Patients who experience
acute ischemic stroke may develop
hyperglycemia, even in the absence of diabetes. In the current study we determined the effects of
acute stroke on hepatic
insulin signaling, TNF-α expression, endoplasmic reticulum (ER) stress, the activities of
c-Jun N-terminal kinase (JNK), inhibitor κB
kinase β (IKK-β), and nuclear factor-κB (NF-κB) pathways. Rats with
cerebral ischemia developed higher
blood glucose, and
insulin levels, and
insulin resistance index, as well as hepatic gluconeogenic
enzyme expression compared with the
sham-treated group. The hepatic TNF-α
mRNA and
protein levels were elevated in
stroke rats in association with increased ER stress, phosphorylation of JNK1/2 and IKK-β
proteins, IκB/NF-κB signaling, and phosphorylation of
insulin receptor-1 (IRS-1) at
serine residue. The basal and
insulin-stimulated
tyrosine phosphorylation of IRS-1 and AKT
proteins was reduced. In addition,
acute stroke increased circulating
catecholamines in association with hepatic
adrenergic signaling activation. After administration of a nonselective β-
adrenergic receptor blocker (
propranolol) before induction of cerebral ischemic injury, hepatic
adrenergic transduction, TNF-α expression, ER stress, and the activation of the JNK1/2, IKK-β, and NF-κB pathways, and
serine phosphorylation of IRS-1 were all attenuated. In contrast, the phosphorylated IRS-1 at
tyrosine site and AKT levels were partially restored with improved poststroke
hyperglycemia and
insulin resistance index. These results suggest that
acute ischemic stroke can activate proinflammatory pathways in the liver by the
catecholamines and is associated with the development of hepatic
insulin resistance.