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 (T-3)-treated rats and Zucker diabetic fatty (ZDF) rats (fa/fa) after a 24-h fast. (H2O)-H-2 and [U-C-13(3)] propionate were administered intraperitoneally, and [3,4-C-13(2)] glucose was administered as a primed infusion for 90 min under ketamine-xylazine anesthesia. C-13 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 H-2 NMR analysis. In T-3-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. C-13 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 H-2 and C-13 NMR analysis of plasma glucose.