Review Article

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

Table 1

Summary of procedures used to reproduce the HAAF phenomenon in diabetic and nondiabetic humans.

SubjectsFasting conditionInsulin dose used to induce antecedent hypoglycaemiaInsulin dose used to induce subsequent hypoglycaemiaDepth and duration of antecedent hypoglycaemiaMethod of glucose assayNumber of antecedent episodesPlasma adrenaline in response to antecedent/subsequent hypoglycaemia (in pg/mL) and method of assaySymptom scores during subsequent hypoglycaemia relative to that of antecedent hypoglycaemia

Type 1 diabetes patients [1417]Overnight fasted prior to all days of experiments [16, 17]
Overnight fasted prior to subsequent episode [14, 15]
1-2 mU/kg/min [1417]1-2 mU/kg/min [1417]2.2–3.3 mmol/L [1417]
1.5–2 hrs [14, 16, 17]
Glucose dehydrogenase method [15]
Glucose oxidase method [14, 16, 17]
1/day for 1 day [14, 16]
2/day for 1 day [17]
1/day for 4 days [15]
380/200; [14]
187/75; [17]
817/545; [15]
300/200; [16]
HPLC [15]
RIA [14, 16, 17]
Reduced neurogenic symptoms and neuroglycopenic symptoms –0.001 [14, 15]
Not measured [17]
No significant change [16]

Type 2 diabetes patients [18]Overnight fasted prior to all days of experiments [18]1-2 mU/kg/min [18]1-2 mU/kg/min [18]2.2–3.3 mmol/L [18]
1.5–2 hrs [18]
Glucose oxidase method [18]2/day for 1 day [18]No significant change in insulin treated patients
[18]
RIA [18]
Reduced neurogenic symptoms and neuroglycopenic symptoms –0.001 [18]

Nondiabetic subjects [1927]Nonfasted [24]
Overnight fasted prior to all days of experiments [1925, 27]
1-2 mU/kg/min [1927]1-2 mU/kg/min [1927]2.2–2.8 mmol/L [2124]
2.9–3.3 mmol/L [19, 20, 23, 25, 27]
40 min–2 hrs [20, 21, 2326]
3 hrs [22]
Glucose oxidase method [2023, 25, 27]
HemoCue handheld device [24, 26]
1/day for 1 day [19]
2/day for 1 day followed by
1/day on day 2 [21]
2/day for 1 day [2227]
1/day for 1 day followed by interval interprandial hypoglycaemia [20]
300–500/150–250;
–0.001 [2022, 25]
800–1000/350–500; –0.01 [19, 23, 26, 27]
No significant change [24]
HPLC [21, 22, 24, 26, 27]
RIA [20, 23]
Not measured [23, 25, 27]
No significant change [22]
Reduced neuroglycopenic symptoms ; no significant change in neurogenic symptoms [24]
Reduced neurogenic symptoms and neuroglycopenic symptoms; –0.001 [1921]

RIA: radioimmunoassay; HPLC: high-performance liquid chromatography.