Enzymes of <i>myo</i>-inositol and inositol lipid metabolism in rats with streptozotocin-induced diabetes

Whiting, P. H.; Palmano, Kate; Hawthorne, J. N.

doi:10.1042/bj1790549

Cited by 88 publications

(44 citation statements)

References 34 publications

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“…A second might be reduced synthesis of endogenous MI from glucose in the tissue preparation. While inositol-1-phosphate synthase activity has been detected in cell-free nerve preparations (28), the capacity of this biosynthetic pathway in nerve to supply MI has not been rigorously evaluated. A third factor could be impairment of Na'-dependent MI uptake, which is known to be competitively inhibited by glucose (29).…”

Section: Resultsmentioning

confidence: 99%

A myo-inositol pool utilized for phosphatidylinositol synthesis is depleted in sciatic nerve from rats with streptozotocin-induced diabetes.

Zhu

Eichberg

1990

Proc. Natl. Acad. Sci. U.S.A.

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Peripheral nerve from experimentally diabetic rats exhibits lowered levels of myo-inositol (MI) and decreased incorporation of [3H]MI into phosphatidylinositol (PI) myo-Inositol (MI) has been suggested to play an important role in the development of experimental diabetic neuropathy (1-3). Mammalian tissues maintain millimolar concentrations of MI, which in peripheral nerve is at least 40-fold higher than in plasma (4, 5). It has long been known that MI content is reduced substantially in peripheral nerve from diabetic animals (1, 4, 6). Evidence from both diabetic nerve preparations and neural cell cultures grown in the presence of elevated medium glucose concentrations indicates that the depletion of cellular MI levels is associated with increased intracellular sorbitol, alterations of inositol phospholipid metabolism, and decreased Na+,K+-ATPase activity (2,7,8), which is critical for the maintenance of resting membrane potential. Impairment of this enzyme has been linked to reduced nerve conduction velocity that is characteristic of both human and experimental diabetes (2). Furthermore, supplementing the diet of diabetic animals with MI tends to restore the cyclitol level, as well as Na',K+-ATPase activity and nerve conduction velocity, to normal (1, 9, 10).There is evidence that both Na+,K+-ATPase activity and a component of phosphatidylinositol (PI) turnover in normal tissues are inhibited by incubation in MI-free medium (11,12). Consequently, reduced MI content in diabetic nerve could reflect depletion of the MI supply that specifically serves as substrate for PI metabolism, which in turn is integral to regulation of Na+,K+-ATPase activity.To investigate this possibility, we have used propranolol, which like several other cationic amphiphilic drugs markedly enhances accumulation of phosphatidyl CMP (CMP-PA) in a number of tissues including iris muscle, pineal gland, and pancreatic islets (13)(14)(15). This occurs because propranolol redirects the metabolism of phospholipids, primarily by inhibiting PA phosphatase (16,17), thereby decreasing the formation of phosphatidylcholine and phosphatidylethanolamine and enhancing the synthesis of PI and phosphatidylglycerol. In the presence of propranolol, the accumulation of CMP-PA, the immediate precursor of the latter two phospholipids, will be determined by its rate of biosynthesis relative to its rate of utilization. The consumption of the liponucleotide is governed by the availability of endogenous MI, since its appearance is prevented by inclusion of sufficient MI in the medium (15,16 9818The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Section: Resultsmentioning

confidence: 99%

A myo-inositol pool utilized for phosphatidylinositol synthesis is depleted in sciatic nerve from rats with streptozotocin-induced diabetes.

Zhu

Eichberg

1990

Proc. Natl. Acad. Sci. U.S.A.

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“…Neither myo-inositol pool size nor synthetic or metabolic flux is sufficiently well characterized in peripheral nerve to permit meaningful quantitative comparison with sodium-dependent myoinositol uptake (17,18,26,42,44,45). Moreover, endoneurial fluid myo-inositol concentration, which may possibly differ from that of plasma (46,47), is unknown.…”

Section: Methodsmentioning

confidence: 99%

Sodium- and energy-dependent uptake of myo-inositol by rabbit peripheral nerve. Competitive inhibition by glucose and lack of an insulin effect.

Greene¹,

Lattimer²

1982

J. Clin. Invest.

147

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A B S T R A C T Experimental diabetes consistently reduces the concentration of free myo-inositol in peripheral nerve, which usually exceeds that of plasma by 90-100-fold. This phenomenon has been explicitly linked to the impairment of nerve conduction in the acutely diabetic streptozocin-treated rat. However, the mechanism by which acute experimental diabetes lowers nerve myo-inositol content and presumably alters nerve myo-inositol metabolism is unknown. Therefore, the effects of insulin and elevated medium glucose concentration on 2-[3H]myo-inositol uptake were studied in a metabolically-defined in vitro peripheral nerve tissue preparation derived from rabbit sciatic nerve, whose free myo-inositol content is reduced by experimental diabetes. The results demonstrate that myo-inositol uptake occurs by at least two distinct transport systems in the normal endoneurial preparation. A sodium-and energy-dependent saturable transport system is responsible for at least 94% of the measured uptake at medium myo-inositol concentrations approximating that present in plasma. This carrier-mediated transport system has a high affinity for myo-inositol (K, = 63 gtM), and is not influenced acutely by physiological concentrations of insulin; it is, however, inhibited by hyperglycemic concentrations of glucose added to the incubation medium in a primarily competitive fashion. Thus, competitive inhibition of peripheral nerve myo-inositol uptake by glucose may constitute a mechanism by which diabetes produces physiologically significant alterations in peripheral nerve myo-inositol metabolism.

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“…Indirect evidence for a role of the polyphosphoinositides in nerve conduction has come from recent studies on sciatic nerves of rats made diabetic by streptozotocin, a treatment that leads to a diabetic neuropathy. Altered PI turnover has been previously implicated in diabetes Whiting et al, 1977), and recently Eichberg and colleagues (Bell et al, 1982;BertiMattera et al, 1985) have demonstrated a substantial increase in "Pi incorporation into PIP2 in diabetic animals. The changes could be reversed by insulin administration.…”

Section: Nerve-impulse Conduction: Role Of Inositide Turnover In Diabmentioning

confidence: 99%

Receptor Activation and Inositol Lipid Hydrolysis in Neural Tissues

Fisher

Agranoff

1987

Journal of Neurochemistry

331

109

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Recent advances in our knowledge of the biochemistry, pharmacology, and cell biology of ligand-induced, stimulated turnover of inositol lipids in such diverse tissues as insect salivary glands, platelets, lymphocytes, and a number of exocrine glands have greatly altered our understanding of intracellular events leading to secretion, contraction, chemotaxis, and other cellular responses. Much of what has been learned regarding ligand-stimulated turnover of inosito1 lipids has come from nonneural systems, so that the presumption that signal transduction via this mechanism mediates significant steps in neural function must still be considered inferential. This reservation has been a major theme of a recent comprehensive review (Hawthorne, 1986). Nevertheless, that the brain contains large amounts of the substrates and enzymes of inositol lipid turnover and its associated second messenger systems and, further, that it is enriched with receptors that are linked to stimulated inositol lipid turnover argue strongly that the phosphoinositides indeed play an important role in brain function. There exist several general reviews on stimulated inositol lipid turnover (Bemidge, 1984;Bemdge and Irvine, 1984;Nishizuka, 1984Nishizuka, , 1986Hokin, 1985;Abdel-Latif, 1986;Downes, 1986;Williamson, 1986), including several that emphasize the nervous system (Downes, 1982(Downes, , 1983Fisher and Agranoff, 1986;Hawthorne, 1986; Nahorski et al., 1986). The present contribution emphasizes developments of neurochemical relevance since a review on the subject in this journal 8 years ago (Hawthorne and Pickard, 1979). CHEMISTRY AND ENZYMOLOGY OF INOSITOL LIPIDS AND INOSITOL PHOSPHATESThe inositol lipids Phosphatidylinositol (PI), depicted in Fig. lA, is a glycerophospholipid in which the sn-1 and sn-2 positions of glycerol are esterified to fatty acids, whereas the sn-3 position is phosphodiesterified to the 1)-1 position of myo-inositol. myo-Inositol is one of nine possible isomers of hexahydroxycyclohexane, which, in its preferred chair conformation, has one axial and five equatorial hydroxyl groups. The molecule can be likened to a turtle (Fig. 1B) in which the four legs and tail are the five equatorial hydroxyls, numbered counterclockwise from above, starting with the right foreleg as position D-1 (Fig. 1 C). The turtle's head is thus the axial hydroxyl at position D-2. The phosplhatidyl group in all of the phosphoinositides is linked to D-1 (the right foreleg).PI is synthesized in brain from a liponucleoiide intermediate, cytidine diphosphodiacylglycerol (CDP-DG) (Agranoff et al., 1958), and inositol in the presAddress correspondence and reprint requests to Dr. B. W. Agranoff at Neuroscience Laboratory Building, University of Michigan, 1103 East Huron, Ann Arbor, MI 48104-1687, U.S.A.Abbreviations used: ACh, acetylcholine; ACTH, corticotropin ( I-24)tetracosapeptide; APB, ~~-2-amino-4-phosphobutyric acid; APV, DL-2-amino-5-phosphonovalerate; CDP-DG, cytidine diphosphodiacylglycerol; DG, 1,2-diacyl-sn-glycerol; GAP, growthassociated ...

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Enzymes of myo-inositol and inositol lipid metabolism in rats with streptozotocin-induced diabetes

Cited by 88 publications

References 34 publications

A myo-inositol pool utilized for phosphatidylinositol synthesis is depleted in sciatic nerve from rats with streptozotocin-induced diabetes.

A myo-inositol pool utilized for phosphatidylinositol synthesis is depleted in sciatic nerve from rats with streptozotocin-induced diabetes.

Sodium- and energy-dependent uptake of myo-inositol by rabbit peripheral nerve. Competitive inhibition by glucose and lack of an insulin effect.

Receptor Activation and Inositol Lipid Hydrolysis in Neural Tissues

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