Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alterations in the level of dietary inositol can significantly influence the concentration of free inositol and inositol-containing phospholipid in the circulation and in selected mammalian tissues and cells. The 1-stearoyl 2-arachidonyl molecular species that commonly predominates in cellular phosphoinositides may be of considerable importance for the functioning of these phospholipids in biological membranes. Retailoring reactions subsequent to the de novo biosynthesis of PI involving the acylation of lyso(1-acyl) PI allow for the preferential enrichment of this phospholipid in arachidonic acid. The impaired release of plasma lipoprotein, increased fatty acid mobilization from adipose tissue, and enhanced fatty acid synthesis in liver have all been implicated as causative factors in the hepatic triacylglycerol accumulation occurring with experimental inositol deficiency. The severe intestinal lipodystrophy that develops in female gerbils consuming inositol-deficient diets is likely mediated by a reduced synthesis of PI and the associated impairment of chylomicron assembly and secretion. Membrane PI can potentially regulate enzyme activities and transport processes as well as providing a source of free arachidonic acid for production of the eicosanoids. There has been mounting evidence recently to indicate that an accelerated turnover of the phosphoinositides may play a key role in mediating cellular responses to external stimuli. The transient rise of phosphoinositide-derived 1,2-diacylglycerol in stimulated cells may serve as a signal for the transmembrane control of protein phosphorylation by activating protein kinase C. Receptor occupancy also elicits the phosphodiesterase-catalyzed release of the second messenger inositol 1,4,5-trisphosphate, which appears to provide for the mobilization of calcium from internal stores. Subnormal levels of free inositol and inositol phospholipid, as found in the nerves of animals with experimental diabetes and in sciatic nerves removed postmortem from diabetic patients, have been implicated in the impaired nerve conduction of human diabetics. Patients with renal failure exhibit a dramatic hyperinositolemia that may have clinical significance. Nutritional intervention may offer an approach for counteracting abnormalities in inositol and inositol phospholipid profiles and associated physiological responses in certain disease states.
 ...
PMID:Metabolism and function of myo-inositol and inositol phospholipids. 242 33

The mechanisms that enable epinephrine (EPI) and lipoxygenase inhibitors to impede insulin secretion are unknown. We examined the possibility that EPI inhibits Ca2+ fluxes as its major mechanism by studying 45Ca efflux from prelabeled, intact rat islets. EPI (2.5 x 10(-7) to 1 x 10(-5) M) inhibited insulin release induced by the influx of extracellular Ca2+ (46 mM K+) or the mobilization of intracellular Ca2+ stores (2 mM Ba2+), but it did not reduce the 45Ca efflux stimulated by either agonist. EPI also nullified insulin release induced by isobutylmethylxanthine or dibutyryl cAMP, with minimal or no effects on 45Ca efflux, and blocked the insulinotropic effects of 12-O-tetradecanoylphorbol-13-acetate (a direct activator of protein kinase C), which is believed primarily to sensitize the exocytotic apparatus to Ca2+ without mobilizing additional Ca2+. Previously we reported that similar effects were induced by inhibitors of pancreatic islet lipoxygenase. In this study, however, pretreatment with either the alpha 2-adrenergic antagonist yohimbine or pertussis toxin did not block the effects of lipoxygenase inhibitors, although either agent did block the effects of EPI. Thus, EPI, via an alpha 2-receptor mechanism, is able to reduce exocytosis largely distal to, or independent of, changes in Ca2+ flux, cAMP formation or its Ca2+-mobilizing action, or generation of protein kinase C activators. Therefore, EPI may reduce the sensitivity of the exocytotic apparatus to Ca2+. Inhibition of islet lipoxygenase may have a similar effect; however, in this case, the effect would have to be unrelated, or distal, to stimulation of alpha 2-receptors.
Diabetes 1988 Jan
PMID:Epinephrine impairs insulin release by a mechanism distal to calcium mobilization. Similarity to lipoxygenase inhibitors. 244 39

