Myo-inositol Depletion Research Articles

Protein kinase C agonists acutely normalize decreased ouabain-inhibitable respiration in diabetic rabbit nerve. Implications for (Na,K)-ATPase regulation and diabetic complications.

Diminished (Na,K)-ATPase activity in diabetic peripheral nerve is attributed to an underlying depletion of free myo-inositol, but no biochemical mechanism linking myo-inositol metabolism and (Na,K)-ATPase has emerged. Since inositol phospholipid turnover releases inositol-(1,4,5)-tris-phosphate and diacylglycerol, two putative "second messengers" that modulate protein kinase C, the effect of protein kinase C agonists on (Na,K)-ATPase activity was examined in diabetic nerve. Phorbol myristate acetate or the diacylglycerol sn-1,2-dioctanoylglycerol acutely normalized depressed ouabain-inhibitable respiration [a measure of (Na,K)-ATPase activity], suggesting that myo-inositol metabolism modulates (Na,K)-ATPase activity via protein kinase C, and that reduced myo-inositol impairs (Na,K)-ATPase activity in diabetic nerve by this mechanism.

Prevention of Defects of Axonal Transport in Experimental Diabetes by Aldose Reductase Inhibitors

Experiments on streptozotocin-diabetic rats have indicated that axonal transport of choline acetyltransferase is reduced in sciatic nerve. Treatment with an aldose reductase inhibitor both prevented and reversed this defect which was related to marked accumulations of sorbitol and fructose. Concurrent with these accumulations the content of myo-inositol in diabetic peripheral nerve is depleted. Further experiments taking account of nerve water content showed that the depletion of myo-inositol was 'real' not apparent. When the level of myo-inositol was maintained, either by feeding myo-inositol or by the inhibition of aldose reductase, the development of defective axonal transport of choline acetyltransferase and choline-containing lipids was prevented.

Aldose reductase inhibitors and late complications of diabetes.

Neuropathy and retinopathy are two potentially serious late complications of diabetes. There is accumulating evidence that the development of these conditions is closely related to increased activity of the polyol pathway, which occurs in certain tissues as a consequence of long term hyperglycaemia. Symptomatic diabetic neuropathy may appear as one of many forms and is frequently accompanied by pain. Diabetic retinopathy is a progressive degeneration of the retina that represents one of the major causes of blindness in the developed world. A good prognosis for either of these conditions is believed to rely on early diagnosis and optimisation of glycaemic control as they become less reversible with progression of cellular damage. A new approach to the treatment of these and other late complications of diabetes may be offered by recently developed drugs, such as sorbinil, that inhibit the enzyme aldose reductase. In various animal models of late complications of diabetes sorbinil and other aldose reductase inhibitors have been shown to reverse some of the biochemical and physiological changes believed to underlie these complications. These include prevention or reversal of the accumulation of sorbitol and depletion of myo-inositol in nerve, lens and renal glomeruli. Sorbinil also counteracts the slowing of nerve conduction velocities, reverses the structural changes of Sipple stages I and II cataracts and prevents proteinuria in diabetic rats. Orally administered sorbinil is absorbed rapidly and reaches steady state plasma concentrations after 6 to 10 days' administration. Its elimination half-life is long (38-52 hours) and much greater than that of another aldose reductase inhibitor, tolrestat (10-12 hours). Within the dose range 50-250 mg about one-third of administered sorbinil appears in the urine as unchanged drug. In the small number of clinical studies of diabetic patients with neuropathies sorbinil has demonstrated limited therapeutic effects. There is now a requirement for studies of its prophylactic use and its therapeutic use in patients with diabetic neuropathy in the early stages of development.

Reduced glomerular sodium/potassium adenosine triphosphatase activity in acute streptozocin diabetes and its prevention by oral sorbinil.

To explore metabolic changes associated with the sorbitol accumulation and myo-inositol depletion observed in glomeruli of rats with experimental diabetes, we examined total and ouabain-inhibited adenosine triphosphatase (ATPase) activity in glomeruli isolated from control and streptozocin (STZ)-diabetic rats. Glomerular Na/K-ATPase activity (ouabain-inhibited) was significantly reduced in diabetic animals, while total (composite) ATPase activity remained unchanged. Treatment with insulin partially restored the Na/K-ATPase activity. Administration of the aldose reductase inhibitor, sorbinil, which normalizes glomerular contents of both sorbitol and myo-inositol in diabetes, completely prevented the diminution of Na/K-ATPase activity. These results establish that glomerular Na/K-ATPase activity is reduced in acute experimental diabetes. The ability of sorbinil to prevent this decrease suggests that it is related to polyol accumulation and/or myoinositol depletion, although an effect of the drug unrelated to its aldose reductase inhibiting property has not been excluded. Since increased polyol pathway flux, decreased myo-inositol, and reduced Na/K-ATPase activity have also been described in peripheral nerve, another tissue in which typical diabetic complications characteristically occur, the consequences of these metabolic changes may be implicated in the pathogenesis of diabetic nephropathy.

