glycogen and Acromegaly

Some patients with severe insulin resistance develop pathological tissue growth reminiscent of acromegaly. Previous studies of such patients have suggested the presence of a selective postreceptor defect of insulin signaling, resulting in the impairment of metabolic but preservation of mitogenic signaling. As the activation of phosphoinositide 3-kinase (PI 3-kinase) is considered essential for insulin's metabolic signaling, we have examined insulin-stimulated PI 3-kinase activity in anti-insulin receptor substrate (IRS)-1 immunoprecipitates from cultured dermal fibroblasts obtained from pseudoacromegalic (PA) patients and controls. At a concentration of insulin (1 nM) similar to that seen in vivo in PA patients, the activation of IRS-1-associated PI 3-kinase was reduced markedly in fibroblasts from the PA patients (32+/-7% of the activity of normal controls, P < 0.01). Genetic and biochemical studies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the insulin receptor, IRS-1, or p85alpha. Insulin stimulation of mitogenesis in PA fibroblasts, as determined by thymidine incorporation, was indistinguishable from controls, as was mitogen-activated protein kinase phosphorylation, confirming the integrity of insulin's mitogenic signaling pathways in this condition. These findings support the existence of an intrinsic defect of postreceptor insulin signaling in the PA subtype of insulin resistance, which involves impairment of the activation of PI 3-kinase. The PA tissue growth seen in such patients is likely to result from severe in vivo hyperinsulinemia activating intact mitogenic signaling pathways emanating from the insulin receptor.

Topics: Acromegaly; Adolescent; Adult; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Female; Fibroblasts; Gene Expression; Glycogen; Humans; Hypoglycemic Agents; Infant, Newborn; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Lymphocytes; Male; Mitogens; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Polymorphism, Single-Stranded Conformational; Signal Transduction; Thymidine; Tumor Cells, Cultured

The human septal cartilage is of ectodermal origin and contributes to midfacial growth and development. Acromegaly is an endocrine disease due to growth hormone (Gh) excess originating from a somatotrophic adenoma of the pituitary gland. Excessive Gh levels lead to high insulin-like growth factor I (IGF I) concentrations, which are known to stimulate cartilage growth in vivo and in vitro. One of the salient clinical pictures is coarsening of the midface and enlargement of the septal cartilage. Septal cartilage was obtained from 8 acromegalic patients during transnasal hypophysectomy and from 10 healthy adults during septoplasty to analyse the following aspects of cartilage biochemistry, metabolism and growth. 1. Intracellular glycogen, the major source of energy of chondrocytes, was determined enzymatically and found to be drastically reduced in acromegaly. 2. Several intracellular enzymes, related to biomatrix degradation, showed a strict local pattern of distribution. Cathepsin B activity, a neutral proteinase degrading both the helical and nonhelical region of the collagen molecule was significantly increased in acromegaly, whereas alkaline phosphatase activity, an enzyme related to mineralization of the cartilage at the chondroosseous junction was depressed in acromegaly. 3. The cell density in some areas of the septal cartilage was increased in acromegaly, whereas the clonal proliferation rate of its chondrocytes in response to serum and growth factors was decreased. Chondrocytes both of healthy adults and acromegalic patients could be effectively stimulated by insulin-like growth factor I and II and to a lesser extent by epidermal growth factor.

Topics: Acromegaly; Adult; Alkaline Phosphatase; beta-N-Acetylhexosaminidases; Cathepsin B; Cathepsin D; Cell Count; Cell Division; Cells, Cultured; Clone Cells; Epidermal Growth Factor; Female; Glycogen; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Male; Nasal Septum

Topics: Acromegaly; Adult; Bromocriptine; Female; Glycogen; Growth Hormone; Humans; Hydrocortisone; Insulin; Levodopa; Male; Middle Aged

Topics: Acromegaly; Adenosine Triphosphatases; Aspartate Aminotransferases; Biopsy; Creatine Kinase; Cytoplasmic Granules; Electromyography; Glycogen; Histocytochemistry; Humans; Hypertrophy; L-Lactate Dehydrogenase; Male; Microscopy, Electron; Middle Aged; Mitochondria, Muscle; Muscles; Myofibrils; Pituitary Neoplasms