Research Grant Award

Young Investigator Award

Miriam Cnop, MD, PhD

Universite Libre De Bruxelles, Brussels, Belgium
Pathogenesis of impaired glucose tolerance and diabetes in Friedreich's ataxia: contribution of insulin resistance and pancreatic beta cell dysfunction

Friedreich's ataxia is caused by mutations in the frataxin gene. The vast majority of patients have large expansions in both copies of the frataxin gene, and the size of this expansion correlates with age at onset and the severity of neurological symptoms. In addition to the neurological problems, patients with Friedreich’s ataxia are at risk of getting increased blood sugar levels, or glucose intolerance, and around 20% progress to overt diabetes. The cause of diabetes in Friedreich's ataxia is poorly understood. Glucose intolerance and diabetes can result from a shortage in insulin secretion by the insulin-producing β cells in the pancreas, from a poor response to insulin in muscle, liver and fat tissues (insulin resistance), or from a combination of both. Previous and contradictory studies addressing the cause of diabetes in Friedreich’s ataxia often used inaccurate methods to measure insulin secretion and sensitivity. They were conducted before the frataxin gene mutation was discovered, and before key concepts for the understanding of glucose tolerance were developed. The aim of the present project is to elucidate why patients with Friedreich's ataxia develop diabetes. Specifically, we will examine the relative role of pancreatic β cell failure and insulin resistance in diabetes development. This will be done using state-of the- art oral and intravenous glucose tolerance tests in Friedreich's ataxia patients, first degree relatives and control subjects. Insufficient insulin production by the β cells and insulin resistance will be correlated with glucose tolerance and with the frataxin gene expansion size. We present preliminary data showing that, while the Friedreich's ataxia patients in our pilot study are young and lean, they have a high prevalence of impaired glucose tolerance and diabetes. They are insulin resistant but do not increase insulin secretion, suggesting that their pancreatic β cells fail to compensate for the increased demand. We expect that this failure underlies progression to diabetes. Based on the understanding of the cause of diabetes in Friedreich's ataxia, optimal diabetes treatment choices will be defined, and novel approaches to prevent the disorder envisaged. This study will form the basis of subsequent studies to characterize the function of frataxin in β cells and/or insulin responsive tissues using animal models.