THE DEVELOPMENT AND IMPLEMENTATION OF AN IN VIVO 2-DEOXYGLUCOSE UPTAKE MODEL TO ASSESS GLUCOSE ASSIMILATION FOLLOWING DRUG TREATMENT IN MICE

CARMELA A LONGANO, Purdue University

Abstract

The purpose of this study was to assess the feasibility and limitations of using the uptake of ('14)C-2-deoxyglucose (('14)C-2DG) in the conscious mouse as a screening model for detecting changes in glucose uptake. The uptake of ('14)C-2DG was measured in gastrocnemius muscle, retroperitoneal fat, liver, cerebral cortex, and blood. Insulin (2 U/kg) sc significantly reduced 2DG levels in blood compared to saline controls but significantly increased 2DG levels in muscle and fat. There was no effect on cerebral cortex 2DG uptake. Hydrocortisone (HC) treatment (300 mg/kg, ip) significantly reduced brain and muscle 2DG uptake. The decreased 2DG uptake in the brain may result from HC-induced hyperglycemia or a reduction in extracellular sorbitol space. The effect of HC on the muscle appears to be a direct effect. Adrenalectomy had no detectable effect on 2DG uptake in peripheral tissues. Acute doses of tolazamide (TZ) 50 mg/kg ip, caused a pronounced elevation of 2DG in muscle and fat. This was similar to the 2DG profile seen with insulin for TZ elevates endogenous insulin levels. Tolazamide also produced an increased uptake of 2DG in brain. The increased 2DG uptake in brain, fat, and muscle did not appear to be a result of lowered blood glucose, and consequently higher 2DG specific activity, produced by TZ. Subchronic treatment with TZ did not change tissue 2DG uptake compared to controls. However, insulin levels were lower than the control group suggesting an enhancement of insulin action. Acute doses of TZ potentiated the decrease in plasma glucose values seen with repeated orbital sinus puncture in viable yellow obese mice. The insulin resistance of viable yellow obese mice was seen in the fat tissue of these animals. Subchronic TZ treatment had no effect on insulin levels or on 2DG tissue uptake in peripheral tissues of these mice. The limitations of the model seem to involve the brain and liver. Increasing glucose concentrations lead to decreased 2DG brain uptake. It also appears that 2DG may not be reflecting glucose assimilation in the liver. However, it appears that the in vivo 2DG uptake model, which uses 2DG transport and phosphorylation as the insulin postreceptor events, is a useful screening method for detecting changes in glucose assimilation following drug therapy in fat and muscle.

Degree

Ph.D.

Subject Area

Pharmacology

COinS