Prevention of Defective Axonal Transport in Streptozocin-diabetic Rats by Treatment with “Statil” (ICI 128436), an Aldose Reductase Inhibitor

This investigation examined the effect of treatment of streptozocin-diabetic rats with the aldose reductase inhibitor "Statil" (25 mg/kg/day p.o.) on axonal transport in cholinergic neurons of the sciatic and vagal nerves and on nerve polyol and sugar levels. Three weeks of experimental diabetes caused deficits in the accumulation of choline acetyltransferase activity proximal to 24-h constrictions in the left sciatic and vagus nerves. These deficits did not develop in age-matched, similarly diabetic rats that were treated with the aldose reductase inhibitor. The inhibitor prevented completely the build-up of sorbitol and markedly reduced the build-up of fructose in the sciatic nerves of the treated diabetic rats. The inhibitor also prevented the depletion of myo-inositol that was seen in the untreated diabetic animals. It is suggested that these findings indicate a possible approach to the elucidation of the pathogenesis of cardiac vagal dysfunction in diabetes mellitus.

Reversal of deficits in axonal transport and nerve conduction velocity by treatment of streptozotocin-diabetic rats with myo-inositol

This study examined the effects of myo-inositol treatment on the deficits of motor nerve conduction velocity and of axonal transport of choline acetyltransferase in rats with streptozotocin-induced diabetes. Motor nerve conduction velocity was measured in seven groups of male rats. Two groups formed nondiabetic controls; one survived for 3 and the other for 6 weeks, then motor nerve conduction velocity was again measured and the accumulation of choline acetyltransferase activity proximal to a 24-h sciatic nerve constriction was estimated. The other five groups were rendered diabetic and subjected to similar measurements. Two diabetic groups were untreated and survived 3 or 6 weeks. The other three groups received myo-inositol for 1, 2, and 3 weeks, respectively, commencing 21 days after induction of diabetes. These groups survived for 4, 5, or 6 weeks, respectively. In all groups surviving for longer than 3 weeks an interim measurement of motor nerve conduction velocity was made 21 days after the start of the experiment (immediately before onset of treatment in the treated groups). In these groups a third measurement was made on the day before death. At death, choline acetyltransferase accumulation was measured and the remainder of the sciatic nerves was assayed for sorbitol and myo-inositol. In the two untreated diabetic groups we found reduced motor nerve conduction velocity, a deficit in the accumulation of choline acetyltransferase proximal to the sciatic nerve constriction, and a marked build-up of nerve sorbitol and a depletion of nerve myo-inositol. All three treated groups showed a reversal of this myo-inositol depletion without a reduction in the nerve sorbitol content. One week of treatment was without effect on nerve conduction velocity or axonal transport. In the 2-week treatment group axonal transport of choline acetyltransferase was similar to controls but the nerve conduction deficit was not reversed. After 3 weeks of treatment choline acetyltransferase accumulation was slightly greater than controls and the motor nerve conduction velocity had increased significantly from the pretreatment value (after 3 weeks' diabetes) and was not significantly less than the prediabetic value.

Motor nerve conduction velocity and nerve polyols in mice with short-term genetic or streptozotocin-induced diabetes

This study examined the relation between sciatic motor nerve conduction velocity and sciatic nerve contents of sorbitol, fructose, and myo-inositol in diabetic mice. Two groups of spontaneously diabetic animals (age 12 to 14 weeks and age 20 weeks) were compared with age-matched controls. In another experiment 17-week-old nondiabetic mice (of the same strain) were administered streptozotocin to induce diabetes and were subject to similar measurements 3 weeks later; age-matched controls were studied concomitantly. The diabetic mice in all groups were hyperglycemic with elevated nerve glucose. Those made diabetic with streptozotocin also showed a weight loss during the 3 weeks of diabetes. However, none of the diabetic groups showed significant deficits of motor nerve conduction velocity or nerve myo-inositol content. No accumulations of sorbitol or fructose were found in the sciatic nerves of the mice with diabetes of either origin. The study concluded that these animals do not have sciatic nerve aldose reductase activity and are not subject to myo-inositol depletion or to motor nerve conduction velocity deficits in short-term diabetes.

