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)

Protein kinase C (PKC) has been suggested as a mediator of insulin's effect on glucose transport, and PKC-mediated modulation of tyrosine kinase activity in the insulin receptor has been implicated in regulating the insulin sensitivity of tissues. Because skeletal muscle is a major target of insulin action, we examined the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), 1-oleoyl-2-acetyl-rac-glycerol, and dioctanoyl diacylglycerol, known activators of PKC, on glucose metabolism in rat skeletal muscles. In contrast to results reported for other tissues, incubation of muscles with PKC activators produced only small increases in glucose transport and had minimal effects on the ability of insulin to stimulate transport. However, TPA treatment of muscles produced a significant decrease in basal glycogen synthesis. Incubation of muscles with TPA did not affect insulin binding or the tyrosine kinase activity of partially purified insulin receptors measured under basal conditions or after stimulation by insulin in situ or in vitro. Our findings do not support activation of PKC as a major mechanism for regulating glucose uptake or insulin receptor activity in skeletal muscle. However, the data do not rule out the possibility that glucose transport in skeletal muscle may respond to physiological activators of PKC.
Diabetes 1988 May
PMID:Minimal effects of phorbol esters on glucose transport and insulin sensitivity of rat skeletal muscle. 328 40

Increased blood flow and vascular permeability of early diabetes have been associated with increased nitric oxide formation in diabetic rats, but the specific nitric oxide synthase responsible is unknown. We examined the modulation of the induction and activity of the inducible NOS isoform by high glucose concentration in a murine macrophage cell line, RAW 264.7, and murine glomerular mesangial cells. Culturing both cell types in high glucose concentration led to significant increases in nitrite production and the mRNA encoding iNOS upon stimulation with LPS plus interferon-gamma, as compared with normal glucose concentration. High glucose also modestly enhanced LPS/IFN-gamma-induced stimulation of the iNOS promoter in transient transfection experiments in mesangial cells. Protein kinase C activation led to enhanced mRNA expression of iNOS, and inhibitors of protein kinase C blocked nitrite accumulation in mesangial cells. These findings suggest that high glucose in combination with stimulation by LPS plus IFN-gamma enhances iNOS expression, and protein kinase C activation may be playing a role in this enhancement.
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PMID:Enhanced expression of inducible nitric oxide synthase in murine macrophages and glomerular mesangial cells by elevated glucose levels: possible mediation via protein kinase C. 753 75

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

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

1. We have previously demonstrated that although rats with streptozotocin-induced diabetes (STZ-D) have decreased behavioral mechanical nociceptive thresholds (hyperalgesia), their C-fiber primary afferent mechanical (von Frey hair) thresholds are not altered. Instead, when stimulated with a standardized sustained suprathreshold mechanical stimulus, C-fibers from STZ-D rats were found to have an increased number of spikes (hyperexcitability). We suggested that this C-fiber hyperexcitability contributes to the behavioral hyperalgesia and that agents that reverse the hyperalgesia may act by decreasing this hyperexcitability. Because protein kinase C activity contributes to C-fiber afferent excitability, we examined the effect of agents that inhibit protein kinases on behavioral mechanical nociceptive thresholds and on the response of C-fiber afferents to sustained mechanical stimulation. 2. The effects of intradermal injection of two protein kinase inhibitors, staurosporine and protein kinase C pseudosubstrate inhibitor peptide [PKC(19-36)], on behavioral mechanical nociceptive thresholds were determined using the Randall-Selitto paw-withdrawal device. These agents increased the mechanical nociceptive threshold of STZ-D rats in a dose-dependent manner but did not alter nociceptive threshold in control rats. 3. The same agents were tested for their effects on single C-fiber mechanical thresholds and excitability in response to suprathreshold (445 g) mechanical stimulation. Intradermal injection of staurosporine or PKC(19-36) significantly reduced the response of C-fibers from STZ-D rats to sustained suprathreshold mechanical stimulation but did not alter the response of C-fibers from control rats to the same stimulation. Neither agent altered mechanical threshold in C-fibers from either STZ-D or control rats. 4. In this study we found that both the mechanical behavioral hyperalgesia and the C-fiber hyperexcitability to mechanical stimuli seen in STZ-D rats are reduced by agents that inhibit protein kinase C. This evidence supports our hypothesis that C-fiber hyperexcitability, in part mediated by PKC activity, contributes to hyperalgesia in this model of diabetic neuropathy.
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PMID:Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat. 798 28

