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

Recent advances in nutritional and biochemical research have substantiated the importance of myo-inositol both as a dietary component and a constituent of cellular phosphatidylinositol. This work has indicated the importance of acyltransferase reactions for the enrichment of membrane phosphatidylinositol in arachidonic acid and the formation of the 1-stearoyl 2-arachidonoyl molecular species which commonly predominate in mammalian tissues. Inositol deficiency in animals has been shown to produce an accumulation of triglyceride in liver, intestinal lipodystrophy, and other abnormalities. Cellular functions elucidated for phosphatidylinositol in biological membranes include mediating cellular responses to external stimuli and serving as a source of arachidonic acid for the biosynthesis of prostaglandins including thromboxane. An alteration in inositol metabolism has been documented in patients with diabetes mellitus and chronic renal failure which has led to clinical interest in modulating dietary inositol levels in the prevention and treatment of human disease.
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PMID:1982 Borden Award lecture. Nutritional, biochemical, and clinical aspects of inositol and phosphatidylinositol metabolism. 671 71

We examined the mechanism of myo-inositol uptake by rabbit renal proximal tubule brush border membrane vesicles and characterized the relationship between the transports of myo-inositol and D-glucose. A 100 mM Na+ electrochemical gradient (extravesicular medium > intravesicular medium) stimulated the initial rate of myo-inositol uptake 20- to 60-fold. Other cation gradients were ineffective. The Na+ myo-inositol co-transport system was shown to be electrogenic. The Na+ electrochemical gradient-dependent uptake of myo-inositol saturated at about 1 mM myo-inositol, with an apparent Km of 94 micro M at an initial 100 mM Na+ gradient. D-Glucose was an inhibitor of the Na+ gradient-dependent uptake of myo-inositol. D-Glucose, but not L-glucose, elicited accelerative exchange diffusion of myo-inositol. myo-Inositol did not significantly inhibit the Na+ gradient-dependent transport of D-glucose. We suggest that D-glucose inhibits myo-inositol uptake by dissipating the membrane potential and sharing the myo-inositol carrier. The inhibition of myo-inositol transport across the brush border membrane by D-glucose explains how glycosuria could produce inosituria in patients with diabetes mellitus.
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PMID:myo-Inositol transport in renal brush border vesicles and it inhibition by D-glucose. 677 22

myo-Inositol transport by a viable rat sciatic-nerve preparation is described. Such 'endoneurial' nerve preparations accumulated myo-inositol by an energy-dependent saturable system. Streptozotocin-diabetes reduced myo-inositol transport into sciatic nerve by approx. 40%. Elevated medium glucose concentration reduced myo-inositol transport into control nerves to a similar extent. Fructose and sorbitol did not inhibit myo-inositol transport. Inclusion of an aldose reductase inhibitor in the medium counteracted the reduced myo-inositol transport caused by elevated glucose concentration. The importance of these results to the problem of diabetic neuropathy is discussed.
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PMID:Transport of myo-inositol into endoneurial preparations of sciatic nerve from normal and streptozotocin-diabetic rats. 687 Aug 6

Fascicles of the sural nerve from each of 20 diabetic patients, mostly with maturity-onset diabetes, were studied by biochemical and pathological techniques, and results were compared to values found in nerve specimens from 15 healthy persons. The sorbitol and fructose content was much more variable in diabetic than in healthy nerves. More than one-third of the diabetic nerves had sorbitol and fructose values above the highest levels for controls. myo-Inositol and scyllo-inositol content was not reduced in diabetic nerves. The sorbitol, fructose, and inositol concentrations could not be related to clinical, neurophysiological, or pathological severity of neuropathy. A comparison of scored symptoms and signs and clinical neurophysiological studies against morphometric and teased fiber studies of sural nerve demonstrated that the former three provide sensitive and reliable measures of severity of neuropathy that can be used for controlled clinical trials of diabetic neuropathy. The presence and type of teased fiber abnormalities could be related to the duration of diabetes and to symptoms of neuropathy. In untreated diabetics without symptoms of neuropathy, a higher than normal frequency of teased fibers showing segmental demyelination and remyelination was found. Untreated diabetics with symptomatic neuropathy showed two kinds of abnormalities: fibers with segmental demyelination and remyelination and fibers undergoing axonal degeneration. In treated diabetics, who often had longstanding neuropathy, the most common abnormalities were fibers undergoing axonal degeneration.
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PMID:Human diabetic endoneurial sorbitol, fructose, and myo-inositol related to sural nerve morphometry. 721 46

