Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation

被引:69
作者
Reno, Candace M. [1 ,2 ]
Puente, Erwin C. [1 ]
Sheng, Zhenyu [3 ]
Daphna-Iken, Dorit [1 ]
Bree, Adam J. [1 ]
Routh, Vanessa H. [3 ]
Kahn, Barbara B. [4 ]
Fisher, Simon J. [1 ,2 ]
机构
[1] Washington Univ, Dept Med, Div Endocrinol Metab & Lipid Res, St Louis, MO 63130 USA
[2] Univ Utah, Dept Internal Med, Div Endocrinol Metab & Diabet, Salt Lake City, UT 84112 USA
[3] Rutgers New Jersey Med Sch, Dept Physiol & Pharmacol, Newark, NJ USA
[4] Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA
关键词
VENTROMEDIAL HYPOTHALAMIC NUCLEUS; CENTRAL-NERVOUS-SYSTEM; TRANSPORTER EXPRESSION; INHIBITED NEURONS; PLASMA-MEMBRANE; BODY-WEIGHT; RAT; RESISTANCE; RECEPTOR; PROTEIN;
D O I
10.2337/db16-0917
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 impaired c-fos activation 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.
引用
收藏
页码:587 / 597
页数:11
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