Opposite Effects of D-Glucose and a Nonmetabolized Analogue of L-Leucine on Respiration and Secretion in Insulin-Producing Tumoral Cells (RINm5F)

D-Glucose increased the cytosolic NADH%/NAD+ ratio (but not the cytosolic NADPH/NADP+ ratio), augmented O₂ uptake, raised the ATP/ADP ratio, decreased ⁸⁶Rb outflow, and stimulated insulin release in tumoral insulin-producing cells of the RINm5Fline, L-Leucine and 4-methyl-2-oxopentanoate also stimulated insulin secretion. In the RINm5F cells, as in normal islet cells, the nonmetabolized analogue of L-leucine, 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH), activated glutamate dehydrogenase, augmented L-[U⁻¹⁴C]glutamine oxidation, and induced a more reduced state of cytosolic redox couples. However, in sharp contrast to either its effect in normal islet cells or that of D-glucose in the tumoral cells, BCH severely decreased O₂ uptake, lowered the ATP/ADP ratio, increased ⁸⁶Rb outflow, and inhibited insulin release in the RINm5F cells. These findings are interpreted to support the concept that the rate of ATP generation represents an essential determinant of the secretory response of insulin-producing cells to nutrient secretagogues.