<scp>NMDA</scp> receptor blockade by memantine does not prevent adaptation to recurrent hypoglycaemia in healthy men

Klement, Johanna; Pais, Isabel Pinto; Strube, Jochen; Lehnert, Hendrik; Peters, Achim; Hallschmid, Manfred; Born, Jan

doi:10.1111/dom.12027

Cited by 6 publications

(12 citation statements)

References 30 publications

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“…Therefore, patients with type 1 diabetes may develop attenuated glucagon release before IAH develops. This reiterates the importance of the sympathoadrenal response in people with diabetes who have IAH [32].…”

Section: Box 2 Investigating Iah In Humansmentioning

confidence: 65%

Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation

Sankar

Khodai

McNeilly

et al. 2020

Trends in Endocrinology & Metabolism

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Impaired awareness of hypoglycaemia (IAH) affects around a quarter of patients with diabetes who receive insulin treatment. This condition is characterised by a progressive reduction in symptomatic and behavioural responses to hypoglycaemia, increasing risk of deeper drops in blood glucose, unconsciousness, and collapse. Thus, patients with IAH experience severe hypoglycaemic episodes more frequently, resulting in significant morbidity and mortality. IAH is thought to develop as a consequence of whole-body adaptations to repeated insulin-induced hypoglycaemia (RH), with widespread deficits in the hypoglycaemia counterregulatory response (CRR). Despite this important insight, the precise pathophysiology by which RH leads to an attenuated CRR is unknown. Studies into the underlying mechanisms of IAH have employed a variety of protocols in humans and experimental species. The use of animal models has many investigational benefits, including the unprecedented increase in the availability of transgenic strains. However, modelling impaired hypoglycaemia-associated counterregulation remains challenging and appropriate interpretation of findings across species and protocols even more so. Here, we review the experimental modelling of IAH and impaired hypoglycaemia-associated counter-regulation, with a focus on understanding species-specific variation in glucose homeostasis. This review will aid investigators in interpreting outputs from different studies in IAH and aid progress in the field. HighlightsImpaired awareness of hypoglycaemia (IAH) is a common and poorly understood complication of insulin-treated diabetes and evolves following repeated episodes of hypoglycaemia.An improved mechanistic understanding of IAH is required and necessitates a robust disease model with which to interrogate changes within the glucoseregulatory network.A large variety of experimental models have been outlined, leading to a lack of consensus among investigators in this field. Appreciating the influence of experimental parameters and physiological differences on findings can aid progress in the field.

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Section: Box 2 Investigating Iah In Humansmentioning

confidence: 65%

Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation

Sankar

Khodai

McNeilly

et al. 2020

Trends in Endocrinology & Metabolism

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“…Thereafter, insulin was stopped and euglycaemia was re‐established. Repeatedly, blood samples were drawn, and hypoglycaemic symptoms and selective attention (assessed using the Stroop test) were assessed . On the first day at 13:00 h, another hypoglycaemic clamp procedure was performed to achieve repeated exposure to hypoglycaemia.…”

Section: Methodsmentioning

confidence: 99%

“…Thereafter, insulin was stopped and euglycaemia was re-established. Repeatedly, blood samples were drawn, and hypoglycaemic symptoms and selective attention (assessed using the Stroop test) were assessed [8]. On the first day at 13:00 h, another hypoglycaemic clamp procedure was performed to achieve repeated exposure to whole-blood glucose (conversion factor to plasma glucose: × 1.1), (B) glucose infusion rates, (C) insulin and (D) C-peptide in the placebo (white triangles) and the modafinil condition (black circles: oral administration of 200 mg modafinil at 08:45h on day 2 as indicated by the arrow).…”

Section: Methodsmentioning

confidence: 99%

Role of γ‐aminobutyric acid signalling in the attenuation of counter‐regulatory hormonal responses after antecedent hypoglycaemia in healthy men

Klement

Mergelkuhl

Born

et al. 2014

Diabetes Obesity Metabolism

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The attenuated counter-regulatory response to hypoglycaemia after antecedent hypoglycaemic episodes has been observed in animals to be associated with an increase in γ-aminobutyric acid (GABA) signalling. We therefore tested the hypothesis that the pharmacological suppression of GABAergic activity during a repeated hypoglycaemic episode enhances counter-regulatory responses. Fourteen healthy men participated in two experimental sessions each comprising three insulin-induced hypoglycaemic episodes. Before the third hypoglycaemic episode, participants received the GABA-antagonistic drug modafinil (200 mg orally) and placebo, respectively. In the placebo condition, the secretion of norepinephrine, adrenocorticotropic hormone, cortisol and growth hormone, and the perception of neuroglycopenic symptoms were attenuated during the third as compared with the first hypoglycaemic episode (each p < 0.05). Modafinil reversed this effect for the noradrenergic response (p < 0.05), while not significantly altering the attenuation of other hormonal responses and symptom perception (p > 0.3). Our findings indicate that increased GABAergic transmission could contribute to aspects of the attenuated counter-regulatory response after recurrent hypoglycaemia in humans.

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“…N-methyl D-aspartate (NMDA) is an excitatory glutamate receptor. It has been implicated in long-term potentiation of memory formation and learning 52 . A study in dogs treated with an NMDA antagonist before undergoing insulin- induced hypoglycemia found a reduction in plasma epinephrine and cortisol levels, suggesting that glutamate stimulates the hypothalamic-pituitary-adrenal and the sympathetic-adrenal axis via NMDA channels 53 .…”

Section: Central Approaches For Modulating Haafmentioning

confidence: 99%

“…A study in dogs treated with an NMDA antagonist before undergoing insulin- induced hypoglycemia found a reduction in plasma epinephrine and cortisol levels, suggesting that glutamate stimulates the hypothalamic-pituitary-adrenal and the sympathetic-adrenal axis via NMDA channels 53 . When given an NMDA antagonist for four days prior to undergoing hypoglycemic studies, healthy human subjects demonstrated reduced cortisol, ACTH, epinephrine, norepinephrine, growth hormone and glucagon secretion, which led the authors to conclude that NMDA antagonists are not effective in preventing the hypoglycemic counter-regulatory response 52 . However, a study found that memantine, an NMDA antagonist, caused an increase in counter-regulatory hormones as well as neuroglycopenic symptoms in healthy adults 54 .…”

Section: Central Approaches For Modulating Haafmentioning

confidence: 99%

Potential Approaches to Prevent Hypoglycemia-Associated Autonomic Failure

Lontchi-Yimagou

You

Carey

et al. 2018

Journal of Investigative Medicine

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Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to 'hypoglycemia-associated autonomic failure' (HAAF), characterized by defective counter-regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(K) channels, adrenergic receptors, serotonin selective receptor inhibitors, γ-aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-à-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control.

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NMDA receptor blockade by memantine does not prevent adaptation to recurrent hypoglycaemia in healthy men

Cited by 6 publications

References 30 publications

Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation

Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation

Role of γ‐aminobutyric acid signalling in the attenuation of counter‐regulatory hormonal responses after antecedent hypoglycaemia in healthy men

Potential Approaches to Prevent Hypoglycemia-Associated Autonomic Failure

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