Impaired cerebral glucose metabolism in myotonic dystrophy: a triplet-size dependent phenomenon

Myotonic dystrophy (DM) is caused by an expansion of a CTG triplet repeat sequence in the 3′-noncoding region of a protein kinase gene, yet the mechanism by which the triplet repeat expansion causes disease remains unknown. Impaired glucose penetration into brain tissues has been described in DM patients and is a phenomenon that remains unexplained. The present study shows that altered brain glucose metabolism is triplet repeat dependent. We studied brain glucose metabolism (CMRGlu, μmol/100 g/min) by the use of positron emission tomography and 18F-fluoro-2-deoxy- d-glucose in 11 ambulatory non-obese DM patients and in 11 age and sex matched healthy subjects. All subjects underwent a glucose tolerance test with plasma insulin determinations. The expansion of CTG triplet repeats was analyzed in patients with the probe cDNA25 after EcoRI digestion. As compared to controls, in DM patients, the CMRGlu was significantly decreased (26.26±5.05 vs. 33.43±2.18, μmol/100 g/min, P=0.004), and after oral glucose loading, plasma insulin levels were significantly higher and plasma glucose levels remained unchanged (respectively, F=11.21, P=0.004 and F=0.20, P=0.66). Subsequently, the glucose/insulin ratio was significantly lower in DM patients ( F=6.25, P=0.02). The length of the expansion of the CTG repeats correlated negatively with the CMRGlu ( r 2=0.63, P=0.003) and positively with the area under the curve for insulin changes over time after oral glucose ( r 2=0.49, P=0.016). We conclude that, in DM patients, the brain metabolism of glucose is impaired in a repeat dependent manner.