Insulin Resistance in Multiple Aspects Of Intermediary Metabolism in Myotonic Dystrophy

Abstract

The responses of circulating intermediary metabolites to a low-dose incremental insulin infusion (basal, 0.005, 0.01, and 0.05 U · kg−1 · h−1) were examined in eight ambulant subjects with the multisystem disorder, myotonic dystrophy. Eight healthy subjects matched for age, gender, and body mass index served as controls. Oral glucose tolerance (75 g) was normal in all subjects. Basal (postabsorptive) hyperinsulinemia was observed in the subjects with myotonic dystrophy (8.4 ± 2.0 v 2.3 ± 0.2 mU/L, P < .01) with increased basal C-peptide levels. Basal blood glycerol (0.09 ± 0.02 v 0.05 ± 0.01 mmol/L, P < .05), lactate (1.14 ± 0.12 v 0.77 ± 0.07 mmol/L, P < .02), and pyruvate (0.08 ± 0.01 v 0.05 ± 0.01 mmol/L, P < .02) were also elevated in these subjects. During the incremental insulin infusion, circulating insulin (F = 8.2, P < .02) and C-peptide (F = 5.1, P < .05) levels were significantly higher in the myotonic subjects. Despite the hyperinsulinemia, circulating concentrations of lactate (F = 9.8, P < .01), pyruvate (7.8, P < .02), and glycerol (F = 7.5, P < .02) were also higher in the subjects with myotonic dystrophy, providing prima facie evidence of insulin resistance in the regulation of these metabolites. During the highest insulin rate, isotopically determined metabolic clearance rate of glucose was significantly lower in the myotonic subjects (3.6 ± 0.4 v 5.5 ± 0.7 mL · kg−1 · min−1, P < .05), indicating impaired peripheral glucose metabolism. ANOVA confirmed parallel, linear dose-response relationships (P < .005) for plasma insulin (log) and glucose, glycerol, nonesterified fatty acids (NEFA), and total ketone bodies (TKB). For glucose (P < .001), glycerol (P < .001), and NEFA (P < .001), the group regression lines for the subjects with myotonic dystrophy lay parallel to those for the control subjects, but with a significant rightward displacement indicative of insulin resistance. No significant displacement was observed between the group regression lines for TKB. These results indicate that myotonic dystrophy is characterized by insulin resistance in the regulation of multiple aspects of carbohydrate metabolism (glucose, lactate, and pyruvate) and lipolysis (NEFA and glycerol).