Protein kinase C (PKC) is activated in rat renal glomerulus within a week of induction of experimental diabetes. Studies in isolated glomeruli and in cultured endothelial and mesangial cells have demonstrated that high ambient concentrations of glucose activate PKC and thus implicate hyperglycemia per se as a mediator of PKC activation in glomerular cells in diabetes. High glucose concentrations activate PKC by increasing cellular levels of diacylglycerol (DAG), the major endogenous modulator of this signalling system. In contrast to physiological extracellular stimuli of PKC that increase cellular DAG levels by receptor-mediated enhancement of membrane inositol phospholipid hydrolysis, in glomerular cells high concentrations of glucose increase DAG by de novo synthesis from glycolytic intermediates. Activation of PKC by glucose or other agonists increases the permeability of endothelial cells to albumin and stimulates matrix protein synthesis in mesangial cells; it thereby may be involved in the pathogenesis of both the functional and structural alterations of the glomerulus in diabetes. Recent studies in isolated glomeruli from diabetic rats have also implicated activation of PKC in suppression of nitric oxide (NO)-mediated increases in glomerular cGMP generation in response to cholinergic stimuli. In mesangial cells, cGMP suppresses PKC-mediated increases in matrix protein synthesis. Thus, impaired NO-mediated cGMP generation in glomeruli of diabetic individuals may amplify matrix protein synthesis in response to hyperglycemia and other stimuli of PKC. These and other observations suggest that activation of the PKC system by hyperglycemia may represent an important pathway by which glucotoxicity is transduced in susceptible cells in diabetes.
Diabetes 1994 Jan
PMID:Activation of protein kinase C in glomerular cells in diabetes. Mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. 826 6

Protein kinase C activity is present in rat prostatic epithelial cells in both cytosolic and membrane subcellular fractions. Partial purification by ion-exchange chromatography and characterization of cofactor requirements showed its behavior as a classical Ca(2+)- and phospholipid-dependent enzyme activated by 1,2-diacylglycerol (or by mimicking agents such as tumor-promoting phorbol esters). Streptozotocin-induced diabetes resulted in an increase of the membrane/cytosolic enzyme ratio suggesting a redistribution of protein kinase C from the cytosolic to the membrane fraction (an index of enzyme activation) that could be reversed toward control conditions by insulin treatment. Differences observed in cofactor requirements for maximal enzyme activation argue for a some distinct expression of protein kinase C isozymes in control and diabetic conditions. These results are a new aspect of the complex set of alterations exhibited by the diabetic prostate in the signal transduction mechanisms that mediate cell functions and proliferation in this gland which could be related to the prostate atrophy and impaired fertility characteristic of this disease.
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PMID:Alteration of protein kinase C activity in diabetic rat prostate. 836 97

The fibronectin content of RMC cultures grown for 8-14 days in medium containing 30 mM (540 mg/dl) D-glucose was increased 30-60% relative to that of control cells cultured in 10 mM (180 mg/dl) glucose. Addition of equiosmolar concentrations (20 mM, 360 mg/dl) of L-glucose, 3-O-methylglucose, or mannitol to 10 mM glucose media did not alter fibronectin accumulation compared with values observed in 10 mM glucose alone. The basal phosphorylation of the 80,000-M(r) MARKS protein, which is a substrate for PKC, and the phosphorylation induced by acute (15-min) exposure of cells to 15% FCS or to 0.1 microM (50 ng/ml) PDBu were all increased in cells grown in 30 mM compared with 10 mM glucose. By contrast, phosphorylation of the 80,000-M(r) protein in response to a maximal concentration of PDBu (1 microM, 500 ng/ml) was not different in cells grown in 30 mM compared with 10 mM glucose. The acute increases in phosphorylation of the 80,000-M(r) protein were blocked by the PKC inhibitor calphostin C. Chronic (7-day) exposure of mesangial cells grown in 10 mM glucose to 0.1 microM of the PKC agonist PDBu also resulted in a sustained 40% increase in 80,000-M(r) phosphorylation and a 20-30% increase in fibronectin accumulation. As assessed by [35S]methionine incorporation, mesangial cell fibronectin synthesis was increased by exposure to PDBu, a finding consistent with earlier observations with 30 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Jan
PMID:Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high-glucose medium. 842 Aug 8

Glomerular accumulation of extracellular matrix in diabetes is a potential regulator of mesangial cell-matrix interactions through transmembrane matrix receptors. We now provide evidence that PG production from rat glomerular mesangial cells is increased by Fn. An increase in PG (measured as PGE) was demonstrated in mesangial cell-enriched glomerular cores after 1-h exposure (149 +/- 8% of timed control) and was sustained over a 24-h period (214 +/- 7%). Increased PG production followed exposure to a chymotryptic fragment (120,000 M(r)) of Fn and occurred concomitant with an increase in particulate PKC activity. A tetrapeptide (Arg-Gly-Asp-Ser) with the Arg-Gly-Asp sequence, contained in Fn and the chymotryptic fragment and recognized by specific membrane receptors (integrin matrix-binding proteins), also raised PG levels. As has been shown previously, exposure to high glucose concentration can increase mesangial cell PGE production (from 677 +/- 61 pg.mg protein-1.2 h-1 at 5.6 mM glucose to 1561 +/- 132 pg.mg protein-1.2 h-1 at 50 mM glucose, P < 0.001). The response to the chymotryptic fragment of Fn also was enhanced by concurrent exposure to high glucose concentration (from 2560 +/- 199 pg.mg protein-1.2 h-1 at 5.6 mM glucose to 4672 +/- 358 pg.mg protein-1.2 h at 50 mM glucose, P < 0.001). Coincubation with H-7, an inhibitor of PKC, abolished the PG response to glucose and the chymotryptic fragment. Involvement of PKC was supported further by abrogation of the effect of chymotryptic fragment in mesangial cells cultured for a prior prolonged period with phorbol ester.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Jan
PMID:Fibronectin-induced increase in mesangial cell prostaglandin release. Effect of hyperglycemia and PKC inhibition. 842 Aug 16


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