Hyperglycaemia and Diabetes Impair Gap Junctional Communication among Astrocytes

Abstract

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.

Regional Neurovascular Coupling and Cognitive Performance in Those with Low Blood Pressure Secondary to High-Level Spinal Cord Injury: Improved by Alpha-1 Agonist Midodrine Hydrochloride

“…37 This study extends these In this study, increasing BP in SCI only partially improved the NVC-PCA response; however, suggesting other CBF regulatory mechanisms may be dysfunctional in SCI. Attenuated NVC, even after midodrine, could be due to a variety of factors outside of low BP, including reduced nitric oxide availability, 38 glucose intolerance, 39 and dyslipidemia. 40 This study clearly showed that NVC of the MCA is preserved to AB levels in those with SCI.…”

Brain Lactate Metabolism: The Discoveries and the Controversies

“…Gap junction-coupled astrocytes can avidly take up lactate from extracellular fluid and are poised to discharge it from their endfeet into perivascular fluid where pulsatile pressure can drive the lactate along the vasculature (Gandhi et al (2009);Ball et al (2007Ball et al ( , 2010 and cited references). Several studies have reported that lactate increases vasodilation by different mechanisms (Hein et al, 2006;Yamanishi et al, 2006;Gordon et al, 2008), and continuous lactate release from the activated brain may serve a signaling function to increase blood flow and fuel delivery to the brain.…”

“…Brain growth and metabolic and functional development have enormous spurts between 10 and 21 days, with slower increases thereafter (Baquer et al, 1975 Yu et al (1984)), and cerebellar granule neurons obtained from B7-day-old postnatal rodents are used as a model system for glutamatergic neurons (Schousboe et al (1985); Hertz et al (1988) and cited references). Harvest age, culture duration, conditions, medium composition, and cellular development during culturing influence characteristics of cultures (Hertz et al (1998), Hertz (2004) and cited references), as well as any acquired pathophysiology during culturing (e.g., 15 to 30 mmol/L glucose causes diabetic complications; Gandhi et al (2010)). The capacity to use glucose or lactate by cultured astrocytes and neurons grown for < 2 weeks in vitro need not be equivalent to the adult brain.…”

“…In pulse-labeling assays, CMR glc is greatly underestimated when assayed with labeled glucose owing to rapid label loss arising from lactate efflux, decarboxylation reactions, and label spreading (Cruz et al, , 2007. Most lactate generated from glucose microinfused into the brain is not locally oxidized (Ball et al, 2010). Lactate dispersal and release can be mediated by astrocytes (Gandhi et al, 2009), and blockade of lactate transporters and gap junctions increase focal label retention in activated structures (Cruz et al, 2007).…”

Choosing an appropriate glucose concentration according to different cell types and experimental purposes is very important

“…D-Glucose concentration in a culture medium for different types of cells might be different because of differences in their physiological state. To those like endothelial cells, macrophages, and astrocytes, 5 mM D-glucose might be appropriate (Huawei et al 2013;Kaplan et al 2010;Gandhi et al 2010). However, to other cells such as cortical or hippocampal neurons, optimal survival rate and neurite growth may require much higher basal Dglucose (e.g., 25 mM), reflecting the fact that neurons have high metabolic rates.…”