title: Hypoglycemia begets hypoglycemia: the order effect in the ASPIRE in-clinic study.
abstract: BACKGROUND
  The ASPIRE in-clinic study established that automatic suspension of insulin with the threshold suspend (TS) feature reduces the duration of induced hypoglycemia. The study's crossover design allowed the effects of antecedent hypoglycemia to be studied.
  
  
  METHODS
  The study enrolled 50 subjects who exercised until plasma glucose (YSI glucose and lactate analyzer; YSI, Inc., Yellow Springs, OH) reached ≤85 mg/dL. Hypoglycemia was evaluated after the YSI value reached <70 mg/dL. In TS experiments, insulin was stopped for 2 h once a sensor glucose (SG) value of ≤70 mg/dL was detected; in control experiments, basal insulin delivery continued. Subjects were randomly assigned to Group A (TS in Period 1; control in Period 2) or Group B (control in Period 1; TS in Period 2). Experiments were separated by 3-10 days.
  
  
  RESULTS
  Hypoglycemia was 63.7 min shorter in Period 1 TS experiments (no preceding control experiment) than in Period 2 TS experiments (one or more preceding control experiment(s)) (P<0.01). The number of experiments prior to a successful TS experiment was lower for Period 1 than for Period 2 (0.36 ± 0.64 vs. 1.57 ± 0.84; P<0.001), as was the cumulative duration of antecedent hypoglycemia (16.6 min vs. 204.6 min; P<0.001). The between-groups difference in hypoglycemia duration was not attributable to differences in SG rates of change, the duration of exercise, or area under the curve of <70 mg/dL × min in the 2 days before the successful experiment (all P>0.3).
  
  
  CONCLUSIONS
  The TS feature's ability to mitigate hypoglycemia was decreased by an episode or episodes of prolonged antecedent hypoglycemia, suggesting hypoglycemia begets hypoglycemia. The effect of antecedent hypoglycemia should be taken into consideration in the design of future experiments assessing strategies to reduce hypoglycemia.
authors.affiliation: 1 University of Colorado Denver , Aurora, Colorado.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Garg
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Brazg
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Bailey
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Buckingham
authors.forename: Robert H
authors.initials: RH
authors.lastname: Slover
authors.forename: David C
authors.initials: DC
authors.lastname: Klonoff
authors.forename: John
authors.initials: J
authors.lastname: Shin
authors.forename: John B
authors.initials: JB
authors.lastname: Welsh
authors.forename: Francine R
authors.initials: FR
authors.lastname: Kaufman
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism*; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015444:Exercise; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage; D007332:Insulin Infusion Systems; D008297:Male; D018670:Monitoring, Ambulatory; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; C517652:hemoglobin A1c protein, human