Hyperglycaemia and diabetes impair gap junctional communication among astrocytes.
Sensory and cognitive impairments have been documented in diabetic humans and animals, but the pathophysiology of diabetes in the central nervous system is poorly understood. Because a high glucose level disrupts gap junctional communication in various cell types and astrocytes are extensively coupled by gap junctions to form large syncytia, the influence of experimental diabetes on gap junction channel-mediated dye transfer was assessed in astrocytes in tissue culture and in brain slices from diabetic rats. Astrocytes grown in 15-25 mmol/l glucose had a slow-onset, poorly reversible decrement in gap junctional communication compared with those grown in 5.5 mmol/l glucose. Astrocytes in brain slices from adult STZ (streptozotocin)-treated rats at 20-24 weeks after the onset of diabetes also exhibited reduced dye transfer. In cultured astrocytes grown in high glucose, increased oxidative stress preceded the decrement in dye transfer by several days, and gap junctional impairment was prevented, but not rescued, after its manifestation by compounds that can block or reduce oxidative stress. In sharp contrast with these findings, chaperone molecules known to facilitate protein folding could prevent and rescue gap junctional impairment, even in the presence of elevated glucose level and oxidative stress. Immunostaining of Cx (connexin) 43 and 30, but not Cx26, was altered by growth in high glucose. Disruption of astrocytic trafficking of metabolites and signalling molecules may alter interactions among astrocytes, neurons and endothelial cells and contribute to changes in brain function in diabetes. Involvement of the microvasculature may contribute to diabetic complications in the brain, the cardiovascular system and other organs.
Gandhi
Gautam K
GK
Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, U.S.A.
Ball
Kelly K
KK
Cruz
Nancy F
NF
Dienel
Gerald A
GA
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D000072259:Connexin 26; D017630:Connexins; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology*; D017629:Gap Junctions / Q000378:metabolism / Q000473:pathology*; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26
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