Brief exposure of hepatocytes to glucagon, angiotensin or the protein kinase C activator TPA (12-O-tetradecanoylphorbol 13-acetate) caused the inactivation of the inhibitory guanine nucleotide regulatory protein Gi. Glucagon-mediated desensitization of glucagon-stimulated adenylate cyclase activity was seen in hepatocytes from both normal rats and those made diabetic with streptozotocin, where Gi is not functionally expressed. Normal glucagon desensitization was seen in hepatocytes from young animals, 6 weeks of age, which had amounts of Gi in their hepatocyte membranes which were some 45% of that seen in mature animals (3.4 pmol/mg of plasma-membrane protein). Streptozotocin-induced diabetes in young animals abolished the appearance of functional Gi in hepatocyte plasma membranes. Pertussis-toxin treatment of hepatocytes from both normal mature animals and those made diabetic, with streptozotocin, blocked the ability of glucagon or angiotensin or TPA to elicit desensitization of adenylate cyclase. The isolated B (binding)-subunit of pertussis toxin was ineffective in blocking desensitization. Neither induction of diabetes nor treatment of hepatocytes with pertussis toxin inhibited the ability of glucagon and angiotensin to stimulate the production of inositol phosphates in intact hepatocytes. Thus (i) Gi does not appear to play a role in the molecular mechanism of glucagon desensitization in hepatocytes, (ii) the G-protein concerned with receptor-stimulated inositol phospholipid metabolism in hepatocytes appears not to be a substrate for the action of pertussis toxin, (iii) in intact hepatocytes, treatment with glucagon and/or angiotensin can elicit the inactivation of the inhibitory G-protein Gi, and (iv) pertussis toxin blocks desensitization by a process which does not involve Gi.
 ...
PMID:Glucagon desensitization of adenylate cyclase and stimulation of inositol phospholipid metabolism does not involve the inhibitory guanine nucleotide regulatory protein Gi, which is inactivated upon challenge of hepatocytes with glucagon. 249 30

We examined the effects of various stimuli on immunoreactive insulin (IRI) and glucagon (IRG) release from perfused pancreases isolated from control and streptozocin-induced diabetic (STZ-D) rats. Diabetes was induced by injecting 30 mg/kg STZ into rats fasted for 16-18 h 12-17 days before our experiments. Glucose (11.1 mM) caused a distinct biphasic pattern of IRI release from the control pancreas, whereas the first phase was marginal and the second phase was absent in the diabetic pancreas. Arginine (20 mM)-induced IRI release was similar in both groups, whereas IRG release was greater in the control rats than in the diabetic rats. Thus, this model of STZ-D simulates a certain class of non-insulin-dependent diabetes mellitus (NIDDM). In these diabetic animals, the cholecystokinin (CCK) analogue ceruletide (620 pM) caused a significantly greater increase in IRI release in the presence of 5.6 mM glucose than in the control rats, but ceruletide caused a similar IRG release in both groups. Because CCK and ceruletide stimulate phosphoinositide turnover in pancreatic islets, we examined the effects of carbachol and phorbol ester TPA on IRI release in the presence of 5.6 mM glucose. Carbachol (10 microM), which is thought to generate similar second messengers as ceruletide, induced greater IRI release in diabetic than in control rats. TPA (100 nM) caused a significantly greater increase in IRI release from the diabetic than the control pancreas. Our results demonstrate that the insulin-releasing mechanism involved in protein kinase C activation is enhanced in this model of NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1989 Aug
PMID:Increased beta-cell secretory responsiveness to ceruletide and TPA in streptozocin-induced mildly diabetic rats. 252 62

