Insulin suppresses ischemic preconditioning-mediated cardioprotection through
Akt-dependent mechanisms.
Authors Fullmer TM, Pei S, Zhu Y, Sloan C, Manzanares R, Henrie B, Pires KM, Cox JE,
Abel ED, Boudina S
Submitted By Submitted Externally on 3/4/2015
Status Published
Journal Journal of molecular and cellular cardiology
Year 2013
Date Published 11/1/2013
Volume : Pages 64 : 20 - 29
PubMed Reference 23994159
Abstract It is believed that the diabetic myocardium is refractory to cardioprotection by
ischemic preconditioning (IPC) mainly because of impaired insulin signaling to
phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB or Akt). However,
human as well as animal studies have clearly showed that the hearts of type 2
diabetic humans and animals may exhibit increased signaling through PI3K-Akt but
yet are resistant to cardioprotection by IPC or ischemic post-conditioning.
Therefore, this study was designed to determine whether activation of insulin
signaling prior to IPC is detrimental for cardioprotection and to assess the
role of insulin receptors (IRs) and Akt in mediating this effect. Wild-type (WT)
hearts, hearts lacking IRs or hearts expressing an active form of Akt (myrAkt1)
were perfused ex vivo using a Langendorff preparation and were subjected to IPC
(3cycles of 5min ischemia followed by 5min reflow before 30min no flow ischemia
and then by 45min reperfusion) in the presence or absence of 1nmol/L insulin.
Interestingly, whereas insulin was protective against I/R (30min no flow
ischemia and 45min reperfusion), it completely abolished cardioprotection by IPC
in WT hearts but not in mice lacking insulin receptors (IRs) in cardiomyocytes
(CIRKO) or in all cardiac cells (TIRKO). The suppression of IPC-mediated
cardioprotection was mediated through downstream signaling to Akt and Gsk3ß. In
addition, transgenic induction of Akt in the heart was sufficient to abrogate
IPC even when insulin was absent, further confirming the involvement of Akt in
insulin's suppression of cardioprotection by IPC. These data provide evidence
that excessive insulin signaling to Akt is detrimental for cardioprotection by
IPC and could explain the failure of the diabetic myocardium to precondition.

Investigators with authorship
E. Dale AbelUniversity of Iowa