Cold-induced dishabituation in rodents exposed to recurrent hypoglycaemia

Keeran Vickneson, Jessica Blackburn, Jennifer R. Gallagher, Mark L. Evans, Bastiaan E. de Galan, Ulrik Pedersen-Bjergaard, Bernard Thorens, Alison D. McNeilly, Rory J. McCrimmon (Lead / Corresponding author)

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Aims/hypothesis: Recurrent hypoglycaemia (RH) in people with diabetes leads to progressive suppression of counterregulatory hormonal responses to subsequent hypoglycaemia. Recently it has been proposed that the mechanism underpinning this is a form of adaptive memory referred to as habituation. To test this hypothesis, we use two different durations of cold exposure to examine whether rodents exposed to RH exhibit two characteristic features of habituation, namely stimulus generalisation and dishabituation.

Methods: In the first study (Stimulus Generalisation study), hyperinsulinaemic hypoglycaemic (2.8 mmol•L-1) glucose clamps were performed in non-diabetic rodents exposed to prior moderate duration cold (4OC for 3 hours) or control conditions). In the second study (Dishabituation Study), rodents exposed to prior RH or saline injections over 4-weeks underwent a longer duration cold (4OC for 4.5 hours) exposure followed 24 hrs later by a hyperinsulinaemic hypoglycaemic (2.8 mmol•L-1) glucose clamp. Output measures were counterregulatory hormone responses during experimental hypoglycaemia.

Results: Moderate duration cold exposure blunted the adrenaline response (15,266 ± 1,920 vs 7,981 ± 1,258 pmol•L-1, Control vs. Cold, P < 0.05) to next day hypoglycaemia in healthy non-diabetic rodents. In contrast, the suppressed adrenaline response (Control 5,912 ± 1,417 vs. RH 1,836 ± 736 pmol•L-1; P < 0.05) that is associated with RH was restored following longer duration cold exposure(RH + Cold 4,756 ± 826 pmol•L-1; P = NS vs control).

Conclusions/interpretation: Non-diabetic rodents exhibit two cardinal features of habituation, namely stimulus generalisation and dishabituation. These findings provide further support for the hypothesis that suppressed counterregulatory responses following exposure to recurrent hypoglycaemia in diabetes result from habituation.
Original languageEnglish
Number of pages6
Early online date17 Mar 2021
Publication statusE-pub ahead of print - 17 Mar 2021


  • Counterregulatory responses
  • Hypoglycaemia
  • Impaired awareness
  • Cold
  • Habituation
  • Type 1 diabetes

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