John C.M. Tsibris

Insulin and insulin-like growth factor I in brain tumors: binding and in vitro effects.

We have measured insulin and insulin-like growth factor I (IGF-I) binding in human gliomas, meningiomas, and normal brain and studied the effect of insulin on the morphology, proliferation, and differentiation of central nervous system tumor and normal fetal cells in culture. Specific 125I-insulin and 125I-IGF-I binding was demonstrated by competition-inhibition binding assays. Insulin binding was measured in plasma membrane preparations from 9 freshly isolated human meningiomas, 4 glioblastomas multiforme (GBMs), a low-grade glioma, a normal adult brain, and a fetal brain. IGF-I binding was measured in similar preparations from 5 meningiomas, 4 GBMs, a low-grade glioma, and a normal adult brain. Incubations were carried out at 4 degrees C for 18 to 20 hours. Meningiomas showed higher specific insulin binding per 0.25 mg of protein than GBMs (19% versus 3%, P less than 0.005), and this difference was not related to small differences observed in insulin degradation. By contrast, IGF-I binding was significantly higher in gliomas than in meningiomas (27% versus 12%, P less than 0.05). Also, IGF-I binding was significantly higher than insulin binding in GBMs (27% versus 3%, P less than 0.03); binding of both IGF and insulin was high in meningiomas. In normal adult brain IGF-I and insulin binding was 7 to 10%. The ability of insulin to support and enhance the growth of central nervous system tumor cells in culture was investigated. Cell cultures were derived from a freshly isolated glioblastoma, a low-grade glioma, and 3 meningiomas.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of sex steroids on insulin binding by target tissues in the rat

The effect of estradiol, progesterone and norgestrel on serum insulin and glucose levels and on insulin binding to adipocytes, hepatocytes and diaphragm muscle cell membranes has been evaluated in castrated male rats. Estradiol administration (5 micrograms/day X 6) significantly increased basal plasma insulin levels and the amount of insulin bound to fat and liver cells as well as muscle cell membranes. Progesterone treatment (5 mg/day X 6) caused a slight increase of basal insulin levels and a decrease of insulin binding to fat cells. Norgestrel treatment (5 mg/day X 6) decreased both insulin levels and the amount of insulin bound to adipocytes; a much lower dose of norgestrel, 6 micrograms/day X 7, also caused a decline in adipocyte insulin binding due to an apparent increase in the dissociation constant of the high affinity binding sites. These studies demonstrate that ovarian sex steroids have a significant effect on insulin binding to target cells. This animal model would assist in determining the mechanisms involved in changes of carbohydrate metabolism which occur during the menstrual cycle, pregnancy, the menopausal state and with the use of oral contraceptives.

The effects of two triphasic oral contraceptives on carbohydrate metabolism in women during 1 year of use

Sixty-one women were randomly assigned to use one of two different triphasic oral contraceptives (OCs), for one years time (Ortho Novum 777, Ortho Pharmaceutical Corp., Raritan, NJ, and Triphasil, Wyeth Laboratories, Philadelphia, PA), containing the progestins norethindrone and levonorgestrel, respectively. The carbohydrate metabolism was evaluated using the oral glucose tolerance test before OC use and at the end of the 12th month. Both plasma glucose and insulin levels were measured. The fasting glucose value in the norethindrone-containing OC group (777) was significantly lower at the 1-year testing. All other values were unchanged. These data demonstrate that the triphasic oral contraceptive preparations currently in use have minimal effects on carbohydrate metabolism.

Guaiacol peroxidase levels in human cervical mucus: A possible predictor of ovulation

Guaiacol peroxidase (G-Px) is an enzyme which in the human uterine epithelium has been found to be inhibited in vitro by estrogens and especially catecholestrogens. This study determines if the concentration of G-Px would vary inversely to plasma estrogens. It is hoped that this enzyme would decrease sufficiently early before ovulation to be useful as a simple predictor of ovulation in women. G-Px was serially measured in cervical mucus during the menstrual cycle of 5 healthy volunteers. Radioimmunoassay measured the following hormones in the plasma samples: 17 beta-estradiol, progesterone, luteinizing and follicle stimulating hormones. In the midcycle, G-Px levels decreased 20- to 100-fold relative to other times of the cycle, the decrease coinciding with the peak of plasma estrogens and probably causally related to them. G-Px levels were not affected by the 2nd peak of plasma estrogens, possibly because of the counter effect of progesterone. Further research should be done to determine possible hormonal control of G-Px activity. G-Px may be central to the structure and function of cervical mucus. They may have bactericidal and spermicidal properties and may play a role in sperm capacitation. The findings in this study may be beneficial in estimating optimal time for intercourse and artificial insemination in infertile patients and improving the efficacy of the periodic abstinence method of contraception by easily identifying the fertile period. In addition, the G-Px assay in cervical mucus is adaptable to a simple sensitive home test because the products of guaiacol oxidation are visible to the naked eye and drastic changes in color production can be easily perceived.

Plasma glucose and insulin levels in women using a levonorgestrel-containing triphasic oral contraceptive for three months

Plasma glucose and insulin levels were measured for three hours after an oral glucose challenge in twenty-nine women before and after using a triphasic oral contraceptive containing ethinyl estradiol and levonorgestrel for three months. There were significant elevations in the glucose levels during the three-month tolerance test, while the insulin levels were unchanged. These data suggest that this OC can alter carbohydrate metabolism and that long-term studies are needed to assess the extent of this metabolic change.

Epidermal Growth Factor and Its Receptor and Their Possible Relationships to Gynecologic Endocrinology

Recent research in endocrinology is beginning to show that paracrine chemical substances such as epidermal growth factor may play important roles in fostering differentiation of epithelia, including tissues in the reproductive tract, raising implications for the understanding of hormone responsiveness and oncogenesis. The current enthusiasm for the study of peptide growth factors,1 epidermal growth factor (EGF), and their cell-surface receptors, is based on the realization that most of them have mitogenic properties and regulate a cascade of events (pleiotropic response) in normally dividing cells. On the other hand, cells that are transformed (after exposure to retroviruses) produce proteins that have extensive primary sequence homology with these peptide growth factors, thus becoming independent of an exogenous supply of mitogens required for their growth. EGF and other peptide growth factors exert their biologic effect through specific receptor proteins located at the plasma membrane. An exciting discovery was made when the primary structure of the EGF receptor was determined and was compared with a data base of all known protein sequences.2–4 Extensive homology was found between the EGF receptor and the protein encoded by a viral oncogene (erbB);oncogenes are genomic sequences in the cellular or viral genome that are considered responsible for the induction of neoplasia