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


METHODS
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 diet alone; 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.


RESULTS
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.


CONCLUSIONS
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.
Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.
Nassrene Y
NY
Elmadhun
Antonio D
AD
Lassaletta
Louis M
LM
Chu
Frank W
FW
Sellke
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D003326:Coronary Circulation; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008687:Metformin / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D013556:Swine, Miniature; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D051272:Glucose Transporter Type 1; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D054839:Retinol-Binding Proteins, Plasma; D008687:Metformin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases