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Role of Excess Glycogenolysis in Fasting Hyperglycemia Among Pre-Diabetic and Diabetic Zucker (fa/fa) Rats

¹ Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas
² Department of Biochemistry, Chonbuk National University Medical School, Chonju, Chonbuk, South Korea
³ Department of Chemistry, University of Texas at Dallas, Richardson, Texas
⁴ Veterans Affairs North Texas Health Care System, Dallas, Texas

Address correspondence and reprint requests to Eunsook S. Jin, PhD, Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8568. E-mail: eunsook.jin{at}utsouthwestern.edu

Abbreviations: FFA, free fatty acid; MAG, monoacetone glucose; NMR, nuclear magnetic resonance; PEP, phosphoenol pyruvate; PEPCK, PEP carboxykinase; PMI, phosphomannose isomerase; TCA, tricarboxylic acid

Sources of plasma glucose and glucose turnover were investigated in 8-week-old (pre-diabetic) and 13-week-old (diabetic) Zucker (fa/fa) rats after a 24-h fast. Intraperitoneal ²H₂O was administered and [3,4-¹³C₂]glucose and [U-¹³C₃]propionate were infused into conscious active rats. ¹³C nuclear magnetic resonance analysis of monoacetone glucose derived from blood glucose indicated that glucose production was increased significantly in 8- and 13-week-old fa/fa rats compared with age-matched Zucker (+/+) rats, and hepatic glycogen was dramatically higher among fa/fa animals regardless of age. Glycogenolysis, essentially 0 in +/+ rats after a 24-h fast, was significant in fa/fa rats (11 ± 6 and 17 ± 7% of glucose production in 8- and 13-week-old rats, respectively), even after a 24-h fast. Tricarboxylic acid (TCA) cycle flux and efflux of carbon skeletons from the cycle (cataplerosis) were both significantly higher in fa/fa rats compared with controls, but net gluconeogenesis from the TCA cycle was not higher because products leaving the cycle were returned to the cycle via a pyruvate cycling pathway. Thus, pyruvate cycling flux increased in proportion to TCA cycle flux, leaving net gluconeogenesis unchanged in fa/fa animals compared with control animals. The distribution of ²H in skeletal muscle glycogen suggested that at least a fraction of glucose molecules entering glycogen pass through phosphomannose isomerase.

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