title: Sodium-coupled glucose cotransporters contribute to hypothalamic glucose sensing.
abstract: Specialized neurons within the hypothalamus have the ability to sense and respond to changes in ambient glucose concentrations. We investigated the mechanisms underlying glucose-triggered activity in glucose-excited neurons, using primary cultures of rat hypothalamic neurons monitored by fluorescence calcium imaging. We found that 35% (738 of 2,139) of the neurons were excited by increasing glucose from 3 to 15 mmol/l, but only 9% (6 of 64) of these glucose-excited neurons were activated by tolbutamide, suggesting the involvement of a ATP-sensitive K(+) channel-independent mechanism. alpha-Methylglucopyranoside (alphaMDG; 12 mmol/l), a nonmetabolizable substrate of sodium glucose cotransporters (SGLTs), mimicked the effect of high glucose in 67% of glucose-excited neurons, and both glucose- and alphaMDG-triggered excitation were blocked by Na(+) removal or by the SGLT inhibitor phloridzin (100 nmol/l). In the presence of 0.5 mmol/l glucose and tolbutamide, responses could also be triggered by 3.5 mmol/l alphaMDG, supporting a role for an SGLT-associated mechanism at low as well as high substrate concentrations. Using RT-PCR, we detected SGLT1, SGLT3a, and SGLT3b in both cultured neurons and adult rat hypothalamus. Our findings suggest a novel role for SGLTs in glucose sensing by hypothalamic glucose-excited neurons.
authors.affiliation: Cambridge Institute of Medical Research, Department of Clinical Biochemistry, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2XY, U.K.
authors.forename: Dervla
authors.initials: D
authors.lastname: O'Malley
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.forename: Anna K
authors.initials: AK
authors.lastname: Simpson
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002478:Cells, Cultured; D005947:Glucose / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008757:Methylglucosides / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051247:Sodium-Glucose Transport Proteins / Q000235:genetics*; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D008757:Methylglucosides; D051247:Sodium-Glucose Transport Proteins; D014044:Tolbutamide; D005947:Glucose; D002118:Calcium