Extrapancreatic insulin effect of glibenclamide.

In eight patients with uncomplicated non insulin dependent diabetes mellitus, serum insulin levels, serum C-peptide levels and blood glucose levels were measured before and after oral administration of glibenclamide 0.1 mg/kg body weight and a test meal, or after a test meal alone. The rise in serum insulin levels persisted longer after glibenclamide. The initial rise in serum insulin was of the same magnitude in both situations, as was the rise in serum C-peptide levels during the entire 5 h study. It is concluded that glibenclamide is able to maintain a more prolonged increase in serum insulin levels by inhibiting the degradation of insulin in the vascular endothelial cells of the liver. The inhibition contributes to the blood glucose lowering effect of glibenclamide.

Stimulation of calcitonin secretory capacity by increased serum levels of testosterone in men treated with tamoxifen.

Previous studies have suggested that sex steroids, including both oestrogen and testosterone, influence calcitonin secretion. However, a negative effect of gonadotrophins on calcitonin has not been excluded. Twelve men with infertility and low-normal serum levels of testosterone were studied before and during tamoxifen therapy. Increases in the serum levels of LH, FSH, testosterone and calcitonin were observed after treatment. Our findings suggest that testosterone has a direct influence on calcitonin secretion.

The effect of age on the renal response to PTH infusion.

The renal responses to PTH infusion were compared in two age groups of healthy subjects. Basal nephrogenous cyclic AMP (NcAMP) was higher (1.68 +/- 0.74 vs. 0.97 +/- 0.50 nmol/dl GF; P less than 0.05) and TmPO4/GFR was lower (0.93 +/- 0.21 vs. 1.16 +/- 0.14 mmol/liter; P less than 0.025) in 10 elderly subjects compared with 12 young adults. Creatinine clearance was decreased in the elderly (84.8 +/- 25.7 vs. 144.7 +/- 43.2 ml/min; P less than 0.005) and serum iPTH tended to be increased (0.15 +/- 0.11 vs. 0.11 +/- 0.03 pmol/liter). Following the infusion of 3 IU bPTH/kg bodyweight, no significant differences in delta NcAMP and delta TmPO4/GFR were seen between the groups. When responses were expressed as percentual change of basal level, elderly subjects showed a % NcAMP of 1831 +/- 1200 which was comparable with 2038 +/- 1503% in young adults. However, the percentual change in TmPO4/GFR was significantly higher in elderly persons (24.2 +/- 11.9 vs. 11.9 +/- 8.0%; P less than 0.01). In young subjects, virtually absent TmPO4/GFR responses were found in 3 cases with a relatively low basal TmPO4/GFR (between 0.92 and 0.98 mmol/liter), but these cases showed normal increases in NcAMP. Elderly subjects retained a considerable delta TmPO4/GFR notwithstanding a basal TmPO4/GFR below 0.92 in seven out of 10 cases. These results confirm the existence of a slight increase in parathyroid activity in the elderly. In addition, they suggest an augmented sensitivity of the renal tubule concerning PO4 reabsorption in elderly subjects. It is speculated that this phenomenon is related to the fall in bone mineral retention in senescence and might reflect a defense mechanism against phosphate overload.

Decrease of serum testosterone by cyproterone acetate accompanied by an unexpected increase of calcitonin secretion capacity.

The interaction between testosterone and calcitonin secretion capacity was studied in 9 patients with prostatic cancer. Treatment with the antiandrogenic agent cyproterone acetate resulted in an expected decrease in serum testosterone but an unexpected and unexplained increase in calcitonin secretion capacity. The previous statement that a positive correlation between sex hormones and calcitonin secretion capacity can be recognized probably requires revision. This unexpected effect of cyproterone acetate had possible additive beneficial advantages for treatment, such as bone mass sparing and its analgesic effect.

