title: Insulin sensitivity is inversely related to cellular energy status, as revealed by biotin deprivation.
abstract: We have reported an early decrease in glycemia in rats fed a biotin-deficient diet with reduced cellular ATP levels, suggesting increased insulin sensitivity. Here, we show that biotin-deprived rats are more tolerant of glucose, as shown by both oral and intraperitoneal glucose tolerance tests, during which insulin plasma levels were significantly diminished in deficient rats compared with controls. Biotin-deficient rats had lower blood glucose concentrations during intraperitoneal insulin sensitivity tests than controls. Furthermore, more glucose was infused to maintain euglycemia in the biotin-deficient rats during hyperinsulinemic euglycemic clamp studies. These results demonstrate augmented sensitivity to insulin in biotin-deprived rats. They are most likely the consequence of an insulin-independent effect of AMPK activation on GLUT4 membrane translocation with increased glucose uptake. In biotin-deficient cultured L6 muscle cells, there was increased phosphorylation of the energy sensor AMPK. We have now confirmed the augmented AMPK activation in both biotin-deprived in vivo muscle and cultured muscle cells. In these cells, glucose uptake is increased by AMPK activation by AICAR and diminished by its knockdown by the specific siRNAs directed against its α1- and α2-catalytic subunits, with all of these effects being largely independent of the activity of the insulin-signaling pathway that was inhibited with wortmannin. The enhanced insulin sensitivity in biotin deficiency likely has adaptive value for organisms due to the hormone promotion of uptake and utilization of not only glucose but other nutrients such as branched-chain amino acids, whose deficiency has been reported to increase insulin tolerance.
authors.affiliation: Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Pediatría, Mexico City, Mexico; Instituto Nacional de Pediatría, Mexico City, Mexico;
authors.forename: Ana
authors.initials: A
authors.lastname: Salvador-Adriano
authors.affiliation: Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Pediatría, Mexico City, Mexico;
authors.forename: Sonia
authors.initials: S
authors.lastname: Vargas-Chávez
authors.affiliation: Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Pediatría, Mexico City, Mexico;
authors.forename: Alain de J
authors.initials: Ade J
authors.lastname: Hernández-Vázquez
authors.affiliation: Instituto Nacional de Pediatría, Mexico City, Mexico; Laboratorio de Nutrición Experimental, Mexico City, Mexico; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ortega-Cuellar
authors.affiliation: Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
authors.forename: Armando R
authors.initials: AR
authors.lastname: Tovar
authors.affiliation: Unidad de Genética de la Nutrición, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Pediatría, Mexico City, Mexico; velare@unam.mx.
authors.forename: Antonio
authors.initials: A
authors.lastname: Velázquez-Arellano
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D028921:Biotinidase Deficiency / Q000097:blood / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004734:Energy Metabolism; D020868:Gene Silencing; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D015854:Up-Regulation; D014886:Weaning
chemical_list: D051275:Glucose Transporter Type 4; C495694:Slc2a4 protein, rat; C543928:Prkaa2 protein, rat; D055372:AMP-Activated Protein Kinases; C568305:Prkaa1 protein, rat
keywords: AMP-activated protein kinase; biotin deficiency; energy deficit; insulin sensitivity; mammalian target of rapamycin