3. Cerebral Adaptation to Recurrent Hypoglycemia

McCrimmon, Rory J.; Öz, Gülin

doi:10.1210/team.9781936704200.ch3

Cited by 8 publications

(9 citation statements)

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“…Consistent with this, rats exposed to repeated moderate hypoglycaemia show less neuronal cell death during subsequent severe hypoglycaemia than their controls . This biological process is often referred to as pre‐conditioning, a neuroprotective response that induces tolerance to the physiological stressor (in this case hypoglycaemia) . Pre‐conditioning is not unique to hypoglycaemia and is a highly conserved means by which cells respond to varied homeostatic challenges such as energy deprivation, ischaemia or temperature extremes.…”

Section: Why Does Exposure To Recurrent Hypoglycaemia Lead To Impairementioning

confidence: 73%

“…This degree of glucose (energy) deprivation represents a profound physiological challenge to the cell, as is evident from the marked counter‐regulatory response hypoglycaemia stimulates in humans without diabetes. It therefore seems likely that in response to this challenge neurons will initiate a survival response that is designed to both prevent cell death and prepare the neuron so that it is better able to survive future episodes of profound glucose (energy) deprivation . Consistent with this, rats exposed to repeated moderate hypoglycaemia show less neuronal cell death during subsequent severe hypoglycaemia than their controls .…”

Section: Why Does Exposure To Recurrent Hypoglycaemia Lead To Impairementioning

confidence: 92%

“… and McCrimmon et al . ). While these mechanisms probably all contribute at least in part to the development of impaired glucose sensing, as yet no clear understanding of the mechanism that drives defective counter‐regulation has emerged.…”

Section: Why Does Exposure To Recurrent Hypoglycaemia Lead To Impairementioning

confidence: 97%

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RD Lawrence Lecture 2015 Old habits are hard to break: lessons from the study of hypoglycaemia

McCrimmon

2016

Diabet. Med.

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Despite the introduction of newer technologies and improved insulin formulations, recurrent hypoglycaemia continues to affect the lives of many people with Type 1 and Type 2 diabetes. Developing strategies or therapies designed to prevent or minimize hypoglycaemia risk is of utmost importance to help individuals safely achieve glycaemic targets. Novel, educational or behavioural approaches need to be based on a clear understanding of the mechanisms underpinning both the detection of hypoglycaemia and why repeated exposure to hypoglycaemia leads to the development of a clinical syndrome referred to as impaired awareness of hypoglycaemia. In the present review, I propose that impaired awareness of hypoglycaemia may represent a form of learning called habituation, a response that, at a cellular level, represents a biological adaptation designed to protect the organism from future exposure to that stressor. In diabetes, this survival response to low glucose is, however, overwhelmed by high systemic insulin levels resulting from exogenous insulin therapy, leading to progressively more severe hypoglycaemia. A recognition of the underlying mechanism means that the development of impaired awareness of hypoglycaemia can perhaps be better understood and explained to individuals with diabetes, and novel therapeutic approaches such as dishabituation or cognitive behavioural therapies can be considered.

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Section: Why Does Exposure To Recurrent Hypoglycaemia Lead To Impairementioning

confidence: 73%

Section: Why Does Exposure To Recurrent Hypoglycaemia Lead To Impairementioning

confidence: 92%

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RD Lawrence Lecture 2015 Old habits are hard to break: lessons from the study of hypoglycaemia

McCrimmon

2016

Diabet. Med.

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“…However, human studies using magnetic resonance spectroscopy or positron emission tomography (PET) have produced conflicting data about the effects of recurrent hypoglycaemia on cerebral glucose uptake and metabolism. This may reflect regional variation in glucose metabolism, or even differences in how neurons and glial cells individually respond to recurrent hypoglycaemia [ 8 , 16 , 17 ].…”

Section: Bringing Light To the Dark Side Of Insulinmentioning

confidence: 99%

Consequences of recurrent hypoglycaemia on brain function in diabetes

McCrimmon

2021

Diabetologia

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The discovery of insulin and its subsequent mass manufacture 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 are more 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. Pre-clinical 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. Graphical abstract

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“…2 Although the mechanisms of HAAF have not been fully elucidated, a picture is emerging in which a series of cerebral adaptations, including altered fuel transport and/or metabolism, lead to defective glucose counter-regulation and impaired hypoglycemia awareness. 3 The cerebral response to hypoglycemia in the healthy brain involves changes in regional blood flow 4,5 and sequential adjustments in cerebral metabolism in order to provide sufficient fuel for brain activity. As the levels of glucose, the principal cerebral energy substrate, drop from 5 to B3 mmol/L in plasma, cerebral metabolic rate of glucose (CMRglc) and cerebral metabolic rate of oxygen (CMRO 2 ) are preserved [6][7][8] despite lower brain glucose uptake.…”

Section: Introductionmentioning

confidence: 99%

Changes in Human Brain Glutamate Concentration during Hypoglycemia: Insights into Cerebral Adaptations in Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes

Terpstra

Moheet

Kumar

et al. 2014

J Cereb Blood Flow Metab

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Hypoglycemia-associated autonomic failure (HAAF) is a condition in which patients with type 1 diabetes (T1D) who experience frequent hypoglycemia develop defective glucose counter-regulation and become unable to sense hypoglycemia. Brain glutamate may be involved in the mechanism of HAAF. The goal of this study was to follow the human brain glutamate concentration during experimentally induced hypoglycemia in subjects with and without HAAF. 1 H magnetic resonance spectroscopy was used to track the occipital cortex glutamate concentration throughout a euglycemic clamp followed immediately by a hypoglycemic clamp. T1D patients with HAAF were studied in comparison to two control groups, i.e., T1D patients without HAAF and healthy controls (n ¼ 5 per group). Human brain glutamate concentration decreased (Pp0.01) after the initiation of hypoglycemia in the two control groups, but a smaller trend toward a decrease in patients with HAAF did not reach significance (P40.05). These findings are consistent with a metabolic adaptation in HAAF to provide higher glucose and/or alternative fuel to the brain, eliminating the need to oxidize glutamate. In an exploratory analysis, we detected additional metabolite changes in response to hypoglycemia in the T1D patient without HAAF control group, namely, increased aspartate and decreased lactate.

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3. Cerebral Adaptation to Recurrent Hypoglycemia

Cited by 8 publications

References 0 publications

RD Lawrence Lecture 2015 Old habits are hard to break: lessons from the study of hypoglycaemia

RD Lawrence Lecture 2015 Old habits are hard to break: lessons from the study of hypoglycaemia

Consequences of recurrent hypoglycaemia on brain function in diabetes

Changes in Human Brain Glutamate Concentration during Hypoglycemia: Insights into Cerebral Adaptations in Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes

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