Decline in Neurophysiological Function After 7 Years in an Adolescent Diabetic Cohort and the Role of Aldose Reductase Gene Polymorphisms
- Keerthi Thamotharampillai, GMEDSC1,
- Albert K.F. Chan, MAPPSTAT1,
- Bruce Bennetts, PHD23,
- Maria E. Craig, PHD134,
- Janine Cusumano1,
- Martin Silink, MD13,
- Peter J. Oates, PHD5 and
- Kim C. Donaghue, PHD13
- 1Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Westmead, NSW, Australia
- 2Department of Molecular Genetics, The Children’s Hospital at Westmead, Westmead, NSW, Australia
- 3University of Sydney, Sydney, NSW, Australia
- 4University of NSW School of Women’s and Children’s Health, Sydney, NSW, Australia
- 5Pfizer Global Research and Development, Groton, Connecticut
- Address correspondence and reprint requests to Prof. Kim C. Donaghue, Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail: kimd{at}chw.edu.au
Abstract
OBJECTIVE—This 7-year longitudinal study examines the potential impact of aldose reductase gene (AKR1B1) polymorphisms on the decline of nerve function in an adolescent diabetic cohort.
RESEARCH DESIGN AND METHODS—Patients with type 1 diabetes (n = 262) were assessed with three cardiovascular autonomic tests (heart rate variation during deep breathing, Valsalva maneuver, and during standing from a lying position) and pupillometry (resting pupil diameter, constriction velocity, and reflex amplitude), thermal, and vibration thresholds on the foot. Genotyping was performed for promoters (C-106T and C-12G), (CA)n dinucleotide repeats, and intragenic BamH1 polymorphism.
RESULTS—Median time between first and last assessment was 7.0 years (interquartile range 5.1–11.1), with a median of five assessments (four to seven) per individual. At first assessment, median age was 12.7 years (11.7–13.9), median duration was 5.3 years (3.4–8.0), and median HbA1c was 8.5% (7.8–9.3). All tests declined over time except for two cardiovascular autonomic tests and vibration discrimination. Faster decline in maximum constriction velocity was found to associate with the Z-2 allele (P = 0.045), Z-2/Z-2 (P = 0.026). Slower decline in hot thermal threshold discrimination associated with Z+2 (P = 0.044), Z+2/Z+2 (P < 0.0005), Z+2/T (P = 0.038), and bb (P = 0.0001).
CONCLUSIONS—Most autonomic and quantitative sensory nerve testings declined over time. AKR1B1 polymorphisms were strongly associated with the rate of decline of these complications.
Footnotes
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A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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- Accepted June 5, 2006.
- Received March 29, 2006.
- DIABETES CARE
