Glucose intolerance in first-degree relatives of patients with Friedreich's ataxia is associated with insulin resistance: Evidence for a closely linked inherited trait

Fantus, I. George; Janjua, Najma A.; Senni, Helen; Andermann, Eva

doi:10.1016/0026-0495(91)90004-g

Cited by 20 publications

(15 citation statements)

References 31 publications

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“…This observation is supported by previous studies that have clearly indicated an increased incidence of diabetes in FA-patients (17,18) together with normal or sometimes increased stimulus-coupled insulin secretion in FA-patients (19)(20)(21)(22) and obligate heterozygous carriers (18,22) of the GAA-tract expansion (i.e., >50 GAA repeats). On the other hand, population-based studies on premutations (i.e., >15 but <51 GAA repeats) and their association with common type 2 diabetes are as inconclusive (23)(24)(25)(26) as studies on the relevance of these premutations on transcription of the -based insulin sensitivity test (Y-axis, linear scale).…”

supporting

confidence: 77%

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

et al. 2000

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Friedreich's ataxia (FA) is an autosomal recessive disease that has been attributed to a GAA triplet repeat expansion in the first intron of the X25/frataxin gene. Impaired glucose tolerance is present in up to 39% of FA patients, and clinically apparent diabetes is seen in ~18% of the affected individuals. Subjects carrying the X25/frataxin GAA repeat in a heterozygous state do not develop FA and, therefore, represent an ideal model to study the underlying metabolic defects that contribute to the diabetes associated with this disorder. In the present study, we have compared 11 first-degree relatives of FA patients (i.e., parents or heterozygous siblings of FA patients) with matched normal control subjects to study the parameters of glucose metabolism. An oral glucose tolerance test revealed diabetes in one of the heterozygous subjects who was excluded from further analyses. Using an octreotide-based quantification of insulin sensitivity, 8 of the remaining 10 study subjects showed pronounced insulin resistance, reflecting a significant difference from the control group (P = 0.001). In conclusion, a heterozygous expansion of the X25/frataxin GAA repeat in healthy individuals is associated with insulin resistance and might be considered a genetic co-factor in the pathogenesis of mitochondrial subtypes of diabetes. Diabetes 49:1604-1607, 2000 F riedreich's ataxia (FA) is phenotypically characterized by progressive ataxia and other neurological alterations in association with hypertrophic cardiomyopathy. The vast majority of FA patients carry a homozygous expansion of an intronic GAA tract of the X25/frataxin gene (1) leading to interference with the transcription of the frataxin gene (2) and subsequently decreasing expression of the frataxin protein (3). Frataxin is expressed in a wide variety of tissues, exhibits mitchondrial localization, and appears to be essential for embryonic development (4) in mice. Frataxin is most abundant in tissues with high metabolic activity, including skeletal muscle and brown fat (5). The characterization of the yeast frataxin homolog suggests a central role in oxidative phosphorylation (6). Furthermore, frataxin was proposed to regulate mitochondrial iron content (7,8) and to decrease oxidative damage to the cell (9,10). Frataxin is a mitochondrial protein that is significantly reduced in FA patients because of decreased transcription subsequent to expanded intronic GAA repeats on both copies of the X25/frataxin gene. Heterozygous carriers for this expansion are phenotypically normal but presumably exhibit a decreased expression of frataxin (2,11). In the present study, these heterozygous individuals were evaluated for alterations in glucose metabolism, specifically incidence of diabetes and insulin resistance.First, first-degree relatives of FA patients were genotyped, as described in RESEARCH DESIGN AND METHODS, to assure the presence of GAA expansions, especially in siblings of the patients. Eleven subjects from 4 different unrelated families were analyzed (8 parents and 3 sibli...

