The evolutionary benefit of insulin resistance.
Insulin resistance is perceived as deleterious, associated with conditions as the metabolic syndrome, type 2 diabetes mellitus and critical illness. However, insulin resistance is evolutionarily well preserved and its persistence suggests that it benefits survival. Insulin resistance is important in various states such as starvation, immune activation, growth and cancer, to spare glucose for different biosynthetic purposes such as the production of NADPH, nucleotides in the pentose phosphate pathway and oxaloacetate for anaplerosis. In these conditions, total glucose oxidation by the tricarboxylic acid cycle is actually low and energy demands are largely met by fatty acid and ketone body oxidation. This beneficial role of insulin resistance has consequences for treatment and research. Insulin resistance should be investigated at the cellular, tissue and whole organism level. The metabolic pathways discussed here, should be integrated in the accepted and valid mechanistic events of insulin resistance before interfering with them to promote insulin sensitivity at any cost.
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands. m.r.soeters@amc.uva.nl
Maarten R
MR
Soeters
Peter B
PB
Soeters
D005075:Biological Evolution; D002952:Citric Acid Cycle / Q000502:physiology; D003924:Diabetes Mellitus, Type 2; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D007657:Ketone Bodies / Q000378:metabolism; D024821:Metabolic Syndrome; D009765:Obesity; D010084:Oxidation-Reduction; D010427:Pentose Phosphate Pathway / Q000502:physiology; D013217:Starvation; D013312:Stress, Physiological / Q000502:physiology
D005227:Fatty Acids; D007657:Ketone Bodies; D005947:Glucose