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Leucine Regulation of Glucokinase and ATP Synthase Sensitizes Glucose-Induced Insulin Secretion in Pancreatic ß-Cells

¹ Department of Pathology and Laboratory Medicine, the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
² Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
³ Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana
⁴ Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Address correspondence and reprint requests to Dr. Zhiyong Gao, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, 803D Abramson, 3615 Civic Center Blvd., Philadelphia, PA 19104-4318. E-mail: gao{at}email.chop.edu

Abbreviations: ATPSß, ATP synthase ß-subunit; KRB, Krebs-Ringer bicarbonate

We have recently shown that leucine culture upregulates ATP synthase ß-subunit (ATPSß) and increases ATP level, cytosolic Ca²⁺, and glucose-induced insulin secretion in rat islets. The aim is to test whether glucokinase expression is also affected in rat islets and its role in glucose sensitization during leucine culture. Leucine culture increased glucose-induced NAD(P)H level at 1 and 2 days but not at 1 week. The half-maximal effective concentration of the glucose response curve for NAD(P)H was left-shifted from 5–7 to 2–3 mmol/l. The effect was dose dependent and rapamycin insensitive. Leucine culture did not affect glyceraldehyde effects on NAD(P)H. Leucine pretreatment for 30 min had no effects on NAD(P)H levels. Leucine culture for 2 days also increased glucose-induced cytosolic Ca²⁺ elevation, ATP level, and insulin secretion. Leucine increase of glucokinase mRNA levels occurred as early as day 1 and lasted through 1 week. That of ATPSß did not occur until day 2 and lasted through 1 week. Leucine effects on both mRNAs were dose dependent. The upregulation of both genes was confirmed by Western blotting. Leucine culture also increased glucose-induced insulin secretion, ATP level, glucokinase, and ATPSß levels of type 2 diabetic human islets. In conclusion, leucine culture upregulates glucokinase, which increases NAD(P)H level, and ATPSß, which increases oxidation of NADH and production of ATP. The combined upregulation of both genes increases glucose-induced cytosolic Ca²⁺ and insulin secretion.

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