Type 2 diabetes and cognitive decline: a question of rectifying potassium?
While the study by Logroscino et al. did confirm the a priori
hypothesis that among women aged 70-81 years type 2 diabetes is associated
with substantial cognitive decline, an additional finding came out
somewhat unexpected. In contrast to diabetic women using insulin
treatment, those who were on oral hypoglycaemic agents performed similarly
to women without diabetes.
Although the manuscript does not provide additional information on
the specific oral agents used, we speculate that this paradoxically
“protective” effect be exerted by sulphonylureas by virtue of their action
on ATP-sensitive potassium channels (KATP channels).(1,2)
Several structural classes of the six-transmembrane domain, voltage-
gated K+ channel are now known.(3) Among others, the KATP channels are
heteromeric complexes of pore-forming inwardly rectifying potassium
channel subunits and regulatory sulfonylurea receptor subunits. KATP
channels are widely distributed throughout the nervous system including
the brain and the highest levels of binding are found in the substantia
nigra and in the hippocampus.(4) Sulfonylureas like glibenclamide block
KATP channels; they are commonly used in the therapy of type 2 diabetes.
Functionally, KATP channels provide a means of linking the electrical
activity of a cell to its metabolic state, and neurotransmitter release
are mediated via KATP channels. For example, the large basal forebrain
neurones that provide the principal ascending cholinergic input to both
the hippocampus and cerebral cortex and whose integrity is vital to
learning and memory processes are modulated by KATP channels.(5)
K channels may be a possible site of Alzheimer’s disease (AD)
pathology. Indeed, changes in Cp20, a specific memory-associated protein
that is a potent regulator of K channels, have been proposed as a possible
pathophysiologic mechanism for the memory loss of AD.(6) In the same way,
tacrine, the prototype of acetylcholinesterase inhibitors, contains a 4-
aminopyridine moiety that resembles that of a K channel blocking agent,(7)
and do behave so in hippocampal neurons preparations.(8) Similar effect
has also been demonstrated for two additional acetylcholinesterase
inhibitors like donepezil,(9) and galantamine.(10)
1. Landi F, Bernabei R, Gambassi G. Non-insulin-dependent diabetes
mellitus and Alzheimer’s disease. J Am Geriatr Soc 1997;45:654-5
2. Bingham E, Hopkins D, Pernet A, Reid H, Macdonald IA, Amiel SA.
The effects of KATP channel modulators on counterregulatory responses and
cognitive function during acute controlled hypoglycaemia in healthy men: a
pilot study. Diabet Med 2003;20:231-7
3. Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA, Clapham DE,
Covarriubias M, Desir GV, Furuichi K, Ganetzky B, Garcia ML, Grissmer S,
Jan LY, Karschin A, Kim D, Kuperschmidt S, Kurachi Y, Lazdunski M, Lesage
F, Lester HA, McKinnon D, Nichols CG, O'Kelly I, Robbins J, Robertson GA,
Rudy B, Sanguinetti M, Seino S, Stuehmer W, Tamkun MM, Vandenberg CA, Wei
A, Wulff H, Wymore RS; International Union of Pharmacology.International
Union of Pharmacology. XLI. Compendium of voltage-gated ion channels:
potassium channels. Pharmacol Rev. 2003;55(4):583-6.
4. Treherne JM, Ashford ML. The regional distribution of
sulphonylurea binding sites in rat brain. Neuroscience 1991;40:523-31
5. Allen TGJ, Brown DA. Modulation of the excitability of cholinergic
basal forebrain neurones by KATP channels. J Physiol 554.2:353-70
6. Kim CS, Han YF, Etcheberrigaray R. Alzheimer and beta-amyloid
treated fibroblasts demonstrate a decrease in a memory associated GTP-
binding protein, Cp20. Proc Natl Acad Sci USA 1995;92:3060-4
7 Wagstaff AJ, McTavish D. Tacrine. A review of its pharmacodynamic
and pharmacokinetic properties, and therapeutic efficacy in Alzheimer
disease. Drugs Aging 1994;4:510-40
8. Li Y, Hu GY. Huperzine A, a nootropic agent, inhibits fast
transient potassium current in rat dissociated hippocampal neurons.
Neurosci Lett 2002;324:25-8
9. Zhong CB, Zhang W, Wang XL. Effect of donepezil on the delayed
rectifier-like potassium current in pyramidal neurons of rat hippocampus
and neocortex. Yao Xue Xue Bao 2002;37:415-8
10. Pan YP, Xu XH, Wang XL. Galantamine blocks delayed rectifier, but
not transient outward potassium current in rat dissociated hippocampal
pyramidal neurons. Neurosci Lett 2003;336:37-40
Rapid Response:
Type 2 diabetes and cognitive decline: a question of rectifying potassium?
