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)

Phosphofructokinase (PFK) is a key rate-limiting enzyme in glycolysis and represents a major control point in the metabolism of glucose. There are at least three known isoforms of PFK in humans, referred to as the muscle, platelet, and liver forms, each of which is differentially expressed in various tissues. The gene for muscle phosphofructokinase, PFKM, is mutated in Tarui disease and conceivably contributes to non-insulin-dependent diabetes mellitus (NIDDM). Based on physical and genetic mapping, we have found that the gene for PFKM does not map to chromosome 1 as previously described, but instead maps to chromosome 12. PCR analysis with a somatic cell hybrid mapping panel using primers derived from intron 6 and exon 18 of the PFKM gene showed consistent amplification of cell lines containing chromosome 12 (concordance, 100%). Fluorescence in situ hybridization analysis with CEPH YAC 762G4, isolated with exon 18 primers, indicated that this clone maps to 12q13, centromeric to the diacylglycerol kinase gene (DAGK) at 12q13. 3. A highly informative genetic marker isolated from YAC 762G4 was used to map PFKM genetically between the CHLC framework markers D12S1090 and D12S390. This placement for 762G4 was significantly proximal to the recently reported locus for a third gene for maturity onset diabetes of the young (MODY). The PFKM-associated microsatellite will be a valuable tool in the evaluation of PFKM in diabetic populations as well as in linkage analysis in families with Tarui disease.
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PMID:Physical and genetic mapping of the muscle phosphofructokinase gene (PFKM): reassignment to human chromosome 12q. 866 Oct 33

Dysfunction of organs has been reported in diabetic rats, suggesting an association with changes in intracellular signal transduction pathways including phosphatidylinositol (PI) turnover. Diacylglycerol (DG) kinase catalyses the phosphorylation of DG, which is considered to play a major physiological role in the metabolism of the intracellular messenger DG. However, no relation between DG kinase activity and any disease in mammalian tissue has been reported to date. In the present study, we investigated whether the changes in DG kinase activity are related to diabetes. Basal resting level of DG kinase activity changed in tissue isolated from diabetic rats. Decreases in resting activity detected in aorta and kidney and agonist-induced responses differed between these tissues. Submaximal increases in basal activity also were detected in vas deferens and hepatocytes. These changes in DG kinase activity resemble the functional changes associated with complications of diabetes, suggesting that changes in PI turnover followed by DG kinase activity are a key element in the complications. It is the first study about the changes in DG kinase activity in mammalian disease.
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PMID:Alternations of diacylglycerol kinase in streptozotocin-induced diabetic rats. 975 14

Insulin resistance of skeletal muscle is fundamental to both syndrome X and its frequent sequel, type II diabetes. In these disorders, excessive exposure of muscle to free fatty acids (FFAs) and their metabolic derivatives appears to play a prominent role in the induction of insulin resistance. Recent evidence suggests that activation of novel isoforms of protein kinase C (PKC) by diacylglycerol may mediate at least part of the adverse impact of FFAs on muscle insulin sensitivity. Vitamin E and fish oil omega-3s, by promoting the activity of diacylglycerol kinase and inhibiting that of phosphatidate phosphohydrolase, should reduce diacylglycerol levels, thus accounting for their documented favorable impact on insulin sensitivity. Thiazolidinediones such as troglitazone, on the other hand, appear to intervene in the signaling pathway whereby PKC down-regulates insulin function. The insulin-sensitizing activity of chromium picolinate may be attributable, at least in part, to increased expression of insulin receptors. In combination with lifestyle modifications which reduce FFA exposure--weight loss, very-low-fat eating, excessive training--these measures can be expected to work in a complementary way to promote increased numbers of insulin receptors that are more functionally competent. As these measures appear to be safe and well-tolerated, they may have utility for the prevention of diabetes as well as its therapy. When they do not prove sufficient to achieve optimal glycemic control, excessive hepatic glucose output and impaired cell response to glucose can be addressed with metformin and sulfonylureas, respectively. The prospects for a rational medical management of type II diabetes, obviating the need for injectible insulin, have never been brighter.
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PMID:Complementary measures for promoting insulin sensitivity in skeletal muscle. 1005 64

We have previously shown that unsaturated fatty acids amplify platelet-derived-growth-factor (PDGF)-induced protein kinase C (PKC) activation in vascular smooth-muscle cells (VSMCs). Diacylglycerol-induced PKC activation is normally terminated by diacylglycerol kinases (DGKs). We thus hypothesized that fatty acids act by inhibiting a DGK. Fractionation of VSMC extracts demonstrated that the DGK alpha isoform was the major DGK activity present. PDGF markedly increased the DGK activity of cultured cells. An inhibitor selective for the DGK alpha isoform, R59949 [3-[2-[4-(bis-(4-fluorophenyl)methylene]piperidin-1-yl)ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone], abolished the growth-factor-induced increase in DGK activity, but had little effect on basal activity. PDGF thus selectively activates DGKalpha. Epidermal growth factor and alpha-thrombin stimulated total DGK activity similarly to PDGF. Activation by epidermal growth factor was sensitive to R59949, again suggesting involvement of DGKalpha. However, the alpha-thrombin-induced activity was unaffected by this agent. Unsaturated fatty acids inhibited growth-factor-induced DGKalpha activation, but had no effect on basal activity. Fatty acids also amplified the PDGF-induced increase in cell diacylglycerol content. These results indicate that inhibition of DGKalpha contributes to fatty-acid-induced amplification of PKC activation. Increased levels of fatty acids in diabetes may thus contribute to chronic PKC activation associated with this disorder.
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PMID:Fatty acids inhibit growth-factor-induced diacylglycerol kinase alpha activation in vascular smooth-muscle cells. 1141 60

1. Dysfunction of vascular contraction in diabetes has been reported; however, the mechanisms are poorly understood. In this study, calcium sensitization involving increases in contraction in streptozotocin-induced diabetic rat aorta was detected. We hypothesize that an alteration in the intracellular signalling system plays a role in the dysfunction of vascular contractility in diabetes. Therefore, diacylglycerol (DG) kinase as a key enzyme of phosphatidylinositol (PI) turnover was investigated. 2. Treatment with norepinephrine (NE) caused time- and dose-dependent activation of DG kinase in control rats. This activation required simultaneous increases in intracellular calcium concentration ([Ca2+]i) and protein kinase C (PKC) activation. I3. n diabetic rats, hyper-reactivity of DG kinase involving inactivation in the resting state and over-activation in NE stimulation was observed. During hyper-reactivity, [Ca2+]i dependency of DG kinase was enhanced. Treatment with 50 mM KCl induced significant escalation in activity; moreover, basal activation of PKC was detected only in diabetes. These results suggested that PKC had been activated in the resting state. In contrast, these conditions were insufficient for DG kinase activation due to the absence of [Ca2+]i elevation. 4. During NE-stimulation, PKC activation was maintained and [Ca2+]i increased. Therefore, DG kinase was activated and an elevation in calcium dependency enhanced this activation. 5. The present study suggested that DG kinase hyper-reactivity in diabetes involved both an increase in [Ca2+]i and basal activation of PKC. This phenomenon may be associated with increased vascular contraction in diabetes mediated by acceleration of PI-turnover.
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PMID:Hyper-reactivity of diacylglycerol kinase is involved in the dysfunction of aortic smooth muscle contractility in streptozotocin-induced diabetic rats. 1202 47