Acute changes in plasma renin activity, plasma aldosterone concentration and plasma electrolyte concentrations following furosemide administration in patients with congestive heart failure--interrelationships and diuretic response.

We studied the effects of furosemide on plasma renin and plasma aldosterone in 8 patients with mild to moderate congestive heart failure. In particular, we tried to correlate these effects with changes in plasma electrolyte concentrations and with the diuretic response on furosemide. We concluded that the diuretic response in patients with congestive heart failure is not dependent on the initial serum renin nor on the initial serum aldosterone concentration. The diuretic response did not correlate either with the changes in serum renin and/or serum aldosterone concentration. Serum renin and serum aldosterone correlated mutually before and after intravenous furosemide. We confirmed the inverse correlation between serum sodium and serum renin. SeNa and SeK correlated at all times with serum aldosterone; SeCl correlated with serum aldosterone only before intravenous furosemide administration. Indirect evidence could be provided that in patients with congestive heart failure a decreased renal blood flow is present, using the urinary beta 2-microglobulin concentration. Aldosterone has again, indirectly, proved to be integrated in the renal magnesium handling.

End-organ resistance to PTH infusion in hypercalcaemic and normocalcaemic patients with solid tumours.

Ten hypercalcaemic patients with solid tumours were studied to evaluate the renal response on PTH infusion as assessed by nephrogenous cAMP excretion and maximum tubular re-absorption of phosphate. In addition, 20 normocalcaemic patients, 11 with an adenocarcinoma and 9 with a squamous cell carcinoma, were studied. All cancer patients had moderately extensive disease. Results were compared with those of 9 patients with primary hyperparathyroidism and with 10 elderly controls. All groups studied had comparable renal function, magnesium and 25-hydroxy-vitamin D levels. Comparable results were obtained in patients with an adenocarcinoma and in controls. cAMP response (delta nephrogenous cAMP) was significantly lower in the hypercalcaemic patients with a solid tumour compared with the controls (8.13 +/- 4.68 nmol/100 ml glomerular filtrate vs 29.52 +/- 25.62 nmol/100 ml glomerular filtrate; P less than 0.005). In the group of patients with primary hyperparathyroidism delta nephrogenous cAMP was 13.41 +/- 7.54 nmol/100 ml glomerular filtrate (P less than 0.06 vs controls). The group of patients with a squamous cell cancer showed an intermediate value of 14.83 +/- 10.74 nmol/100 ml glomerular filtrate (P less than 0.025 vs the normocalcaemic adenocarcinoma patients, but NS vs controls). In two hypercalcaemic patients with a solid tumour in whom PTH infusion was repeated after normalization of serum calcium no influence on renal responsiveness was observed. Responses of maximum tubular re-absorption of phosphate were lowest in the group of hypercalcaemic patients with a solid tumour and in the patients with primary hyperparathyroidism compared with controls (0.11 +/- 0.10 vs 0.22 +/- 0.09 mmol/l and 0.09 +/- vs 0.22 +/- 0.09 mmol/l; P less than 0.025 and P less than 0.005, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The renal sensitivity for endogenous parathormone in patients with primary hyperparathyroidism, vitamin D deficiency and renal stones.

Baseline levels and increases in urinary cyclic AMP excretion (UcAMP) and immunoreactive parathormone (iPTH) were studied before and during infusion of EDTA in euparathyroid patients with renal stones (n=11), patients with primary hyperparathyroidism (PHP; n=14) and patients with vitamin D deficiency (n = 12). In all three groups, EDTA evoked a significant rise in iPTH and UcAMP. In patients with PHP and in those with vitamin D deficiency, there was a sufficiently close relationship between increments in iPTH (delta iPTH) and in UcAMP (delta UcAMP) (r = 0.90, P less than 0.001 and r = 0.67, P less than 0.02, respectively) to use this model to assess renal sensitivity for changes to endogenous PTH levels. We quantified sensitivity of the kidney for PTH, by calculating the ratio delta UcAMP/delta TPTH for the three studied groups. The ratio was comparable in patients with renal stones (16.7 +/- 10.3) and PHP (13.8 +/- 4.9, P greater than 0.10), but was significantly increased in patients with vitamin D deficiency (33.2 +/- 17.9; P less than 0.01 versus patients with renal stones and P less than 0.01 versus patients with PHP). Within the group of patients with PHP there was no correlation between baseline serum calcium concentrations and the ratio delta UcAMP/delta TPTH. It is concluded that in patients with vitamin D deficiency, renal sensitivity to PTH is increased compared with patients with PHP and euparathyroid patients with renal stones, perhaps an expression of a teleological useful adaptation of end organ sensitivity.

