David Barzilai

Correlation between insulin clearance and insulin responsiveness: Studies in normal, obese, hyperthyroid, and Cushing's syndrome patients

Insulin clearance and secretion determine the plasma insulin concentration. To elucidate the significance of these parameters in man, we employed the euglycemic insulin clamp technique to measure insulin sensitivity, insulin responsiveness, and insulin clearance, and we calculated the basal insulin delivery rate. In 27 patients (six normal, six obese, ten hyperthyroid, and five with Cushings syndrome), insulin was infused at rates of 0.3, 1, 3, or 10 mU/Kg/min, and insulin concentration and glucose utilization were measured. C-peptide concentrations were measured before and during insulin infusion and decreased significantly, indicating a reduction of endogenous insulin secretion to 62% of basal in normals and a similar reduction in the other groups. Maximal responsiveness to insulin was a glucose utilization rate of 450 +/- 20 mg/min/m2 in normals, unchanged in obese, 42% increased in hyperthyroid, and 34% decreased in Cushings syndrome patients. Sensitivity to insulin was decreased in all three abnormal groups. Insulin clearance rates were 1,050 +/- 80 mL/min/m2 for normals, not significantly changed in obese, 45% increased in hyperthyroid, and 33% decreased in Cushings syndrome patients. All three abnormal groups showed hyperinsulinemia compared to normal. The basal insulin delivery rates were calculated as 7.0 +/- 0.3 mU/min/m2, with a threefold increase in obese and in hyperthyroid and no significant change in Cushings syndrome patients. Insulin clearance correlated well with insulin responsiveness (r = .65, P less than 0.001), but poorly with insulin sensitivity (r = .36).(ABSTRACT TRUNCATED AT 250 WORDS)

Pellagra as the presenting manifestation of Crohn's disease.

An 18-yr-old woman hospitalized with classical signs of pellagra was found to have Crohns disease of the small and large bowel as well as malabsorption of nicotinic acid and iron. The symptoms of pellagra disappeared after intramuscular treatment with nicotinic acid, while the malabsorption was corrected following steroid therapy for the Crohns disease. Pellagra should thus be added to the list of complications of Crohns disease that are secondary to malabsorption. Although this complication seems to be very rare, it may be worthwhile to check for nicotinic acid malabsorption in untreated cases of Crohns disease in order to determine its real prevalence.

The dual effect of calcium on aromatization by cultured human trophoblast

To study the effect of calcium ion on aromatization of an androgenic precursor to estradiol by the placenta, cultured term trophoblasts were used as a model system. Secretion of estradiol into the culture medium was regarded as indicating aromatization, since cells cultured with no androgenic precursors produced only insignificant amounts of estradiol. EGTA, verapamil and ionophore A23187 inhibited aromatization, while trifluoperazine, an inhibitor of the calcium-calmodulin complex, interfered with the stimulatory effect of cyclic AMP on aromatization. We conclude that calcium ion has an essential role in the aromatization of 4-androstene-3,17-dione to estradiol. The calcium-calmodulin complex is required for activation of aromatase by cyclic AMP. However, when flooded with calcium by ionophore A23187, the trophoblast is unable to effectively buffer calcium, and aromatization is inhibited.

Thyrotoxicosis Induced by Amiodarone, a New Efficient Antiarrhythmic Drug With High Iodine Content

Amiodarone is an antiarrhythmic agent with high iodine content. Ten patients treated with amiodarone developed thyrotoxicosis. I131 uptakes were negligible, and TT3 levels low in relation to TT4 levels, and sometimes even normal.Cessation of amiodarone caused thyroid functions to return to normal in one to five months, unrelated to propylthiouracil treatment. Eight of the patients had normal thyroid glands on radioscan or palpation. All patients tested had normal TRH tests.Thyrotoxicosis is a relatively common complication of amiodarone treatment, probably caused by its high iodine content. It is possible in apparently normal thyroid glands, suggesting failure of the homeostatic mechanisms controlling thyroid synthesis and release in these patients.Amiodarone is very efficient in controlling tachyarrhythmias and angina pectoris, situations in which thyrotoxicosis is dangerous. Thyroid function tests should therefore be drawn periodically, and the complication considered whenever tachyarrhythmias worsen on treatment with amiodarone.

The effect of inhibitors on insulin regulation of hormone secretion by cultured human trophoblast

The effect of insulin in physiological concentrations on hormone secretion by human term trophoblast cell culture was studied in relation to insulin control of glucose transport and utilization. Specific inhibitors to these 2 functions were added to the culture, either alone to test for a dose response or with insulin. 2-Deoxy-D-glucose, which inhibits glycolysis, did not change the pattern of response of estradiol and placental lactogen (hPL) secretion to insulin. Phloridzin, an inhibitor of glucose transport, interfered with the stimulatory effect of insulin on hPL secretion, but stimulated insulin inhibition of estradiol secretion when added by itself. The results indicate that hPL response to insulin is dependent on glucose transport, but is independent of glycolysis. Estradiol response is dependent on glucose transport, but is independent of glycolysis.

