title: Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta-adrenergic sensitivity in type 1 diabetes.
abstract: BACKGROUND
  Lack of awareness of hypoglycemia is a major limiting factor in the management of type 1 diabetes.
  
  
  OBJECTIVE
  To examine whether reduction in the number of episodes of hypoglycemia restores hypoglycemia awareness by influencing beta-adrenergic sensitivity in patients with type 1 diabetes.
  
  
  METHODS
  Controlled interventional study.
  
  
  METHODS
  Research unit and outpatient diabetes clinic of a university hospital.
  
  
  METHODS
  10 men with type 1 diabetes and hypoglycemia unawareness (mean age [+/-SD], 46 +/- 16 years; mean duration of diabetes, 20 +/- 10 years).
  
  
  METHODS
  Strict avoidance of hypoglycemia.
  
  
  METHODS
  beta-Adrenergic sensitivity was measured by isoproterenol testing before and at 2 and 4 months after strict avoidance of hypoglycemia. Hypoglycemia awareness and catecholamine response were measured by performing hypoglycemic clamp (glucose level, 3 mmol/L [54 mg/dL]) before and after 4 months of avoidance of hypoglycemia.
  
  
  RESULTS
  After 4 months, the mean (+/-SE) number of episodes of hypoglycemia (glucose level < 3.9 mmol/L [70 mg/dL]) decreased from 8.4 +/- 0.9 to 1.4 +/- 0.3 per week (P < 0.001). Hemoglobin A(1c) values increased from 0.068 +/- 0.003 (6.8% +/- 0.3%) to 0.077 +/- 0.003 (7.7% +/- 0.3%) (P < 0.001). Autonomic symptom scores during hypoglycemic clamp increased from 1.8 +/- 0.6 to 3.3 +/- 0.7 (P = 0.004) and did not significantly differ from those of normal participants (4.7 +/- 0.8) (P > 0.2). Although catecholamine responses to hypoglycemia were unchanged, the dose of isoproterenol necessary to increase heart rate by 25 beats/min (IC(25)) decreased from 1.96 +/- 0.43 microgram before treatment to 1.09 +/- 0.17 microgram after 4 months of treatment (P = 0.01), a value similar to that in normal participants (0.85 +/- 0.20 microgram) (P > 0.2). Improvements in beta-adrenergic sensitivity (change in IC(25)(-1)) were correlated with improvements in autonomic symptoms (r = 0.65; P = 0.04).
  
  
  CONCLUSIONS
  Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing beta-adrenergic sensitivity.
authors.affiliation: Medizinische Universitätsklinik Tübingen, Otfried-Müller-Strabetae 10, 72076 Tübingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Fritsche
authors.forename: N
authors.initials: N
authors.lastname: Stefan
authors.forename: H
authors.initials: H
authors.lastname: Häring
authors.forename: J
authors.initials: J
authors.lastname: Gerich
authors.forename: M
authors.initials: M
authors.lastname: Stumvoll
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D004837:Epinephrine / Q000097:blood; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D007328:Insulin / Q000008:administration & dosage; D007545:Isoproterenol; D008297:Male; D008875:Middle Aged; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012044:Regression Analysis; D018709:Statistics, Nonparametric
chemical_list: D001786:Blood Glucose; D004837:Epinephrine; D006442:Glycated Hemoglobin; D007328:Insulin; D007545:Isoproterenol; D011943:Receptors, Adrenergic, beta