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

Diabetes mellitus is associated with typical patterns of long term vascular complications which vary with the organ involved. The microvascular kidney disease (Olgemoller and Schleicher, 1993) is characterized by thickening of the capillary basement membranes and increased deposition of extracellular matrix components (ECM), while loss of microvessels with subsequent neovascularisation is predominant in the eye and peripheral nerves. On the other hand macrovascular disease is characterized by accelerated atherosclerosis. These complications are dependent on long term hyperglycemia. Specific biochemical pathways linking hyperglycaemia to microvascular changes were proposed: the polyol pathway (Greene et al., 1987), non-enzymatic glycation of proteins (Brownlee et al., 1988), glucose autooxidation and oxidative stress (Hunt et al., 1990), hyperglycemic pseudohypoxia (Williamson et al., 1993) enhanced activation of protein kinase C by de novo-synthesis of diacyl glycerol (Lee et al., 1989; DeRubertis and Craven 1994) and others. These pathways are not mutually exclusive (Larkins and Dunlop, 1992; Pfeiffer and Schatz, 1992). They may be linked to alterations in the synthesis of growth factors particularly since atherosclerosis and angioneogenesis are associated with increased proliferation of endothelial and smooth muscle cells. Increased synthesis of ECM components is stimulated by growth factors like transforming growth factor beta (TGF beta) (Derynck et al., 1984) and insulin-like growth factor I (IGF-I) (Moran et al., 1991). This review will summarize some of the recent evidence for an involvement of growth factors in diabetic vascular complications and will attempt to assign their emergence in the sequence of events leading to vascular complications.
Exp Clin Endocrinol Diabetes 1995
PMID:Diabetic microvascular complications and growth factors. 762 Nov 7

Inhibition of Na+,K(+)-ATPase activity by hyperglycemia could be an important etiological factor of chronic complications in diabetic patients. The biochemical mechanism underlying hyperglycemia's inhibitory effects has been thought to involve the alteration of the protein kinase C (PKC) pathway since agonists of PKC can normalize hyperglycemia-induced inhibition of Na+,K(+)-ATPase activity. Paradoxically, elevated glucose levels and diabetes have been shown to increase PKC activities in vascular cells. The present study tested the hypothesis that the inhibition of Na+,K(+)-ATPase activity is mediated by the sequential activation of PKC and cytosolic phospholipase A2 (cPLA2). In cultured rat vascular smooth muscle cells (VSMC), increasing glucose levels in the medium from 5.5 to 22 mM elevated cPLA2 activity and increased [3H]arachidonic acid release and PGE2 production by 2.3-, 1.7- and 2-fold, respectively. Similar increases in cPLA2 activity were also induced by elevated glucose levels in human VSMC and rat capillary endothelial cells. The activation of cPLA2 was mediated by PKC since the increases in cPLA2 phosphorylation and enzymatic activity were inhibited by the PKC inhibitor GFX. In contrast, elevation of glucose levels decreased Na+,K(+)-ATPase activity as measured by ouabain-sensitive 86Rb uptake by twofold in rat VSMC. Surprisingly, both PMA, a PKC agonist, and GFX, a PKC inhibitor, were able to prevent glucose-induced decreases in 86Rb uptake. Further, the PLA2 inhibitor AACOCF3 abolished both glucose-induced activation of cPLA2 and the decrease in 86Rb uptake. These data indicated that hyperglycemia is inhibiting Na+,K(+)-ATPase activity by the sequential activation of PKC and cPLA2, resulting in the liberation of arachidonic acid and increased the production of PGE2, which are known inhibitors of Na+,K(+)-ATPase.
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PMID:Identification of the mechanism for the inhibition of Na+,K(+)-adenosine triphosphatase by hyperglycemia involving activation of protein kinase C and cytosolic phospholipase A2. 763 66

We have characterized effects of d-alpha-tocopherol (vitamin E) on activation of protein kinase C (PKC) and diacylglycerol (DAG) levels in retinal tissues of diabetic rats and correlated its effects to diabetes-induced changes in retinal hemodynamics. Membrane PKC specific activities were increased by 71% in streptozocin-induced diabetic rats compared with controls (P < 0.05). Western blot analysis showed that membrane PKC-beta II was increased by 133 +/- 5% (P < 0.05). Injection of d-alpha-tocopherol (40 mg/kg ip) every other day prevented the increases in membrane PKC specific activity and PKC-beta II protein by immunoblots. Diabetes-induced increases in DAG levels were also normalized by d-alpha-tocopherol treatment of 2 wk duration. Physiologically, angiographic abnormalities of retinal hemodynamics based on computerized video-based fluorescein angiography and associated with increases of DAG and membranous PKC levels were also prevented by d-alpha-tocopherol treatment in diabetic rats. The effect of d-alpha-tocopherol on retinal vascular cells was also studied. Exposure of retinal endothelial cells to 22 mM glucose for 3 days increased total DAG and [3H]palmitate-labeled DAG levels by 35 +/- 8 and 50 +/- 8% (P < 0.05), respectively, compared with exposure to 5.5 mM glucose. The presence of d-alpha-tocopherol (50 micrograms/ml) prevented the increases in total DAG and [3H]palmitate-labeled DAG levels in cells exposed to 22 mM glucose. These findings suggested that treatment with d-alpha-tocopherol can prevent diabetes-induced abnormalities in rat retinal blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. 765 41

The aim of this study was to determine how the contractile responses to 5-hydroxytryptamine (5-HT) are altered in aortas from rats with streptozotocin-induced diabetes and to explore the possible mechanisms of the altered vascular reactivity to 5-HT in diabetes. In the presence of extracellular Ca2+ (2.5 mM), the contractile responses to stimulation of 5-HT2 receptors with 5-HT were greater in aortas from diabetic rats as compared with those from age-matched controls. Similarly, phorbol-12,13-dibutyrate (PDBu) (> or = 30 nM) induced significantly greater contractions in diabetic aortas. The enhanced contractile responses of diabetic aortas to 5-HT and PDBu were abolished in the presence of 1 microM nifedipine. Pretreatment with 20 nM staurosporine caused a complete inhibition of the contractile responses to 5-HT in both control and diabetic aortas. In contrast to those to 5-HT and PDBu, the contractile responses to high K+ (40 mM) were markedly diminished in diabetic aortas. The nifedipine-sensitive uptake of 45Ca2+ induced by 5-HT was significantly greater in diabetic aortas than in controls, whereas that induced by high K+ was significantly less in diabetics. The phasic contractions produced by 5-HT in Ca(2+)-free medium were significantly attenuated in diabetic aortas, but those produced by norepinephrine were unchanged. Accumulation of [3H]inositol monophosphate (IP1) in aortic strips prelabeled with myo-[3H]inositol was increased to a similar extent by 5-HT and norepinephrine in control rats, but the 5-HT-induced increase in [3H]IP1 accumulation was significantly less than the norepinephrine-induced one in diabetics. These findings indicate that the extracellular Ca(2+)-dependent contractions mediated by 5-HT2 receptors are enhanced in aortas from diabetic rats, and this is presumably related to a greater influx of Ca2+ through transmembrane Ca2+ channels as a consequence of increased protein kinase C activated processes. On the other hand, the contraction induced by release of Ca2+ from intracellular stores in response to 5-HT is diminished in these tissues, possibly due to the impaired phosphoinositide response.
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PMID:Enhanced 5-HT2 receptor mediated contractions in diabetic rat aorta: participation of Ca2+ channels associated with protein kinase C activity. 765 79

We have previously shown that intraperitoneal injection of H-7, an inhibitor of PKC, restores completely the activity of Na(+)-K(+)-ATPase in sciatic nerve of diabetic mice; however, the effect was transient, with a half-life of approximately 1 h under the conditions used. This work assessed whether calphostin C, a new more potent and specific inhibitor of PKC, is also able to restore the activity of Na(+)-K(+)-ATPase in sciatic nerve of ALX-induced diabetic mice and also assessed if continuous administration of H-7 or calphostin C can afford sustained recovery of the ATPase. Small amounts of calphostin C (i.e., 2 micrograms/kg) restore entirely the activity of the enzyme. Larger doses (e.g., 30 micrograms/kg) can be administered with equal results. The ED50 was approximately 0.5 micrograms/kg. This indicates that calphostin C is approximately 20,000 times more potent than H-7 in restoring the ATPase activity in diabetic mice. A single intraperitoneal injection of 1 or 10 micrograms/kg of calphostin C maintains the enzyme for 4 and 8 h, respectively. Administration of H-7 by continuous delivery from micro-osmotic pumps implanted in the back of the mice maintains the Na(+)-K(+)-ATPase for 24 h, although the activity decreases thereafter. This is the result of instability of H-7 in solution. Continous administration of calphostin C maintains the activity of the ATPase at nearly normal values for at least 2 wk. The results support the hypothesis that, in sciatic nerve tissue of diabetic animals, the activity of PKC is increased, leading to higher phosphorylation of Na(+)-K(+)-ATPase, which results in the decreased activity observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Feb
PMID:Sustained recovery of Na(+)-K(+)-ATPase activity in sciatic nerve of diabetic mice by administration of H7 or calphostin C, inhibitors of PKC. 767 26

Gap junctional intercellular communication (GJIC) is important in coordinating the cells in maintaining tissue homeostasis and in regulating signal transmission. We examined the effect of elevated glucose on GJIC activity in cultured bovine aortic endothelial cells. GJIC activity was assessed by quantitating the transfer from cell to cell of directly microinjected fluorescent dye molecules. GJIC was activated in the subconfluent monolayer. In this condition, exposing the cells to elevated glucose (400 mg/dl) for 24 hrs significantly inhibited GJIC activity, as compared with low glucose (100 mg/dl). This inhibition of GJIC activity induced by elevated glucose was mimicked by addition of 12-O-tetradecanoylphorbol-13-acetate and was restored by addition of staurosporin (10(-8)M), a PKC inhibitor. These results suggest that inhibition of GJIC activity induced by elevated glucose probably through activation of PKC may be involved in the vascular endothelial cell dysfunction associated with diabetes.
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PMID:Inhibition of intercellular communication via gap junction in cultured aortic endothelial cells by elevated glucose and phorbol ester. 769 98

In many tissues, hyperglycemia alters the activities of the Na(+)-dependent myo-inositol (Na/MI) transporter, Na(+)-K(+)-ATPase, and protein kinase C (PKC). However, little is known concerning adaptive changes in renal proximal tubular function after acute or chronic hyperglycemia. We examined hyperglycemia-induced changes in Na/MI transport, Na(+)-K(+)-ATPase activity, and PKC activity using three proximal tubule-like cell lines (JTC12, LLC-PK1, and OK/E cells) and primary cultures of human proximal tubular epithelium (HK cells) cultured for varying periods in low- or high-glucose media, myo-Inositol (MI) transport was mediated by a high-affinity (Km approximately 50 mumol/l) Na(+)-dependent saturable process in the four cell lines. Hyperglycemia produced a time-dependent and persistent increase in Na/MI transport in all cell lines. Chronic hyperglycemia increased the Km for MI transport in LLC-PK1 cells and increased the Vmax in both LLC-PK1 and JTC12 cells. Glucose competitively inhibited Na/MI transport in all low-glucose cells and in high-glucose HK, JTC12, and OK/E cells but had no effect on transport in high-glucose LLC-PK1 cells. Acute hyperglycemia also produced time-dependent increases in Na(+)-K(+)-ATPase activity in all cell lines, a change that persisted only in HK cells. A 24-h exposure to high glucose had no effect on PKC activity in any of the cell lines but increased Ca/phospholipid-dependent PKC activity in membrane fractions from chronically high-glucose LLC-PK1 and OK/E cells. These data suggest that hyperglycemia causes acute changes in proximal tubule function and long-lived adaptive responses in Na/MI transport and the PKC signaling pathway.
Diabetes 1995 Apr
PMID:Hyperglycemia-induced changes in Na+/myo-inositol transport, Na(+)-K(+)-ATPase, and protein kinase C activity in proximal tubule cells. 769 15

