Differing mechanisms of hepatic glucose overproduction in triiodothyronine-treated rats vs. Zucker diabetic fatty rats by NMR analysis of plasma glucose

The metabolic mechanism of hepatic glucose overproduction was investigated in 3,3′-5-triiodo-L-thyronine (T₃)-treated rats and Zucker diabetic fatty (ZDF) rats (fa/fa) after a 24-h fast. ²H₂O and [U-¹³C₃]propionate were administered intraperitoneally, and [3,4-¹³C₂]glucose was administered as a primed infusion for 90 min under ketamine-xylazine anesthesia. ¹³C NMR analysis of monoacetone glucose derived from plasma glucose indicated that hepatic glucose production was twofold higher in both T ₃-treated rats and ZDF rats compared with controls, yet the sources of glucose overproduction differed significantly in the two models by ²H NMR analysis. In T₃-treated rats, the hepatic glycogen content and hence the contribution of glycogenolysis to glucose production was essentially zero; in this case, excess glucose production was due to a dramatic increase in gluconeogenesis from TCA cycle intermediates. ¹³C NMR analysis also revealed increased phosphoenolpyruvate carboxykinase flux (4X), increased pyruvate cycling flux (4X), and increased TCA flux (5X) in T ₃-treated animals. ZDF rats had substantial glycogen stores after a 24-h fast, and consequently nearly 50% of plasma glucose originated from glycogenolysis; other fluxes related to the TCA cycle were not different from controls. The differing mechanisms of excess glucose production in these models were easily distinguished by integrated ²H and ¹³C NMR analysis of plasma glucose.