Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical observations indicate that diabetes leads to micro- and macroangiopathy involving endothelial dysfunction. Because recent studies indicate an antiangiopathic effect of celiprolol, but not of metoprolol, in type 1 diabetes, we investigated the direct influence of exposure to high D-glucose concentrations on endothelial cells and the possible effects of both beta-blockers. Nine different chronic treatments were carried out on cultured porcine aortic endothelial cells: 1) 5 mmol/l D-glucose ("normoglycemic" cells), 2) 5 mmol/l D-glucose plus 15 mmol/l L-glucose (osmotic control), 3) 5 mmol/l D-glucose plus 0.5 micromol/l celiprolol, 4) 5 mmol/l D-glucose plus 0.05 micromol/l metoprolol, 5) 5 mmol/l D-glucose plus 0.5 micromol/l celiprolol plus 5 micromol/l propranolol, 6) 20 mmol/l D-glucose ("hyperglycemic" cells), 7) 20 mmol/l D-glucose plus 0.5 micromol/l celiprolol, 8) 20 mmol/l D-glucose plus 0.05 micromol/l metoprolol, and 9) 20 mmol/l D-glucose plus 0.5 micromol/l celiprolol plus 5 micromol/l propranolol. Using the Fura-2 technique, application of either 1 nmol/l bradykinin or 1 micromol/l ATP to the normoglycemic endothelial cells led to a significant increase in intracellular calcium, whereas the hyperglycemic cells showed significantly less reactivity to both agents. Exposure of endothelial cells to L-glucose did not show any difference to normoglycemic controls. Coadministration of 20 mmol/l glucose and celiprolol demonstrated that the alteration of the calcium signal induced by high D-glucose concentrations could be significantly antagonized with celiprolol. In contrast, coincubation with metoprolol failed to normalize the calcium signal. This effect of celiprolol was completely abolished in the presence of propranolol. In normoglycemic cells, none of the beta-blockers influenced the intracellular calcium response to bradykinin or ATP. These results indicate that chronic treatment with high D-glucose concentrations leads to an impairment of calcium signaling, which might be ameliorated by celiprolol.
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PMID:Influence of chronic exposure to high concentrations of D-glucose and long-term beta-blocker treatment on intracellular calcium concentrations of porcine aortic endothelial cells. 951 47

Human alpha-endosulfine is an endogenous regulator of the beta-cell K(ATP) channels. The recombinant alpha-endosulfine inhibits sulfonylurea binding to beta-cell membranes, reduces cloned K(ATP) channel currents, and stimulates insulin secretion from beta-cells. These properties led us to study the human ENSA gene that encodes alpha-endosulfine. Here, we describe the isolation, the partial characterization, and the chromosomal localization of the ENSA gene. The ENSA gene appears to be a 1.8-kb-long sequence that contains the transcription initiation site located 528 bp upstream of the initiation codon. The ENSA gene is intronless, and a single copy gene seems to be present in the genome. Finally, the ENSA gene co-localizes on human chromosome 14 (14q24.3-q31) with a locus for susceptibility to type 1 diabetes called IDDM11; thus, the ENSA gene represents an IDDM11 candidate.
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PMID:Isolation, characterization, and chromosomal localization of the human ENSA gene that encodes alpha-endosulfine, a regulator of beta-cell K(ATP) channels. 1048 Jun 22

Mesenteric arteries were isolated from the spontaneous diabetic BB rats, non diabetic BB rats and regular Wistar control rats. Gross morphology indicated that the mesenteric vascular bed of the control Wistar rats had a normal development of mesenteric fat pad around the vessels, while that of the diabetic BB rats showed drastically reduced perivascular fat pad, suggesting greater mobilization of fat for energy consumption in the hyperglycemic state of diabetes mellitus. The perivascular mesenteric fat pad of the non-diabetic BB rats was intermediate between those of the Wistar control and diabetic BB rats. The wet weight of the mesenteric arteries following removal of fat, vein and connective tissues was significantly greater in diabetic BB rats than in the corresponding controls. Microsomal membranes isolated from the mesenteric arteries of diabetic BB rats showed increased alkaline phosphatase and 5'-nucleotidase activities compared to those isolated from the two groups of non-diabetic control rats. Acid phosphatase activities were higher in both BB rat groups compared to the Wistar group. The total Ca2+ uptake by the microsomes of mesenteric arteries in the presence of ATP was not different among three experimental groups, but the ATP dependent active transport of Ca2+ was significantly increased and the passive Ca2+ binding was significantly reduced in diabetic group compared to the other two non-diabetic groups. Our results demonstrate that in the spontaneously diabetic BB rats, alterations in both structural and functional parameters may underline the vascular complications associated with type I diabetes mellitus in humans.
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PMID:Membrane abnormalities of vascular smooth muscle of mesenteric arteries of spontaneous diabetic BB rats. 1059 73