We have characterized a plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phospholipase C (PLC) and a cytosolic phosphatidylinositol (PI)-specific PLC in human liver. Epinephrine, 1 x 10(-5) M, and vasopressin, 1 x 10(-8) M, stimulated PIP2-PLC which was enhanced by guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S). PI-PLC stimulation was not observed by these agents. Insulin and insulin-like growth factors (IGF-I and IGF-II) in the presence and absence of GTP gamma S did not stimulate PIP2-PLC or PI-PLC in plasma membranes and cytosol preparations nor phosphoinositide breakdown in isolated human hepatocytes. Furthermore, serendipitly we found that PIP2-PLC activity was increased in liver membranes from obese patients with type II diabetes when compared to obese and lean controls. We conclude that in human liver, insulin and IGFs are not members of the family of hormones generating inositol trisphosphate (IP3) as a second messenger. Furthermore, the increased PIP2-PLC in diabetic liver may result in: (a) increased intracellular concentrations of IP3 and thus increased Ca2+, which has been postulated to induce insulin resistance; and (b) increased diacylglycerol and thus increased protein kinase C which phosphorylates the insulin receptor at serine residues inactivating the insulin receptor kinase. While the mechanism of increased PIP2-PLC activity in diabetes is unknown, it may initiate a cascade of events that result in insulin resistance.
 ...
PMID:Effect of insulin and insulin-like growth factors I and II on phosphatidylinositol and phosphatidylinositol 4,5-bisphosphate breakdown in liver from humans with and without type II diabetes. 254 Jan 78

We have found a defect in the ouabain-sensitive Na+, K+-ATPase (Na+ pump, EC 3.6.1.37) of erythrocytes from streptozocin diabetic rats. This defect was accompanied by an increase in cell volume and osmotic fragility and a decrease in the cytosolic K+/Na+ ratio. There was also a doubling in the time needed for diabetic erythrocytes to pass through 4.7-micron channels in a polycarbonate filter. Our data are consistent with a primary defect in the erythrocyte Na+ pump and secondary changes in cell volume, osmotic fragility, K+/Na+ ratio, and cell filterability. All were reversed or prevented in vivo by insulin or the aldose reductase inhibitor Sorbinil. Protein kinase C agonists (phorbol ester and diacylglycerol) and agonist precursor (myoinositol) reversed the Na+ pump lesion, suggesting that protein kinase C-dependent phosphorylation of the 100-kDa subunit regulates Na+ pump activity and that insulin can influence erythrocyte protein kinase C activity. Ouabain inhibition of the erythrocyte Na+ pump also produced increases in cell size and reductions in rates of filtration. Theoretical treatment of the volume changes also predicts reduction in filterability as a consequence of cell swelling. We suggest that enlarged erythrocytes could play a role in the evolution of the microvascular changes of diabetes mellitus.
 ...
PMID:Reversible sodium pump defect and swelling in the diabetic rat erythrocyte: effects on filterability and implications for microangiopathy. 254 40

Retinal capillary pericyte is a cell type selectively lost in early diabetic retinopathy. The physiological function of pericytes is not yet clearly identified, although it probably has contractile properties. We determined the specific binding of endothelin 1, a 21-amino acid peptide with potent vasoconstrictive action, and the stimulation of diacylglycerol/protein kinase C (DAG/PKC) pathway in cultured retinal capillary pericytes by endothelin. A single specific binding site for 125I-labeled endothelin was identified, with an apparent Kd of 1.3 nM and a maximal binding capacity of approximately 1-2 x 10(5) sites/cell. Endothelin (100 nM) increased total cellular DAG content by 15% at 5 min and 24% at 10 min. When pericytes were labeled isotopically with [3H]glycerol, endothelin stimulated [3H]DAG formation by 100% at 10 min and 88% at 30 min. After 10 min of endothelin treatment, PKC activities were increased by 60 and 100% in the membranous and cytosolic pools, respectively. We conclude that bovine retinal capillary pericytes possess numerous high-affinity specific binding sites for endothelin that mediate the action of endothelin by the stimulation of the DAG/PKC pathway in pericytes. These findings suggest that endothelin is a regulator of the contractile properties of pericytes, which may be adversely affected in diabetic retinopathy.
Diabetes 1989 Dec
PMID:Characterization of endothelin receptors and effects of endothelin on diacylglycerol and protein kinase C in retinal capillary pericytes. 839 Feb 75

