Cognitive and neural hippocampal effects of long-term moderate recurrent hypoglycemia

Ewan C. McNay (Lead / Corresponding author), Anne Williamson, Rory J. McCrimmon, Robert S. Sherwin

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    Abstract

    Recurrent hypoglycemia is the most feared complication of intensive insulin therapy for type 1 diabetes. Study of the cognitive impact of recurrent hypoglycemia in humans has been hampered by difficulty in controlling for prior glycemic history and diabetes status; there have been no prospective studies. We used a rat model of recurrent hypoglycemia with hypoglycemia for 3 h, once weekly, from 1 month of age. At 4, 8, and 12 months of age, cohorts were tested on a hippocampally dependent spatial memory task, during which hippocampal extracellular fluid (ECF) glucose and lactate were measured using microdialysis. At 4 months, recurrent hypoglycemia improved euglycemic task performance (76 +/- 4 vs. 64 +/- 3% for controls) and reversed the task-associated dip in ECF glucose seen in controls. However, recurrent hypoglycemia impaired performance in animals tested when hypoglycemic (45 +/- 4 vs. 55 +/- 2%). Recurrent hypoglycemia preserved euglycemic task performance across age: at 12 months, both task performance (62%) and ECF glucose changes in euglycemic recurrently hypoglycemic animals resembled those of 4-month-old control animals, whereas control animals' performance deteriorated to chance (44%) by 8 months. At 12 months, hippocampal slice physiology was assessed, with results paralleling the cognitive findings: slices from recurrently hypoglycemic rats showed improved gamma-aminobutyric acid (GABA)ergic inhibition at euglycemia but much greater loss of this tone at low bath glucose. Our data show that moderate weekly hypoglycemia prevented age-related decline in hippocampally cognitive function and cognitive metabolism, at least when euglycemic. The impact of recurrent hypoglycemia on cognition is multifaceted and includes both metabolic and electrophysiological components.
    Original languageEnglish
    Pages (from-to)1088-1095
    Number of pages8
    JournalDiabetes
    Volume55
    Issue number4
    DOIs
    Publication statusPublished - Apr 2006

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    Hypoglycemia
    Extracellular Fluid
    Task Performance and Analysis
    Hypoglycemic Agents
    Glucose
    Cognition
    Microdialysis
    Type 1 Diabetes Mellitus
    Baths
    gamma-Aminobutyric Acid
    Lactic Acid
    History
    Prospective Studies
    Insulin

    Cite this

    McNay, Ewan C. ; Williamson, Anne ; McCrimmon, Rory J. ; Sherwin, Robert S. / Cognitive and neural hippocampal effects of long-term moderate recurrent hypoglycemia. In: Diabetes. 2006 ; Vol. 55, No. 4. pp. 1088-1095.
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    title = "Cognitive and neural hippocampal effects of long-term moderate recurrent hypoglycemia",
    abstract = "Recurrent hypoglycemia is the most feared complication of intensive insulin therapy for type 1 diabetes. Study of the cognitive impact of recurrent hypoglycemia in humans has been hampered by difficulty in controlling for prior glycemic history and diabetes status; there have been no prospective studies. We used a rat model of recurrent hypoglycemia with hypoglycemia for 3 h, once weekly, from 1 month of age. At 4, 8, and 12 months of age, cohorts were tested on a hippocampally dependent spatial memory task, during which hippocampal extracellular fluid (ECF) glucose and lactate were measured using microdialysis. At 4 months, recurrent hypoglycemia improved euglycemic task performance (76 +/- 4 vs. 64 +/- 3{\%} for controls) and reversed the task-associated dip in ECF glucose seen in controls. However, recurrent hypoglycemia impaired performance in animals tested when hypoglycemic (45 +/- 4 vs. 55 +/- 2{\%}). Recurrent hypoglycemia preserved euglycemic task performance across age: at 12 months, both task performance (62{\%}) and ECF glucose changes in euglycemic recurrently hypoglycemic animals resembled those of 4-month-old control animals, whereas control animals' performance deteriorated to chance (44{\%}) by 8 months. At 12 months, hippocampal slice physiology was assessed, with results paralleling the cognitive findings: slices from recurrently hypoglycemic rats showed improved gamma-aminobutyric acid (GABA)ergic inhibition at euglycemia but much greater loss of this tone at low bath glucose. Our data show that moderate weekly hypoglycemia prevented age-related decline in hippocampally cognitive function and cognitive metabolism, at least when euglycemic. The impact of recurrent hypoglycemia on cognition is multifaceted and includes both metabolic and electrophysiological components.",
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    Cognitive and neural hippocampal effects of long-term moderate recurrent hypoglycemia. / McNay, Ewan C. (Lead / Corresponding author); Williamson, Anne; McCrimmon, Rory J.; Sherwin, Robert S.

