Solomon A. Kaplan

Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion.

Six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, compared with controls after oral glucose (P less than 0.05). As an indicator of insulin sensitivity, in vitro proliferation of erythrocyte progenitor cells of PCOD subjects exposed to physiologic concentrations of insulin was significantly blunted (P less than 0.001). Monocyte insulin receptor binding was not impaired in the PCOD subjects. Three of the PCOD patients were treated with a long-acting gonadotropin-releasing hormone agonist for 6 months, which resulted in marked suppression of ovarian androgen secretion but no demonstrable changes in in vivo or in vitro indicators of insulin resistance. Thus insulin resistance in PCOD subjects appears to be unrelated to ovarian hyperandrogenism (or acanthosis or obesity). Although certain tissues are insulin-resistant in PCOD patients, the ovary may remain sensitive and overproduce androgens in response to high circulating insulin levels.

The insulin receptor

Cells are endowed with specific cognitive molecules that function as receptors for hormones, neurotransmitters, and other intercellular messengers. The receptor molecules may be present in the plasma membrane, cytoplasm, or nucleus. When occupied by the messenger, the receptor is coupled to the cellular machinery that responds to the message-bearing molecules. For some hormones the events following attachment of the messenger to the receptor are well known. An example is the generation of cAMP after combination of glucagon with its receptor and the series of steps culminating in activation of phosphorylase. In the case of many other messengers, including insulin, the nature of these coupling steps is not known. Receptors are subject to the regulatory processes of synthesis, degradation, and conformational change; alterations in receptor properties may have significant effects on the qualitative and quantitative responses of the cell to the extracellular messenger. The insulin receptor is located in the plasma membrane, is composed of two pairs of subunits, and has a molecular weight of about 350,000. It is located in cells such as adipocytes, hepatocytes, and skeletal muscle cells as well as in cells not considered to be typical target organ cells. Insulin receptors in nonfetal cells are downregulated by exposure of the cells to high concentrations of insulin. Other factors that regulate insulin binding include muscular exercise, diet, thyroid hormones, glucocorticoids, androgens, estrogens, and cyclic nucleotides. The fetus has high concentrations of insulin receptors in several tissues. These begin to appear early in fetal life and may outnumber those found in adult tissues. Fetal insulin receptors are unusual in that they may not undergo downregulation but may experience the opposite when exposed to insulin in high concentrations. Thus the offspring of a mother with poorly controlled diabetes may be placed in double jeopardy by fetal hyperinsulinemia and augmented insulin binding by the receptors. Many disorders in children and adults are associated with changes in the properties of the insulin receptor. In general, the alterations have been measured in receptor-bearing cells that are readily accessible, such as circulating monocytes and erythrocytes. The receptors on these cells generally reflect the status of receptors on the major target organs of insulin, although exceptions are known, and conclusions drawn from studies of receptors on circulating cells must be made with caution.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum 17-α-hydroxyprogesterone, progesterone, estradiol, and testosterone in the diagnosis and management of congenital adrenal hyperplasia

The value of determining concentrations of serum 17-α-hydroxyprogesterone, progesterone, estradiol, and testosterone in the diagnosis and management of congenital adrenal hyperplasia was studied. The values recorded were compared with established criteria of control: growth rate, advancement of bone age, degree of virilization, and 24-hour urine excretion of 17-ketosteroids and pregnanetriol. Serum 17-OHP concentrations were diagnostic in five new patients with CAH; they ranged from 100–312 ng/ml (50 to 450-fold above normal); serum progesterone concentrations ranged from 7–24 ng/ml (2 to 50-fold above normal). In the long-term management no one serum steroid concentration alone could be relied upon to determine adequacy of control. It appears that several variables, including diurnal variation, timing of the sample in relation to the last dose of a glucocorticoid, and chronic suppression of the hypothalamic-pituitary-adrenal axis, in addition to the degree of control, may affect a single serum steroid determination. When an acceptable range of normal in CAH for concentration of serum 17-OPH was broadened to 4 ng/ml and for progesterone to 1 ng/ml, there was a fairly good correlation of serum steroid concentrations with degree of control.

Echocardiography reveals a high incidence of bicuspid aortic valve in Turner syndrome

The most common cardiac defect in Turner syndrome has been described previously as coarctation of the aorta. We have evaluated 35 consecutive patients with Turner syndrome by clinical examination and by M-mode and two-dimensional echocardiography. Twelve patients (34%) had isolated, nonstenotic bicuspid aortic valve. A high correlation (82%) existed between the presence of a systolic ejection click and echocardiographic evidence of a bicuspid aortic valve. These data indicate that bicuspid aortic valve may be the most common cardiac anomaly in Turner syndrome.

