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Effects of Glucose and Amino Acids on Free ADP in ßHC9 Insulin-Secreting Cells

From the Department of Biochemistry and Molecular Pharmacology, Thomas Jefferson University College of Medicine, Philadelphia, Pennsylvania.

Address correspondence and reprint requests to Dr. Peter Ronner, Department of Biochemistry and Molecular Pharmacology, 233 South 10th St., 245 BLSB, Thomas Jefferson University, Philadelphia, PA 19107-5541. E-mail: peter.ronner{at}mail.tju.edu .

Stimulation of insulin release by glucose is widely thought to be coupled to a decrease in the activity of ATP-sensitive K⁺ channels (K_ATP channels) that is caused by a decreased concentration of free ADP. To date, most other investigators have reported only on total cellular ADP concentrations, even though only a small fraction of all ADP is free and only the free ADP affects K_ATP channels. We tested the hypothesis that amino acids elicit insulin release via a decrease in the activity of K_ATP channels owing to a decrease in the level of free ADP. We estimated the concentration of free ADP in ßHC9 hyperplastic insulin-secreting cells based on the cell diameter and on luminometric measurements of ATP, phosphocreatine, and total creatine. The concentration of free ADP fell exponentially as the concentration of glucose increased. A physiological mixture of amino acids greatly stimulated insulin release at 0-30 mmol/l glucose but affected the concentration of free ADP only to a minor degree and significantly so only at 2 mmol/l glucose. In the presence of 2-deoxyglucose and NaN₃, amino acids were unable to stimulate insulin release. When K_ATP channels were held open with diazoxide (and the plasma membrane partially depolarized with high extracellular KCl), amino acids still stimulated insulin release. We conclude that amino acid—induced insulin release depends on two components: a yet-unknown amino acid sensor and K_ATP channels, which serve to attenuate hormone release when cellular energy stores are low. We propose that glucose-induced insulin release may be regulated similarly by two components: glucokinase and K_ATP channels.

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