The effects of KATP channel modulators on counterregulatory responses and cognitive function during acute controlled hypoglycaemia in healthy men: a pilot study.
OBJECTIVE
To examine the effects of agents that alter potassium adenosine triphosphate (KATP) channel activity in beta-cells on cognitive function and counterregulatory hormone responses during acute hypoglycaemia, given the physiological similarities between the pancreatic beta-cell and the hypothalamic glucose-sensitive neurones (GSN) and the widespread distribution of sulphonylurea receptors in neuronal cells throughout the brain.


METHODS
Ten healthy males were studied on four occasions and in random order underwent three stepped hypoglycaemic (plasma glucose aims: 3.4, 2.8, 2.4 mmol/l) and one euglycaemic (plasma glucose aim: 5 mmol/l) insulin clamps. Prior to each hypoglycaemic study, volunteers received either 10 mg glibenclamide, or 5 mg/kg diazoxide or placebo orally. Cognitive function, symptom scores and counterregulatory hormone responses were measured at each glycaemic level.


RESULTS
There was no statistically significant effect of either drug on the symptoms generated or the counterregulatory hormonal response during hypoglycaemia. However, cognitive function was better preserved during hypoglycaemia in the glibenclamide-treated arm, particularly four-choice reaction time which deteriorated at a plasma glucose 2.5 mmol/l compared with 3.0 mmol/l with diazoxide (P = 0.015) and 2.9 mmol/l with placebo (P = 0.114).


CONCLUSIONS
Single doses of pharmacological agents which alter membrane KATP channel activity do not affect the counterregulatory response to hypoglycaemia but may modify cognitive function during cerebral glucopenia. The unexpected effects of glibenclamide on cortical function suggest a novel action of sulphonylureas that warrants further investigation.
Bingham
E
E
GKT School of Medicine, Denmark Hill Campus, London, UK. emma.bingham@kcl.ac.uk
Hopkins
D
D
Pernet
A
A
Reid
H
H
Macdonald
I A
IA
Amiel
S A
SA
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003071:Cognition; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D003981:Diazoxide / Q000008:administration & dosage; D015309:Glucose Clamp Technique / Q000379:methods; D005905:Glyburide / Q000008:administration & dosage; D006728:Hormones / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D010865:Pilot Projects; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage
D001786:Blood Glucose; D006728:Hormones; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D003981:Diazoxide; D005905:Glyburide