Effect of insulin and glucose infusion on myocardial infarction size in uraemic rats.
The post myocardial infarction (MI) mortality rate is high in renal patients. One possible explanation is the reduced ischemia tolerance caused by uraemia. Previous investigations showed larger MI size in uraemic rats when compared with sham-operated controls. To explore a possible link between uraemic insulin resistance syndrome and MI size in uraemia, we studied an intervention model with administration of insulin and glucose during acute MI in subtotally nephrectomized (SNX) rats and sham-operated controls. In 16 SNX rats and 16 sham-operated controls, the left coronary artery was ligated for 60 min, followed by reperfusion for 90 min. To visualize the perfused myocardium, lissamine-green ink was injected. The nonperfused area (lissamine exclusion) and the area of total infarction (TTC stain) were assessed in sections of the left ventricle (LV) using image analysis. While eight SNX rats and eight sham-operated controls were treated with a placebo during the procedure, the other animals received an insulin bolus of 85 mU/kg and then a continuous insulin infusion of 8 mU/kg per minute. Blood glucose levels were clamped to baseline levels with an infusion of 25% glucose. Insulin receptor substrates (IRS-1 and IRS-2) and glucose transporter (GLUT 4) were studied by western blot in another seven SNX and seven sham-operated controls without further intervention. The infarcted area, given as a proportion of the nonperfused risk area, was not different in sham-operated controls treated with a hyperinsulinaemic clamp versus untreated (0.55 +/- 0.07 vs. 0.51 +/- 0.13, p = 0.477). The eight SNX animals treated with the hyperinsulinaemic clamp utilized significantly less glucose to stabilize baseline glucose levels when compared with the sham-operated controls (5,637 vs. 3,207 microl Glc 25%, p = 0.007). The infarcted area was significantly lower in SNX rats treated with the hyperinsulinaemic clamp compared to non-treated SNX animals (0.56 +/- 0.06 vs. 0.79 +/- 0.09, p < 0.001). SNX rats with the insulin clamp had the same infarcted area size as sham-operated controls (0.56 +/- 0.06 vs. 0.51 +/- 0.13, p = 0.357). Western blotting did not show any change in the expression of GLUT 4 and IRS-1/IRS-2 in SNX animals when compared with sham-operated controls. The size of MI in uraemic rats is significantly reduced by a glucose/insulin infusion. The results suggest an insulin resistance in uraemic rats with similar benefits of glucose/insulin application during acute MI, as found in diabetic individuals. Further analysis did not reveal a down regulation in GLUT 4 and IRS-1/IRS-2.
Dikow
Ralf
R
Department of Nephrology, University Hospital of Heidelberg, Heidelberg, Germany. ralfdikow@yahoo.de
Wasserhess
Caroline
C
Zimmerer
Katrin
K
Kihm
Lars Philipp
LP
Schaier
Matthias
M
Schwenger
Vedat
V
Hardt
Stefan
S
Tiefenbacher
Christiane
C
Katus
Hugo
H
Zeier
Martin
M
Gross
Lisa Marie
LM
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005947:Glucose / Q000008:administration & dosage*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007263:Infusions, Parenteral; D007328:Insulin / Q000008:administration & dosage*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014511:Uremia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; C495694:Slc2a4 protein, rat; D005947:Glucose