Concentration of Myo-inositol in Skeletal Muscle of the Rat Occurs without Active Transport

Molitoris, Bruce A.; Karl, Irene E.; Daughaday, William H.

doi:10.1172/jci109728

Cited by 28 publications

(16 citation statements)

References 21 publications

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“…The mechanism(s) relating intracellular free MI and sodium-potassium ATPase function are unclear. The strikingly high intracellular MI concentration characteristic of many mammalian cell lines has no welldefined biological role, although its major metabolic activity is reversible incorporation into membrane phosphoinositide (2,25). Since tissue MI levels influence nondiabetic peripheral nerve phosphoinositide turnover (19), abnormalities in diabetic peripheral nerve phosphoinositide metabolism (26-28) may reflect altered tissue free MI levels (2).…”

Section: Methodsmentioning

confidence: 99%

Impaired rat sciatic nerve sodium-potassium adenosine triphosphatase in acute streptozocin diabetes and its correction by dietary myo-inositol supplementation.

Greene¹,

Lattimer²

1983

J. Clin. Invest.

265

132

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A B S T R A C T Nerve conduction impairment in ex-perimental diabetes has been empirically but not mechanistically linked to altered nerve myo-inositol metabolism. The phospholipid-dependent membranebound sodium-potassium ATPase provides a potential mechanism to relate defects in diabetic peripheral nerve myo-inositol-phospholipid metabolism, impulse conduction, and energy utilization. Therefore, the effect of streptozocin-induced diabetes mellitus and dietary myo-inositol supplementation on rat sciatic nerve sodium-potassium ATPase was studied. ATPase activity was measured enzymatically in sciatic nerve homogenates from 4-wk streptozocin diabetic rats and age-matched controls either fed a standard or 1% myoinositol supplemented diet. The sodium-potassium ATPase components were assessed by ouabain inhibition or the omission of sodium and potassium ions. Diabetes reduced the composite ATPase activity recovered in crude homogenates of sciatic nerve. The 40% reduction in the sodium-potassium ATPase was selectively prevented by 1% myo-inositol supplementation (which preserved normal nerve conduction). Thus, in diabetic peripheral nerve, abnormal myo-inositol metabolism is associated with abnormal sodiumpotassium ATPase activity. The mechanism of the effect of dietary myo-inositol to correct diabetic nerve conduction may be through changes in a sodium-potassium ATPase, possibly via changes in myo-inositolcontaining phospholipids. Received for publication 15 March 1983 and in revised form 13 May 1983. defects in peripheral nerve (1, 2). Furthermore, the histologically demonstrable axonal degeneration and segmental demyelination are thought to reflect longstanding metabolic derangements in diabetic peripheral nerve Schwann cells and/or axons (2). These unknown metabolic abnormalities alone presumably explain the acute and rapidly reversible conduction impairment in newly diagnosed human diabetes (2).Nerve conduction defects in acutely diabetic animals resemble the metabolically mediated conduction impairment in human diabetics (3-6). In the acute streptozocin diabetic rat, where diabetic nerve metabolism and function are readily compared, impaired nerve conduction has been linked to an alteration in peripheral nerve myo-inositol (MI)' metabolism (3, 7, 8) that results from insulin deficiency and/or hyperglycemia (3) (an analogous alteration in MI metabolism was recently demonstrated in human diabetic nerve [9]). In vitro studies with rabbit peripheral nerve suggest that competitive inhibition of sodium-dependent MI uptake by hyperglycemic glucose concentrations may contribute to this fall in diabetic nerve MI content (10), as may increased polyol-pathway metabolism (8,11,12).The relationship between altered MI metabolism and impaired nerve function is poorly understood. Recent single-node voltage-clamp studies in peripheral nerve from the spontaneously-diabetic BB rat ascribe impaired nerve conduction to a reduction in the resting axonal transmembrane sodium potential, possibly attributable to reduced sodium-pump ac...

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Section: Methodsmentioning

confidence: 99%

Impaired rat sciatic nerve sodium-potassium adenosine triphosphatase in acute streptozocin diabetes and its correction by dietary myo-inositol supplementation.

