Abstract
The phenacylimidazolium compound LY177507 was shown by Harris et al. (Harris, R. A., Yamanuchi, K., Roach, P. J., Yen, T. T., Dominiani, S. J., and Stephens, T. W. (1989) J. Biol. Chem. 264, 14674-14680) to stimulate glycogen synthesis greatly in isolated rat hepatocytes. We extended studies with this compound, designated proglycosyn (Yamaguchi, K., Stephens, T. W., Chikadar, K., Depaoli-Roach, A., And Harris, R. A. (1991) Diabetes 40, (Suppl. 1) 102 (abstr.] employing hepatocytes from normal and streptozotocin diabetic rats. Proglycosyn is more effective than amino acids in stimulating glycogen synthesis. In cells incubated with glucose, lactate, or dihydroxyacetone the effect of glutamine and proglycosyn was synergistic. In cells incubated with glucose plus lactate, or glucose plus dihydroxyacetone, the stimulation by the two agonists was additive. Proglycosyn diverted the gluconeogenic flux from glucose to glycogen. The maximal rates of glycogen deposition attained in the presence of glutamine and proglycosyn from cells incubated with glucose plus lactate, or glucose plus dihydroxyacetone, where about 80 and 110 mumols/h/g of liver, respectively. Proglycosyn depressed glycogenolysis in hepatocytes of fed rats and stimulated glycogen synthesis from lactate and dihydroxyacetone. The incorporation of [U-14C]glucose and [U-14C]lactate in these cells occurred in the presence of glycogen breakdown or exceeded net production, indicating the occurrence of recycling of glycogen in hepatocytes of fed rats. Hepatocytes from fasted streptozotocin diabetic rats contained high levels of glycogen. Glycogenolysis was markedly depressed by proglycosyn. Glycogen synthesis from lactate and dihydroxyacetone in these cells was stimulated by glutamine and proglycosyn in a fashion similar to that in cells from fasted control rats, and the rates of glycogen synthesis were similar in cells of control and diabetic rats. With glucose as sole substrate, glutamine did not stimulate glycogen synthesis. When both agonists were present, there was a marked synergism and substantial glycogen formation. Streptozotocin diabetic rats prior to the onset of cachexia have a normal capacity for glycogen synthesis.
Highlights
The phenacylimidazolium compound LY 177507was mine, alanine, proline, and asparagine) markedly stimulate shown by Harris et al
I n cells incubated withglucose plus lactate,o r glucose showed that the stimulation of glycogen synthesis is closely correlated withswelling of the hepatocytesinduced by amino acids
We report of glutamineand proglycosyn from cellsincubated here studies with thiscompound using hepatocytes from with glucose plus lactate, or glucose plus dihydroxy- normal and streptozotocin diabetic rats
Summary
Proglycosyn markedly depressed glucose synthesis from these compounds. It was shown that glucose The lactate concentration in the medium increased to 1-1.5 stimulates glycogen synthesis from gluconeogenic substrates mM. Such animals used up to 12 days after streptozotocin injectionexhibit all thcelassical symptoms of diabetes but do noltose much weight Hepatocytes preparedfrom such fasted (but not fed) rats form glycogen in the presence of glutamine from lactate ordihydroxyacetone a t nearly normal.
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