Reduced heart rate variability in the diabetic heart is reversed by inhibition of glycogen synthase kinase 3β activity

      Decreased heart rate variability (HRV) associated with diabetic autonomic neuropathy is a risk factor for sudden death. Parasympathetic stimulation of the heart involves acetylcholine activation of the G protein-coupled K+ channel, (GIRK1)2/(GIRK4)2. We have previously demonstrated that expression of GIRK1 is decreased in the hearts of the Type I diabetic Akita mouse in association with a marked decrease in the negative chronotropic effect of the acetylcholine analog carbamylcholine. Increased Glycogen synthase kinase 3β (GSK3β), whose activity is inhibited by phosphorylation in response to insulin, has recently been implicated in the pathogenesis of diabetes, cancers and neurodegenerative diseases. Here we studied the role of inhibition of GSK3β by Lithium in the treatment of parasympathetic dysfunction in the Akita mouse. We compared HRV in wild type (WT) mice and in Akita mice, as well as in Akita mice before and after a 10 day implantation of slow release insulin pellets and before and after 7–10 days of treatment with Lithium supplemented chow. We computed normalized spectral power of the HF component (HFnorm) as an indication for parasympathetic modulation of heart rate from telemetry ECG recordings after beta-blockade with an IP injection of 1 mg/kg propranolol. The effects of Lithium on GIRK1 and GIRK4 expression was determined by Western blot analysis.
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