Tibial motor nerve conduction velocity was measured in rats, before and two months after the induction of diabetes with streptozotocin. A second group of diabetic animals was also administered 1% dietary myoinositol supplements. An analysis of variance was performed on these data. Myoinositol supplements had no effect whatsoever. The period of diabetes had a statistically significant and quantitatively marginal effect (a decrease of 2.2 m s-1) on conduction velocity. This is considerably less than in previous reports. The reasons for this are discussed. Tibial motor nerve conduction velocity was also measured in a group of alloxan-diabetic rabbits two months after the induction of diabetes and in an age-matched control group. Conduction velocity was again slightly but significantly less in the diabetic animals.
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PMID:Nerve conduction velocity in experimental diabetes in the rat and rabbit. 722 47

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

Myo-Inositol depletion as a result of hyperglycemia is considered one of the leading contributors to chronic diabetic complications. We investigated the possible mechanisms through which elevated extracellular glucose levels affect the loss of intracellular myo-inositol in rat lens. Short-term incubation (up to 4 h) in solutions with elevated glucose concentrations revealed a concentration-dependent inhibition of myo-inositol influx. This inhibition was caused by both an increase of the transport coefficient and a decrease of maximal flux and thus was a mixed competitive and noncompetitive inhibition. If polyol accumulation was prevented with sorbinil, an aldose reductase inhibitor, the inhibition of myo-inositol influx was partially reduced. The remaining inhibition was the result of an increased transport coefficient without a change in maximal flux and therefore represents a strictly competitive inhibition. A similar competitive inhibition was observed with the nonmetabolizable glucose analogue L-glucose, which cannot be converted to polyol. Longer exposure (16 h) to solutions with high glucose concentrations resulted in an inhibition that correlated with high lens polyol levels. This inhibition persisted after the lenses were returned to solutions with normal glucose concentrations and was the result of a decrease of maximal flux without a significant change in transport coefficient, a strictly noncompetitive inhibition. The noncompetitive inhibition associated with polyol accumulation and the competitive inhibition due to extracellular glucose were additive. Lens myo-inositol depletion after exposure to elevated glucose concentrations thus resulted from a competitive inhibition caused by the interaction of extracellular glucose with the myo-inositol carrier and a noncompetitive inhibition associated with polyol accumulation.
Diabetes 1993 Dec
PMID:Mechanisms for D-glucose inhibition of myo-inositol influx into rat lens. 824 20

An inositol phosphoglycan that is the polar head group of a glycosyl phosphatidylinositol has been considered as a putative mediator of insulin action. To gain insight into the functions of this hormone during development, the relationships between insulin, insulin receptors, glycosyl phosphatidylinositol, and inositol phosphoglycan were studied. Glycosyl phosphatidylinositol was isolated and characterized in fetal liver as early as day 15 of intrauterine life. In isolated hepatocytes from fetal and adult rats labeled with [3H]glucosamine, [3H]galactose, or [3H]myo-inositol, these molecules were incorporated into glycosyl phosphatidylinositol. In hepatocytes labeled with [3H]glucosamine and then allowed to react with [1-14C]IAI, the [3H]glycosyl phosphatidylinositol was purified as the 14C-labeled amidinated lipid. Glycosyl phosphatidylinositol molecules from fetal and adult cells were sensitive to hydrolysis by a phosphatidylinositol-specific phospholipase C from B. cereus. The product of this hydrolysis inhibits the activity of a cAMP-dependent protein kinase, whereas this effect was abolished by nitrous acid deamination. In isolated hepatocytes from adult animals, an inverse correlation between extracellular insulin and the number of insulin receptors and the cellular content of glycosyl phosphatidylinositol was observed. However, in fetal hepatocytes insulin failed to reduce the glycosyl-phosphatidylinositol content when labeled either with [1-14C]isethionyl acetimidate or [3H]glucosamine, whereas insulin-like growth factor I produced a significant hydrolysis of glycosyl phosphatidylinositol. Fetal and adult hepatocytes were incubated with insulin or inositol phosphoglycan after which glycogen phosphorylase activities were determined. Inositol phosphoglycan mimicked the action of insulin on both forms of the enzyme from adult hepatocytes, whereas in fetal cells insulin did not change, and purified inositol phosphoglycan reduced the activities of glycogen phosphorylase. These findings suggest a dissociation between insulin receptor occupancy and the expected hormonal effects in fetal hepatocytes. This could be related to alterations at a postreceptor level.
Diabetes 1993 Sep
PMID:Insulin does not induce the hydrolysis of a glycosyl phosphatidylinositol in rat fetal hepatocytes. 834 37