Macrovascular complications in diabetes are associated with exaggerated growth responses of vascular smooth muscle cells. We studied the effect of high glucose media on the growth responses of vascular smooth muscle cells from the left anterior descending (LAD) coronary artery of young sheep. Experiments were conducted in DMEM containing 5.5 or 25 mmol/l glucose and mitogenic responses assessed by 3H-thymidine incorporation. In the absence of growth factors there was a slight and variable response to high glucose but the maximum response to platelet derived growth factor-bb (PDGF-bb) (100 ng/ml) was increased more than 2-fold. Transforming growth factor-beta1 (1 ng/ml) caused a 100% increase of the PDGF-bb response in both normal and high glucose media. The acute stimulatory effect of high glucose was not affected by pre-incubation of the cells for 24 h in the high glucose medium. The mitogenic response occurring in the presence of PDGF-bb and high glucose was totally inhibited by the tyrosine kinase inhibitors (imatinib and genistein) and could not be mimicked by increasing diacylglycerol in low glucose media with the diacylglycerol kinase inhibitor, R59949. In conclusion, high glucose, per se, only very weakly stimulates smooth muscle cell growth but it interacts positively to potentiate the responses to the vascular derived growth factors PDGF and TGF-beta1. The effect of high glucose is transduced via receptor tyrosine kinases and may not involve diacylglycerol that is subject to diacylglycerol kinase catabolism. The data provide explanations for the accelerated vascular smooth muscle cell proliferation in diabetes.
Diabetes Res Clin Pract 2003 Feb
PMID:High glucose potentiates mitogenic responses of cultured ovine coronary smooth muscle cells to platelet derived growth factor and transforming growth factor-beta1. 1256 Jan 58

The effect of the thromboxane A(2) analog 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F(2alpha) (U46619) on spontaneous phasic contractions in the mouse portal vein was studied. U46619 induced concentration-dependent (1-100 nM) increases in amplitude, frequency, and contractile period (ON-time) of the contraction. Both amplitude and ON-time were enhanced significantly under high-glucose (HG; 4-fold greater than normal) conditions. This hyperactivation may be associated with portal vein dysfunction in diabetes. However, the mechanisms remain unclear. HG enhanced the U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibition suppressed accumulation under normal conditions; however, this suppression was not observed under HG conditions. The HG-induced enhancement of U46619-induced contraction was inhibited by protein kinase C (PKC) inhibition. This finding indicated that accumulated DG might increase PKC activity. Activated PKC stimulated DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed the HG-induced enhancement of contraction. Increased myo-inositol incorporation was detected under HG conditions, indicating an acceleration of phosphatidylinositol (PI) turnover. This acceleration was inhibited by PKC and DG kinase inhibitors. These findings indicated that HG treatments increased DG synthesis derived from incorporated glucose, PKC, and DG kinase activation. These responses induce hyperactivation of the amplitude and contractile period of contraction mediated by acceleration of PI turnover. This series of responses may be involved in the dysfunction of the portal vein under the HG conditions occurring with diabetes.
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PMID:Enhancement effect under high-glucose conditions on U46619-induced spontaneous phasic contraction in mouse portal vein. 1260 90

Rat models of insulin-dependent (streptozotocin-induced) and independent (Otsuka Long-Evans Tokushima Fatty (OLETF)) diabetes had sustained and transient increases in blood glucose levels. Over-contraction due to norepinephrine was seen exclusively in streptozotocin rat aorta. Contraction was enhanced under high-glucose conditions in OLETF rats. In order to understand the association between these patterns of changes, total diacylglycerol was measured as a key element of phosphatidylinositol-turnover due to the conversion of some incorporated glucose into diacylglycerol. Streptozotocin rats had enhanced basal diacylglycerol. Both diacylglycerol kinase (metabolic enzyme of diacylglycerol) and total phosphatidylinositol turnover activities also increased on norepinephrine stimulation, independent of extracellular glucose level. On the other hand, diacylglycerol, diacylglycerol kinase and phosphatidylinositol turnover in OLETF rats increased under high glucose conditions in the absence of norepinephrine treatment. These results indicated that diacylglycerol and diacylglycerol kinase-mediated phosphatidylinositol turnover acceleration was influenced by an increase in glucose levels in OLETF rats or by receptor-mediated signals in streptozotocin rats including glucose desensitization based on submaximal incorporation. We suggest that the alteration of vascular dysfunction is induced by different factors in each type of diabetes.
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PMID:Dysfunction of aorta involves different patterns of intracellular signaling pathways in diabetic rats. 1282 38