The modulation of placental lactogen secretion by calcium: studies with cultured human term trophoblast

Previous reports have documented the negative regulatory effect of calcium ion on the secretion of human placental lactogen by the placenta. Human term trophoblasts were dispersed from term placenta and maintained in monolayer cell culture. Incubation of the cultured trophoblast with EGTA produced a dose-dependent stimulation of placental lactogen secretion. The calcium ionophore A23187 inhibited hormone secretion. This inhibitory effect was eliminated by the addition of the calcium-calmodulin complex inhibitor trifluoperazine. It is concluded that calcium exerts a negative regulatory effect on the secretion of placental lactogen by a mechanism which requires the action of the calcium-calmodulin complex.

THE ROLE OF CALCIUM ION IN LUTEAL FUNCTION IN THE RAT

The regulatory role of calcium ion was investigated in isolated 10-day-old corpora lutea incubated in vitro. The corpora lutea were induced in immature rats by a single injection of PMSG (15 i.u.) on day 30. We examined the effect of various incubation conditions on the increase (about 7-fold) in cyclic AMP (cAMP) concentration by LH (5 micrograms/ml) and its reversal by PGF2 alpha (10 microM). In calcium-free medium (+0.5 mM EGTA) the stimulation by LH was only slightly impaired, and PGF2 alpha was fully effective in suppressing it. Similarly, both LH and PGF2 alpha acted normally in the presence of 100 microM verapamil, a blocker of calcium uptake. Trifluoperazine (TFP, 3-300 microM) a potent inactivator of calmodulin, did not interfere with the action of PGF2 alpha. The effect of LH was increased by TFP (30 and 300 microM); this was probably due to inhibition of calmodulin-dependent phosphodiesterase, since the increase of the response to LH by IBMX (0.5 mM) plus TFP (30 microM) was similar to that by IBMX alone. Finally, the uptake of radioactive calcium was not increased by PGF2 alpha in the absence or presence of LH. These results do not support the suggestion that calcium ion mediates the hormonal regulation of cAMP in the rat corpus luteum.

Glucoregulatory hormone influence on hepatic glucose production in the elderly

Hepatic glucose production was measured by tracer method in 9 elderly and 9 young subjects after an overnight fast. Blood samples were analyzed for glucoregulatory hormone levels.Hepatic glucose production was similar in elderly and young subjects.Significant hormone changes in the elderly included higher glucose and insulin levels and decreased glucagon. Nonsignificant decreases were seen in cortisol and urinary catecholamines, as well as a nonsignificant increase in growth hormone values. However, growth hormone was significantly correlated with hepatic glucose production in elderly (r = 0.79; p < 0.005), but not in young subjects.We conclude that elderly subjects are able to maintain normal hepatic glucose production despite changes in glucoregulatory hormones. The rate of hepatic glucose production may be related to growth hormone level in elderly, but not in young subjects.

Natural killer cell activity in post-necrotic cirrhotic patients as related to hepatitis-B virus infection and plasma zinc levels

In view of the suggested physiological role of natural killer (NK) cells in immunosurveillance and defence against viral infections, we have investigated the relationship between hepatitis B virus (HBV) infection and NK activity against K-562 cells in patients with post-necrotic cirrhosis. Overall, the NK activity in cirrhotic patients did not differ from age- and sex-matched controls. However, cirrhotic males with evidence of HBV infection with or without HBs antigenemia tend to have lower NK activity than controls. Cirrhotic males without evidence of HBV infection do not differ from controls. Such a trend was not observed in the female cirrhotic patients examined. In addition significantly reduced NK activity was observed in cirrhotic patients with low plasma zinc levels. This relationship is of interest because of the known association between zinc deficiency and various immunodeficiencies.

Inhibition by vanadate of cyclic AMP production in rat corpora lutea incubated in vitro

Vanadate, a normal constituent of cells, has been reported to affect a variety of enzymes involved in phosphate transfer; the findings regarding adenylate cycle vary with the tissue and experimental system. In the corpus luteum, cyclic AMP (cAMP) stimulates steroidogenesis; and prostaglandin F2 alpha, which induces luteal regression, inhibits luteinizing hormone (LH)-induced cAMP accumulation. We examined the influence of orthovanadate on cAMP concentration in isolated corpora lutea from pseudopregnant rats. With 2 mM vanadate, basal cAMP level was unaffected, but LH-induced cAMP accumulation was inhibited by 45-68%. Lower doses of vanadate (0.2-1 mM) were almost as effective. When added simultaneously with LH, vanadate was inhibitory within 25 min, but no inhibition occurred when vanadate was added for 30 min to tissue pretreated with LH for 60 min. The decrease in cAMP accumulation was observed also when corpora lutea were exposed to vanadate in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.5 mM), indicating that vanadate inhibits cAMP synthesis. Vanadate may increase cytosolic calcium by inhibiting ion pumps in cell membranes. Thus, we examined the effect of vanadate in corpora lutea incubated in calcium-depleted medium and found that vanadate still inhibited cAMP formation. Vanadyl sulfate (0.4 and 2 mM) reduced the LH-induced cAMP accumulation as effectively as vanadate. Thus, the use of vanadate as a tool for exploring physiological regulators of luteal adenylate cyclase should be considered.