Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. Signal., 13 July 2010
Vol. 3, Issue 130, p. ec213
[DOI: 10.1126/scisignal.3130ec213]


Diabetes Radical Autonomic Insufficiency

Nancy R. Gough

Science Signaling, AAAS, Washington, DC 20005, USA

A major complication in diabetes is autonomic insufficiency, which can produce a range of symptoms, including cardiac arrhythmias and circulatory problems, pain and numbness in the extremities, defective thermoregulation, and gastrointestinal problems. Campanucci et al. showed that in both type 1 and type 2 mouse models of diabetes, nerve-evoked excitatory postsynaptic potentials (EPSPs) were reduced in the superior cervical ganglion (SCG), which suggests that increased circulating glucose and not changes in insulin per se were influencing sympathetic responsiveness. Analyses of SCG neurons cultured in low or high concentrations of glucose showed that high concentrations of glucose resulted in increased production of reactive oxygen species and the accumulation of protein adducts of 4-hydroxy-2-nonenal (HNE), a product of lipid peroxidation. The neurons cultured in high concentrations of glucose, but not those cultured in low concentrations of glucose, also showed use-dependent reduction (rundown) in the activity of the nicotinic acetylcholine receptor (nAChR), a cationic channel responsible for cholinergic-mediated sympathetic nerve activity. Addition of antioxidants prevented the glucose-mediated rundown. The {alpha}3 subunit of the nAChR has a conserved cysteine (C239), and high concentrations of glucose failed to cause use-dependent rundown of an {alpha}3C239A mutant introduced into SCG from {alpha}3-null mice. Introduction of the {alpha}3C239A mutant into {alpha}3-null mice that were made diabetic by chemical destruction of the pancreatic β cells protected the mice from the reduction in EPSPs and also prevented the diabetes-associated reduction in two endpoints of sympathetic activity: sympathetic stimulation of heart rate and thermoregulation. As Diano and Horvath discuss, this reduction in sympathetic activity may be an adaptive response to chronically increased glucose as the body attempts to reduce hepatic gluconeogenesis and glucose release. Thus, it remains to be determined whether interfering with this reduction in sympathetic activity would be detrimental for glycemic control in diabetic patients, although it seems that it could improve the symptoms associated with autonomic insufficiency.

V. Campanucci, A. Krishnaswamy, E. Cooper, Diabetes depresses synaptic transmission in sympathetic ganglia by inactivating nAChRs through a conserved intracellular cysteine residue. Neuron 66, 827–834 (2010). [Online Journal]

S. Diano, T. L. Horvath, A sympathetic view on free radicals in diabetes. Neuron 66, 809–811 (2010). [Online Journal]

Citation: N. R. Gough, Radical Autonomic Insufficiency. Sci. Signal. 3, ec213 (2010).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882