In the insulin-secreting, glucose-insensitive islet cell subclone RINm5F, the distribution of protein kinase C (PKC) activity in the cytosol and membrane fractions was determined, and the activation of the enzyme, as reflected in its translocation to the membrane fraction, was characterized in conjunction with insulin release. DL-Glyceraldehyde (15 mM) evoked a rapid redistribution of PKC from the cytosol to the membrane fraction; insulin release increased concomitantly. When monitored over 5 min with 15 mM glyceraldehyde, membrane stabilization of PKC reached a maximum at 30 s and decreased thereafter; insulin release occurred at a high rate for the first 15 s and diminished thereafter. With 2-20 mM glyceraldehyde, a dose-dependent increase in membrane stabilization of PKC occurred and was accompanied by a matching increase in insulin release. Exogenous 1,2-dioctanoyl-sn-glycerol (100 microM) induced a rapid membrane stabilization of PKC and concomitant stimulation of insulin release. Glucose (15 mM) failed to evoke any redistribution of PKC or release of insulin. Depletion of total PKC activity by 95% induced by 18-h incubations with 2 microM 12-O-tetradecanoylphorbol-13-acetate resulted in a 67-91% reduction in glyceraldehyde-induced insulin release. We conclude that in the RINm5F islet beta-cell subclone 1) the rapid activation of PKC, which occurs in response to the administration of glyceraldehyde, a nutrient secretagogue, plays an amplifying role in the initiation of stimulated insulin release; and 2) the failure of the activation of PKC may be responsible for the insensitivity to glucose.
Diabetes 1989 Nov
PMID:Insulin release in RINm5F cells and glyceraldehyde activation of protein kinase C. 269 72

Six weeks after induction of diabetes, the rate of ouabain-sensitive 86Rb+ accumulation, a parameter which reflects Na+ + K+-ATPase pumping activity, was significantly reduced in endoneurial preparations of sciatic nerve from untreated diabetic rats compared with that in control rats (Trial, 1, 0.19 +/- 0.09 versus 0.48 +/- 0.13 pmol/min per mg wet weight of tissue, p less than 0.001; Trial 2, 0.27 +/- 0.16 versus 0.47 +/- 0.18, p less than 0.01). This decrease in ouabain-sensitive 86Rb+ uptake was not observed in nerves from diabetic rats maintained on sorbinil (an aldose reductase inhibitor) or myo-inositol diets. Protein kinase C activity was demonstrated in the soluble fraction of a sciatic nerve homogenate by assaying for lipid-activated, Ca+-dependent phosphorylation of calf thymus histone. No significant difference in the time course of kinase C activity was observed between cytosol fractions of nerve homogenates from control and diabetic rats (control, 6.22 +/- 0.97 pmol 32P incorporated/mg cytosol protein in 50 min; diabetic, 5.32 +/- 0.71). Three low molecular weight neural proteins (each with Mr less than 29,000) were identified as substrates for protein kinase C.
 ...
PMID:Reduced Na+ + K+-ATPase activity in peripheral nerve of streptozotocin-diabetic rats: a role for protein kinase C? 284 Mar 14

Linolenic acid, a polyunsaturated fatty acid, has an insulin synergizing stimulatory effect on adipocyte lipogenesis. Since phorbol esters are also known to exert a similar effect through the activation of protein kinase C, and since they have fatty acid moieties, we investigated whether linolenic acid exerted its stimulatory effect through protein kinase C activation and whether calcium was involved in this mechanism. Our experiments show that H7, an inhibitor of protein kinase C; verapamil, a calcium blocker; and calmodulin inhibitors inhibited basal, insulin- and linolenic acid-stimulated lipogenesis. They also negated the insulin synergizing effect of linolenic acid. We conclude that linolenic acid, and possibly other unsaturated fatty acids, exert their stimulatory effect through stimulation of protein kinase C, calcium entry and calmodulin activation. These three processes are also important in maintaining basal lipogenesis.
Diabetes Res 1988 Jul
PMID:The effect of polyunsaturated fatty acids on rat adipocyte lipogenesis: the role of protein kinase C, calcium and calmodulin. 290 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>