Metformin alters the insulin signaling pathway in ischemic cardiac tissue in a swine model of metabolic syndrome

Abstract

The purpose of this study is to evaluate the effect of metformin on insulin signaling in ischemic cardiac tissue in a swine model of metabolic syndrome. Ossabaw miniswine were fed either a regular diet (Ossabaw control [OC]) or a hypercaloric diet (Ossabaw high cholesterol [OHC], Ossabaw high cholesterol with metformin [OHCM]). After 9 weeks, all animals underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. OHC animals were continued on a hypercaloric dietalone; the OHCM group was supplemented with metformin in addition to the hypercaloric diet. Seven weeks after ameroid placement, myocardial perfusion was measured and ischemic cardiac tissue was harvested for protein expression and histologic analysis. The OHC and OHCM groups had significantly higher body mass indices and serum insulin levels compared with the OC group. There were no differences in myocardial perfusion in the chronically ischemic territories. In the OHC group, there was upregulation of both an activator of insulin signaling insulin receptor substrate 1, and an inhibitor of insulin signaling phosphorylated insulin receptor substrate 2. In the OHCM group, there was upregulation of activators of insulin signaling including phosphorylated adenosine monophosphate-activated protein kinase α, protein kinase B, phosphorylated protein kinase B, mammalian target of rapamycin, phosphorylated mammalian target of rapamycin, and phosphoinostitide 3-kinase, and upregulation of inhibitors including phosphorylated insulin receptor substrate 1, phosphorylated insulin receptor substrate 2, and retinol binding protein 4. Histologic analysis demonstrated increased expression of glucose transporter 1 at the plasma membrane in the OHCM group, but there was no difference in cardiomyocyte glycogen stores among groups. Metformin treatment in the context of metabolic syndrome and myocardial ischemia dramatically upregulates the insulin signaling pathway in chronically ischemic myocardium, which is at the crossroads of known metabolic and survival benefits of metformin.