Decreased renal clearance of digoxin in chronic congestive heart failure.

Renal digoxin clearance was compared in patients suffering from atrial fibrillation with well preserved cardiac function (n = 9; salt intake +/- 170 mmol daily) and patients with chronic congestive heart failure (n = 10; salt intake 50 mmol daily and maintenance treatment with diuretics). There was no difference between the groups concerning digoxin dosage, creatinine clearance, diuresis or sodium excretion in the urine. Digoxin clearance in chronic heart failure proved to be significantly lower than in atrial fibrillation (48 +/- 21 vs 71 +/- 36 ml X min-1, p less than 0.05), and Cdig/Ccreat was similarly reduced at 0.73 +/- 0.15 compared to 1.09 +/- 0.27 (p less than 0.005). Steady state serum digoxin concentration was significantly higher in patients with congestive heart failure (1.44 +/- 0.47 vs 0.87 +/- 0.33 micrograms X 1(-1), p less than 0.01). Chronic congestive heart failure is a state with reduced digoxin clearance by the kidney, which could lead to digoxin intoxication not explicable by overdose, reduced renal function or the effect of interacting drugs.

Thyroid function in healthy normal, low birthweight and preterm infants.

To delineate more precisely the role of gestational age, weight at birth and thyroid status at birth on the postnatal changes in thyroid hormone levels, serum T4, T3, TSH and in some cases FT3I were measured at birth and at 3-4 h, 24-30 h, 6-9 days and 13-20 days. Subjects studied were healthy appropriate-for-date (AFD) and small-for-date (SFD) term neonates and healthy AFD and SFD preterm children. At birth T4 and T3 are related to both gestational age and weight with T4 and T3 showing lower values in preterm and SFD term neonates than in AFD term children. After birth T4 and T3 concentrations show a better correlation with gestational age than with weight at birth. For TSH no correlation was found at birth, a positive correlation at 24-30 h, no correlation at 6-9 days and a negative correlation at 13-20 days both with gestational age and weight at birth. In term and close-to-term infants (36 weeks) individual T4 levels at 6-7 days show a close relationship with those at birth; in the younger children (34 and 35 weeks) lower T4 values are found, despite equal cord blood values. The individual cord blood FT3I/TSH values correlate well with those at 6-7 days of age. It is concluded that after birth all children have changing T4 and T3 values, but the pattern and level are influenced by the maturity of the child and its thyroid status at birth measured by T4 and by the FT3I/TSH ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in nephrogenous cyclic AMP excretion and plasma cyclic AMP following treatment of hyperthyroidism.

