAD, we identified by autoradiography and immunoblotting ADP-ribosylation (ADP-R) of the trimeric G-protein Galpha(s) and Galpha(olf) subunits (45 kDa) induced by cholera toxin in M1 (120,000g) and M2 (70,000g) subcellular fractions containing plasma membranes, insulin granules, and mitochondria. This ADP-R indicates that these two fractions contain functionally competent Galpha subunits for adenylyl cyclase activation. Prolonged exposure of HIT-T15 cells to high glucose (25 mM instead of 6 mM) specifically reduced the ADP-R in Galpha(s) and Galpha(olf) subunits in the M1 fraction only, despite the clear increase of their accumulation in this compartment. A similar alteration in the ADP-R of the M1-associated Galpha(s) and Galpha(olf) subunits was observed in pancreatic islets isolated from fasted and fed rats. These results may explain, at least in part, the undesirable effects of sustained hyperglycemia on the cAMP-dependent process of insulin secretion in diabetes.
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PMID:Decreased ADP-ribosylation of the Galpha(olf) and Galpha(s) subunits by high glucose in pancreatic B-cells. 1077 86

Superoxide anion plays important roles in vascular disease states. Increased superoxide production contributes to reduced nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of vascular disease. We measured superoxide production by NAD(P)H oxidase in human blood vessels and examined the relationships between NAD(P)H oxidase activity, NO-mediated endothelial function, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations and direct measurements of vascular superoxide production were determined in human saphenous veins obtained from 133 patients with coronary artery disease and identified risk factors. The predominant source of vascular superoxide production was an NAD(P)H-dependent oxidase. Increased vascular NAD(P)H oxidase activity was associated with reduced NO-mediated vasorelaxation. Furthermore, reduced endothelial vasorelaxations and increased vascular NAD(P)H oxidase activity were both associated with increased clinical risk factors for atherosclerosis. Diabetes and hypercholesterolemia were independently associated with increased NADH-dependent superoxide production. The association of increased vascular NAD(P)H oxidase activity with endothelial dysfunction and with clinical risk factors suggests an important role for NAD(P)H oxidase-mediated superoxide production in human atherosclerosis. The full text of this article is available at http://www.circresaha.org. Key Words:atherosclerosis endothelium superoxide nitric oxide diabetes Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na(+) Channel Marieke W. Veldkamp, Prakash C. Viswanathan, Connie Bezzina, Antonius Baartscheer, Arthur A.M. Wilde, Jeffrey R. Balser Abstract-The congenital long-QT syndrome (LQT3) and the Brugada syndrome are distinct, life-threatening rhythm disorders linked to autosomal dominant mutations in SCN5A, the gene encoding the human cardiac Na(+) channel. It is believed that these two syndromes result from opposite molecular effects: LQT3 mutations induce a gain of function, whereas Brugada syndrome mutations reduce Na(+) channel function. Paradoxically, an inherited C-terminal SCN5A mutation causes affected individuals to manifest electrocardiographic features of both syndromes: QT-interval prolongation (LQT3) at slow heart rates and distinctive ST-segment elevations (Brugada syndrome) with exercise. In the present study, we show that the insertion of the amino acid 1795insD has opposite effects on two distinct kinetic components of Na(+) channel gating (fast and slow inactivation) that render unique, simultaneous effects on cardiac excitability. The mutation disrupts fast inactivation, causing sustained Na(+) current throughout the action potential plateau and prolonging cardiac repolarization at slow heart rates. At the same time, 1795insD augments slow inactivation, delaying recovery of Na(+) channel availability between stimuli and reducing the Na(+) current at rapid heart rates. Our findings reveal a novel molecular mechanism for the Brugada syndrome and identify a new dual mechanism whereby single SCN5A mutations may evoke multiple cardiac arrhythmia syndromes by influencing diverse components of Na(+) channel gating function. The full text of this article is available at http://www.circresaha.org. Key Words: Na(+) channel inactivation long-QT syndrome Brugada syndrome
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PMID:UltraRapid communications : vascular superoxide production by NAD(P)H OxidaseAssociation with endothelial dysfunction and clinical risk factors 1080 75


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