Expression of Myoinositol Transporters in Nervous System Tissues in the Course of Experimental Diabetes
Authors: Santos Cláudia Ferreira , Farias Vanessa Ximenes , Uchôa Pablo Nascimento , Aquino Camila Peixoto , Fonteles Manassés Claudino , Nascimento Nilberto Robson Falcão 
Published: November 2023

Decreased levels of myoinositol have been constantly found in nerves of diabetic patients and in several animal models of diabetic neuropathy (ND). Cotransporters such as sodium/myoinositol (SMIT1 e SMIT2) and hydrogen/myoinositol (HMIT), regulate the intracellular concentration of myoinositol, which is an organic osmolyte and a substrate for phosphoinositide synthesis. The aim of the present study was to measure the mRNA and protein levels of the myoinositol cotransporters in tissues gathered from the central (cerebral cortex, hippocampus, cerebellum and striatum) and peripheral nervous system (sciatic nerve and dorsal root ganglia ‐DRG), during the course of experimental diabetic neuropathy. Male Wistar rats (180–250g), injected with streptozotocin (STZ, 60mg/Kg;i.p.) were used as experimental models. The Animal Research Ethics Committee of the Ceara State University approved all the experimental protocols under #11518153‐9/68. Euglycemic (E) or 4, 8 or 12‐week STZ‐diabetic rats (DB) were used for the analysis of mRNA and protein levels of SMIT1, SMIT2 or HMIT. In addition, the level of glycosylation or phosphorylation of these transporters were measured. We observed a significant reduction in the mRNA levels for SMIT1 in both sciatic nerve, dorsal root ganglia, cerebral cortex, hippocampus, striatum and cerebellum (by 36,9%, 31%, 55%, 47%, 39% and 52,4, respectively) in the 4‐week Diab group when compared to the euglycemic group. The mRNA level for SMIT2 is up‐regulated in both GRD and cerebral cortex and down‐regulated in the cerebellum in the 4‐week Diab group. The mRNA for HMIT was not altered in all tissues, except by a down‐regulation in the hippocampus (47.5%, 58.1% and 51.1% in 4, 8 e 12‐week diabetic rats, respectively. On the other hand the protein level of SMIT1 decreased by 42,5%, 41.3% and 44.8% in the sciatic nerve after 4,8 or 12 weeks of diabetes, respectively. In addition, there was a decrease by 64.3% and 58% of HMIT protein band intensity in membrane and cytosolic fractions, respectively, in the sciatic nerve of the 4‐week diab group. In DRG there was an increase of 2,26 fold and 86.3% for SMIT1 and HMIT cytosolic protein levels in the 12‐week diab group. In the central nervous system tissues, neither SMIT1 nor SMIT2 protein levels were altered. An exception to this was the cerebral cortex where the protein levels of SMIT2 were 75% higher in the 4‐week Diab group. Remarkably, there was an increase of 8.4, 2.2, 9.7 and 8.5 fold in the expression of HMIT in cytosolic fractions of cerebral cortex, hippocampus, striatum and cerebelum, respectively in the 8‐week Diab group. The expression of rate‐limiting enzymes in the inositol metabolism, i.e. myoinositol 3 phosphate synthase (MIPS) and myoinositol oxygenase (MIOX) is not changed by experimental diabetes in the sciatic nerve, DRG or hippocampus. The level of O‐glycosylation and phosphorylation of HMIT in the hippocampus increases as well as the level of phosphorylation of SMIT1 in the sciatic nerve, during the course of diabetes. There are important changes in the level of expression of myoinositol cotransporters in the course of diabetes on both central and peripheral nervous system.

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