Effect of 2 weeks of theophylline on glucose counterregulation in patients with type 1 diabetes and unawareness of hypoglycemia
Abstract
BACKGROUND AND 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.
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The large variability in glycaemic thresholds in type 1 diabetes can probably be explained by different prior hypoglycaemia exposure rates between individuals, the loss of glucagon secretion within years after diagnosis, blunted catecholamine responses and impaired hypoglycaemic awareness.
“This large variability in glycaemic thresholds in type 1 diabetes can probably be explained by different prior hypoglycaemia exposure rates between individuals [7], the loss of glucagon secretion within years after diagnosis [9, 10], blunted catecholamine responses and impaired hypoglycaemic awareness [11, 12].”
From Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review (2022) · cites this paper as [10]
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Defective Counterregulation and Hypoglycemia Unawareness in
Reno, C. M., Litvin, M., Clark, A. L., & Fisher, S. J. (2013)
- Authors
- DEGALAN, B., TACK, C., LENDERS, J., LUTTERMAN, J., & SMITS, P.
- Affiliations
- Radboud University Nijmegen (NL)
- Corresponding author
- SMITS, P
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2003-07
- Volume
- 74
- Issue
- 1
- Pages
- 77-84
- ISSN
- 0009-9236 (ISSN-L)
- OpenAlex
- W2081006191
- Cited by
- 12
- References
- 25
- Citations by year
- 2024: 1 · 2022: 2 · 2021: 1 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 0.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- theophylline, hypoglycemia unawareness, type 1 diabetes, glucose counterregulation, hypoglycemia, growth hormone, epinephrine, norepinephrine, cortisol, sweating, cardiovascular response, hyperinsulinemic hypoglycemic clamp, drug tolerance
- MeSH terms
- Adult, Analysis of Variance, Blood Glucose, Diabetes Mellitus, Type 1, Double-Blind Method, Female, Humans, Hypoglycemia, Male, Middle Aged, Theophylline, Glucose Clamp Technique, Cross-Over Studies, Area Under Curve
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