Plasma cyclic AMP (PcAMP) concentration and the excretion of cyclic AMP/dl GF were estimated in 11 thyrotoxic patients before and after medical treatment. PcAMP concentrations were significantly higher during hyperthyroidism (2.30 +/- 0.69 vs 1.88 +/- 0.71 nmol/dl; P less than 0.05), and total urinary cyclic AMP (TcAMP) excretion showed no significant changes (3.24 +/- 0.64 vs 3.44 +/- 1.77 nmol/dl GF). Nephrogenous (NcAMP) excretion rose significantly (1.00 +/- 0.82 vs 1.68 +/- 1.31 mmol/dl GF; P less than 0.025). The increase in NcAMP excretion correlated significantly with the decrease in serum T3 levels (r = -0.46; P less than 0.05). Serum iPTH levels showed no significant change. Both the serum Ca, corrected for serum total protein and TmPO4/GFR declined after treatment (respectively 2.44 +/- 0.13 vs 2.33 +/- 0.08 mmol/l; P less than 0.05 and 1.18 +/- 0.29 vs 1.05 +/- 0.22 mmol/l; P less than 0.05). It is concluded that the rise in NcAMP excretion corroborates the concept of increasing parathyroid activity following the treatment of hyperthyroidism.

Diminution of prolactin and increase of thyrotrophin response to thyrotrophin releasing hormone occurring independently of changes in basal level of these hormones during treatment of hypothyroidism.

In order to study the effect of rising thyroid hormone levels in hypothyroidism upon prolactin responses to TRH, in relation to changes in basal prolactin concentration and to changes in TSH responses, we followed 18 patients by performing TRH tests before and after 14, 28, 42 and 56 d on gradually increasing levothyroxine dosages, plus a final test when euthyroidism was achieved. Basal prolactin rose initially, at day 14, followed by a return on days 28, 42 and 56 to a level similar to the pretherapeutic value, while at euthyroidism prolactin had fallen below the original value. The area under the prolactin response curve on TRH stimulation was unchanged at 14 d, notwithstanding the rise of basal prolactin concentration. At 28, 42 and 56 d the responses declined progressively along with basal prolactin concentrations that remained equivalent to the pretreatment level. The TSH response to TRH rose at 14, 28, and 42 d along with a continuous downward course of basal TSH. Thus, substitution with L-thyroxine inhibited the responsivity of prolactin but enhanced that of TSH to TRH. The fact that these changes occurred in opposite directions, appears to rule out a negative feed-back effect of T4 on hypothalamic TRH secretion. The effects on responses were shown to occur independently of those on basal secretion of prolactin and TSH.

Thyroxine and triiodothyronine levels in Snell mice.

Since no data are available concerning thyroid hormone levels in Snell dwarf mice from birth on, a cross-sectional study was performed of L-thyroxine (T4) and L-triiodothyronine (T3) levels in blood or serum as a function of age of several litters, starting at birth. In normal Snell mice T4 levels in blood and serum are changing with age. T4 increases during the first 2 weeks of age and declines thereafter, until adult levels of about 50 nmol/l are reached at 21 days of age. Serum T3 values are in the range of 2-3 nmol/l. They do not show such an age-related pattern. From birth on in each litter there was a clear separation between animals with low T4 levels in blood and the others. This separation was possible at all subsequent days until 9 days of age, when dwarfs can be recognized by eye. Above that age the low T4 values were associated with dwarfism. This suggests that dwarfs are hypothyroid already at birth. Serum T3 in dwarfs falls below the normal range only after 4 weeks of age, resulting in a lower T4/T3 ratio than normal. The half life time of exogenous T4 in serum of dwarfs is in the range of 13-18 h and not different from normal. For T3 t1/2 is 9.5-11.1 h. Dwarf mice become euthyroid by treatment with 0.1 microgram T4 per day. 1 microgram T4 was needed to reach a physiological level of T3. These data suggest that the peripheral conversion of T4 to T3 is slower in dwarfs than in normals. Treatment with hGH, prolactin, glucagon, insulin, testosterone and oestradiol had no influence on serum T4. As expected TSH was stimulatory. Similar results were obtained for serum T3, with the exception of prolactin which caused slightly increased levels of serum T3.

Renal clearance of digoxin in man after sodium loading or furosemide treatment.

