Diabetes in Friedreich’s Ataxia

Incidence of diabetes in Friedreich’s Ataxia patients

The incidence of diabetes in people with Friedreich’s ataxia is high, with about 10 percent of FA patients developing diabetes and 20 percent developing glucose intolerance, a mild form of diabetes.

Studies have shown that the higher risk among FA patients of developing diabetes is associated with the age of onset and the number of GAA repeats in the FXN gene, the genetic cause of FA; patients who developed FA at a younger age or those who had a higher number of GAA repeats were more inclined to develop diabetes.

Symptoms of diabetes

The diabetic symptoms of FA are similar to the general symptoms of diabetes and include extreme thirst, frequent urination, weight loss, fatigue, and blurry vision.

How diabetes develops

Diabetes is a condition in which blood sugar levels are abnormally high over a long period of time. In healthy people, blood glucose levels are regulated by a hormone called insulin produced by the beta cells located in the pancreas (an organ that helps in digestion). Insulin promotes the absorption of glucose from the blood into fat, liver, and skeletal muscle cells.

In diabetic patients, high blood glucose levels may result from both defects in insulin secretion (by the pancreatic β-cells) and insulin resistance, a condition in which cells fail to take up glucose in response to insulin.

How diabetes develops in Friedreich’s Ataxia

Previous studies have suggested that both insulin deficiency, caused by β-cell dysfunction and death, and insulin resistance, and an interplay between these two, contribute to blood sugar abnormalities in patients with FA. Several case reports described ketoacidosis in Friedreich’s ataxia patients, the hallmark of absolute insulin deficiency as a consequence of the loss of insulin-producing β-cells. In other studies, insulin resistance was demonstrated at the whole body and cellular level in FA.

Therefore, patients with FA develop diabetes due to insufficient insulin secretion by the pancreatic β-cells, in a context of increased insulin requirements because of insulin resistance. While insulin resistance is frequently present in FA, β-cell dysfunction and death are prerequisites for the development of diabetes.

Insulin resistance and impaired insulin secretion can be attributed to mitochondrial dysfunction within the cells.

Insulin resistance in FA

Frataxin deficiency in liver, fat and muscle cells leads to mitochondrial dysfunction and insufficient energy production, which may lead to resistance (non-responsiveness) of these cells to insulin, either directly or indirectly.

Impaired insulin secretion in FA

Clinical studies in humans and data from in vivo and in vitro models suggest that insulin secretion is impaired due to both β-cell dysfunction and death. Mitochondria play a crucial role, in both processes.

β-cell dysfunction

The inability of the cells to take up blood glucose is a source of stress for the pancreatic β-cells, which are also stressed by the lack of frataxin protein and the subsequent disruption of mitochondrial function. In the β-cells, mitochondria are important for optimal insulin secretion. Mitochondria are essential for the sensing of nutrients by the β-cells and for the generation of signals that trigger and amplify insulin secretion known as stimulus-secretion coupling. As a result, there is an impaired insulin secretion in β-cells due to the disruption of mitochondrial function as well as stress caused by insulin resistance.

β-cell death

Mitochondrial dysfunction in the β-cells also increases the production of harmful reactive oxygen species (ROS), which trigger cell death by a process called apoptosis. Stress signals converge on the mitochondria triggering the apoptotic pathway.

Thus, both pancreatic β-cell dysfunction and death contribute to insulin deficiency, which is central to the development of diabetes in Friedreich’s ataxia.


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