The effect of the thromboxane A(2) analogue U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2)(alpha)) on sustained contraction in the mouse aorta was investigated. U46619 induced concentration-dependent (1 - 100 nM) increases in contraction. These contractile responses were enhanced significantly under high-glucose-physiological salt solution (HG-PSS) (2-fold greater than normal-PSS) conditions. This hyperactivation may be associated with aortic dysfunction in diabetes. However, the mechanisms remain unclear. HG-PSS enhanced U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibitor (U73122) suppressed DG accumulation under normal conditions; however, suppression was not observed under high-glucose conditions. The HG-PSS-induced enhancement of contraction was inhibited by protein kinase C (PKC) inhibitor (calphostin C). This result indicated that accumulated DG might increase PKC activity, which then stimulates DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed HG-PSS-induced enhancement of contraction. Increased myo-inositol incorporation was detected under high-glucose conditions, indicating an acceleration of phosphatidylinositol (PI)-turnover. Moreover, rho kinase inhibitor (Y27632) suppressed U46619-induced contraction exclusively in normal-PSS. These findings indicated that HG-PSS treatment increases DG synthesis derived from incorporated glucose, PKC and DG kinase activation, and enhances the U46619-induced contraction via acceleration of PI-turnover. This series of responses may be involved in the dysfunction of aorta under high-glucose conditions occurring in association with diabetes.
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PMID:High-glucose enhances a thromboxane A2-induced aortic contraction mediated by an alteration of phosphatidylinositol turnover. 1289 Aug 93

1. Diacylglycerol kinase (DG kinase) is a key enzyme in vascular contraction; however, alterations of the regulatory mechanisms in vascular dysfunction are poorly understood. In this study, the effect of a novel DG kinase inhibitor, stemphone, on vascular contraction was investigated. 2. The conventional DG kinase inhibitor, 6-[2-(4-[(4-fluorophenyl)phenyl-methylene]-1-piperidinyl)ethyl]-7-methyl-5H-thiazolo [3,2-alpha] pyrimidine-5-one (R59022) (0.1-30 microm), inhibited thromboxane A(2) analogue 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (U46619)-induced sustained contractions in mouse aorta and porcine coronary artery in a dose-dependent manner. Treatment with stemphone did not affect contractions in these tissues. However, stemphone significantly inhibited (>0.3 microm) U46619-induced spontaneous phasic contraction in mouse portal vein. This inhibitory effect was not detected following R59022 treatment in portal vein. Therefore, stemphone demonstrated selectivity in terms of portal vein contraction. 3. Under high glucose (22.2 mm) conditions, U46619-induced contraction was enhanced in these three types of vascular tissue. Inhibitory effects of R59022 were attenuated under these conditions; however, effects of stemphone were observed. These results indicated that stemphone could inhibit portal vein contraction under high glucose conditions, for example, diabetes. These data suggested the possibility that DG kinase may be a target of hyperportal pressure. 4. Total mass of DG was enhanced under high glucose conditions. DG was derived from incorporated glucose via de novo synthesis in the absence of phospholipase C pathway mediation. This enhanced DG under high glucose conditions activated a calcium-independent protein kinase C (PKC). This PKC was associated with calcium-independent DG kinase activation. Treatment with stemphone also inhibited calcium-independent DG kinase. These signal transduction pathways were distinguishable from a DG-PKC pathway under normal glucose conditions. 5. The present investigation suggested that stemphone selectively inhibited overcontraction of portal vein induced by high glucose levels. This phenomenon was attributable to inhibition of calcium-independent DG kinase activation that occurred under high glucose conditions mediated by both DG synthesized from glucose and calcium-independent PKC activation.
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PMID:Novel diacylglycerol kinase inhibitor selectively suppressed an U46619-induced enhancement of mouse portal vein contraction under high glucose conditions. 1528 83


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