We examined effect of insulin or 12-O-tetradecanoyl phorbol 13-acetate (TPA) on the subcellular redistribution of protein kinase C isoforms in rat adipocytes. Total Mono Q column-elutable novel PKCs (nPKCs) which are Ca(2+)-independent and phospholipid-dependent protein kinases, decreased in the cytosolic fraction and increased in the membrane fraction during treatment with insulin or phorbol ester for 10 min. Immunoblot analysis of novel PKCs, -epsilon, -delta and -zeta, showed that insulin stimulated the translocation of these PKC isoforms from cytosol to membrane, similar to the translocation of conventional Ca2+/phospholipid-dependent PKCs (cPKCs), -alpha, -beta, and -gamma. Phorbol esters stimulated the translocation of PKC-alpha, -beta, -gamma, -epsilon and -delta, but not PKC-zeta. These results suggest that (a) insulin and phorbol esters similarly stimulate the translocation of each PKC isoform except for PKC-zeta, and (b) the translocation of both nPKCs and cPKCs occurs during insulin and TPA actions in rat adipocytes.
Diabetes Res Clin Pract 1994 Dec 16
PMID:Phorbol ester and insulin stimulate protein kinase C isoforms in rat adipocytes. 770 99

Diabetes is characterized by hyperglycemia, a relative lack of insulin, and an inclination to vascular disease and neuropathy. The link between diabetes and vascular disease is not understood, but autonomic dysfunction could partly account for alterations in reactivity of diabetic blood vessels to neurotransmitters and circulating hormones. Changes in local control of vascular tone, such as imbalance in production of relaxing and contracting factors by the endothelium, may be related to the initiation and maintenance of abnormal vascular reactivity characteristically seen in diabetic vascular complications. The emphasis is to discuss functional changes of blood vessel adrenergic neuroeffector mechanisms and endothelial cell dysfunction, together with the complex interrelationship of cyclooxygenase catalysis, protein kinase C activity, sodium-potassium ATPase activity, and flux through the polyol pathway. This review focuses on the common mechanisms by which hyperglycemia causes changes in vascular function.
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PMID:Diabetes and vascular disease: functional alterations in adrenergic neurotransmission and endothelium. 774 65

We tested the hypothesis that liver protein kinase C (PKC) is increased in non-insulin-dependent diabetes mellitus (NIDDM). To this end we examined the distribution of PKC isozymes in liver biopsies from obese individuals with and without NIDDM and in lean controls. PKC isozymes alpha, beta, epsilon and zeta were detected by immunoblotting in both the cytosol and membrane fractions. Isozymes gamma and delta were not detected. There was a significant increase in immunodetectable PKC-alpha (twofold), -epsilon (threefold), and -zeta (twofold) in the membrane fraction isolated from obese subjects with NIDDM compared with the lean controls. In obese subjects without NIDDM, the amount of membrane PKC isozymes was not different from the other two groups. We next sought an animal model where this observation could be studied further. The Zucker diabetic fatty rat offered such a model system. Immunodetectable membrane PKC-alpha, -beta, -epsilon, and -zeta were significantly increased when compared with both the lean and obese controls. The increase in immunodetectable PKC protein correlated with a 40% elevation in the activity of PKC at the membrane. Normalization of circulating glucose in the rat model by either insulin or phlorizin treatment did not result in a reduction in membrane PKC isozyme protein or kinase activity. Further, phlorizin treatment did not improve insulin receptor autophosphorylation nor did the treatment lower liver diacylglycerol. We conclude that liver PKC is increased in NIDDM, a change that is not secondary to hyperglycemia. It is possible that PKC-mediated phosphorylation of some component in the insulin signaling cascade contributes to the insulin resistance observed in NIDDM.
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PMID:Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: an alteration not due to hyperglycemia. 776 36


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