regarding glucose levels in the brain , hypothalamic glucose levels are regulated from 0.7 to 4.5
when blood glucose levels fall to ~2.8 mmol / l during hypoglycemia , brain glucose levels also decline to ~0.3 mmol / l3 . according to a longstanding dogma , sglt1 is a highaffinity transporter for glucose .
in fact , panayotovaheiermann et al.4 determined that sglt1 in rats and humans had a similar km of ~0.4 mmol / l for glucose .
based on this report , fan et al.1 concluded that sglt1 should be saturated under physiological blood glucose levels , and the amount of glucose entering neurons through sglt1 would start decreasing only under hypoglycemia .
they developed and proved this hypothesis indirectly through their experiments in which the augmentation of counterregulatory responses to hypoglycemia was recognized in sglt1 knockeddown rats with acute or recurrent hypoglycemic bout(s ) .
fan et al.1 knocked down the expression levels of sglt1 messenger ribonucleic acid in rat vmh using microinjections of an adenoassociated viral vector containing the sglt1 short hairpin ribonucleic acid .
these rats were exposed to recurrent bouts or a single bout of hypoglycemia induced by hyperinsulinemichypoglycemic clamp procedures . during hypoglycemia ,
the glucose infusion rate decreased , glucagon and epinephrine levels increased , and hepatic glucose production increased in sglt1 knockeddown rats .
their research design , consisting of an sglt1 knockeddown model and a recurrent hypoglycemia model , was elegant .
first , they examined no transport capacity of glucose through sglt1 in the knockeddown vmh .
in general , transport capacity depends on both the copy number and the turnover rate of the transporter proteins .
direct verification of reduced electrical discharge frequency in the neurons infected with sglt1 short hairpin ribonucleic acid is expected in the future .
second , a recent study4 showed that human sglt1 has a relatively lower affinity for dglucose , inconsistent with the previously reported value ; that is , k0.5 2 mmol / l versus km 0.4 mmol / l . as
hummel et al.5 proved the kinetics of glucose transport using only human sglt1 , the characteristics might vary in rat sglt1 .
readers should carefully interpret the report by fan et al.1 , and consider the possible differences between humans and rodents .
iatrogenic hypoglycemia in diabetic patients currently invites serious clinical attention because of its possible influence on quality of life and cardiovascular motility .
impaired glucose counterregulation response is one of the most important factors that elicit severe and/or recurrent bouts of hypoglycemia .
although the mechanisms of the impairment have not yet been fully expounded , it appears acceptable that glucose sensing and assembling metabolic information from the periphery in cns contributes to the deficit .
in addition to ge neurons as aforementioned , other crucial participants , glucoseinhibited or glucoseinhibited neurons , have been defined , investigated and characterized as key players in the counterregulatory response to hypoglycemia .
they increase the frequency of spontaneous action potential discharge through an interaction between adenosine monophosphate activated protein kinase ( ampk ) and nitric oxide . in recurrently hypoglycemic model rats or type 1 diabetic model rats ,
fan et al.1 also reported that the counterregulatory responses were amplified by the activation of ampk in the vmh with aminoimidazole carboxamide ribonucleotide .
in contrast , the counterregulatory responses were lessened in neuronal nitric oxide synthase knockedout mice .
when considering the recent finding from fan 's laboratory1 , vmh glucosesensing neurons have three distinct mechanisms for detecting hypoglycemia : ( i ) the katp channel pathway in ge neurons ; ( ii ) the sglt1 pathway in ge neurons ; and ( iii ) the ampk  nitric oxide pathway in glucoseinhibited neurons .
in addition to these vmh neurons , there are several contributors to glucosesensing mechanisms , including orexin neurons in lateral hypothalamus , neuropeptide y neurons in arcuate nucleus and lateral hypothalamus , and hypothalamic glial cells .
in particular , as fan et al.1 also specified in their recent study , numerous hypothalamic glial cells express various glucosesensing molecules .
an increasing body of evidence suggests that hypothalamic glial cells might play a relevant role in glucose sensing and fuel homeostasis utilizing a glial metabolic substrate lactate . to develop applicable therapeutic strategies to prevent hypoglycemia
, we must clarify the interaction and integration of inter/intracellular crosstalk among these glucosesensing cells mediated by various neurotransmitters and neuroendocrine hormones ; for example .
for instance , it was recently shown that serotonin , a monoamine neurotransmitter , has an important role in regulating adrenomedullary responses to glucoprivation at the perifornical hypothalamus6 .
it has also been reported that the administration of selective serotonin reuptake inhibitors augments the counterregulatory responses to hypoglycemia .
hence , as several types of cells throughout the cns have been proven to be glucosesensing cells , we must consider the vast heterogeneity among these cells , and carefully investigate this research field with welldesigned studies in the future . in conclusion ,
fan et al.1 proved a novel type of ge neurons , which detect hypoglycemia through decreasing glucose entry through sglt1 . to conquer hypoglycemia unawareness , which limits an appropriate approach to tight control of the blood glucose level ,
the work achieved by fan et al.1 releases an alternative pathway to approach and resolve the problem .
 in the central nervous system , especially in the hypothalamus , the energy status in the body is assessed by glucosesensing neurons since glucose is the major fuel in the central nervous system . 
 glucose sensing mechanisms also have a significant role in prevention of hypoglycemic bouts . in a recent report 
 , fan and colleagues proved a novel type of glucoseexited neurons which detect hypoglycemia through decreasing glucose entry via sglt1 . 

 
Neural SGLT1 Alters Neural Excitability Only Under Glucoprivation
Clarification of GlucoseSensing Mechanism in the CNS Will Provide a Useful Solution Methodology for Hypoglycemia
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