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supporting

confidence: 77%

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

et al. 2000

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“…Friedreich's ataxia is associated with T2D in up to 20% of the patients. Glucose intolerance in Friedreich's ataxia is associated with insulin resistance [153,154]. While not established in humans, β-cell specific disruption of the frataxin gene in mice caused free radicals-induced damage in pancreatic islets, and diabetes developed with increased age because of decreased ß-cell mass, islet number and size [155].…”

Section: B Genetic Aspects Of Ros Production Ros Defenses and Cellumentioning

confidence: 99%

Reactive Species, Cellular Repair and Risk Factors in the Onset of Type 2 Diabetes Mellitus: Review and Hypothesis

Fridlyand¹,

Philipson²

2006

CDR

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Insulin resistance (IRe) and a failure of insulin secretion are the major features of the early pathophysiology of type-2 diabetes mellitus (T2D) but the etiology is still not well understood. We suggest that: 1. The cellular mechanisms that protect against oxidative stress per se are capable of creating a reactive species-dependent IRe. 2. Reactive species-induced mitochondrial dysfunction can lead to disruption of lipid metabolism, increased intracellular lipid content, and can also contribute to lipid-dependent IRe in myocytes and adipocytes. 3. Metabolic secretagogues that stimulate insulin secretion by the activation of initial steps in the glucose-stimulated insulin secretion pathway can also lead to increased reactive species production and cellular destruction contributing to beta-cell damage and apoptosis. These events that underlie the repair mechanisms in beta-cells, muscle and adipocytes, are important factors in the early etiology of T2D, leading to both IRe and decreased insulin secretion. This hypothesis is supported by data from multiple disciplines and includes aging, obesity and genetic factors in promoting multiple failures in this system leading to the onset of T2D. On the basis of this hypothesis therapeutic strategies should be directed towards increasing insulin secretion and reducing IRe without increasing reactive species production or concentration. Pharmacological or other approaches that result in the activation of mitochondrial biogenesis could be beneficial for both IRe and T2D.

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“…The elevated insulin levels in the presence of normal or elevated glucose levels suggests some degree of insulin resistance in the subjects with Rett syndrome. impaired glucose tolerance and elevated insulin levels have been identified in a number of inherited and ac quired neurologic disorders that are characterized by muscle wasting and decreased physical activity, including Friedreich's ataxia [30], Huntington's chorea [31], amyo trophic lateral sclerosis [32], Parkinson's disease [33], and myotonic dystrophy [34], All of these disorders are char acterized by markedly decreased physical activity, which has long been known to cause impaired glucose tolerance [35] , Many arguments have been presented to support the hypothesis that the impaired glucose tolerance in these disorders is not due solely to the decreased activity of the subjects, and there are probably a number of causes for the insulin resistance found in these disorders. The present study did not permit us to determine if our find ings in subjects with Rett syndrome were due to limited physical activity (5 of the 10 subjects were nonambulato ry) or to another abnormality intrinsic to Rett syndrome.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities of Thyroid Function and Glucose Control in Subjects with Rett Syndrome

et al. 1995

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We have identified subtle abnormalities of thyroid function and glucose control in patients with Rett syndrome. The mean serum total thyroxine (T₄) concentration was significantly lower in a group of subjects with Rett syndrome (6.9 ± 1.5 μg/dl, n = 34; p < 0.0001) than the adult reference range (8.5 ± 1.75 μg/dl, n = 200). This difference remained significant even for the 17 subjects not taking anticonvulsants (7.6 ± 1.5 μg/dl; p < 0.05 vs. adult reference). The difference was more marked when compared to age-adjusted normals, with 10 subjects having a serum total T₄ concentration below normal for age including 3 of 17 of the subjects not taking anticonvulsants. This decrease in serum total T₄ concentration was not due to changes in binding proteins as measured by 3,5,3’-triiodothyronine resin uptake, and was associated with a decreased concentration of thyroid-stimulating hormone (1.7 ± 1.6 mU/l, n = 23 vs. 2.5 ± 1.0 mU/l, n = 200; p < 0.01). Oral glucose tolerance tests were performed in 10 of the subjects with Rett syndrome. They had a delay in the peak glucose and insulin concentrations. Glucose levels were elevated at 1 and 2 hours (p < 0.05), and insulin levels were elevated at 1, 2, and 3 hours (p < 0.05). Two subjects fulfilled criteria for impaired glucose tolerance.

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Glucose intolerance in first-degree relatives of patients with Friedreich's ataxia is associated with insulin resistance: Evidence for a closely linked inherited trait

Cited by 20 publications

References 31 publications

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

Reactive Species, Cellular Repair and Risk Factors in the Onset of Type 2 Diabetes Mellitus: Review and Hypothesis

Abnormalities of Thyroid Function and Glucose Control in Subjects with Rett Syndrome

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