Gender differences in hypertrophy, insulin resistance and ischemic injury in the aging type 2 diabetic rat heart.
Aging and diabetes in women increase their susceptibility to myocardial ischemic injury, but the cellular mechanisms involved are not understood. Consequently, we studied the influence of gender on cardiac insulin resistance and ischemic injury in the aging of Goto-Kakizaki (GK) rat, a model of type 2 diabetes. Male and female GK rats had heart/body weight ratios 29% (P < 0.0001) and 53% (P < 0.0001) higher, respectively, than their sex-matched controls, with the female GK rat hearts significantly more hypertrophied than the male (P < 0.001). Glucose transporter (GLUT) 1 protein levels were the same in all hearts, but GLUT4 protein levels were 28% lower (P < 0.01) in all GK rat hearts compared with their sex-matched controls. In isolated, perfused hearts, insulin-stimulated (3)H-glucose uptake rates were decreased by 23% (P < 0.05) and 40% (P < 0.05) in male and female GK rat hearts, respectively, compared with their controls, with the female significantly more insulin resistant than the male GK rat hearts (P < 0.05). Protein kinase B protein levels and insulin-stimulated phosphorylation were the same in all hearts. During low-flow ischemia, glucose uptake was 59% lower (P < 0.001) in female, but the same as controls in male, GK rat hearts. Consequently, recovery of contractile function during reperfusion was 30% lower (P < 0.05) in female, but the same as controls in male GK rat hearts. We conclude that the aging female type 2 diabetic rat heart has increased insulin resistance and greater susceptibility to ischemic injury, than non-diabetic or male type 2 diabetic rat hearts.
University Laboratory of Physiology, University of Oxford, Oxford, OX1 3PT, England, UK. Martine.Desrois@medecine.univ-mrs.fr
Martine
M
Desrois
Robert J
RJ
Sidell
Dominique
D
Gauguier
Carol L
CL
Davey
George K
GK
Radda
Kieran
K
Clarke
D000375:Aging; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000209:etiology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D005260:Female; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000032:analysis / Q000378:metabolism; D009124:Muscle Proteins / Q000032:analysis / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism; D009206:Myocardium / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D012737:Sex Factors
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose