Effect of 2 weeks of theophylline on glucose counterregulation in patients with type 1 diabetes and unawareness of hypoglycemia.
OBJECTIVE
A single dose of theophylline improves hypoglycemia unawareness in type 1 diabetic patients. Prolonged theophylline use is, however, associated with emergence of tolerance. This study investigated whether prolonged use of theophylline retains efficacy for counterregulatory defects in patients with type 1 diabetes and hypoglycemia unawareness.


METHODS
Experiments were performed with 12 subjects with type 1 diabetes and hypoglycemia unawareness. All subjects participated in a crossover study of 2 randomly scheduled 15-day study periods during which 250 mg theophylline twice daily or matching placebo was used. On the final day of each period, hyperinsulinemic (360 pmol x m(-2) x min(-1)) hypoglycemic (5.0, 3.5, 2.5 mmol x L(-1)) glucose clamps were used to assess counterregulatory and cardiovascular responses.


RESULTS
Under normoglycemic conditions, there were no differences between theophylline and placebo. Under hypoglycemic conditions, theophylline enhanced responses of growth hormone, symptoms, heart rate, and pulse pressure (all P <.05), induced sweating at higher plasma glucose levels (P =.039), and reduced exogenous glucose requirements (P =.018). Hypoglycemia-induced responses of epinephrine, norepinephrine, and cortisol were not enhanced by theophylline.


CONCLUSIONS
Prolonged use of theophylline has a sustained effect on cardiovascular, metabolic, and symptom responses to hypoglycemia in patients with type 1 diabetes and hypoglycemia unawareness. Whether these results translate into clinical benefit remains to be determined.
de Galan
Bastiaan E
BE
Department of Medicine, University Medical Center Nijmegen, The Netherlands.
Tack
Cees J
CJ
Lenders
Jacques W
JW
Lutterman
Jos A
JA
Smits
Paul
P
D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism*; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D015309:Glucose Clamp Technique / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D013806:Theophylline / Q000008:administration & dosage*
D001786:Blood Glucose; D013806:Theophylline