Insulin Receptor and Glucose Transporters in the Mammalian Cochlea

Abstract

Insulin receptors are expressed on nerve cells in the mammalian brain, but little is known about insulin signaling and the expression of the insulin receptor (IR) and glucose transporters in the cochlea. We performed immunohistochemistry and gene/protein expression analysis to characterize the expression pattern of the IR and glucose transporters in the mouse organ of Corti (OC). We also performed glucose uptake assays to explore the action of insulin and the effects of pioglitazone, an insulin sensitizer, on glucose transport in the OC. Western blots of protein extracts from OCs showed high expression of IR and glucose transporter 3 (GLUT3). Immunohistochemistry demonstrated that the IR is specifically expressed in the supporting cells of the OC. GLUT3 was found in outer and inner hair cells, in the basilar membrane (BM), the stria vascularis (SV), Reissner’s membrane and spiral ganglion neurons (SGN). Glucose transporter 1 (GLUT1) was detected at low levels in the BM, SV and Reissner’s membrane, and showed high expression in the SGN. Fluorescence glucose uptake assays revealed that hair cells take up glucose and that addition of insulin (10 nM or 1 µM) approximately doubled the rate of uptake. Pioglitazone conferred a small but nonsignificant potentiation of glucose uptake at the highest concentration of insulin. Gene expression analysis confirmed expression of IR, GLUT1 and GLUT3 mRNA in the OC. Pioglitazone significantly upregulated IR and GLUT1 mRNA expression, which was further increased by insulin. Together, these data show that insulin-stimulated glucose uptake occurs in the OC and may be associated with upregulation of both the IR and GLUT1.

Inner ear is a target for insulin signaling and insulin resistance: evidence from mice and auditory HEI-OC1 cells

“…31 Interestingly, adiponectin, one of the major adipokines released from adipocytes, was suggested to be a mediator of obesity-associated, age-related hearing impairment. 32 The finding that classical insulin signaling, involving the PI3-kinase/PKB node, takes place in HEI-OC1 cells agrees with a recent study showing the expression of the insulin receptor in supporting cells of the organ of Corti from mouse 17 and also with the expression of insulin signaling components in the human saccule sensory epithelium. 19 20 Regarding the PI3-kinase/PKB signaling node, several studies have demonstrated that a decrease in PI3-kinase/PKB signaling in the organ of Corti cells is associated with hearing loss.…”

“…The organ of Corti was recently shown to express the insulin receptor. 17 To investigate whether the cochlea could be a direct target for insulin signaling, we used HEI-OC1 auditory cells as a model for organ of Corti cells.…”

“…Glucose is considered to be the primary energy source for the cochlea and interestingly, insulin-dependent glucose uptake in the organ of Corti was recently reported. 17 Although there is no indication that cells from the stria vascularis express insulin receptors, 17 we plan to investigate them in the near future because of their key role in the production of the endolymph. However, we anticipate problems in separating the contribution of cells from the cochlea and the stria vascularis since the composition of the endolymph and the endocochlear potential depends both on the active electrogenic extrusion of K + into the scala media by the stria vascularis and by the passive drainage of K + from scala media, largely through the hair cells in the organ of Corti.…”

Insulin-like Growth Factor 1 Signaling in Mammalian Hearing

“…Unlike humans, mice and rats have two functional insulin genes: Ins1 and Ins2 [73]. The organ of Corti is a target tissue for insulin in the mouse, which shows expression of the high-affinity insulin receptor (IR) [74]. Insulin was shown to influence both protein and lipid metabolism in the inner ear [75], although the mechanisms underlying the association between diabetes and inner ear dysfunction are not yet known.…”

Protective effects of alpha-lipoic acid on hair cell damage in diabetic zebrafish model

“…Diabetic hearing loss is a prevalent complication, similar to peripheral neuropathy, and is characterized by changes in cochlear structure and the loss of hair cells (HCs) that be caused by hyperglycemic damage to the vasculature and neural system in the inner ear [ [1] , [2] , [3] ]. In addition, hyperglycemia could directly cause HC loss via the glucose toxicity-induced intracellular stress, because HCs use glucose as an energy source and glucose is transported by several glucose transporters (GLUTs), such as GLUT3 and GLUT10; glucose is required for mechanotransduction as well as ATP synthesis [ 4 , 5 ]. However, hearing loss as a diabetes complication is poorly understood in clinical settings, and there are no specific treatment for this condition.…”