While the study by Logroscino et al. did confirm the a priori
hypothesis that among women aged 70-81 years type 2 diabetes is associated
with substantial cognitive decline, an additional finding came out
somewhat unexpected. In contrast to diabetic women using insulin
treatment, those who were on oral hypoglycaemic agents performed similarly
to women without diabetes.
Although the manuscript does not provide additional information on
the specific oral agents used, we speculate that this paradoxically
“protective” effect be exerted by sulphonylureas by virtue of their action
on ATP-sensitive potassium channels (KATP channels).(1,2)
Several structural classes of the six-transmembrane domain, voltage-
gated K+ channel are now known.(3) Among others, the KATP channels are
heteromeric complexes of pore-forming inwardly rectifying potassium
channel subunits and regulatory sulfonylurea receptor subunits. KATP
channels are widely distributed throughout the nervous system including
the brain and the highest levels of binding are found in the substantia
nigra and in the hippocampus.(4) Sulfonylureas like glibenclamide block
KATP channels; they are commonly used in the therapy of type 2 diabetes.
Functionally, KATP channels provide a means of linking the electrical
activity of a cell to its metabolic state, and neurotransmitter release
are mediated via KATP channels. For example, the large basal forebrain
neurones that provide the principal ascending cholinergic input to both
the hippocampus and cerebral cortex and whose integrity is vital to
learning and memory processes are modulated by KATP channels.(5)
K channels may be a possible site of Alzheimer’s disease (AD)
pathology. Indeed, changes in Cp20, a specific memory-associated protein
that is a potent regulator of K channels, have been proposed as a possible
pathophysiologic mechanism for the memory loss of AD.(6) In the same way,
tacrine, the prototype of acetylcholinesterase inhibitors, contains a 4-
aminopyridine moiety that resembles that of a K channel blocking agent,(7)
and do behave so in hippocampal neurons preparations.(8) Similar effect
has also been demonstrated for two additional acetylcholinesterase
inhibitors like donepezil,(9) and galantamine.(10)
1. Landi F, Bernabei R, Gambassi G. Non-insulin-dependent diabetes
mellitus and Alzheimer’s disease. J Am Geriatr Soc 1997;45:654-5
2. Bingham E, Hopkins D, Pernet A, Reid H, Macdonald IA, Amiel SA.
The effects of KATP channel modulators on counterregulatory responses and
cognitive function during acute controlled hypoglycaemia in healthy men: a
pilot study. Diabet Med 2003;20:231-7
3. Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA, Clapham DE,
Covarriubias M, Desir GV, Furuichi K, Ganetzky B, Garcia ML, Grissmer S,
Jan LY, Karschin A, Kim D, Kuperschmidt S, Kurachi Y, Lazdunski M, Lesage
F, Lester HA, McKinnon D, Nichols CG, O'Kelly I, Robbins J, Robertson GA,
Rudy B, Sanguinetti M, Seino S, Stuehmer W, Tamkun MM, Vandenberg CA, Wei
A, Wulff H, Wymore RS; International Union of Pharmacology.International
Union of Pharmacology. XLI. Compendium of voltage-gated ion channels:
potassium channels. Pharmacol Rev. 2003;55(4):583-6.
4. Treherne JM, Ashford ML. The regional distribution of
sulphonylurea binding sites in rat brain. Neuroscience 1991;40:523-31
5. Allen TGJ, Brown DA. Modulation of the excitability of cholinergic
basal forebrain neurones by KATP channels. J Physiol 554.2:353-70
6. Kim CS, Han YF, Etcheberrigaray R. Alzheimer and beta-amyloid
treated fibroblasts demonstrate a decrease in a memory associated GTP-
binding protein, Cp20. Proc Natl Acad Sci USA 1995;92:3060-4
7 Wagstaff AJ, McTavish D. Tacrine. A review of its pharmacodynamic
and pharmacokinetic properties, and therapeutic efficacy in Alzheimer
disease. Drugs Aging 1994;4:510-40
8. Li Y, Hu GY. Huperzine A, a nootropic agent, inhibits fast
transient potassium current in rat dissociated hippocampal neurons.
Neurosci Lett 2002;324:25-8
9. Zhong CB, Zhang W, Wang XL. Effect of donepezil on the delayed
rectifier-like potassium current in pyramidal neurons of rat hippocampus
and neocortex. Yao Xue Xue Bao 2002;37:415-8
10. Pan YP, Xu XH, Wang XL. Galantamine blocks delayed rectifier, but
not transient outward potassium current in rat dissociated hippocampal
pyramidal neurons. Neurosci Lett 2003;336:37-40
Competing interests:
None declared
Competing interests: No competing interests