@article{b4292583f51c41078ffcad17a8173ba2,
title = "Hyperinsulinaemic-hypoglycaemic glucose clamps in human research: a systematic review of the literature",
abstract = "Aims/hypothesis The hyperinsulinaemic-hypoglycaemic glucose clamp technique has been developed and applied to assess effects of and responses to hypoglycaemia under standardised conditions. However, the degree to which the methodology of clamp studies is standardised is unclear. This systematic review examines how hyperinsulinaemic-hypoglycaemic clamps have been performed and elucidates potential important differences.Methods A literature search in PubMed and EMBASE was conducted. Articles in English published between 1980 and 2018, involving adults with or without diabetes, were included.Results A total of 383 articles were included. There was considerable variation in essential methodology of the hypoglycaemic clamp procedures, including the insulin dose used (49-fold difference between the lowest and the highest rate), the number of hypoglycaemic steps (range 1-6), the hypoglycaemic nadirs (range 2.0-4.3 mmol/l) and the duration (ranging from 5 to 660 min). Twenty-seven per cent of the articles reported whole blood glucose levels, most venous levels. In 70.8% of the studies, a dorsal hand vein was used for blood sampling, with some form of hand warming to arterialise venous blood in 78.8% of these. Key information was missing in 61.9% of the articles.Conclusions/interpretation Although the hyperinsulinaemic-hypoglycaemic clamp procedure is considered the gold standard to study experimental hypoglycaemia, a uniform standard with key elements on how to perform these experiments is lacking. Methodological differences should be considered when comparing results between hypoglycaemic clamp studies.",
keywords = "blood, caffeine, counterregulatory response, diabetes, diabetes mellitus, equivalent hypoglycemia, glucagon, human, hyperinsulinaemic-hypoglycaemic clamp, hypoglycaemia, insulin, subsequent hypoglycemia, symptoms, systematic review, type 1 diabetes, type 2 diabetes, unawareness, Type 2 diabetes, Hyperinsulinaemic-hypoglycaemic clamp, Systematic review, UNAWARENESS, EQUIVALENT HYPOGLYCEMIA, BLOOD, GLUCAGON, Human, Hypoglycaemia, Diabetes mellitus, CAFFEINE, COUNTERREGULATORY RESPONSE, SYMPTOMS, INSULIN, SUBSEQUENT HYPOGLYCEMIA, Type 1 diabetes, Diabetes",
author = "T.W. Fabricius and C.E.M. Verhulst and P.L. Kristensen and C.J. Tack and R.J. McCrimmon and S. Heller and M.L. Evans and S.A. Amiel and T.R. Pieber and {de Galan}, B.E. and U. Pedersen-Bjergaard and {Hypo-RESOLVE Consortium}",
note = "Funding Information: This review 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{\textquoteright}s Horizon 2020 research and innovation programme and the EFPIA, the T1D Exchange, JDRF, the International Diabetes Federation (IDF), and the Leona M. and Harry B. Helmsley Charitable Trust. Funding Information: The authors would like to acknowledge the support of J. Meelby, Information Specialist, Library and Information Services at Nordsj?llands Hospital, Denmark, for her assistance with the systematic search strategy. Some of the data were presented as an abstract at the Annual Dutch Diabetes Research Meeting in 2019 and as a presentation at the EASD Annual Meeting 2020. TWF: None. CEMV: None. PLK has received lecture fees from AstraZeneca. RJM has served on advisory boards for Novo Nordisk and Sanofi, and has received lecture fees from Novo Nordisk and Sanofi. MLE has served on advisory boards and/or received speaker/travel support from Novo Nordisk, Medtronic, Abbott Diabetes Care, Roche, Pila Pharma, Dexcom, Eli Lilly, Astra Zeneca and Zucara. SH has served on advisory boards for Sanofi-Aventis, Eli Lilly, Novo Nordisk and Zealand Pharma, and received lecture fees from Novo Nordisk and AstraZeneca. TRP has received research support from AstraZeneca and Novo Nordisk (paid directly to the university); has served on advisory boards for Adocia, Arecor, AstraZeneca, Eli Lilly, Novo Nordisk and Sanofi; and has received lecture fees from Novo Nordisk. BEDG has received research support from Novo Nordisk. 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. The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2021",
month = apr,
doi = "10.1007/s00125-020-05361-8",
language = "English",
volume = "64",
pages = "727–736",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer",
number = "4",
}