Leptin reduces glucose transport and cellular ATP levels in INS-1 beta-cells.
Leptin suppresses insulin secretion by opening ATP-sensitive K(+) (K(ATP)) channels and hyperpolarizing beta-cells. We measured the intracellular concentration of ATP ([ATP](i)) in tumor-derived beta-cells, INS-1, and found that leptin reduced [ATP](i) by approximately 30%, suggesting that the opening of K(ATP) channels by leptin is mediated by decreased [ATP](i). A reduction in glucose availability for metabolism may explain the decreased [ATP](i), since leptin (30 min) reduced glucose transport into INS-1 cells by approximately 35%, compared to vehicle-treated cells. The twofold induction of GLUT2 phosphorylation by GLP-1, an insulin secretagogue, was abolished by leptin. Therefore, the acute effect of leptin could involve covalent modification of GLUT2. These findings suggest that leptin may inhibit insulin secretion by reducing [ATP](i) as a result of reduced glucose availability for the metabolic pathway. In addition, leptin reduced glucose transport by 35% in isolated rat hepatocytes that also express GLUT2, suggesting that glucose transport may also be altered by leptin in other glucose-responsive tissues such as the liver.
Lam
N T
NT
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Cheung
A T
AT
Riedel
M J
MJ
Light
P E
PE
Cheeseman
C I
CI
Kieffer
T J
TJ
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D005934:Glucagon / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000378:metabolism*; D051273:Glucose Transporter Type 2; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011498:Protein Precursors / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D051273:Glucose Transporter Type 2; D020738:Leptin; D009004:Monosaccharide Transport Proteins; D010446:Peptide Fragments; D015221:Potassium Channels; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; D005934:Glucagon; D005947:Glucose