    In: Diabetes, Vol. 55, No. 4, 04.2006, p. 1088-1095.

    Research output: Contribution to journalArticle

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    AU - Sherwin, Robert S.

    N1 - M1 - 4 McNay, Ewan C Williamson, Anne McCrimmon, Rory J Sherwin, Robert S eng DK 20495/DK/NIDDK NIH HHS/ NS 45792/NS/NINDS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2006/03/29 09:00 Diabetes. 2006 Apr;55(4):1088-95.

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    N2 - Recurrent hypoglycemia is the most feared complication of intensive insulin therapy for type 1 diabetes. Study of the cognitive impact of recurrent hypoglycemia in humans has been hampered by difficulty in controlling for prior glycemic history and diabetes status; there have been no prospective studies. We used a rat model of recurrent hypoglycemia with hypoglycemia for 3 h, once weekly, from 1 month of age. At 4, 8, and 12 months of age, cohorts were tested on a hippocampally dependent spatial memory task, during which hippocampal extracellular fluid (ECF) glucose and lactate were measured using microdialysis. At 4 months, recurrent hypoglycemia improved euglycemic task performance (76 +/- 4 vs. 64 +/- 3% for controls) and reversed the task-associated dip in ECF glucose seen in controls. However, recurrent hypoglycemia impaired performance in animals tested when hypoglycemic (45 +/- 4 vs. 55 +/- 2%). Recurrent hypoglycemia preserved euglycemic task performance across age: at 12 months, both task performance (62%) and ECF glucose changes in euglycemic recurrently hypoglycemic animals resembled those of 4-month-old control animals, whereas control animals' performance deteriorated to chance (44%) by 8 months. At 12 months, hippocampal slice physiology was assessed, with results paralleling the cognitive findings: slices from recurrently hypoglycemic rats showed improved gamma-aminobutyric acid (GABA)ergic inhibition at euglycemia but much greater loss of this tone at low bath glucose. Our data show that moderate weekly hypoglycemia prevented age-related decline in hippocampally cognitive function and cognitive metabolism, at least when euglycemic. The impact of recurrent hypoglycemia on cognition is multifaceted and includes both metabolic and electrophysiological components.

    AB - Recurrent hypoglycemia is the most feared complication of intensive insulin therapy for type 1 diabetes. Study of the cognitive impact of recurrent hypoglycemia in humans has been hampered by difficulty in controlling for prior glycemic history and diabetes status; there have been no prospective studies. We used a rat model of recurrent hypoglycemia with hypoglycemia for 3 h, once weekly, from 1 month of age. At 4, 8, and 12 months of age, cohorts were tested on a hippocampally dependent spatial memory task, during which hippocampal extracellular fluid (ECF) glucose and lactate were measured using microdialysis. At 4 months, recurrent hypoglycemia improved euglycemic task performance (76 +/- 4 vs. 64 +/- 3% for controls) and reversed the task-associated dip in ECF glucose seen in controls. However, recurrent hypoglycemia impaired performance in animals tested when hypoglycemic (45 +/- 4 vs. 55 +/- 2%). Recurrent hypoglycemia preserved euglycemic task performance across age: at 12 months, both task performance (62%) and ECF glucose changes in euglycemic recurrently hypoglycemic animals resembled those of 4-month-old control animals, whereas control animals' performance deteriorated to chance (44%) by 8 months. At 12 months, hippocampal slice physiology was assessed, with results paralleling the cognitive findings: slices from recurrently hypoglycemic rats showed improved gamma-aminobutyric acid (GABA)ergic inhibition at euglycemia but much greater loss of this tone at low bath glucose. Our data show that moderate weekly hypoglycemia prevented age-related decline in hippocampally cognitive function and cognitive metabolism, at least when euglycemic. The impact of recurrent hypoglycemia on cognition is multifaceted and includes both metabolic and electrophysiological components.

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