title: Restoration of self-awareness of hypoglycemia in adults with long-standing type 1 diabetes: hyperinsulinemic-hypoglycemic clamp substudy results from the HypoCOMPaSS trial.
abstract: OBJECTIVE
  Impaired awareness of hypoglycemia (IAH) and defective counterregulation significantly increase severe hypoglycemia risk in type 1 diabetes (T1D). We evaluated restoration of IAH/defective counterregulation by a treatment strategy targeted at hypoglycemia avoidance in adults with T1D with IAH (Gold score ≥4) participating in the U.K.-based multicenter HypoCOMPaSS randomized controlled trial.
  
  
  METHODS
  Eighteen subjects with T1D and IAH (mean ± SD age 50 ± 9 years, T1D duration 35 ± 10 years, HbA1c 8.1 ± 1.0% [65 ± 10.9 mmol/mol]) underwent stepped hyperinsulinemic-hypoglycemic clamp studies before and after a 6-month intervention. The intervention comprised the HypoCOMPaSS education tool in all and randomized allocation, in a 2 × 2 factorial study design, to multiple daily insulin analog injections or continuous subcutaneous insulin infusion therapy and conventional glucose monitoring or real-time continuous glucose monitoring. Symptoms, cognitive function, and counterregulatory hormones were measured at each glucose plateau (5.0, 3.8, 3.4, 2.8, and 2.4 mmol/L), with each step lasting 40 min with subjects kept blinded to their actual glucose value throughout clamp studies.
  
  
  RESULTS
  After intervention, glucose concentrations at which subjects first felt hypoglycemic increased (mean ± SE from 2.6 ± 0.1 to 3.1 ± 0.2 mmol/L, P = 0.02), and symptom and plasma metanephrine responses to hypoglycemia were higher (median area under curve for symptoms, 580 [interquartile range {IQR} 420-780] vs. 710 [460-1,260], P = 0.02; metanephrine, 2,412 [-3,026 to 7,279] vs. 5,180 [-771 to 11,513], P = 0.01). Glycemic threshold for deterioration of cognitive function measured by four-choice reaction time was unchanged, while the color-word Stroop test showed a degree of adaptation.
  
  
  CONCLUSIONS
  Even in long-standing T1D, IAH and defective counterregulation may be improved by a clinical strategy aimed at hypoglycemia avoidance.
authors.affiliation: Corresponding author: Mark L. Evans, mle24@cam.ac.uk.
authors.forename: Lalantha
authors.initials: L
authors.lastname: Leelarathna
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Little
authors.forename: Emma
authors.initials: E
authors.lastname: Walkinshaw
authors.forename: Horng Kai
authors.initials: HK
authors.lastname: Tan
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lubina-Solomon
authors.forename: Kavita
authors.initials: K
authors.lastname: Kumareswaran
authors.forename: Annette P
authors.initials: AP
authors.lastname: Lane
authors.forename: Thomas
authors.initials: T
authors.lastname: Chadwick
authors.forename: Sally M
authors.initials: SM
authors.lastname: Marshall
authors.forename: Jane
authors.initials: J
authors.lastname: Speight
authors.forename: Daniel
authors.initials: D
authors.lastname: Flanagan
authors.forename: Simon R
authors.initials: SR
authors.lastname: Heller
authors.forename: James A M
authors.initials: JA
authors.lastname: Shaw
authors.forename: Mark L
authors.initials: ML
authors.lastname: Evans
mesh_terms: D000328:Adult; D001364:Awareness; D001786:Blood Glucose / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000517:prevention & control* / Q000523:psychology*; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage*; D007332:Insulin Infusion Systems; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin