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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

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Original languageEnglish
Pages (from-to)1601-1612
Number of pages12
JournalDiabetologia
Volume65
Issue number10
DOIs
Accepted/In press2022
PublishedOct 2022

Bibliographical note

Funding Information: The authors would like to acknowledge the support of J. Meelby (Information Specialist, Library and Information Services at Nordsjællands Hospital, Denmark) for her assistance with the systematic search strategy. PLK has received lecture fees from AstraZeneca, Sanofi and Novo Nordisk. CJT has received research support from AstraZeneca, served on advisory boards for Bayer, Boehringer-Ingelheim, MSD and Novo Nordisk, and has received lecture fees from AstraZeneca and Novo Nordisk. RJM has served on advisory boards for Novo Nordisk and Sanofi and has received lecture fees from Novo Nordisk and Sanofi. SRH has served on advisory boards for Sanofi-Aventis, Eli Lilly, Novo Nordisk, Zealand Pharma and has received lecture fees from Novo Nordisk and AstraZeneca. MLE has received speakers/writers’ fees, acted on advisory board, and/or had research collaborations with/acted as a triallist for Eli Lilly, Novo Nordisk, Sanofi, Medtronic, Dexcom, Roche, Astra Zeneca, Zucara, Abbott Diabetes Care, Pila Pharma, Imcyse, Ypsomed and Provention. SAA has served on advisory boards for Medtronic and Novo Nordisk in the last year and given a lecture at a Sanofi-sponsored educational meeting. UP-B has served on advisory boards for AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, Novo Nordisk and Zealand Pharma and has received lecture fees from AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis and Novo Nordisk. BDG has received research support from Novo Nordisk. UP-B and BDG are both associate editors for Diabetologia but were not involved in the handling of the manuscript during the editorial process. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. TWF, CV, UP-B and BDG designed the study. TWF and CV selected the articles, appraised the articles and extracted data for the review. TWF analysed the data. TWF and CV wrote the first version of the manuscript with input from UP-B and BDG. All other authors contributed to interpretation of the data, critical reading and providing comments and edits to the manuscript for important intellectual content. All authors gave final approval of the version to be published. TWF and CV are guarantors of the work. Funding Information: This article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. The JU receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, International Diabetes Federation (IDF) and The Leona M. and Harry B. Helmsley Charitable Trust. Publisher Copyright: © 2022, The Author(s).

King's Authors

Abstract

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: [Figure not available: see fulltext.]

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