Peripheral Unresponsiveness to Human Growth Hormone in Laron Dwarfism

IN 1966 Laron and his associates described a severe form of dwarfism associated with high levels of circulating immunoreactive human growth hormone.1 Laron dwarfism is usually a familial disorder, ...

Role of adenosine 3', 5'-monophosphate in maturation of fetal lungs.

Extract: Fetal lung cyclic AMP phosphodiesterase, cyclic AMP, phosphatidyl choline, and incorporation of precursors into phosphatidyl choline were measured in rabbits after maternal administration of hydrocortisone phosphate and aminophylline. Both agents inhibited lung phosphodiesterase activity and augmented cyclic AMP concentrations (Table 1). Aminophylline administration was associated with a significant increase in lung saturated phosphatidyl choline (Table 2). Incorporation of [14C]choline and [3H]methionine was increased by both aminophylline and hydrocortisone (Table 3).Speculation: Aminophylline, which inhibits cyclic AMP phophodiesterase as its primary mode of action, has effects similar to hydrocortisone on incorporation of labeled precursors into phosphatidyl choline. Cyclic AMP, therefore, may be a mediator of maturation of lung phosphatidyl choline synthesis and/or secretion in the fetus, and pharmacologic agents which enhance cyclic AMP levels in the lungs may also enhance synthesis of phosphatidyl choline.

Regulation of fetal lung phosphatidyl choline synthesis by cortisol: role of glycogen and glucose.

Summary: Twenty pregnant rabbits were studied in pairs. Half were given cortisol subcutaneously on days 24. 25, and 26 of gestation in dosage of 2 nig/kg/day. Half served as controls and received saline. The fetal lungs were studied on the 27th day of gestation by incubating lung slices in the presence of [6-14C]glucose. Glucose consumption significantly increased in the tissues from animals treated with cortisol, 17.61 ± 5.56 (SD) μmol/g wet lung versus 14.28 ± 5.78 (SD) μmol/g in the controls (P < 0.05). The glycogen content of tissues treated with cortisol was significantly reduced compared to the controls, 2.42 ± 0.97 (SD) mg/g wet lung versus 3.81 ± 1.05 (SD) mg/g (P < 0.05). Treatment with cortisol resulted in significantly enhanced incorporation of the 14C label into glycogen and phosphatidl choline (Tables 3 and 4). These data suggest that glucocorticoids affect fetal lung phosphatidyl choline production by promoting glycogenolysis and increasing glucose incorporation into phosphatidyl choline.Speculation: Diminished glycogen content of the fetal lung in the latter part of gestation may reflect increasing utilization for phosphatidyl choline synthesis. Adenosine 3′,-5′-monophosphate (cyclic AMP) increases which occur after glucocorticoid administration may be responsible for activation of glycogen phosphorylases in the lung as they are in the liver. If insulin inhibits glycogenolysis in the lung as it does in the liver, insulin may inhibit phosphatidyl choline synthesis in the lung by preventing glycogen and glucose From serving as precursors.

Selective ACTH insensitivity, achalasia and alacrima : A multisystem disorder presenting in childhood

Summary: A 3½-year-old male is described with the rare triad of ACTH insensitivity, achalasia, and alacrima. Adrenal insufficiency presented with hypoglycemia and hyperpigmentation at age 2½ years. Achalasia was diagnosed at age 3½ years and alacrima, retrospectively, had been present since birth.Evaluation of adrenal function revealed complete resistance of the glucocorticoid-producing zonas fasciculata and reticularis to both endogenous and exogenous ACTH. No chemical evidence was found for the presence of either an abnormal ACTH molecule or a circulating antibody to ACTH. Additionally, adrenal miner-alocorticoid function was clearly responsive to both exogenous ACTH and to perturbations of the renin-angiotensin system. Only glucocorticoid deficiency due to selective ACTH resistance was documented.Shortly after diagnosis, glucocorticoid production could be stimulated by intravenous theophylline administration. Presumably, this agent, whose intracellular actions may be mediated by either enhancement of cyclic AMP action or alterations in calcium transport, circumvented the usual interaction of ACTH with its receptor and thereby stimulated steroidogenesis. The responsiveness to theophylline was lost 1 year later, perhaps as a result of final atrophy of the zonas fasciculata and reticularis secondary to lack of effective ACTH stimulation; thus, our patient appears to have a unique syndrome characterized by ACTH insensitivity and a multifocal defect of the autonomie, specifically parasympathetic, nervous system, resulting in achalasia and alacrima. A putative pathogenic defect linking hormone-receptor cyclic AMP-mediated processes with abnormalities in parasympathetic neuronal innervation or receptor-mediated transmitter function, as may occur in achalasia and alacrima, remains to be demonstrated.

