title: Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation.
abstract: GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impairedc-fosactivation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.
authors: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO.|Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors: Candace M
authors: CM
authors: Reno
authors: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO.
authors: Erwin C
authors: EC
authors: Puente
authors: Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, NJ.
authors: Zhenyu
authors: Z
authors: Sheng
authors: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO.
authors: Dorit
authors: D
authors: Daphna-Iken
authors: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO.
authors: Adam J
authors: AJ
authors: Bree
authors: Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, NJ.
authors: Vanessa H
authors: VH
authors: Routh
authors: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
authors: Barbara B
authors: BB
authors: Kahn
authors: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO sfisher@u2m2.utah.edu.|Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors: Simon J
authors: SJ
authors: Fisher
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D059305:Diet, High-Fat; D004837:Epinephrine / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000235:genetics*; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006706:Homeostasis / Q000235:genetics; D007003:Hypoglycemia / Q000235:genetics*; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D066298:In Vitro Techniques; D019469:Indinavir / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D016760:Proto-Oncogene Proteins c-fos; C495693:Slc2a4 protein, mouse; D019469:Indinavir; D005934:Glucagon; D005947:Glucose; D004837:Epinephrine