Milan Kapadia

Synthesis and Secretion of Insulin-like Growth Factor II by a Leiomyosarcoma with Associated Hypoglycemia

We describe a case of recurrent hypoglycemia apparently caused by secretion of insulin-like growth factor II (IGF-II) by a leiomyosarcoma. A 67-year-old woman presented with recurrent severe hypoglycemia and a large mass in the thorax. During hypoglycemia, plasma cortisol was elevated, but insulin and growth hormone levels were low. After resection of a large leiomyosarcoma, the hypoglycemia resolved. After an eight-year remission, both the tumor and symptomatic hypoglycemia recurred. During a second operation a second large tumor was removed, with relief of the patients hypoglycemia. The tumor contained high concentrations of IGF-II mRNA and 2100 ng of IGF-II immunoreactive peptide per gram. Filtration through a BioGel P-60 gel column established that 77 percent of the IGF-II was present as a larger molecule, demonstrating incomplete processing of the pro-IGF-II peptides. A similar fraction of high-molecular-weight IGF-II was present in the serum, indicating that the tumor was the chief source of IGF-II. The high-molecular-weight IGF-II found in both the tumor and serum was fully reactive with the IGF-II receptor. Radioimmunoassay showed that the concentrations of insulin-like growth factor I (IGF-I) in tumor and serum were low, suggesting feedback inhibition of growth hormone secretion by IGF-II. Eight months after reoperation, plasma concentrations of IGF-I and IGF-II were normal, and high-molecular-weight IGF-II was virtually undetectable. We conclude that the most likely cause of this patients recurrent hypoglycemia was IGF-II produced by the leiomyosarcoma.

Insulin-like growth factors I and II of nonmammalian sera ☆

We have compared the insulin-like growth factors (IGFs) of a number of mammalian and nonmammalian vertebrate sera. Sera were subjected to acid gel filtration through G-75 Sephadex and separate binding protein and free IGF fractions were pooled. The IGF pools were subjected to flatbed isoelectric focusing and the concentration of IGF I in the fractions was detected with an immunoassay using 125I-hIGF I and the somatomedin C antibody of Underwood and Van Wyk. IGF II in the fractions was detected with either the 125I-IGF rat placental membrane RRA or the 125I-IGF II serum binding protein assay. One or more basic peaks of IGF I immunoactivity were detected in all the mammalian sera studied (human, guinea pig, rat, bovine, kangaroo, and opossum) and all the nonmammalian species studied (chicken, turtle, toad, and trout). Neutral and slightly acidic peaks of IGF II receptor reactivity were observed in human, cow, and guinea pig serum. No distinct peaks of IGF II were observed in adult rat, opossum, or kangaroo serum. Distinct peaks of IGF II activity in the neutral to slightly acidic range were clearly recognized in chicken and turtle serum, no such peaks were recognized in toad and trout serum. All mammalian sera studied contained acid stable, binding proteins with high affinity, saturable binding of 125I-IGF II. None of the nonmammalian sera studied contained demonstrable specific 125I-IGF II binding. These observations document the presence of separate IGF I and IGF II peptides in chickens and turtles but only IGF I in amphibians and fish. These observations indicate that the gene duplication giving rise to two separate IGFs arose before reptilian evolution. The acquisition of a specific IGF binding protein is limited to mammals.

Reduced 125I-hGH binding by serum of dwarf pigs but not by serum of dwarfed poodles.

1. Normal and growth-deficient poodle and swine strains were characterized for serum growth hormone-binding protein (GH-BP) content as well as other growth-related hormones, and the relationship between these factors and body size was examined. 2. GH-BPs were found in all strains of pigs and poodles. Concentrations of GH-BPs (as expressed by specific bindings) did not vary among the poodle breeds, but did correlate with body size in pigs. 3. Insulin-like growth factors (IGFs) I and II were decreased 71 and 44% respectively in miniature compared to standard size poodles. 4. Only the Yucatan micro pig strain had reduced serum IGF-I concentrations compared to normal controls. 5. Growth hormone concentrations however were normal to elevated in all micro and miniature pig strains. 6. Serum triiodothyronine concentrations were reduced in Yucatan mini and micro pigs in spite of normal circulating levels of thyroxine. 7. Body size reductions in the swine and dog strains are probably attributable to different primary defects of various growth related hormones or hormone receptors. 8. Each species breed therefore could serve as a model for a different human growth-deficient condition.