Greene¹,

Lattimer²

1983

J. Clin. Invest.

265

132

View full text Add to dashboard Cite

show abstract

“…It has been postulated (17), but never demonstrated, in peripheral nerve (20). Although myo-inositol synthesis has been observed in crude homogenates of peripheral nerve (26), the relative importance of active concentration, intracellular sequestration (20), and endogenous synthesis in the maintenance of nerve myo-inositol concentrations is unknown (17,18,20). In the studies presented here, we demonstrate that myo-inositol uptake occurs in endoneurial tissue via a sodiumand energy-dependent, ouabain-inhibitable, high affinity, carrier mediated transport system.…”

mentioning

confidence: 96%

“…In contrast to most other carbohydrates, myo-inositol is maintained at high intracellular concentrations by most tissues. Both endogenous synthesis from glucose and active concentration from plasma have been invoked to explain this phenomenon (19,20). Active concentration of myo-inositol has been described in kidney (21), small intestine (22), choroid plexus (23), ciliary body (24), and ocular lens (25).…”

mentioning

confidence: 99%

“…Active concentration of myo-inositol has been described in kidney (21), small intestine (22), choroid plexus (23), ciliary body (24), and ocular lens (25). It has been postulated (17), but never demonstrated, in peripheral nerve (20). Although myo-inositol synthesis has been observed in crude homogenates of peripheral nerve (26), the relative importance of active concentration, intracellular sequestration (20), and endogenous synthesis in the maintenance of nerve myo-inositol concentrations is unknown (17,18,20).…”

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confidence: 99%

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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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“…It is unclear why fibroblast mytr inositol content varies by as much as 5-fold in the different cell lines and provokes the consideration of how relevant the measurement of total cell myo-inositol is to fibroblast metabolism. Molitoris et al (37) suggested that mvc~inositol is largely sequestered or bound in skeletal muscle tissue. Several investigators have also alluded to the presence of more than one pool of mj3tr inositol in certain cells or tissues (23.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Glucose and Galactose Toxicity on Myo-inositol Transport and Metabolism in Human Skin Fibroblasts in Culture

et al. 1994

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ABSTRACT. Myo-inositol transport and metabolism were studied in cultured human skin fibroblasts exposed to potentially toxic levels of glucose or galactose. Although variable among I I different cell lines, the myo-inositol level in confluent cells, ranging from 10-50 nmol/mg protein, was constant with passage. A high-affinity transport system for myo-inositol had an apparent Kt of 55 pM and V, of 16 pmol/min/mg protein. No obvious relationship existed between cellular levels and transport capacity. Dependency on sodium was complex. When medium sodium was lowered to 23 mM, myo-inositol uptake ceased after about 1 h. However, the initial rate of myo-inositol uptake only showed a sodium dependence at low myo-inositol concentrations. Both phloretin and phloridzin inhibited myo-inositol uptake. Phloridzin had a Ki of 60 pM. and phloretin was either a noncompetitive or uncompetitive inhibitor. Glucose and galactose were only weak competitive inhibitors, with a K1 of 30 mM and 65 mM, respectively. After 24 h of incubation with myo-[2-3Hjinositol, only 10% of the total cell label was incorporated into phospholipid. Compared with control media with 5 mM glucose, the incubation of confluent cells in media with 20 mM glucose had little effect on intracellular glucose and sorbitol, whereas cells incubated in control media supplemented with 5 mM galactose showed a large increase in galactose and polyol levels. In media with more than 200 WM of myo-inositol, neither treatment had an effect on myo-inositol levels after 24 h. The uptake and incorporation of 11 pM myo-[2-3Hjinositol and incorporation into phospholipid were studied after cells had been previously exposed for 24 to 48 h to media supplemented with 15 mM glucose or galactose. Compared with controls, fibroblasts with a 24-h exposure to 20 m M glucose showed a 10% decrease in myo-inositol uptake. When the exposure was extended to 48 h, preconditioning with galactose as well as glucose elicited the same 10% reduction in uptake. Phosphoinositide labeling in fibroblasts exposed to 20 mM glucose was reduced in parallel. These cells offer a unique opportunity for the study of sugar toxicity in human tissue: they can be exposed to high levels of glucose without significant glucose or polyol accumulation~or can be made to accumulate polyol by exposure to moderate levels of galactose. The expression of a hexose-induced reduction in myo-inositol transport required 24 to 48 h of exposure of the fibroblasts to elevated concentrations of glucose or galactose and may not be related to a competitive inhibitory

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Concentration of Myo-inositol in Skeletal Muscle of the Rat Occurs without Active Transport

Abstract: A B S T R A C T The cellular uptake of nonphosphorylated mnyo-inositol (MI) and its incorporation into phosphoinositide in the rat epitrochlearis muscle was measured.

Cited by 28 publications

References 21 publications

Impaired rat sciatic nerve sodium-potassium adenosine triphosphatase in acute streptozocin diabetes and its correction by dietary myo-inositol supplementation.

Impaired rat sciatic nerve sodium-potassium adenosine triphosphatase in acute streptozocin diabetes and its correction by dietary myo-inositol supplementation.

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

The Effect of Glucose and Galactose Toxicity on Myo-inositol Transport and Metabolism in Human Skin Fibroblasts in Culture

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