Nerve conduction abnormalities in peripheral nerves from diabetic patients may be early indicators for the future development of symptomatic neuropathy. In this study, three weeks of experimental diabetes in the rat caused a significant decrease in motor nerve conduction velocity measured in vivo (45.3 +/- 3.6 m/s; mean +/- S.D.) compared to controls (57.7 +/- 4.5 m/s). myo-Inositol administration to diabetic rats (500 mg/rat per day) for the duration of the study, partially prevented this decrease (50 +/- 4.4 m/s). An analogue of myo-inositol, PP56 (D-myo-inositol-1,2,6-trisphosphate), at a dose of 24 mg/rat per day completely prevented this reduction in diabetic rats (53.4 +/- 5.8 m/s). Resistance to hypoxic conduction block was determined in vitro in endoneurial preparations and was assessed as the decline in compound action potential amplitude over a 40 min period of hypoxia. Compound action potential amplitude (as % of initial value +/- S.D.) was significantly greater in diabetic preparations compared with controls at 40 min of hypoxia (76.1 +/- 9.1 vs. 54.8 +/- 14.7 respectively). Treatment to diabetic rats with myo-inositol did not significantly affect this value (79.9 +/- 16.6) but PP56 treatment partially prevented the increased resistance to hypoxic conduction block (69.4 +/- 16.0). This study demonstrates that these acute abnormalities of nerve function in early experimental diabetes may be attenuated by the administration of PP56, possibly acting via a vascular mechanism.
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PMID:Effects of treatment with myo-inositol or its 1,2,6-trisphosphate (PP56) on nerve conduction in streptozotocin-diabetes. 836 54

Glucose-induced insulin secretion is desensitized during long-term exposure of pancreatic islet beta-cells to elevated glucose levels. This study characterizes an in vitro model of glucose-induced desensitization in cultured isolated islets of the rat. Insulin secretion in desensitized islets cultured with 11 mM glucose for 4-7 days was progressively reduced compared with the normal freshly isolated (fresh) islets. When desensitized islets were returned to a basal concentration of glucose (5.5 mM) for up to 2 h, the glucose sensitivity of insulin secretion was restored to normal (recovered islets). Carbachol and L-arginine also reversed the effects of desensitization. However, basal insulin release was elevated in desensitized and recovered islets. Sodium-dependent myo-inositol uptake was reduced during desensitization by up to 49% within 4 days. myo-Inositol uptake was restored to normal in a time-dependent manner during recovery of islets at 5.5 mM glucose. The recovery of myo-inositol uptake paralleled that of insulin release. The apparent transport constant for myo-inositol uptake was significantly increased during desensitization, whereas the maximum uptake was not changed. myo-Inositol supplementation (35 or 250 microM) during islet culture did not alter myo-inositol uptake or insulin secretion in desensitized islets. Na(+)-K(+)-ATPase activity, but not 5'-nucleotidase activity, in desensitized islets was also inhibited by 65 and 47% when compared with fresh islet and recovered islet Na(+)-K(+)-ATPase activity, respectively. Thus, cultured islets represent an appropriate model to study biochemical parameters associated with the onset and reversibility of glucose desensitization of insulin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Oct
PMID:Insulin secretion, myo-inositol transport, and Na(+)-K(+)-ATPase in glucose-desensitized rat islets. 839 25


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