Slow orthograde axonal transport of radiolabelled protein in sciatic motoneurones of rats with short-term experimental diabetes: effects of treatment with an aldose reductase inhibitor or myo-inositol.

This study examined the effect of streptozotocin diabetes of 5 weeks duration on the profile of slow orthogradely transported radiolabelled protein in rat sciatic motoneurones. The diabetic rats showed a retardation of the tail of the slow-component profile. This selective retardation was unaffected by treatment with an aldose reductase inhibitor, although this treatment reduced the accumulation of sorbitol and prevented the depletion of myo-inositol in the sciatic nerves of the treated diabetic rats. Other groups, treated with myo-inositol, had normal or elevated sciatic nerve myo-inositol levels in the presence of accumulated sorbitol. The axonal transport profiles from both control and diabetic myoinositol-treated groups gave normal tail velocities but an altered shape such that retardation of the tail of the profile may have been present in both. The study concludes that rats with 5 weeks streptozotocin diabetes show retardation of the velocity of the most slowly transported proteins in sciatic motoneurones, and that this defect is not linked to the polyol pathway.

Prevention and reversal of defective axonal transport and motor nerve conduction velocity in rats with experimental diabetes by treatment with the aldose reductase inhibitor Sorbinil.

This investigation was designed to determine whether the aldose reductase inhibitor Sorbinil prevented the development of or reversed defects of nerve conduction and axonal transport in streptozotocin-diabetic rats. Untreated diabetes of either 3 or 6 wk duration caused a fall in sciatic motor nerve conduction velocity (MNCV) of 6-9 m/s (P less than 0.001) and significantly reduced the accumulation of axonally transported choline acetyltransferase activity against a 24-h sciatic nerve crush. These functional defects were associated with accumulation of sorbitol and depletion of myo-inositol in the sciatic nerve. Treatment with Sorbinil (25 mg/kg/day, p.o.) throughout the period of diabetes prevented the development of all these abnormalities in both 3- and 6-wk diabetic groups. In a second study, three groups of rats were subject to 3 wk untreated diabetes followed by Sorbinil treatment (as above) for 1, 2, or 3 wk to determine whether the abnormalities expected from 3 wk of untreated diabetes could be reversed. One week of treatment significantly elevated both MNCV and choline acetyltransferase accumulation (P less than 0.05). The longer treatments progressively ameliorated these defects such that the group that received Sorbinil for the second 3 wk of a 6-wk diabetic period gave values that were similar to controls and to diabetic rats that had been given Sorbinil throughout their diabetes. Sorbitol accumulation was markedly reduced by only 1 wk of Sorbinil treatment, but the normalization of myo-inositol levels required 2 wk of treatment. These findings indicate that Sorbinil treatment in diabetic rats prevented and reversed both Sorbitol accumulation and depletion of nerve myo-inositol in the sciatic nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue Content and Metabolism of myo-Inositol in Normal and Lipodystrophic Gerbils

Experiments were conducted to evaluate the effect of diet and sex difference on the development of an intestinal lipodystrophy due to myo-inositol deficiency. Tissue contents of free and lipid-bound myo-inositol as well as the activities of L-myo-inositol-1-phosphate synthase (EC 5.5.1.4) and phosphatase (EC 3.1.3.25), and myo-inositol oxygenase (EC 1.13.99.1) were determined in male and female gerbils under various conditions. The enzyme study proved that the essentiality of dietary myoinositol for this species was not due to the lack of such enzyme activity. The lower susceptibility of male gerbils to myo-inositol deficiency could be explained by the contribution of the biosynthesis of myo-inositol in the testis, as shown by a difference between intact and castrated animals. Although feeding coconut oil to the myo-inositol-deficient female gerbils produced greater myo-inositol depletion as well as a more severe intestinal lesion than the feeding of safflower oil, the difference in myo-inositol status could be only in part responsible for different degrees of lipodystrophy. Additionally, neither dietary type of fat nor exogenous myo-inositol altered the activities of either hepatic or intestinal synthase and phosphatase, or kidney oxygenase. Thus, this study indicates that both sex and dietary factors might influence myo-inositol status to varying extents, but the diet-induced change in tissue myo-inositol was not reflected by the enzyme activity as measured in vitro.