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Distinguishing Features of Leucine and -Ketoisocaproate Sensing in Pancreatic ß-Cells

Departments of Pathology and Laboratory Medicine (Z.G., R.A.Y., S.S.S., R.K.W., B.A.W.), Biochemistry and Biophysics (Z.G., G.L., H.N., C.B., F.M.M.), University of Pennsylvania School of Medicine; and Department of Pathology and Laboratory Medicine (Z.G., R.A.Y., S.S.S., R.K.W., B.A.W.), The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Dr. Franz M. Matschinsky, Diabetes Research Center, 501 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, Pennsylvania 19104-6015. E-mail: matsch{at}mail.med.upenn.edu.

Culturing rat islets in high glucose (HG) increased 1-¹⁴C--ketoisocaproate (KIC) oxidation compared with culturing them in low glucose. Leucine caused insulin secretion (IS) in low glucose but not in HG rat islets, whereas KIC did so in both. Pretreatment with HG for 40 min abolished leucine stimulation of IS by mouse islets and prevented the cytosolic Ca²⁺ rise without inhibiting IS and Ca²⁺ increments caused by KIC. When islets were pretreated without glucose and glutamine, aminooxyacetic acid (AOA) markedly decreased KIC effects. When islets were pretreated without glucose and with glutamine, AOA potentiated leucine effects but attenuated KIC effects. AOA stimulated glutamine oxidation in the presence but not the absence of ±2-amino-2-norbornane-carboxylic acid, a nonmetabolized leucine analog. Pretreatment with HG and glutamine partially reversed AOA inhibition of KIC effects. Glucose increased intracellular ATP and GTP, whereas it decreased ADP and GDP in ßHC9 cells. Glutamate dehydrogenase activity of ßHC9 cell extracts was increased by leucine and attenuated by GTP, but it was potentiated by ADP. In conclusion, leucine and KIC stimulated ß-cells via distinct mechanisms. Glutamate dehydrogenase is the sensor of leucine, whereas transamination plays an important role in KIC stimulation of pancreatic ß-cells.

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