Nathaniel R Greeley1, Sean Regner2, Steve Willi3, David R Lynch4. 1. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States. Electronic address: greeleyn@gmail.com. 2. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States. Electronic address: seanregner@gmail.com. 3. Division of Endocrinology and Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, United States. Electronic address: willi@email.chop.edu. 4. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Department of Neurology, University of Pennsylvania Medical School, Philadelphia, PA, United States; Department of Pediatrics, University of Pennsylvania Medical School, Philadelphia, PA, United States. Electronic address: lynchd@mail.med.upenn.edu.
Abstract
OBJECTIVES: To evaluate the relationship between disease features in Friedreich ataxia and aberrant glucose metabolism. METHODS: Fasting glucose, fasting insulin and random HbA1C were obtained in 158 patients with Friedreich ataxia. Regression analysis evaluated glucose, insulin, and homeostatic model assessment (HOMA) of insulin resistance (IR) and beta-cell function (ß) in relation to age, BMI, sex, and genetic severity. Categorical glucose values were analyzed in relation to other FRDA-associated disease characteristics. RESULTS: In the FRDA cohort, age and GAA repeat length predicted fasting glucose and HbA1c levels (accounting for sex and BMI), while insulin and HOMA-IR were not predicted by these parameters. Within the cohort, average BMI was consistently lower than the national average by age and was marginally associated with insulin levels and HOMA-IR. Within juvenile subjects, insulin and HOMA-IR were predicted by age. Controlling for age and genetic severity, diabetes-related measures were not independent predictors of any quantitative measure of disease severity in FRDA. Glucose handling properties were also predicted by the presence of a point mutation, with 40% of individuals heterozygous for point mutations having diabetes, compared to 4.3% of subjects who carried two expanded GAA repeats. INTERPRETATION: In FRDA, aberrant glucose metabolism is linked to increasing age, longer GAA repeat length on the shorter allele, frataxin point mutations, and increasing BMI. The effect of age to some degree may be mediated through changes in BMI, with increasing age associated with increases in BMI, and with HOMA-IR and insulin increases in children.
OBJECTIVES: To evaluate the relationship between disease features in Friedreich ataxia and aberrant glucose metabolism. METHODS: Fasting glucose, fasting insulin and random HbA1C were obtained in 158 patients with Friedreich ataxia. Regression analysis evaluated glucose, insulin, and homeostatic model assessment (HOMA) of insulin resistance (IR) and beta-cell function (ß) in relation to age, BMI, sex, and genetic severity. Categorical glucose values were analyzed in relation to other FRDA-associated disease characteristics. RESULTS: In the FRDA cohort, age and GAA repeat length predicted fasting glucose and HbA1c levels (accounting for sex and BMI), while insulin and HOMA-IR were not predicted by these parameters. Within the cohort, average BMI was consistently lower than the national average by age and was marginally associated with insulin levels and HOMA-IR. Within juvenile subjects, insulin and HOMA-IR were predicted by age. Controlling for age and genetic severity, diabetes-related measures were not independent predictors of any quantitative measure of disease severity in FRDA. Glucose handling properties were also predicted by the presence of a point mutation, with 40% of individuals heterozygous for point mutations having diabetes, compared to 4.3% of subjects who carried two expanded GAA repeats. INTERPRETATION: In FRDA, aberrant glucose metabolism is linked to increasing age, longer GAA repeat length on the shorter allele, frataxin point mutations, and increasing BMI. The effect of age to some degree may be mediated through changes in BMI, with increasing age associated with increases in BMI, and with HOMA-IR and insulin increases in children.
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Authors: Maya Patel; Ashley McCormick; Jaclyn Tamaroff; Julia Dunn; Jonathan A Mitchell; Kimberly Y Lin; Jennifer Farmer; Christian Rummey; Susan L Perlman; Martin B Delatycki; George R Wilmot; Katherine D Mathews; Grace Yoon; Joseph Hoyle; Manuela Corti; S H Subramony; Theresa Zesiewicz; David Lynch; Shana E McCormack Journal: Neurol Genet Date: 2021-11-12
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