Preclinical and manifest diabetes mellitus in young patients with friedreich's ataxia: no evidence of immune process behind the islet cell destruction

Abstract

Friedreich's ataxia is known to be associated with diabetes mellitus in up to 20% of the patients. However, type, development and course of diabetes mellitus are not well characterised. We report on 3 patients (2 female and 1 male, age 13-20 years) with the combination of Friedreich's ataxia and diabetes mellitus. Diabetes mellitus was characterised as follows: (1) it was strictly insulin-dependent and ketosis-prone, (2) the average insulin requirement was 1 U/kg body weight, (3) the HLA haplotype was not typical of Type 1 (insulin-dependent) diabetes mellitus, (4) there were no positive immune parameters typical of Type 1 diabetes at the clinical onset of diabetes mellitus and (5) there was no remission. To evaluate a preclinical phase as in common autoimmune Type 1 diabetes, i.v. glucose tolerance tests (0.5 g glucose/kg body weight) were performed in 8 patients with Friedreich's ataxia without diabetes mellitus. Seven patients had normal early phase insulin response. In contrast, the glucose disappearance rate was slow in 4 and normal in 3 patients. One of the 8 patients showed a prediabetic metabolic state: the early-phase insulin response was abolished and the glucose disappearance rate was abnormal. The results suggest that diabetes in Friedreich's ataxia is caused by a loss of islet cells similar to common Type 1 diabetes but without HLA-association and without serologic evidence for autoimmune destruction of the islet cells.

Central role and mechanisms of β‐cell dysfunction and death in friedreich ataxia–associated diabetes

“…Diabetes in FRDA has been attributed to insulin deficiency, 21,22 but more recently emphasis was placed on the role of insulin resistance, with some studies reporting normal insulin secretion. 19,23–28,47 The present study confirms that FRDA patients, although young and having a rather low BMI, have increased body fat and are insulin resistant.…”

“…21 One causal factor for FRDA diabetes was proposed to be nonautoimmune β -cell loss. 22 Other studies reported no difference in insulin output, 23 and demonstrated insulin resistance at the whole body and cellular level. 19,24–26 Using 31 P magnetic resonance spectroscopy, impaired muscular mitochondrial function was demonstrated in vivo in FRDA patients, 27,28 similar to findings in insulin-resistant offspring of T2D patients.…”

Functional genomic analysis of frataxin deficiency reveals tissue-specific alterations and identifies the PPARγ pathway as a therapeutic target in Friedreich’s ataxia

“…FRDA patients are insulin resistant before being diabetic (9), and higher incidence of glucose intolerance and insulin resistance has been reported in family members of FRDA patients (42,43). However, other reports suggest a primary beta-cell involvement in FRDA (44), and a pathogenic mechanism primarily involving beta-cell failure has been proposed based on studies in other mitochondrial disorders (45,46) and on the pancreatic conditional frataxin knock-out (6). Here, we confirm that insulin resistance is present in all tested non-diabetic FRDA patients, strongly supporting the hypothesis suggested by our gene expression data that insulin target tissues are relevant in the pathogenesis of diabetes in FRDA.…”

Friedreichs ataxia in a diabetic patient

“…Однако в литературе описаны случаи инсулинозависимого СД при АФ, обусловленного потерей ост-ровковых клеток, но без HLA-ассоциации и аутоиммунной де-струкции β-клеток. Связь между геном атаксии Фридрейха и геном, определяющим предрасположенность к СД, не вы-явлена [16].…”