Biomedical subjects
Publications and source records attributed to B Draznin.
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The effect of metabolic inhibitors, 2,4-dinitrophenol (DNP) and NaF, on insulin binding and degradation has been studied in cultured Buffalo rat liver (BRL) cells. In control studies, 1.8 fmol of 125I-insulin binds to 1.2 x 10(6) cells, possessing approximately 40,000 receptor sites per cell with binding affinity of 5.52 x 10(-8) M. When the cells were preincubated with increasing concentrations of either DNP or NaF, a dose- and time-dependent decrease in both insulin binding and degradation was observed. The total amount of 125I-insulin bound to BRL cells preincubated with metabolic inhibitors was reduced to 1.2 fmol per 1.2 x 10(6) cells. The point of 1/2 B max was achieved in the presence of 50 ng/ml of native insulin, 1.7 times that of the control level. The number of receptor sites was unaffected by either DNP or NaF, but an average affinity profile revealed a decrease in the affinity of the ATP-depleted cells for insulin (KD: 7.31 x 10(-8) M and 7.06 x 10(-8) M in DNP- and NaF-treated cells, respectively). The decrease in insulin binding and degradation following the exposure of the BRL cells to the metabolic inhibitors was associated with a 20% reduction in intracellular ATP and adenylate energy charge. DNP and NaF did not affect the equilibrium constant for the myokinase catalyzed reaction and the intracellular concentration of hypoxanthine was stable, confirming the integrity of the cells during the experiments. It is suggested that ATP levels must remain intact to maintain normal insulin receptor affinity. Furthermore, the rate of insulin degradation by ATP-depleted cells is slower than that of intact cells. It is conceivable that the depression of insulin degradation by partially ATP-depleted cells results from either diminished binding or decreased endocytosis and lysosomal activity, all of which appear to be energy dependent.
To study the possible mechanisms involved in growth retardation associated with hypothyroidism, serum T4, GH, the GH-dependent somatomedin, insulin-like growth factor (IGF), and its carrier protein (CP) were measured in hypothyroid rats and their age-matched controls. Three groups of rats were studied: infant, immature, and adult. Marked hypothyroidism (serum T4, less than 1 microgram/dl) was produced in experimental animals by providing them with drinking water containing 0.05% propylthiouracil. Infant and immature hypothyroid rats weighed markedly less than normal controls and had significantly reduced serum levels of GH, IGF, and CP. Normal adult rats, treated with propylthiouracil for 60 days, also weighed considerably less than control animals and exhibited a significant drop in serum GH, IGF, and CP during this period. The administration of bovine GH to hypothyroid adult rats for 7 days did not restore either IGF or CP levels to normal, indicating that their decrease in serum was, in part, a direct result of hypothyroidism per se. These results indicate that serum levels of GH, IGF, and CP are at least partly under thyroid hormone control. Furthermore, these studies suggest that the growth retardation associated with hypothyroidism may be mediated through somatomedin activity.
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A 36-year-old man had estrogen-induced galactorrhea and oligospermia. He had been taking an unknown amount of estrogen for a year. While hypogonadism, manifested by decreased libido and potency, was apparent at the time of estrogen administration, galactorrhea appeared two months after estrogen was discontinued. Normal skull film, tomogram views of the sella turcica, and computerized axial tomography scan suggested that long-term estrogen administration caused sustained hyperprolactinemia with levels that ranged between 21 and 83 ng/mL throughout the ensuing year. Prolonged thyroid-stimulating hormone and prolactin luteinizing hormone response to luteinizing hormone-releasing hormone were believed to be evidence of a derangement in the hypothalamic control of pituitary hormone secretion. A year after he stopped taking estrogen, the patient gradually regained his potency, his prolactin level declined, the galactorrhea disappeared, and spermatogenesis returned to normal.
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The effect of short-term treatment with diphenylhydantoin (DPH) on the insulin secretion patterns during OGTT and on the daily insulin profile was studied in obese patients. DPH treatment for 3 days with a dose of 300 mg/die (100 mg, 3 times daily) significantly decreased the insulin release after glucose ingestion, but did not alter the basal insulin level. No effect on the fasting glucose concentration as well as on the glucose profiles during OGTT was observed after short-term DPH treatment. A smaller decrease of plasma free fatty acid concentration during OGTT performed after DPH administration confirmed the inhibitory effect of the drug on insulin release. Short-term DPH treatment was also shown to decrease markedly the postpradial insulin release in obese patients. No difference was noted between plasma 11-OHCS and serum HGH concentrations during OGTT before and after DPH treatment. The possible therapeutic role of DPH in obesity is discussed.
DNA from non-diabetic Caucasians (n = 16), Blacks (n = 22), Hispanics (n = 13) and Japanese (n = 21), as well as DNA from 34 Caucasian, 19 Black, 19 Hispanic and 20 Japanese non-insulin-dependent diabetes mellitus (NIDDM) patients were examined for restriction fragment length polymorphism (RFLP) after digestion with enzymes BglII and XbaI, and hybridization with the glucose transporter probe, hGT2-2. There were significant differences in the incidence of the RFLPs between Caucasians and Blacks, both controls and patients with NIDDM. Digestion with XbaI revealed a higher incidence of the homozygotic state for allele I in NIDDM Caucasians (12 vs. 0%) than in controls. In NIDDM Blacks and Hispanics, we found a high incidence of a combination of two traits: 42% of the Black and 47% of the Hispanic NIDDM patients were homozygous for the BglII allele I and heterozygous for XbaI. Only 23% of non-NIDDM Blacks or Hispanics had this combination (P less than 0.05). There was no association between RFLP frequency and NIDDM among Japanese subjects. These data support the influence of race on both BglII and XbaI RFLPs. The homozygotes for XbaI in Caucasians and the presence of two specific traits in Blacks and Hispanics appear with higher frequency in NIDDM.
The effects of glucose (16.7 mM), potassium (50 mM), forskolin (20 microM), dibutyryl cyclic AMP (1 mM) and arachidonic acid (82 microM) upon insulin release and cytosolic free calcium concentrations ([Ca2+]i) were investigated in normal rat pancreatic islets. Potassium, forskolin and dibutyryl cyclic AMP significantly raised [Ca2+]i, but elicited only minimal insulin release. In the absence of extracellular Ca2+, glucose evoked insulin release, but failed to augment [Ca2+]i. Arachidonic acid increased [Ca2+]i both in Ca-depleted and -repleted medium, but promoted insulin release only in Ca2+-repleted environment. These new observations clearly demonstrate by direct measurements that although [Ca2+]i is an important factor in exocytotic insulin release, its effect is subject to amplification or antagonism.