In uremia, accelerated muscle protein degradation results from activation of the ATP-ubiquitin proteasome proteolytic pathway. Like uremia, other conditions (e.g., acidosis and diabetes) activate this pathway in rat muscles and are associated with excess glucocorticoids (GC) and impaired insulin action. To define the stimuli responsible for muscle wasting in IDDM, the roles of glucocorticoids, insulinopenia and acidosis in streptozotocin (STZ) - induced diabetes were studied. Proteolysis in isolated epitrochlearis muscles from acutely (3d) diabetic rats was 52% higher than pair-fed, sham-injected rats; this increase was eliminated by an inhibitor of the proteasome or by blocking ATP synthesis. In muscles of STZ-diabetic rats, the levels of ubiquitin-conjugated proteins and mRNAs encoding ubiquitin, the ubiquitin-carrier protein, E2(14k) and the C3, C5 and C9 proteasome subunits were increased. Transcription of ubiquitin and C3 proteasome subunit genes in muscle was also increased by IDDM. Oral NaHCO(3) eliminated acidemia but did not prevent accelerated muscle proteolysis. Corticosterone excretion was higher in IDDM rats and adrenalectomy (ADX) prevented these catabolic responses; physiologic doses of glucorcoticoids restored the excessive protein catabolism in ADX-STZ rats. Giving IDDM rats replacement insulin also normalized protein degradation in muscles. In conclusion, reduced insulin together with physiologic levels of glucocorticoids activate the ubiquitin-proteasome pathway by a mechanism that includes enhancing ubiquitin conjugation and proteolysis by the proteasome. The balance between these stimuli could regulate muscle proteolysis in uremia.
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PMID:The balance between glucocorticoids and insulin regulates muscle proteolysis via the ubiquitin-proteasome pathway. 1068 43

Nitric oxide (NO) is assumed to contribute to the impairment of B-cell function in type 1 diabetes mellitus (IDDM). In the present paper we show that in mouse B-cells with intact metabolism authentic NO (20 microM) led to a biphasic effect on the K(+)(ATP) current, namely a transient increase and a consecutive almost complete inhibition. This resembles closely the effect that we have observed previously with the NO donor S-nitrosocysteine (SNOC, 1 mM) suggesting that merely NO caused both phases of this effect. We now demonstrate that the rise in the current amplitude was accompanied by a depolarization of the mitochondrial membrane potential DeltaPsi and a concomitant reduction in the ATP/ADP ratio. Thus, it seems likely that the increase in current amplitude is due to the interference of NO with cell metabolism. The subsequent inhibition of the K(+)(ATP) current is assumed to be caused by a direct effect on the channel since K(+)(ATP) single channel current activity measured in excised patches was strongly reduced by authentic NO and SNOC. Our data reveal new insights into the mechanisms underlying the biphasic action of NO on K(+)(ATP) channels in pancreatic B-cells.
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PMID:Dual effect of NO on K(+)(ATP) current of mouse pancreatic B-cells: stimulation by deenergizing mitochondria and inhibition by direct interaction with the channel. 1070 20

