Abnormal regulation of intermediary metabolism after oral glucose ingestion in myotonic dystrophy

The responses of plasma insulin and blood intermediary metabolites to oral glucose (75 g) were determined in 10 subjects with myotonic dystrophy. Results were compared with responses in 10 normal control subjects matched for age, sex, and body mass index. Fasting hyperinsulinemia was observed in the myotonic subjects (7.5 +/- 1.6 v 2.4 +/- 0.4 mU/L; P less than .005) and plasma insulin concentration remained significantly higher following oral glucose (F = 38.09; P less than .001). Total cumulative insulin release was markedly higher in the myotonic subjects (4,984.3 v 1,286.6 mU/L; P less than .0001). Basal blood glucose concentration was normal (4.8 +/- 0.2 v 4.7 +/- 0.1 mmol/L), although overall blood glucose was elevated in the myotonic subjects following oral glucose ingestion (F = 5.37; P less than .05). Glucose tolerance was normal in all subjects. Fasting blood lactate was higher in the myotonic subjects (1.31 +/- 0.13 v 0.94 +/- 0.08 mmol/L; P less than .05) and remained significantly elevated following the ingestion of glucose (F = 7.22; P less than .02). Blood pyruvate response was also higher in the myotonic subjects (F = 5.88; P less than .05). Basal blood glycerol was elevated in the myotonic subjects (0.12 +/- 0.02 v 0.05 +/- 0.01 mmol/L; P less than .005) and remained elevated following oral glucose (F = 11.31; P less than .005). No significant overall differences were observed in ketone bodies, alanine, or fatty acids between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin secretion in patients with myotonic dystrophy and their relatives

Summary Oral glucose, i.v. tolbutamide and i.v. arginine tolerance tests were performed in 11 patients with myotonic dystrophy and 9 of their clinically unaffected relatives. Five of the myotonic patients had glucose intolerance; 7 had exaggerated immunoreactive insulin (IRI) response to glucose. One of the 9 relatives demonstrated glucose intolerance and none had exaggerated insulin response to glucose. Three relatives, all obese, hyperresponded to arginine and one of them also responded excessively to tolbutamide. The results indicate that an exaggerated IRI response to glucose is common in myotonic dystrophy. Enhanced responses to other stimuli are less frequent. Although glucose intolerance occurred in half of the patients, the fact that the highest IRI levels were seen in non-diabetic patients suggests that this excessive response may protect against glucose intolerance. Our studies in relatives do not support the potential usefulness of testing for hyperinsulinemia in the early detection of myotonic dystrophy. Presented at the 9th International Diabetes Federation Congress in New Delhi, India, November 2, 1976.     

Glucocorticoid metabolism and adrenocortical reactivity to ACTH in myotonic dystrophy

Dysfunction of the hypothalamic-pituitary-adrenal axis might contribute to metabolic disturbances frequently encountered in myotonic dystrophy. We hypothesized that abnormal adrenocortical sensitivity to ACTH and/or glucocorticoid metabolism could be important in myotonic dystrophy. We assessed diurnal rhythmicity of saliva cortisol, adrenocortical reactivity by a low-dose (1 microg) Synacthen test, and glucocorticoid metabolism in blood and urine in 42 myotonic dystrophy patients (22 males) and 50 controls (27 males). CTG triplet repeat expansions were quantified by Southern blot. Diurnal rhythmicity of saliva cortisol was flattened in both men and women with myotonic dystrophy, with significantly increased afternoon/evening levels (P < 0.013). The cortisol response to ACTH was associated with increased (CTG)(n) expansions in myotonic dystrophy men and women (P < 0.01). Male myotonic dystrophy patients also had increased activation of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1. Both men and women with myotonic dystrophy had an increased 5alpha/5beta-reductase ratio (P < 0.05 and P < 0.01, respectively). Cortisol metabolites were related to the genetic defect in myotonic dystrophy men (P < 0.05), whereas ratios reflecting 11beta-hydroxysteroid dehydrogenase type 1 activity in myotonic dystrophy women were positively associated with obesity (P < 0.05). Increased 11beta-hydroxysteroid dehydrogenase type 1 activity and adrenocortical reactivity to ACTH are related to the genetic defect in myotonic dystrophy men, whereas abnormal glucocorticoid metabolism is associated with alterations in body composition in female myotonic dystrophy patients. These disturbances may explain altered circulating cortisol levels and contribute to features of the metabolic syndrome in myotonic dystrophy.     

Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial

Aim/hypothesis  

To assess whether low-dose glucocorticoid treatment induces adverse metabolic effects, as is evident for high glucocorticoid doses.     

