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

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Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review
Diabetologia ( IF 8.4 ) Pub Date : 2022-07-22 , DOI: 10.1007/s00125-022-05749-8
Clementine E M Verhulst ₁ , Therese W Fabricius ₂ , Steven Teerenstra ₃ , Peter L Kristensen _{2,

4} , Cees J Tack ₁ , Rory J McCrimmon ₅ , Simon Heller ₆ , Mark L Evans ₇ , Stephanie A Amiel ₈ , Ulrik Pedersen-Bjergaard _{2,

4} , Bastiaan E de Galan _{1,

9,

10} ,

Affiliation

Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands.
Department of Endocrinology and Nephrology, Nordsjællands Hospital, Hillerød, Denmark.
Section Biostatistics, Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
School of Medicine, University of Dundee, Dundee, Scotland.
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
Wellcome Trust/MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Centre, Maastricht, the Netherlands.
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.

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

中文翻译：

1 型糖尿病患者和非 1 型糖尿病患者反调节激素的血糖阈值和对低血糖的症状反应：系统评价

目标/假设

据报道，对低血糖的生理反调节反应是分层组织的，激素反应通常先于症状意识，自主神经反应先于神经低血糖反应。为了更准确地比较 1 型糖尿病患者或非 1 型糖尿病患者激活这些反应的阈值，我们对阶梯式高胰岛素血症-低血糖葡萄糖钳夹进行了系统评价。

方法

在 PubMed 和 EMBASE 中进行了文献检索。我们纳入了 1980 年至 2018 年间发表的文章，这些文章涉及患有或不患有 1 型糖尿病的人的高胰岛素血症阶梯式低血糖葡萄糖钳夹。主要排除标准如下：其他患者群体；钳夹不是主要干预措施；和不充分的钳位描述。对反调节激素的血糖阈值和/或对低血糖的症状反应进行了估计，并使用广义对数秩检验对区间删失数据进行了比较，其中区间直接提取或根据研究提供的数据计算得出。血糖阈值定义为响应超过平均基线测量或正常血糖控制钳的 95% CI 的葡萄糖水平。

结果

共纳入 63 篇文章，其中 37 篇论文包括 1 型糖尿病患者（n = 559；67.4% 男性，年龄 32.7±10.2 岁，BMI 23.8±1.4 kg/m ²），51 篇论文包括非糖尿病患者（n =733；72.4% 为男性，年龄 31.1±9.2 岁，BMI 23.6±1.1 kg/m ² )。与非糖尿病对照个体相比，在 1 型糖尿病患者中，肾上腺素（3.8 [3.2–4.2] vs 3.4 [2.8–3.9 mmol/l]）、去甲肾上腺素（3.2 [3.2–3.7 mmol/l]）的中位 (IQR) 血糖阈值] vs 3.0 [2.8–3.1] mmol/l），皮质醇（3.5 [3.2–4.2]）vs 2.8 [2.8–3.4] mmol/l）和生长激素（3.8 [3.3–3.8] vs. 3.2 [3.0–3.3] ] mmol/l) 糖尿病患者的血糖水平低于非糖尿病患者（所有p≤0.01)。同样，尽管自主神经（中位数 [IQR] 3.4 [3.4-3.4] vs 3.0 [2.8-3.4] mmol/l）和神经低血糖症（中位数 [IQR] 3.4 [2.8-N/A] vs 3.0 [3.0-3.1] mmol/l） /l) 症状反应是在 1 型糖尿病患者的较低葡萄糖水平下引起的，每个亚组的自主神经和神经低血糖症状的阈值没有差异。