Our brain runs on glucose: in contrast to cells elsewhere, which will generally take their fuel where they can find it, neurons and glia both rely on a constant supply of glucose from blood for their metabolic support (with some of that glucose being metabolised by astrocytes into lactate which is then exported for subsequent use by neurons). Unsurprisingly, acute interruption of this supply by systemic hypoglycemia produces marked cognitive impairment and leads eventually to coma and death. The consequences of acute hypoglycemia, including effects on cognitive and neural functions, are relatively well-understood. In addition and unsurprisingly, repeated severe hypoglycemia causes both significant neuronal death and cognitive impairment [1
]. However, in recent years the impact on the brain and on cognitive functions of repeated, moderate interruptions of glucose supply, which cause little or no loss of neurons in hippocampus or cortex [3
], has become of increasing interest. This interest is primarily the result of increased hypoglycemic incidence as a side-effect of advances in therapy for diabetes, but might also be of wider interest because of a potential relationship with the emerging practice of caloric restriction as an aid to long-term physical and mental health. The present review will examine data from both animal and human studies at a variety of levels of analysis. The primary conclusion drawn will be that the long-term consequences of moderate repeated hypoglycemia can be significant, but in general appear to be potentially beneficial at most times. There is, however, significant acerbation of the impact of further
episodes of hypoglycemia on cognitive function, so that this risk should be recognised and borne in mind by those receiving or initiating protocols likely to produce such hypoglycemia.
The most common cause of hypoglycemia in modern Western society is the use of exogenous insulin as a therapeutic agent for treatment of diabetes. Hypoglycemia has historically been primarily seen in individuals with type I diabetes mellitus (T1DM), but increasingly is also being experienced by patients with type 2 diabetes (T2DM) as a result of more aggressive therapy. Over the past two decades, the gold standard for treatment of T1DM has been intensive insulin therapy, aimed at aggressively preventing hyperglycemia and associated neuropathies. While successful, this treatment approach has also resulted in a marked increase in frequency of hypoglycemia subsequent to insulin administration [5
]. The long term consequences of such recurrent moderate hypoglycemia (RH) for brain and cognitive functions remain controversial not least because of the difficulty in human studies of accurately parsing the effects of RH from such confounds as duration of diabetes, age of onset, hyperglycemic neuropathies, and so on. Notwithstanding the uncertainty with regard to the neural and cognitive impact of RH, hypoglycemia has become the most feared side-effect of insulin therapy [6
], with widespread concern for e.g. the possibility of neural damage because of interrupted fuel supply.
There are several good reviews of the diminution of counter-regulatory hormonal responses following RH, with the attendant impairment to systemic glucose homeostasis in the face of further hypoglycemic episodes (e.g. [7
]). The systemic and glucose-sensing changes in response to RH, and mechanisms of hypoglycemia detection and counterregulation, are outside the scope of this mini-review which will focus solely on brain, and primarily cognitive, effects of RH.