To evaluate the influence of different types of natriuresis on the renal clearance of digoxin (Cldig) and the Cldig/Clcr ratio, studies were performed in which sodium-depleted patients were placed on a moderately high sodium diet for 6 days. In another group natriuresis was evoked by furosemide. In the first study, in 10 patients, there was a 10-fold increase in Na excretion and a small rise in diuresis (V) and Clcr, which was accompanied by an increase in Cldig from 57.5 +/- 32, and 60.7 +/- 27.3 (duplicate measurements) to 103.9 +/- 55.4 (p less than 0.01) and 103.8 +/- 46.5 ml min-1 (p less than 0.01). Cldig/Clcr rose from 0.60 +/- 0.24 and 0.61 +/- 0.16 to 0.91 +/- 0.31 and 0.91 +/- 0.21, respectively (both p less than 0.005). Serum digoxin concentration declined from 1.24 +/- 0.35 and 1.19 +/- 0.40 to 1.02 +/- 0.35 and 0.97 +/- 0.32 micrograms/l (both p less than 0.01) during the high sodium diet. In the furosemide-induced natriuresis (6 patients), changes in Na excretion and V were a multiple of those caused by Na loading, but the Cldig/Clcr ratio was not increased. The results are in accordance with the concept of digoxin backdiffusion in the proximal tubules, which is dependent on proximal Na reabsorption. In the more distal segments of the nephron, where the action of furosemide occurs, there does not appear to be any transtubular movement of digoxin.

Familial benign hypercalcaemia. Study of a large family.

Twenty-seven hypercalcaemic subjects were identified in three generations of a family. There were no clinical complications of chronic hypercalcaemia, but five had had parathyroid surgery which was unsuccessful in four. Twenty of the twenty-seven subjects were compared with twenty-four normocalcaemic controls from the same family and the findings were also compared with those from forty patients with surgically proven primary hyperparathyroidism. The relation between the serum and urinary calcium levels was studied by means of an oral calcium loading test. The ratio of calcium clearance to creatinine clearance was normal in this family (but elevated in the patients with primary hyperparathyroidism) and the concentration of parathyroid hormone was normal, as was the total urinary excretion of cyclic AMP. Thus, there was no evidence of either suppressed or increased parathyroid activity in this familial condition. Basal urinary calcium excretion was normal under steady-state conditions indicating that the hypercalcaemia could not be attributed to either increased bone resorption or increased calcium absorption from the gut. In accordance with this, the serum levels of 1,25-dihydroxycholecalciferol were normal. The hypercalcaemia in this condition can be accounted for in full by an increase in renal tubular reabsorption of calcium, and thus differs from that of primary hyperparathyroidism in which there is increased production of calcium from gut and/or bone as well as an increase in renal tubular reabsorption of calcium. Although the serum phosphate and renal tubular reabsorption of phosphate were both low in patients with familial benign hypercalcaemia, they were not as low as in patients with the same degree of hypercalcaemia due to primary hyperparathyroidism. The changes in phosphate transport in familial benign hypercalcaemia could be explained as a secondary effect of the increased filtered load of calcium in the kidney. The tendency towards hypermagnesaemia in our patients, which contrasts with a tendency towards hypomagnesaemia in primary hyperparathyroidism, could also be explained as a secondary effect of the abnormality of renal tubular reabsorption of calcium. Increased renal tubular calcium reabsorption and persistent normal functioning of the parathyroid glands in the face of hypercalcaemia remain the sole definite abnormalities of the syndrome.

The need for a sufficient number of low level sera in comparisons of different serum vitamin B12 assays.

Eight radiochemical methods for the assay of vitamin B12 in serum were compared with the microbiological assay with Lactobacillus leichmannii ATCC 7830 using 198 individual sera of patients. There was a good agreement between the results of most samples with some kits and the microbiological assay. However, especially in the sera of vitamin B12-deficient patients large discrepancies between the results could occur. These variations were due to both the kits used and the performance of the assays in different laboratories. A sufficient number of non-pooled sera of vitamin B12-deficient patients should be included in investigations to validate radiochemical methods.