Challenges in Modelling Hypoglycaemia-Associated Autonomic Failure: A Review of Human and Animal Studies

Senthilkumaran, Manjula; Zhou, Xin‐Fu; Bobrovskaya, Larisa

doi:10.1155/2016/9801640

Cited by 15 publications

(14 citation statements)

References 61 publications

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“…The imperfect pharmacokinetic and pharmacodynamic regulation of insulin requires careful consideration when administering the drug for treatment. A single episode of antecedent hypoglycemia can reduce the sympathoadrenal response to subsequent hypoglycemia, with repeated episodes of hypoglycemia leading to the development of HAAF (50). Established HAAF, together with impaired awareness of hypoglycemia, increases the risk of developing severe hypoglycemia, potentially leading to coma or death (6, 7).…”

Section: Discussionmentioning

confidence: 99%

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Kakall

Kavurma

Cohen

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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The impaired ability of the autonomic nervous system to respond to hypoglycemia is termed “hypoglycemia-associated autonomic failure” (HAAF). This life-threatening phenomenon results from at least two recent episodes of hypoglycemia, but the pathology underpinning HAAF remains largely unknown. Although naloxone appears to improve hypoglycemia counterregulation under controlled conditions, hypoglycemia prevention remains the current mainstay therapy for HAAF. Epinephrine-synthesizing neurons in the rostroventrolateral (C1) and dorsomedial (C3) medulla project to the subset of sympathetic preganglionic neurons that regulate peripheral epinephrine release. Here we determined whether or not C1 and C3 neuronal activation is impaired in HAAF and whether or not 1 wk of hypoglycemia prevention or treatment with naloxone could restore C1 and C3 neuronal activation and improve HAAF. Twenty male Sprague-Dawley rats (250–300 g) were used. Plasma epinephrine levels were significantly increased after a single episode of hypoglycemia ( n = 4; 5,438 ± 783 pg/ml vs. control 193 ± 27 pg/ml, P < 0.05). Repeated hypoglycemia significantly reduced the plasma epinephrine response to subsequent hypoglycemia ( n = 4; 2,179 ± 220 pg/ml vs. 5,438 ± 783 pg/ml, P < 0.05). Activation of medullary C1 ( n = 4; 50 ± 5% vs. control 3 ± 1%, P < 0.05) and C3 ( n = 4; 45 ± 5% vs. control 4 ± 1%, P < 0.05) neurons was significantly increased after a single episode of hypoglycemia. Activation of C1 ( n = 4; 12 ± 3%, P < 0.05) and C3 ( n = 4; 19 ± 5%, P < 0.05) neurons was significantly reduced in the HAAF groups. Hypoglycemia prevention or treatment with naloxone did not restore the plasma epinephrine response or C1 and C3 neuronal activation. Thus repeated hypoglycemia reduced the activation of C1 and C3 neurons mediating adrenal medullary responses to subsequent bouts of hypoglycemia.

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Section: Discussionmentioning

confidence: 99%

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Kakall

Kavurma

Cohen

et al. 2019

American Journal of Physiology-Endocrinology and Metabolism

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“…In rats, after 3 weeks of this RH protocol, the dose of insulin is decreased by 25% to prevent the development of severe hypoglycaemia requiring rescue [69]. Interestingly, the effect of two antecedent hypoglycaemic episodes on the same day, compared with one, does not seem to produce a greater attenuation in adrenaline release on subsequent hypoglycaemia in rats [84]. Therefore, if IAH represents a form of neuronal adaptation such as habituation, an effect may be encountered only with a greater number of hypoglycaemia episodes and by allowing more time between episodes for cellular modification.…”

Section: Depth and Number Of Antecedent Hypoglycaemia Episodesmentioning

confidence: 99%

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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“…ingest carbohydrates), aimed at restoring glucose levels. Overall, it is generally considered that hypoglycaemia first elicits autonomic symptoms, hence termed warning symptoms, followed by neuroglycopenic symptoms, usually thought to reflect cerebral glucopenia [2].…”

Section: Introductionmentioning

confidence: 99%

Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review

Verhulst

Fabricius

Teerenstra³

et al. 2022

Diabetologia

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Aim/hypothesis The physiological counterregulatory response to hypoglycaemia is reported to be organised hierarchically, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To compare thresholds for activation of these responses more accurately between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic–hypoglycaemic glucose clamps. Methods A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Key exclusion criteria were as follows: data were previously published; other patient population; a clamp not the primary intervention; and an inadequate clamp description. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using generalised logrank test for interval-censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% CI of the mean baseline measurement or euglycaemic control clamp. Because of the use of interval-censored data, we described thresholds using median and IQR. Results A total of 63 articles were included, whereof 37 papers included participants with type 1 diabetes (n=559; 67.4% male sex, aged 32.7±10.2 years, BMI 23.8±1.4 kg/m2) and 51 papers included participants without diabetes (n=733; 72.4% male sex, aged 31.1±9.2 years, BMI 23.6±1.1 kg/m2). Compared with non-diabetic control individuals, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 [3.2–4.2] vs 3.4 [2.8–3.9 mmol/l]), noradrenaline (3.2 [3.2–3.7] vs 3.0 [2.8–3.1] mmol/l), cortisol (3.5 [3.2–4.2]) vs 2.8 [2.8–3.4] mmol/l) and growth hormone (3.8 [3.3–3.8] vs. 3.2 [3.0–3.3] mmol/l) all occurred at lower glucose levels in people with diabetes than in those without diabetes (all p≤0.01). Similarly, although both autonomic (median [IQR] 3.4 [3.4–3.4] vs 3.0 [2.8–3.4] mmol/l) and neuroglycopenic (median [IQR] 3.4 [2.8–N/A] vs 3.0 [3.0–3.1] mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. Conclusions/interpretation People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia. There was a considerable variation in the methodology of the articles and the high insulin doses in most of the clamps may affect the counterregulatory responses. Funding This article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. Registration This systematic review is registered in PROSPERO (CRD42019120083). Graphical abstract

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Challenges in Modelling Hypoglycaemia-Associated Autonomic Failure: A Review of Human and Animal Studies

Cited by 15 publications

References 61 publications

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia

Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation

Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review

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