Insulin regulation of leptin synthesis and secretion in humans: the model of myotonic dystrophy

OBJECTIVE: Myotonic dystrophy (MyD) is a systemic disorder in which insulin resistance is well recognized. In the present study we have characterized plasma leptin levels in patients with MyD and in age, sex and body mass index (BMI) matched controls and assessed the influence of leptin on the clinical manifestations of MyD. DESIGN AND PATIENTS: Body composition, plasma leptin, fasting and post-oral glucose tolerance test insulin, IGF-I and IGFBP3 were studied in 34 MyD patients and 33 controls. MEASUREMENTS: Body composition was measured using a bioelectrical impedance analyzer, and circulating levels of insulin, leptin, IGF-I, IGFBP3 were measured by IRMA or RIA. Insulin sensitivity was modelled according to a homeostasis model assessment (HOMA) computer-solved model. RESULTS: Percentage body fat was higher in patients than in controls (25.6 +/- 2.28% vs 18.8 +/- 1.53%, P = 0.013). Insulin levels, both fasting and after oral glucose were higher in patients than in controls, and insulin sensitivity was lower in patients than in controls. Serum leptin was higher in patients than in controls (20.98 +/- 3.11 micrograms/l vs 10.4 +/- 1.31 micrograms/l, P = 0.004), and higher in women than in men, both in patients and in controls. In patients, leptin levels were correlated with age, BMI, fasting insulin, insulin area under curve and lower insulin sensitivity, whereas leptin levels were not correlated with body fat or other parameters of body composition. In controls, leptin levels were correlated with BMI and body fat. The results were evaluated using logistic regression models for each of the 2 populations. In the model of MyD, insulin resistance and age correctly identified higher leptin levels in relation to controls out of 87.88% of patients, and in the model of controls male sex with a negative correlation and BMI correctly identified their leptin levels out of 84.33% cases. CONCLUSIONS: These findings show that MyD provides a different model of leptin regulation in humans, and suggest that in MyD patients there are correlations between leptin and insulin resistance and age, irrespective of body fat. In contrast, leptin levels in controls, correlate with sex and BMI. The data on leptin in this population of patients can not be related aetiologically to the muscle disease itself.     

Molecular genetics of myotonic dystrophy

Myotonic muscular dystrophy (DM) has been shown to be caused by the expansion of an unstable triplet nucleotide repeat sequence located in the 3' untranslated region of a gene coding for a putative serine-threonine protein kinase. Isolation of genomic and cDNA clones for the DM kinase have significantly simplified the genetic diagnosis of DM. The cellular localization, enzymatic activity, and role in the pathophysiology of DM of the kinase protein are as yet unknown.     

Cardiovascular manifestations of myotonic dystrophy

Patients with myotonic dystrophy, the most common neuromuscular dystrophy in adults, have a high prevalence of arrhythmic complications with increased cardiovascular mortality and high risk for sudden death. Sudden death prevention is central and relies on annual follow-up and prophylactic permanent pacing in patients with conduction defects on electrocardiogram and/or infrahisian blocks on electrophysiological study. Implantable cardiac defibrillator therapy may be indicated in patients with ventricular tachyarrhythmia.     

Hyperproinsulinaemia in patients with myotonic dystrophy

Summary Hyperinsulinaemia is a reported feature of the inherited multisystem disorder myotonic dystrophy. This phenomenon has been attributed to a compensatory beta cell response to tissue insulin resistance. In this study, circulating concentrations of insulin, proinsulin, and split proinsulin molecules were determined after an overnight fast in ten patients with myotonic dystrophy using two-site monoclonal antibody-based immunoradiometric assays. Results were compared with ten healthy control subjects matched for age, gender, and body mass index. Oral glucose tolerance (75 g), as defined by World Health Organization criteria, was normal in all subjects. Fasting plasma immunoreactive insulin concentration, as determined using a conventional radioimmunoassay, was almost three times higher (p<0.005) in the myotonic dystrophy patients than the healthy control subjects. By contrast, fasting concentrations (mean±SEM) of C-peptide (0.75±0.09 vs 0.52±0.03 nmol/l, p=0.07) and immunoradiometrically-determined insulin (60±12 vs 38±4 pmol/l, p=0.09) were not significantly different between the groups. Fasting concentrations of proinsulin (10.3±2.9 vs 1.6±0.3 pmol/l, p<0.01), and 32–33 split proinsulin (7.8±2.5 vs 2.9±0.4 pmol/l, p<0.05) were significantly elevated in the patients with myotonic dystrophy. Accordingly, the mean fasting proinsulininsulin ratio, expressed as a percentage, was significantly increased in the myotonic patients (20±5 vs 4±1%, p<0.01). The overall C-peptide response to the oral glucose challenge was significantly greater in the myotonic patients compared with the healthy control subjects (p<0.001). These results provide corroborative evidence of increased beta-cell secretion in myotonic dystrophy. In addition, myotonic dystrophy is characterised by elevated plasma concentrations of proinsulin-like molecules which may cross-react in insulin radioimmunoassays.     

