Some info on IGF and MMD
1: J Clin Endocrinol Metab. 1995 Dec;80(12):3715-23.
Metabolic and clinical response to recombinant human insulin-like growth factor
I in myotonic dystrophy--a clinical research center study.
Vlachopapadopoulou E, Zachwieja JJ, Gertner JM, Manzione D, Bier DM, Matthews
DE, Slonim AE.
Department of Pediatrics, New York Hospital-Cornell Medical Center, New York
10021, USA.
Muscle weakness and wasting in myotonic dystrophy (MyD) are believed to be due
to a decrease in muscle protein synthesis, secondary to insulin resistance. A
4-month, randomized, double blind, placebo-controlled trial was undertaken to
assess whether recombinant human insulin-like growth factor I (rhIGF-I) may
overcome the insulin resistance. Patients received either 5 mg rhIGF-I (n = 7)
or placebo (n = 9), sc, twice daily. Glucose metabolism was assessed by stable
label iv glucose tolerance test, amino acid metabolism by L-[13C] leucine
turnover, body composition by dual energy x-ray absorptiometry and N excretion,
and muscle response by manual muscle strength and neuromuscular function. In the
treated group, the insulin sensitivity index, insulin action, and glucose
disposal all increased (P < 0.05). Leucine flux and leucine incorporation into
protein increased (P < 0.05), and the rate of leucine oxidation to leucine
turnover decreased (P < 0.05), findings indicative of increased protein
synthesis. Body weight and lean body mass increased, whereas percent body fat
decreased (P < 0.05). An increase in manual muscle strength of 0.42 +/- 0.30 (P
< 0.02) and in neuromuscular function of 17.5 +/- 11.7 (P < 0.02) occurred in
the four patients who received a rhIGF-I dose greater than 70 micrograms/kg,
whereas a more modest response occurred in the three patients who received a
dose less than 70 micrograms/kg. Two patients showed dramatic improvement. Long
term rhIGF-I therapy appears to cause metabolic and muscle improvement in
treated MyD patients.
2. Endocrinology. 1999 Sep;140(9):4244-50.
Insulin-like growth factor I circumvents defective insulin action in human
myotonic dystrophy skeletal muscle cells.
Furling D, Marette A, Puymirat J.
Department of Medicine, Laval University Medical Research Center, University
Hospital Center of Quebec, Canada.
Primary human skeletal muscle cell cultures derived from muscles of a myotonic
dystrophy (DM) fetus provided a model in which both resistance to insulin action
described in DM patient muscles and the potential ability of insulin-like growth
factor I (IGF-I) to circumvent this defect could be investigated. Basal glucose
uptake was the same in cultured DM cells as in normal myotubes. In DM cells, a
dose of 10 nM insulin produced no stimulatory effect on glucose uptake, and at
higher concentrations, stimulation of glucose uptake remained significantly
lower than that in normal myotubes. In addition, basal and insulin-mediated
protein synthesis were both significantly reduced compared with those in normal
cells. In DM myotubes, insulin receptor messenger RNA expression and insulin
receptor binding were significantly diminished, whereas the expression of GLUT1
and GLUT4 glucose transporters was not affected. These results indicate that
impaired insulin action is retained in DM cultured myotubes. The action of
recombinant human IGF-I (rhIGF-I) was evaluated in this cellular model. We
showed that rhIGF-I is able to stimulate glucose uptake to a similar extent as
in control cells and restore normal protein synthesis level in DM myotubes.
Thus, rhIGF-I is able to bypass impaired insulin action in DM myotubes. This
provides a solid foundation for the eventual use of rhIGF-I as an effective
treatment of muscle weakness and wasting in DM.
3: Am J Clin Nutr. 2004 Aug;80(2):357-64.
Postabsorptive and insulin-stimulated energy and protein metabolism in patients
with myotonic dystrophy type 1.
Perseghin G, Comola M, Scifo P, Benedini S, De Cobelli F, Lanzi R, Costantino F,
Lattuada G, Battezzati A, Del Maschio A, Luzi L.
Internal Medicine Section of Nutrition/Metabolism, Universita Vita e Salute San
Raffaele, Istituto Scientifico H San Raffaele, via Olgettina 60, 20132 Milan,
Italy. perseghin.gianluca@hsr.it
BACKGROUND: Exaggerated insulin resistance was described as the major metabolic
abnormality in myotonic dystrophy type 1 (DM1). We reported recently that the
severity of the impairment in insulin-stimulated glucose metabolism in these
patients was overestimated. OBJECTIVE: The aim was to dissect out insulin action
with respect to whole-body energy homeostasis and glucose, protein, and lipid
metabolism in patients with DM1 to assess the relevance of insulin resistance to
the heterogeneous clinical manifestations of this syndrome. DESIGN: Ten
nondiabetic patients with DM1 and 10 matched healthy control subjects were
studied by means of 1) dual-energy X-ray absorptiometry; 2) a
euglycemic-hyperinsulinemic clamp (40 mU. m(-2). min(-1)) combined with a
primed, continuous infusion of [6,6-d(2)]glucose and [1-(13)C]leucine; 3)
indirect calorimetry; and 4) localized (1)H magnetic resonance spectroscopy of
the calf muscles. RESULTS: Patients with DM1 had less lean body mass, greater
fat mass, and greater intramyocellular lipid contents than did healthy control
subjects. Energy expenditure and glucose and lipid metabolism did not differ
significantly between the groups. In contrast, markers of proteolysis were
higher in DM1 patients in the postabsorptive and insulin-stimulated conditions
and were associated with lower plasma concentrations of insulin-like growth
factor 1 (P < 0.03) and higher plasma concentrations of tumor necrosis factor
alpha receptor 2 (P = 0.04). CONCLUSIONS: Despite greater body fat and
intramyocellular lipid contents in patients with DM1, insulin sensitivity was
not significantly different between patients and control subjects. In contrast,
the loss of lean body mass in patients with DM1 was associated with abnormal
postabsorptive and insulin-stimulated regulation of protein breakdown. Lower
plasma insulin-like growth factor 1 concentrations and higher tumor necrosis
factor system activity might be involved in the muscle wasting of DM1.
