title: Supranutritional selenium intake from enriched milk casein impairs hepatic insulin sensitivity via attenuated IRS/PI3K/AKT signaling and decreased PGC-1α expression in male Sprague-Dawley rats.
abstract: Selenium (Se)-enriched milk provides antioxidant benefits and has therapeutic potential against cancer. However, both antidiabetic and prodiabetic effects have been attributed to Se. Our objective was to evaluate the effect of Se-enriched milk casein on insulin sensitivity in rats when given at the requirement of 0.25 ppm Se and supranutritionally on both low- and high-fat diets. Two hundred sixteen male Sprague-Dawley rats were fed low- or high-fat diets containing one, two or eight times the Se requirement in a randomized block design. After 7 weeks, 72 rats were subjected to the hyperinsulinemic-euglycemic clamp with [3-3H]glucose infusion to estimate glucose fluxes. Tissues were collected from the remaining 144 rats 8 min after ip saline or insulin injection. During hyperinsulinemic-euglycemic clamps, glucose infusion rate was 22% lower (P=.058), and endogenous glucose production was 76% higher (P=.054) when Se content increased from one to eight times the requirement on low-fat diets, indicating impaired hepatic insulin sensitivity. Se also decreased the ability for insulin to stimulate Akt phosphorylation at Thr308. Hepatic oxidation state and expression of selenoprotein P and glutathione peroxidase-1 were unaffected while expression of insulin receptor substrate (IRS)-1 and-2 and PPARγ coactivator-1α (PGC-1α) decreased with supranutritional Se and high-fat intake. In addition, hepatic expression of regulatory and catalytic subunits of phosphatidylinositol 3-kinase (PI3K) decreased with supranutritional intake of Se. Se intake from enriched casein up to eight times the requirement impairs hepatic insulin sensitivity in a mechanism similar to fat feeding, via attenuated IRS/PI3K/Akt signaling and decreased PGC-1α expression.
authors.affiliation: Department of Animal Biosciences, University of Guelph, Guelph, Ontario, Canada. Electronic address: pstahel@uoguelph.ca.
authors.forename: Priska
authors.initials: P
authors.lastname: Stahel
authors.affiliation: Department of Animal Biosciences, University of Guelph, Guelph, Ontario, Canada. Electronic address: jungmi@uoguelph.ca.
authors.forename: Julie J
authors.initials: JJ
authors.lastname: Kim
authors.affiliation: Department of Animal Biosciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Scott R L
authors.initials: SR
authors.lastname: Cieslar
authors.affiliation: Department of Animal Biosciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Warrington
authors.affiliation: Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada. Electronic address: ctxiao@uhnres.utoronto.ca.
authors.forename: Changting
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Department of Animal Biosciences, University of Guelph, Guelph, Ontario, Canada. Electronic address: jcant@uoguelph.ca.
authors.forename: John P
authors.initials: JP
authors.lastname: Cant
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000009:adverse effects*; D002364:Caseins / Q000008:administration & dosage / Q000009:adverse effects; D059305:Diet, High-Fat / Q000009:adverse effects; D019587:Dietary Supplements / Q000009:adverse effects*; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D055504:Insulin Receptor Substrate Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012643:Selenium / Q000008:administration & dosage / Q000009:adverse effects*; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D002364:Caseins; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000081082:Phosphoinositide-3 Kinase Inhibitors; C501429:Ppargc1a protein, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D012643:Selenium
keywords: Hepatic insulin sensitivity; Hyperinsulinemic–Euglycemic clamp; Insulin signaling; Milk casein; Selenium