title: Reduced insulin clearance and lower insulin-degrading enzyme expression in the liver might contribute to the thrifty phenotype of protein-restricted mice.
abstract: Nutrient restriction during the early stages of life usually leads to alterations in glucose homeostasis, mainly insulin secretion and sensitivity, increasing the risk of metabolic disorders in adulthood. Despite growing evidence regarding the importance of insulin clearance during glucose homeostasis in health and disease, no information exists about this process in malnourished animals. Thus, in the present study, we aimed to determine the effect of a nutrient-restricted diet on insulin clearance using a model in which 30-d-old C57BL/6 mice were exposed to a protein-restricted diet for 14 weeks. After this period, we evaluated many metabolic variables and extracted pancreatic islet, liver, gastrocnemius muscle (GCK) and white adipose tissue samples from the control (normal-protein diet) and restricted (low-protein diet, LP) mice. Insulin concentrations were determined using RIA and protein expression and phosphorylation by Western blot analysis. The LP mice exhibited lower body weight, glycaemia, and insulinaemia, increased glucose tolerance and altered insulin dynamics after the glucose challenge. The improved glucose tolerance could partially be explained by an increase in insulin sensitivity through the phosphorylation of the insulin receptor/protein kinase B and AMP-activated protein kinase/acetyl-CoA carboxylase in the liver, whereas the changes in insulin dynamics could be attributed to reduced insulin secretion coupled with reduced insulin clearance and lower insulin-degrading enzyme (IDE) expression in the liver and GCK. In summary, protein-restricted mice not only produce and secrete less insulin, but also remove and degrade less insulin. This phenomenon has the double benefit of sparing insulin while prolonging and potentiating its effects, probably due to the lower expression of IDE in the liver, possibly with long-term consequences.
authors.affiliation: Department of Structural and Functional Biology,Institute of Biology, State University of Campinas (UNICAMP),PO Box 6109,Campinas,SP,CEP 13083-865,Brazil.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Rezende
authors.affiliation: Department of Structural and Functional Biology,Institute of Biology, State University of Campinas (UNICAMP),PO Box 6109,Campinas,SP,CEP 13083-865,Brazil.
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Camargo
authors.affiliation: Department of Structural and Functional Biology,Institute of Biology, State University of Campinas (UNICAMP),PO Box 6109,Campinas,SP,CEP 13083-865,Brazil.
authors.forename: Renato C S
authors.initials: RC
authors.lastname: Branco
authors.affiliation: Department of Structural and Functional Biology,Institute of Biology, State University of Campinas (UNICAMP),PO Box 6109,Campinas,SP,CEP 13083-865,Brazil.
authors.forename: Ana P G
authors.initials: AP
authors.lastname: Cappelli
authors.affiliation: Department of Structural and Functional Biology,Institute of Biology, State University of Campinas (UNICAMP),PO Box 6109,Campinas,SP,CEP 13083-865,Brazil.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Boschero
authors.affiliation: Department of Structural and Functional Biology,Institute of Biology, State University of Campinas (UNICAMP),PO Box 6109,Campinas,SP,CEP 13083-865,Brazil.
authors.forename: Everardo M
authors.initials: EM
authors.lastname: Carneiro
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D015536:Down-Regulation; D002149:Energy Intake; D004734:Energy Metabolism; D015971:Gene Expression Regulation, Enzymologic; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011897:Random Allocation; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014886:Weaning; D015430:Weight Gain
chemical_list: D007328:Insulin; D011972:Receptor, Insulin; D007339:Insulysin