Table 1.

Comparison of brain glucose-sensing and blood glucose-sensing models

Model	Sensing mechanism	Hypoglycemia detection	Explanation for relative hypoglycemia
Brain glucose sensing	Detection of glucose in brain ISF by glucose-sensing neurons in hypothalamus and elsewhere.	The level of glucose in brain ISF drops below a critical threshold.	Sustained hyperglycemia reduces glucose transport across the BBB and into brain ISF, thereby lowing the brain glucose level for any blood glucose level.
Blood glucose sensing	Brain areas involved in glucose homeostasis receive afferent input regarding the circulating glucose level from glucose-sensing neurons that supply the vasculature and brain areas that lack a BBB.	The blood glucose level drops below a critical threshold.	Sustained hyperglycemia impairs glucose sensing by afferent neurons supplying the vasculature, such that the brain perceives the blood glucose level to be lower than it truly is.