Aim/hypothesis: The physiological counterregulatory response to hypoglycaemia is reportedly hierarchically organized, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To more accurately compare thresholds for activation of these responses 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. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using methods 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% confidence interval of the mean baseline measurement or euglycaemic control clamp.

Results: A total of 63 articles were included. Compared to non-diabetic controls, 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) mmol/l 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 than in those without diabetes (all p ≤ 0.01). Similarly, although both autonomic (3.4 (3.4-3.4) vs. 3.0 (2.8-3.4) mmol/l) and neuroglycopenic (3.4 (2.8-∞ 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.