Increased evidence suggests that apoptosis is the main mode of beta-cell death in early type 1 diabetes. Cytokines mediate beta-cell apoptosis, and in this article, we discuss some of the cytokine-modified genes that may contribute to beta-cell survival or death. The gene encoding for the inducible form of nitric oxide synthase is induced by interleukin (IL)-1beta or IL-1beta plus gamma-interferon in rodent and human islets, respectively. This leads to nitric oxide (NO) formation, which contributes to a major extent to beta-cell necrosis and to a minor extent to the process of beta-cell apoptosis. The main mode of cell death induced by cytokines in human beta-cells is apoptosis, whereas cytokines lead to both necrosis and apoptosis in rat and mouse beta-cells. It is suggested that the necrotic component in rodent islets is due to NO-induced mitochondrial impairment and consequent decreased ATP production. Human islets, possessing better antioxidant defenses, are able to preserve glucose oxidation and ATP production, and can thus complete the apoptotic program after the death signal delivered by cytokines. We propose that this death signal results from cytokine-induced parallel and/or sequential changes in the expression of multiple proapoptotic and prosurvival genes. The identity of these "gene modules" and of the transcription factors regulating them remains to be established.
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PMID:beta-cell apoptosis and defense mechanisms: lessons from type 1 diabetes. 1127 5

We measured the activities of total Na+, K+-ATPase (Na, K-ATPase), its alpha1 and alpha2/alpha3 isoforms and the angiotensin-converting enzyme (ACE) in the microvascular and neural compartments of the retina, and/or retinal pigment epithelium (RPE) of streptozotocin (STZ)-diabetic rats. The effect of captopril, an ACE inhibitor on Na, K-ATPase activities was also determined and correlated to morphological changes. Insulin-dependent diabetes mellitus was induced by a single intraperitoneal injection of STZ (60 mg/kg) in male Long-Evans rats. ACE activity was inhibited by captopril (10 mg/kg given in the drinking water) for 1 month. Na, K-ATPase activity was measured spectrophotometrically or by a radioassay (32P-labeled ATP). The activity of ACE was determined by a radioassay using tritiated benzoyl-gly-gly-gly as substrate. Both the alpha1 and alpha2/alpha3 isoforms of Na, K-ATPase were present in the microvascular and neural compartments of retinas, whereas only one isoform, the alpha2/alpha3, was found in the RPE. In 2-month diabetic rats, the activity of the alpha2/alpha3 isoform was reduced in both the microvascular and neural compartments of retinas, while the activity of the alpha1 isoform was reduced only in the neural isolates. ACE activity was significantly decreased in the retinal neural compartment and unaltered in the microvascular compartment from 2-month diabetic rats. In 5-month diabetic rats, Na, K-ATPase activity was moderately but not significantly reduced in RPE preparations. Ultrastructural studies revealed a significant deepening of basal infoldings in the RPE and a noticeable increase in the size of the extracellular space between the basal infoldings of 5-month diabetic animals. Captopril stimulated Na, K-ATPase activity in the neural retina, but not in the RPE. Diabetes-induced morphological changes in the RPE were not improved by captopril. An enlargement of intercellular space between the RPE cells was a frequent finding in the treated group. In conclusion, captopril stimulated Na, K-ATPase activity in the neural retina of diabetic rats. This stimulation seems to be beneficial to the neural retina. ACE inhibition, however, did not improve RPE morphological changes. Although the clinical significance of increased intercellular spacing between RPE cells in treated animals is not clearly established, we speculate that it might contribute to an increased alteration of their barrier function. Additional studies are necessary to assess both the desirable and adverse effects of captopril and other ACE inhibitors in the retinas of diabetic patients.
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PMID:Biochemical and ultrastructural studies in the neural retina and retinal pigment epithelium of STZ-diabetic rats: effect of captopril. 1177 81