Electrocardiographic findings in myotonic dystrophy.

Sixty five patients with myotonic dystrophy, from a defined population in northern Sweden with an extremely high prevalence of this disease, were examined by electrocardiography. The patients were subdivided into three groups according to the severity of the disease. Abnormal electrocardiograms were found in 6 (35%) patients with mild disease, 12 (50%) patients with moderate disease, and 23 (96%) patients with severe disease. First degree atrioventricular block and left anterior hemiblock were the most commonly encountered abnormalities in patients with mild and moderate disease, whereas atrial fibrillation and flutter, abnormal Q waves, and repolarisation abnormalities were more common in patients with severe disease. This study shows that the heart is often affected by myotonic dystrophy. These effects can be detected by electrocardiography in early and mild forms of the disease. The effect on the heart is progressive and clinically important atrial arrhythmias and electrocardiographic abnormalities which are useful in differential diagnosis are common in severe forms of the disease.     

Dermal lymphatics in myotonic dystrophy.

Myotonic dystrophy is an hereditary disorder of several organ systems. Skeletal muscle is a principal target organ, but abnormalities also occur in the peripheral microcirculation. Because morphological and functional changes in the dermal blood microcirculation may affect interstitial fluid drainage of the skin, we examined dermal lymphatic morphology in adult patients with myotonic dystrophy. Skin biopsies were taken from the big toe from patients with myotonic dystrophy (age 18-50 years) and subjected to light and electron microscopy; five healthy subjects served as controls. The salient findings in myotonic dystrophy were ultrastructural changes of the lymphatic endothelial cells and the fibrillar elements that surround the lymphatic wall. These abnormal lymphatic findings are interpreted in light of changes in the blood microvasculature and loose connective tissue in this disorder.     

Cortisol-induced changes in some aspects of the intermediary metabolism of Salvelinus fontinalis.

Cortisol was administered to brook charr (Salvelinus fontinalis) in the form of slow-release intraperitoneal implants (a) to investigate the effect of chronic cortisol stimulation (up to 60 days) on various aspects of intermediary metabolism, and (b) to determine whether such cortisol-induced changes were comparable to those seen in chronically fasted charr. Except for fish sampled at 1 and 6 h after implantation, there was no consistent increase in the plasma cortisol levels of the cortisol-implanted animals. Nevertheless, there were significant treatment effects (particularly after 60 days) on certain metabolite levels, and key hepatic enzymes, including a lowering of plasma glucose and hepatic glycogen concentrations, increased activities of FBPase, G6PDH, GK, and G3PDH, and reduced activities of PFK. When taken together these changes are indicative of a direct or indirect gluconeogenic action of cortisol, in which metabolites other than amino acids (possibly glycerol) are utilized as substrates. These metabolic changes differed from those found in food-deprived brook charr which appeared to use proteins, as well as lipids, as energy sources.     

Universality in intermediary metabolism

We analyze the stoichiometry, energetics, and reaction concentration dependence of the reductive tricarboxylic acid (rTCA) cycle as a universal and possibly primordial metabolic core. The rTCA reaction sequence is a network-autocatalytic cycle along the relaxation pathway for redox couples in nonequilibrium reducing environments, which provides starting organic compounds for the synthesis of all major classes of biomolecules. The concentration dependence of its reactions suggests it as a precellular bulk process. We propose that rTCA is statistically favored among competing redox relaxation pathways under early-earth conditions and that this feature drove its emergence and also accounts for its evolutionary robustness and universality. The ability to enhance the rate of core reactions creates an energetic basis for selection of subsequent layers of biological complexity.     

Procainamide for dyspnea in myotonic dystrophy

We report the case of a patient with myotonic dystrophy who developed tachypnea and severe dyspnea without respiratory failure. Myotonia of inspiratory muscles was diagnosed on the grounds of marked prolongation of transdiaphragmatic pressure (Pdi) decay during sniffs. In view of the recognized sensory role of inspiratory muscles in dyspnea, it was hypothesized that antimyotonic therapy might relieve dyspnea in this patient. Procainamide therapy induced a decrease in half relaxation time of Pdi during sniffs and yielded a striking clinical improvement with cessation of tachypnea and dyspnea. Later, this beneficial effect was maintained by tocainide after procainamide was stopped because of a lupus syndrome. We conclude that myotonia of respiratory muscles can cause severe dyspnea that can be improved by antimyotonic therapy.