Oral Presentation The International Congress of Neuroendocrinology 2014

Brain glucokinase plays a central role in the maintenance of blood glucose homeostasis (#123)

Emmanuel Ogunnowo-Bada 1 , Chris Riches 1 , Nicholas Heeley 1 , Lea Brochard 1 , Jing Xia 2 3 , Jeffrey W Dalley 2 3 4 , Mark L Evans 1
  1. Wellcome-Trust Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
  2. Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom
  3. Department of Psychology, University of Cambridge, Cambridge, United Kingdom
  4. Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom

Specialised glucose-sensing neurons within the brain help maintain blood glucose by triggering counterregulatory responses (CRR) to hypoglycaemia and/or controlling hepatic glucose flux. Examining the mechanisms which trigger these homeostatic responses, we hypothesised that these neurons use glucokinase (GK) as part of their pathway for detecting hypoglycaemia and also controlling glucose turnover. To overcome limitations with specificity of previous experimental approaches, we created neuronal-specific GK knockout (KO) mice by crossing mice expressing cre ­recombinase under nestin promoter with GK ­floxed mice. We anticipated that they would display an amplified CRR to hypoglycaemia and also show an impaired glucose turnover during glucose tolerance tests (GTT).

Consistent with a brain specific KO, hypothalamic but not liver GK activity was reduced in heterozygous neuronal GK KO compared with nes­cre­-/-­.GKlox/WT (WTcre) (n=9 vs 6, Vmax 10 ± 1.3 vs 13 ± 0.7mU/mg, p<0.01). Female neuronal homozygous GK KO mice (nes­cre+/-­.GKlox/lox) showed impaired glucose tolerance during intraperitoneal GTT compared with nes­cre+/­-.GKWT/WT (WTGK mice) (p<0.05).

During 150-minute hyperinsulinaemic (10mU/kg/min) hypoglycaemic (3mM) clamp studies, dextrose infusion rates (DIR) at the end of studies were significantly reduced in homozygous neuronal GK KO mice compared with WTCre and WTGK control groups (n=13 vs 8 vs 6; 6.4 ± 1.2 vs 12.5 ± 2.1 vs 15.6 ± 2.9 mg/kg/min, p<0.01). In keeping with reduced DIR, plasma epinephrine at the end of clamp was significantly increased in homozygous GK KO compared to controls (2520 ± 651 vs 690 ± 170 vs 858 ± 255 pg/ml, p < 0.05).

In keeping with our hypothesis, our data suggest that neuronal GK, presumably through its role in glucose-sensing, plays a central role in the maintenance of blood glucose.