Introduction: Insulin dependent type I diabetes mellitus (TIDM) can be well-controlled with the use of exogenous insulin, however during illness, poor management of TIDM, failure of the insulin pump to deliver insulin, or prior to a diagnosis of TIDM, glucose levels can rise drastically resulting in a condition called diabetic ketoacidosis (DKA). DKA accounts for a majority of hospitalizations due to diabetes, especially in children, and accounts for a significant number of deaths. ET-1 has been found to regulate insulin response and has been implicated in insulin resistance. The present study was conducted to determine the involvement of ET-1 and ET receptors in DKA and to find out whether ETA receptor antagonists can be used to improve the treatment of DKA. Methods: Male Sprague-Dawley rats weighing 300 to 350 g (Harlan, Indianapolis, IN) were injected IP with 150 mg/kg of streptozotocin (STZ) in 0.05 mol/L citrate buffer, pH 4.3 to induced diabetes, while non-diabetic control rats received an IP injection of 0.05 mol/L citrate buffer. Baseline blood glucose and ketone levels were estimated before STZ injection and then measured on day three and four to ensure the onset of hyperglycemia and ketoacidosis. Significantly elevated blood ketone levels (>20mg/dL), and blood glucose levels (>400 mg/dL) developed on day four after STZ injection indicating the development of DKA. The following groups were studied: Group 1: Control (non-diabetic) animals administered citrate. Animals that developed DKA were divided in five additional groups. Group II: DKA animals without treatment; Group III: DKA animals given saline; Group IV: DKA animals given saline and insulin 1.5 u/kg/hr; Group V: DKA animals given saline, insulin 1.5 u/kg/hr and BMS-182874 (9 mg/kg) and Group VI: DKA animals given saline, insulin 1.5 u/kg/hr and BQ123 (1 mg/kg). Results: DKA was successfully induced in rats, as shown by increased blood glucose, ketone and decreased blood pH by day 4 of STZ injection. Saline+insulin treatment produced significant reduction in blood glucose and ketones. Saline+insulin treatment in DKA rats increased the plasma and brain ET-1 levels which were not affected by BMS-182874 or BQ123 treatment. There was no change in the expression of ETB receptors in the brain, however, ETA receptor expression increased in DKA rats and was not altered following treatment with insulin, BMS-182874 or BQ123. Animals in insulin+saline group showed a significant increase (160%) in cerebral blood perfusion compared to base line. This increase in cerebral perfusion was attenuated by BQ123 or BMS-182874. Treatment with BQ123 also improved blood pH and ketones in DKA rats. Conclusions: It can be concluded that ETA receptor antagonists maybe of therapeutic use in the management of DKA and its complications.
© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins