Energy metabolism in myotonic dystrophy

Myotonic distrophy (MyD), the most common adult form of muscular dystrophy, is often complicated by diabetes. MyD is dominantly inherited and is due to heterozygosity for a tri-nucleotide repeat expansion mutation in a protein kinase gene which was suggested to induce derangement of RNA metabolism able to reduce insulin receptor expression. To test whether the abnormal RNA metabolism or a specific malfunction of protein kinase gene induces defective energy metabolism and insuline resistance prior to the onset of diabetes, we studied 10 MyD patients (2 glucose intolerant) and 10 matched healthy subjects, by means of (a) dual X-ray energy absorption, (b) euglycemic-hyperinsulinemic clamp ( 1 mU/Kg/min) combined with primed-continuous infusion of [6,6-d2]-glucose and [1-13C]-leucine, (c) indirect calorimetry, and (d) oral glucose tolerance test (OGTT) to explore insulin-dependent glucose, lipid and protein metabolism. MyD reduced Jean body mass (LBM: 36 ± 3 vs 46 ± 3 Kg; P < 0.02) and increased fat mass. Nevertheless, resting energy expenditure (33.4 ± 0.9 vs 33.8 ± 1.5 kcal/kg/day; P = 0.83), insulin-stimulated glucose metabolism [7.22 ± 0.22 vs 8.48 ± 0.80 mg/(kg LBM · min); P = 0.49], and lipid metabolism in the postabsortive and clamp conditions were comparable to normals. Proinsulin concentrations were increased in MyD patients (P = 0.01) and the intact proinsulin/insulin ratio (23 ± 4 vs 10 ± 1%; P < 0.01) was twofold higher in MyD. Circulating proinsulin levels also failed to be normally regulated during suppressing (clamp) or stimulating (OGTT) conditions. Markers of proteolysis (ELF: endogenous leucine flux) in the postabsorptive [203 ± 15 vs 146 ± 9 μmol/(kg LBM · h); P < 0.02] and insulin-stimulated conditions (ELF suppression during the insulin clamp: 11 ± 3 vs 18 ± 2%; P < 0.05) were higher in MyD than in normals and they were associated to reduced plasma insulin-like growth factor (IGF-1: 125 ± 18 vs 212 ± 8 ng/ml; P < 0.03) and increased plasma α-tumor necrosis factor receptor-2 (TNFR-2: 1919 ± 212 vs 1401 ± 172 pg/ml, P = 0.04). In summary, in MyD, energy metabolism was preserved but the severe loss of LBM was associated with abnormal postabsorptive and insulin-stimulated regulation of protein breakdown. Insulin resistance with respect to glucose metabolism was lacking, and a higher risk to develop type 2 diabetes is more likely due to abnormal insulin secretion. The combination of reduced circulating IGF-1 levels and increased TNF system activity may be responsible for the increased protein breakdown which is involved in muscle wasting in MyD