Ontogeny of the mammalian insulin receptor: Studies of human and rat fetal liver plasma membranes

Abstract Insulin binding to human fetal plasma liver membranes was studied in preparations segregated into three pools according to length of gestation: 15–18 weeks (Pool A), 19–25 weeks (Pool B), and 26–31 weeks (Pool C). Receptor numbers, calculated by extrapolation of Scatchard plots to the X axis, increased from 25 × 1010 sites per 100 μg protein in the youngest group (Pool A) to 46 × 1010 sites per 100 μg protein in Pool B. No further increase in receptor number was seen in Pool C. The affinity constant for insulin at tracer concentrations, K e (“empty site”), was 1.53 × 108 M−1 in Pool A and was only slightly higher than K f (“filled site”). K e was higher in Pool B, 1.75 × 108 M−1, and in Pool C reached a value of 5.63 × 108 M−1. In Pool C K f was 2.3 × 108 M−1. Insulin binding of liver plasma membranes from rat fetuses aged 14, 16, 18, and 21 (term) days and adults was also studied. Maximum binding capacity tended to increase with gestational age and was 130 × 1010 sites per 100 μg protein at term, which was in excess of that found in adult rats (89–90 × 1010). In addition, K e increased from 0.75 × 108 M−1 at 14 days to 3.02 × 108 M−1 at term, a value higher than that found in pregnant and nonpregnant adults. Dissociation of insulin in the presence of high concentrations of insulin was significantly enhanced in tissues from 18-day and term fetuses and adults, but not in membranes from fetal rats aged 14 and 16 days. These data appear to indicate that site-site interactions are not present in early fetal existence. These changes in insulin binding with increased length of gestation are not ascribable to changes in relative proportions of hematopoietic and parenchymal tissue. Human fetal plasma liver membranes demonstrated elevated insulin binding with increased gestational age, but comparison of fetal and adult liver could not be done. However, newborn human infants have been shown to have a higher capacity for binding insulin to circulating monocytes than adults. Also, human fetuses apparently lack the capability to diminish monocyte receptors in the presence of hyperinsulinemia. These experiments show that an increase in insulin receptor binding capacity and affinity also occurs in the liver of the rat fetus at term as compared to the adult rat. The reasons and mechanisms underlying enhanced capacity for insulin binding by fetal and newborn members of human and rodent species are not known.

Stimulation of phosphatidylcholine synthesis by fatty acids in fetal rabbit type II pneumocytes

After 24 h exposure to 0.1 mM oleate or 0.1 mM palmitate there was a 2- and 1.7-fold increase, respectively, in the incorporation of choline into the lipids of type II pneumocytes. Palmitate increased the labeling of disaturated phosphatidylcholine (PC) from 23.0% of total labeled PC in control cultures to 56.6% and oleate decreased labeling of disaturated PC to 9.4%. The percentage of total cellular radioactivity found in the lipid fraction was also markedly higher in the fatty acid-treated cells (83.3% for oleate and 78.7% for palmitate) than in control cultures (64.0%). Radioactivity in water-soluble choline metabolites was correspondingly lower, with phosphocholine representing more than 95% of the label in both control and experimental cultures. After a 3 h pulse-chase period, oleate and palmitate significantly increased the percentage of total cellular radioactivity in PC and decreased the percentage in phosphocholine. Similar results were obtained by adding melittin (1-2 micrograms/ml) or phospholipase C (0.05 U/ml) to the culture medium. The stimulation of PC synthesis by fatty acids was demonstrated as early as 1 h after exposure to oleate or palmitate and at all concentrations from 0.025 to 0.25 mM. Cytidylyltransferase activity in total cell homogenates was also enhanced by long-term exposure to fatty acids and short-term addition of fatty acids or phospholipase C and melittin to the culture medium. A similar increase in cytidylyltransferase activity was found in the 100 000 X g particulate fraction of type II cells exposed to fatty acids, whereas no differences were found between the cytosolic fractions of control and treated cells. These results support the concept that an increase in intracellular level of fatty acids either from an exogenous source or following the activation of endogenous phospholipases regulates PC synthesis in fetal type II pneumocytes.