Consequences of recurrent hypoglycaemia on brain

function in diabetes 

Rory J. McCrimmon

Diabetologia volume 64, pages971–977(2021)



The discovery of insulin and its subsequentmassmanufacture transformed the lives of people with type 1 and 2 diabetes. Insulin, however, was a drug with a ‘dark side’. It brought with it the risk of iatrogenic hypoglycaemia. In this short review, the cellular consequences of recurrent hypoglycaemia, with a particular focus on the brain, are discussed. Using the ventromedial hypothalamus as an exemplar, this review highlights how recurrent hypoglycaemia has an impact on the specialised cells in the brain that are critical to the regulation of glucose homeostasis and the counterregulatory response to hypoglycaemia. In these cells, recurrent  hypoglycaemia initiates a series of adaptations that ensure that they aremore resilient to subsequent hypoglycaemia, but this leads to impaired hypoglycaemia awareness and a paradoxical increased risk of severe hypoglycaemia. This review also highlights how hypoglycaemia, as an oxidative stressor, may also exacerbate chronic hyperglycaemia-induced increases in oxidative stress and inflammation, leading to damage to vulnerable brain regions (and other end organs) and accelerating cognitive decline. Preclinical research indicates that glucose recovery following hypoglycaemia is considered a period where reactive oxygen species generation and oxidative stress are pronounced and can exacerbate the longer-term consequence of chronic hypoglycaemia. It is proposed that prior glycaemic control, hypoglycaemia and the degree of rebound hyperglycaemia interact synergistically to accelerate oxidative stress and inflammation, which may explain why increased glycaemic variability is now increasingly considered a risk factor for the complications of diabetes.


Some text from the article


This year is the centenary of the discovery of insulin by

Frederick Banting and Charles Best in Professor John

Macleod’s department in Toronto (ON, Canada) in the

summer of 1921. There can be little doubt about the impact

of their discovery, which has transformed the lives of millions

of people with both type 1 and 2 diabetes in the 100 years

since. At the same time, it was soon discovered that insulin

therapy was not without risk. Physicians reported that exogenous

insulin, when delivered in excess, led to a low blood

glucose; the ‘hypoglycaemic reaction’. It was also soon apparent

that repeated exposure to low glucose led to, ‘reactions

[that] differ so much from the original ones that patients

became dangerously unaware of their onset’ [1].

Glucose homeostasis is fundamental to survival in most

vertebrate species. As such, we have evolved a number of

counterregulatory mechanisms designed to restore glucose

homeostasis when glucose levels fall below the normal range.

Over the last few decades, we have learnt that, in humans,

there exists an integrated network of specialised glucosesensing

cells, found in certain key parts of the brain and in

the periphery, that are able to monitor and respond to

prevailing glucose levels, as well as integrate glucose homeostasis

with other aspects of whole-body energy status [2, 3].

We also recognise that, in response to recurrent

hypoglycaemia, these specialised glucose-sensing cells adapt,

leading (through mechanisms still not entirely worked out) to

a clinical syndrome called impaired awareness of

hypoglycaemia. Moreover, there is increasing evidence that,

in addition to making individuals susceptible to severe

hypoglycaemia, these adaptations may also have consequences

in terms of end-organ disease. In this short review, I

will briefly discuss the cellular consequences of

hypoglycaemia, focusing on the impact of recurrent

hypoglycaemia in the brain. This will be illustrated by

outlining the ways in which recurrent hypoglycaemia affects

cells in glucose-sensing regions of the brain (leading to

impaired awareness of hypoglycaemia and severe

hypoglycaemia), as well as how recurrent hypoglycaemia

may affect other brain regions, potentially amplifying the

tissue damage that results from chronic hyperglycaemia.



The value of insulin in the management of diabetes and the

evidence in support of intensive insulin therapy targeting nearnormalisation

of glycaemic control to minimise the micro- and

macrovascular complications of diabetes is overwhelming.

However, hypoglycaemia remains a relatively common adverse

effect of insulin therapy that has consequences for the individual

and their carers. Asides from the immediate cognitive and

emotional impacts of acute hypoglycaemia, impaired

hypoglycaemia awareness is a consequence of repeated exposure

to hypoglycaemia that carries a high risk for severe

hypoglycaemia. Epidemiological and pre-clinical research also

indicates that recurrent hypoglycaemia may exacerbate chronic

hyperglycaemia-induced increases in oxidative stress and

inflammation, leading, in particular, to damage in vulnerable

brain regions and accelerated cognitive decline.

There remain many unanswered questions that hopefully

future research will be able to shed light on. For instance, do

the effects of recurrent hypoglycaemia on specialised glucosesensing

neurons occur through a single signalling defect or

multiple pathways given the complexity of the hypoglycaemic

response? Moreover, is there actually a ‘defect’ in sensing or

are glucose-sensing neurons just less responsive to low

glucose? If the latter, do the major changes specifically occur

in the specialised neuron or in the periphery (e.g., adrenal

gland)? It is also uncertain whether these effects are reversible

in all people through strict hypoglycaemic avoidance or

whether, in some, these may prove irreversible as a consequence

of long-term damage to critical components of this

homeostatic defence mechanism.

When we consider other consequences of recurrent

hypoglycaemia on the brain, we also need clarity on the actual

level of hypoglycaemia that is clinically significant, which

may or may not be 3.0 mmol/l as recently proposed by the

International Hypoglycaemia Study Group [42]. It is also

possible that recurrent hypoglycaemia has consequences in

other metabolically active tissues, such as the heart and

kidney, whereby the interaction between prior glycaemic

control, hypoglycaemia and the degree of rebound

hyperglycaemia may explain why increased glycaemic variability

is considered a risk factor for complications in multiple

organ systems [43].


Supplementary Information The online version contains a slideset of the

figures for download, which is available to authorised


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