+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons



Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons



Diabetes 51(7): 2056-2065



Specialized neurons utilize glucose as a signaling molecule to alter their firing rate. Glucose-excited (GE) neurons increase and glucose-inhibited (GI) neurons reduce activity as ambient glucose levels rise. Glucose-induced changes in the ATP-to-ADP ratio in GE neurons modulate the activity of the ATP-sensitive K(+) channel, which determines the rate of cell firing. The GI glucosensing mechanism is unknown. We postulated that glucokinase (GK), a high-Michaelis constant (K(m)) hexokinase expressed in brain areas containing populations of GE and GI neurons, is the controlling step in glucosensing. Double-label in situ hybridization demonstrated neuron-specific GK mRNA expression in locus ceruleus norepinephrine and in hypothalamic neuropeptide Y, pro-opiomelanocortin, and gamma-aminobutyric acid neurons, but it did not demonstrate this expression in orexin neurons. GK mRNA was also found in the area postrema/nucleus tractus solitarius region by RT-PCR. Intracarotid glucose infusions stimulated c-fos expression in the same areas that expressed GK. At 2.5 mmol/l glucose, fura-2 Ca(2+) imaging of dissociated ventromedial hypothalamic nucleus neurons demonstrated GE neurons whose intracellular Ca(2+) oscillations were inhibited and GI neurons whose Ca(2+) oscillations were stimulated by four selective GK inhibitors. Finally, GK expression was increased in rats with impaired central glucosensing (posthypoglycemia and diet-induced obesity) but was unaffected by a 48-h fast. These data suggest a critical role for GK as a regulator of glucosensing in both GE and GI neurons in the brain.

(PDF emailed within 0-6 h: $19.90)

Accession: 010718847

Download citation: RISBibTeXText

PMID: 12086933

DOI: 10.2337/diabetes.51.7.2056


Related references

CO - expression of glucokinase with glucose transporter and insulin receptor mRNA in ventromedial hypothalamic nucleus glucosensing neurons. Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 830 15, 2003

Glucosensing neurons do more than just sense glucose. International Journal of Obesity 25(Suppl. 5): S68-S72, 2001

Arcuate glucosensing neurons respond to physiologic changes in extracellular glucose. Society for Neuroscience Abstracts 27(2): 2513, 2001

Glucose-6-phosphatase overexpression lowers glucose 6-phosphate and inhibits glycogen synthesis and glycolysis in hepatocytes without affecting glucokinase translocation. Evidence against feedback inhibition of glucokinase. Journal of Biological Chemistry 274(35): 24559-24566, 1999

Fasting enhances the response of arcuate neuropeptide Y-glucose-inhibited neurons to decreased extracellular glucose. American Journal of Physiology. Cell Physiology 296(4): C746-C756, 2009

Recurrent hypoglycemia reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus nucleus. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 291(5): R1283-7, 2006

The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes 53(8): 1959-1965, 2004

Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54(1): 15-22, 2005

Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 294(3): R784-R792, 2007

Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 54(1): 15-22, 2004

Insulin blunts the response of glucose-excited neurons in the ventrolateral-ventromedial hypothalamic nucleus to decreased glucose. American Journal of Physiology. Endocrinology and Metabolism 296(5): E1101-9, 2009

Hyperglycemia impairs glucose and insulin regulation of nitric oxide production in glucose-inhibited neurons in the ventromedial hypothalamus. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 293(2): R592-R600, 2007

AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. American Journal of Physiology. Cell Physiology 297(3): C750-C758, 2009

Gut glucose metabolism in rainbow trout: implications in glucose homeostasis and glucosensing capacity. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 299(1): R19-R32, 2010

Glucose, insulin, and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 292(4): R1418-R1428, 2006