1. The early stage of type 1 diabetes mellitus (DM) is characterized by renal hyperfiltration, which promotes the eventual development of diabetic nephropathy. The hyperfiltration state is associated with afferent arteriolar dilation and diminished responsiveness of this vascular segment to a variety of vasoconstrictor stimuli, whereas efferent arteriolar diameter and vasoconstrictor responsiveness are typically unaltered. 2. The contractile status of preglomerular vascular smooth muscle appears to be tightly coupled to membrane potential (E(m)) and its influence on Ca(2+) influx through voltage-gated channels. Efferent arteriolar tone is largely independent of electromechanical events. Hence, defective electromechanical mechanisms in vascular smooth muscle should engender selective changes in preglomerular microvascular function, such as those evident during the early stage of DM. 3. Afferent arteriolar contractile responses to K(+)-induced depolarization and BAYK8644 are diminished 2 weeks after onset of DM in the rat. Similarly, depolarization-induced Ca(2+) influx and the resulting increase in intracellular [Ca(2+)] are abated in the preglomerular microvasculature of diabetic rats. The intracellular [Ca(2+)] response to depolarization is rapidly restored by normalization of extracellular glucose levels. These observations suggest that hyperglycaemia in DM impairs regulation of afferent arteriolar voltage-gated Ca(2+) channels. 4. Dysregulation of E(m) may also contribute to afferent arteriolar dilation in DM. Vasodilator responses to pharmacological opening of ATP-sensitive K(+) channels are exaggerated in afferent arterioles from diabetic rats. Moreover, blockade of these channels normalizes afferent arteriolar diameter in kidneys from diabetic rats. These observations suggest that increased functional availability and basal activation of ATP-sensitive K(+) channels promote afferent arteriolar dilation in DM. 5. We propose that dysregulation of E(m) (involving ATP- sensitive K(+) channels) and a diminished Ca(2+) influx response to depolarization (involving voltage-gated Ca(2+) channels) may act synergistically to promote preglomerular vasodilation during the early stage of DM.
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PMID:Altered electromechanical coupling in the renal microvasculature during the early stage of diabetes mellitus. 1190 74

Nosologically, Alzheimer disease may not be considered to be a single disorder in spite of a common clinical phenotype. Only a small proportion of about 5% to 10% of all Alzheimer cases is due to genetic mutations (type I) whereas the great majority of patients was found to be sporadic in origin. It may be assumed that susceptibility genes along with lifestyle risk factors contribute to the causation of the age-related sporadic Alzheimer disease (type II). In this context, the desensitization of the neuronal insulin receptor similar to not-insulin dependent diabetes mellitus may be of pivotal significance. This abnormality along with a reduction in brain insulin concentration is assumed to induce a cascade-like process of disturbances including cellular glucose, acetylcholine, cholesterol, and ATP associated with abnormalities in membrane pathology and the formation of both amyloidogenic derivatives and hyperphosphorylated tau protein. Sporadic Alzheimer disease may, thus, be considered to be the brain type of diabetes mellitus II. Experimental evidence is provided and discussed.
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PMID:The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. 1195 56

Proinflammatory cytokine-mediated pancreatic beta-cell dysfunction is a key pathological event in type I diabetes mellitus. Lisofylline (LSF), an anti-inflammatory agent, has been shown to protect pancreatic islets from IL-1 beta-induced inhibitory effects on insulin release. However, the mechanism of LSF action is not known. Increasing evidence suggests that the mitochondria play an important role in regulating the beta-cell insulin release capacity and the control of cellular viability. To examine the direct effects of LSF on beta-cells, insulin-secreting INS-1 cells were exposed to a combination of recombinant IL-1 beta, TNF alpha, and IFN gamma with or without LSF for 18 h. Basal and glucose-stimulated static insulin release were measured using RIA. INS-1 cell viability was determined using in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and LIVE/DEAD dual fluorescence labeling. To evaluate INS-1 mitochondrial function, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolism, change in mitochondrial membrane potential, and intracellular ATP levels were assessed. Cytokine addition reduced basal (7.8 +/- 0.30 vs. 10.0 +/- 0.46 ng/ml.h; P < 0.005), glucose-stimulated insulin secretion (11.6 +/- 0.86 vs. 17.4 +/- 1.86 ng/ml.h; P < 0.005), and MTT metabolism in INS-1 cells. Over 40% of the cytokine-treated beta-cells exhibited nuclear DNA breakage, whereas the control cell death rate remained at 1-2%. Simultaneous application of LSF and cytokines to INS-1 cells restored insulin secretion, MTT metabolism, mitochondrial membrane potential, and cell viability to control levels. LSF increased beta-cell MTT metabolism as well as insulin release and glucose responsiveness. In summary, proinflammatory cytokines lead to a reduction of glucose-induced insulin secretion, mitochondrial activity, and viability in INS-1 cells. LSF at concentrations achievable in vivo protected beta-cells from the cytokine effects. The mechanism of LSF-induced protection may be by promoting mitochondrial metabolism.
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PMID:Lisofylline, a novel antiinflammatory agent, protects pancreatic beta-cells from proinflammatory cytokine damage by promoting mitochondrial metabolism. 1202 Nov 99


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