Through demonstration of stimulus generalisation and dishabituation between two physiological stressors, cold and hypoglycaemia, this paper provides further evidence in support of the hypothesis that suppression of CRR following recurrent hypoglycaemia results from habituation. These findings, if supported by additional studies in people with type 1 diabetes and shown to also extend to psychological and behavioural responses to hypoglycaemia, may provide a framework for considering management strategies both for the avoidance and reversal of IAH.
In the present study, cold was chosen as an alternate physiological stimulus, as previous research had shown an alteration in stress responses to cold exposure in type 1 diabetes suggesting that there might be shared components within each homeostatic response . Our findings support this hypothesis through demonstrating stimulus generalisation and dishabituation between these two physiological stressors. Moreover, because stimulus generalisation is thought to occur centrally, as opposed to a change in primary sensory afferents , our data suggest that habituation to recurrent hypoglycaemia may result from changes in key central nervous system integrative centres. However, the possibility that adaptations in peripheral organs (e.g. adrenal or peripheral sensors) also contribute to habituation cannot be excluded.
The different duration of cold exposure followed pilot studies showing the noradrenaline response to cold was augmented by 4.5 h vs 3 h exposure and it was anticipated a stronger stimulus would be required for dishabituation. However, in Experiments 1 and 2 both control groups exhibited stimulus generalisation, so this may not have been required and the difference in outcomes seems to have been determined more by prior habituation to hypoglycaemia than the strength of the alternate stimulus.
In contrast to stimulus generalisation, cold exposure increased CRR in rodents who had been habituated to hypoglycaemia. It is of note that the clear between-group differences in adrenaline response to subsequent hypoglycaemia were not reflected by significant differences in GIR (although the pattern of change was similar), which may be a result of the high insulin concentrations used in the clamp procedure attenuating those differences. Overall, the demonstration of a response to cold exposure in RH rodents that is consistent with cold dishabituation, combined with our previous study using HIT in rodents , lends further support to the hypothesis that the adaptation to recurrent hypoglycaemia is through the specialised form of adaptive memory, referred to as habituation.
This study has a number of limitations. First, while dishabituation leads to a restoration of the habituated response, it is possible that: (1) this effect is only transient; or (2) the individual may habituate to the dishabituating stimulus limiting the therapeutic utility of this approach . An ongoing clinical study, HIT4HYPOS , will directly address this question through examining the impact of a 4 week HIT programme in people with type 1 diabetes who have impaired awareness of hypoglycaemia. Second, while we have studied two of the cardinal features of habituation, there remain a number of other criteria that need to be tested in order to establish habituation as the mechanism that underpins the development of IAH in humans. Third, a limitation of the rodent model is that it only enables assessment of CRR to hypoglycaemia, whereas people with IAH also demonstrate suppression of symptomatic, psychological and behavioural responses. Despite this, it should be recognised that mice, rats and other model systems all respond to recurrent hypoglycaemia in a very similar way to humans , and we have recently demonstrated in humans with long-standing type 1 diabetes the partial reversal of three important facets of IAH, namely hormonal, symptomatic and cognitive performance following a single episode of HIT .
In summary, in this paper we have demonstrated in the rodent model that dishabituation with cold exposure leads to, at least temporary, recovery of CRR to subsequent hypoglycaemia. Furthermore, we have demonstrated stimulus generalisability between cold and hypoglycaemia, providing further evidence that the reduced responsiveness to hypoglycaemia that follows recurrent exposure develops though habituation. This new understanding, if confirmed by other researchers, may lead to the development of novel approaches to the treatment of IAH.