During the past decade, our appreciation of the original experiments with myo-inositol supplementation in diabetic rats has greatly expanded. The effects of myo-inositol on nerve conduction are now explained by concepts that were largely unappreciated in 1976, including the fundamental role of phosphoinositide metabolism in cell regulation and the importance of the activity of sodium-potassium-ATPase in nerve conduction. Aldose reductase inhibitors firmly link defects in myo-inositol metabolism to activation of the polyol pathway in diabetes; the resulting "sorbitol-myo-inositol hypothesis" has been extended from its application to the lenses and peripheral nerves to most of the tissues involved with diabetic complications. These biochemical mechanisms provide a new framework within which to explore the complex interactions between hyperglycemia and the vascular, genetic, and environmental variables in the pathogenesis of diabetic complications. It is anticipated that these endeavors will result in the appearance of new classes of therapeutic agents, the first of which--the aldose reductase inhibitors--has emerged from the laboratory and is now undergoing extensive clinical testing. These efforts are very likely to result in the appearance of new treatment methods that may dramatically lighten the burden of chronic complications in patients with diabetes.

Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications.

Lipids of nervous tissue: composition and metabolism.

Potential role and therapeutic interests of myo-inositol in metabolic diseases.

Inositol phospholipids and inositol phosphates mediate well-established functions in signal transduction and in Ca2+ homeostasis in the CNS and non-neural tissues. More recently, there has been renewed interest in other roles that both myo-inositol and its highly phosphorylated forms may play in neural function. We review evidence that myo-inositol serves as a clinically relevant osmolyte in the CNS, and that its hexakisphosphate and pyrophosphorylated derivatives may play roles in such diverse cellular functions as DNA repair, nuclear RNA export and synaptic membrane trafficking.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2002.01041.x

Inositol and higher inositol phosphates in neural tissues: homeostasis, metabolism and functional significance

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, 1984, 1986; Hokin, 1985; Abdel-Latif, 1986; Downes, 1986; Williamson, 1986), including several that emphasize the nervous system (Downes, 1982, 1983; Fisher 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).

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Receptor activation and inositol lipid hydrolysis in neural tissues.

Acute diabetes with ketosis was induced in rats by intraperitoneal streptozotocin and also a milder form of diabetes without ketosis by injecting less of the drug. The acutely diabetic rats were killed 72h after injection and the others after either 2 or 13 weeks. Free and lipid myo-inositol was then measured in various tissues and body fluids by g.l.c. of the trimethylsilyl ether. Serum inositol was increased in the acutely diabetic group, whereas liver inositol was decreased. Brain and kidney inositol concentrations were increased in the mildly diabetic animals at 13 weeks and there was a progressive decrease in sciatic-nerve inositol. Lipid inositol of sciatic nerve was decreased in the acutely diabetic group only. Brain lipid inositol concentration was decreased in mild diabetes at 13 weeks. Possible implications of these findings in relation to diabetic neuropathy was discussed.

/pdf/free-and-lipid-myo-inositol-in-tissues-from-rats-with-acute-1m2449as7f.pdf

Free and lipid myo-inositol in tissues from rats with acute and less severe streptozotocin-induced diabetes.

Diabetes, with only mild ketosis, was induced in male rats by a single injection of streptozotocin. After 12 weeks the specific activities of enzymes concerned with the metabolism of inositol and of inositol lipids were measured in various tissues. Inositol 1-phosphate synthase (EC 5.5.1.4) was most active in testis and the activity was significantly less in diabetic rats than in controls on a similar diet. Inositol oxygenase (EC 1.13.99.1), which converts myo-inositol into glucuronic acid, was also less active in kidney from diabetic animals. CDP-diacylglycerol-inositol phosphatidyltransferase (EC 2.7.8.11) and phosphatidylinositol 4-phosphate kinase (EC 2.7.1.68) showed decreased specific activities in brain and sciatic nerve of diabetic rats. By contrast the diabetic state did not affect the specific activities of phosphatidylinositol kinase (EC 2.7.1.67) or phosphatidylinositol 4,5-bisphosphate phosphatase (EC 3.1.3.36) in these tissues. The results are discussed in relation to diabetic neuropathy.

/pdf/enzymes-of-myo-inositol-and-inositol-lipid-metabolism-in-12gyius3tl.pdf

P H Whiting

Papers

Free and lipid myo-inositol in tissues from rats with acute and less severe streptozotocin-induced diabetes.

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