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

1 The Mary Nell and Ralph B. Rogers Magnetic Resonance Center, Department of Radiology, University of Texas Southwestern Medical Center, Dallas; 2 Department of Chemistry, University of Texas at Dallas, Richardson; and 3 Veterans Affairs North Texas Health Care System, Dallas, Texas Submitted 11 August 2004 ; accepted in final form 17 November 2004 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. 2 H 2 O and [U- 13 C 3 ]propionate were administered intraperitoneally, and [3,4- 13 C 2 ]glucose was administered as a primed infusion for 90 min under ketamine-xylazine anesthesia. 13 C 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 2 H 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. 13 C NMR analysis also revealed increased phospho enol pyruvate carboxykinase flux (4 x ), increased pyruvate cycling flux (4 x ), and increased TCA flux (5 x ) 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 2 H and 13 C NMR analysis of plasma glucose. gluconeogenesis; glycogenolysis; type 2 diabetes; thyroid hormone; isotopes; nuclear magnetic resonance Address for reprint requests and other correspondence: E. S. Jin, The Mary Nell and Ralph B. Rogers Magnetic Resonance Center, 5801 Forest Park Road, Dallas, TX 75235-9085 (E-mail: eunsook.jin{at}utsouthwestern.edu )