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Published on: November 16, 2011
The effects of KATP channel modulators on counterregulatory responses and cognitive function during acute controlled
Aims:
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.
Insights
Agents altering potassium adenosine triphosphate (KATP) channels did not affect hormone responses to low blood sugar. However, glibenclamide improved cognitive function during hypoglycemia, suggesting a novel effect on brain function.
Area of Science:
- Neuroendocrinology
- Metabolic Medicine
- Pharmacology
Background:
- Pancreatic beta-cells and hypothalamic glucose-sensitive neurons share physiological similarities.
- Sulfonylurea receptors are widely distributed in neuronal cells, suggesting potential brain effects.
- Potassium adenosine triphosphate (KATP) channels play a role in both insulin secretion and neuronal function.
Purpose of the Study:
- To investigate the impact of KATP channel modulators on cognitive function during hypoglycemia.
- To assess the effect of these agents on counterregulatory hormone release in response to low blood glucose.
- To explore the potential for novel actions of sulfonylureas in the brain.
Main Methods:
- A randomized, placebo-controlled study involving 10 healthy males.
- Three stepped hypoglycemic clamp procedures and one euglycemic clamp.
- Administration of glibenclamide, diazoxide, or placebo prior to hypoglycemic challenges.
- Measurement of cognitive function, symptom scores, and counterregulatory hormones at various glucose levels.
Main Results:
- Neither glibenclamide nor diazoxide significantly altered counterregulatory hormone responses or symptom perception during hypoglycemia.
- Cognitive function, specifically four-choice reaction time, was better preserved with glibenclamide during hypoglycemia.
- Glibenclamide demonstrated a protective effect on cognitive performance at lower plasma glucose levels compared to placebo and diazoxide.
Conclusions:
- Pharmacological agents modulating KATP channel activity do not influence the counterregulatory hormonal response to hypoglycemia.
- These agents may, however, impact cognitive function during states of cerebral glucopenia (low brain glucose).
- The observed effect of glibenclamide on cortical function suggests a previously unrecognized action of sulfonylureas, meriting further research.
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