The effect of dietary phytosphingosine on cholesterol levels and insulin sensitivity in subjects with the metabolic syndrome.

BACKGROUND: Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA) levels in rodents and improves insulin sensitivity. OBJECTIVE: To study the effect of dietary supplementation with PS on cholesterol and glucose metabolism in humans. METHODS: Twelve men with the metabolic syndrome (MetS) (according to the International Diabetes Federation (IDF) criteria; age 51+/-2 years (mean+/-s.e.m.); body mass index (BMI) 32+/-1 kg/m(2)) were randomly assigned to 4 weeks of PS (500 mg twice daily) and 4 weeks of placebo (P) in a double-blind cross-over study, with a 4-week wash-out period between both interventions. At the end of each intervention anthropometric measures and serum lipids were measured and an intravenous glucose tolerance test (IVGTT) was performed. RESULTS: Phytosphingosine did not affect body weight and fat mass compared with P. PS decreased serum total cholesterol (5.1+/-0.3 (PS) vs 5.4+/-0.3 (P) mmol/l; P<0.05) and low-density lipoprotein (LDL)-cholesterol levels (3.1+/-0.3 (PS) vs 3.4+/-0.3 (P) mmol/l; P<0.05), whereas it did not alter serum triglyceride and high-density lipoprotein (HDL)-cholesterol levels. In addition, PS lowered fasting plasma glucose levels (6.2+/-0.3 (PS) vs 6.5+/-0.3 (P) mmol/l; P<0.05). PS increased the glucose disappearance rate (K-value) by 9.9% during the IVGTT (0.91+/-0.06 (PS) vs 0.82+/-0.05 (P) %/min; P<0.05) at similar insulin levels, compared with P, thus implying enhanced insulin sensitivity. PS induced only minor gastrointestinal side effects. CONCLUSION: Dietary supplementation of PS decreases plasma cholesterol levels and enhances insulin sensitivity in men with the MetS.

Skeletal effects of two years of treatment with low physiological doses of recombinant human growth hormone (GH) in patients with adult-onset GH deficiency.

A low bone mass in adults with childhood-onset GH deficiency (GHD) is likely to be caused by deficient bone accretion during childhood and early adulthood, whereas a decreased bone mass in patients with adult-onset GHD is likely to be caused by an imbalance in bone remodeling. Data on bone mineral density (BMD) and biochemical parameters of bone metabolism and data on response of these parameters to treatment with GH are scarce in patients with adult-onset GHD. It has been suggested that in patients with GHD, GH at the relatively high dose originally used may have beneficial effects on the skeleton. To address the question as whether lower, more physiological doses would have similar effects on the skeleton, we studied 47 patients with adult-onset GHD (27 women and 20 men, range 26-70 yr) randomized to receive one of three recombinant human GH (rhGH) dose regimens: 0.6 IU/day, 1.2 IU/day, or 1.8 IU/day as part of a study examining optimal GH dose replacement therapy. After 24 weeks of treatment, the dose of rhGH was individually adjusted to maintain the concentration of serum insulin growth factor-I within the normal laboratory reference range. Biochemical parameters of bone metabolism were measured at baseline and after 24 and 52 weeks and 2 yr of treatment. BMD of the lumbar spine was measured at baseline and after 52 weeks and 2 yr of treatment. Parameters of bone metabolism generally fell within the low-normal range and increased in a dose-dependent manner at 24 weeks of treatment. Between 24 and 52 weeks of rhGH treatment, mean serum osteocalcin levels and alkaline phosphatase activity further increased, whereas mean 24-h urine hydroxyproline/creatinine and N-telopeptide/creatinine excretion remained unchanged. After 52 weeks of treatment, serum alkaline phosphatase activity and 24-h urine hydroxyproline/ creatinine excretion decreased, although not to pretreatment levels. Mean BMD at the lumbar spine (Z-score) was normal at baseline (-0.20 +/- 0.16) and increased during treatment (at 2 yr of treatment: 0 +/- 0.20; P < 0.005). Our data suggest that a low physiological dose of rhGH, individually adjusted to maintain serum insulin-like growth factor I levels within the normal laboratory reference range, increased bone turnover in favor of bone formation, as suggested by the significant, albeit small increase in BMD observed after 2 yr of treatment. Further studies are required to establish whether in patients with adult-onset GHD the preservation and/or increase in bone mass observed with the use of physiological doses of rhGH could be maintained with longer-term treatment.

Danaparoid sodium lowers proteinuria in diabetic nephropathy.

Diabetic nephropathy is a progressive renal disease with thickening of the glomerular basement membrane and mesangial expansion and proliferation as histological hallmarks. The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in diabetic nephropathy proportionally to the degree of proteinuria. Danaparoid sodium is a mixture of sulfated glycosaminoglycans consisting mainly of heparan sulfate. The study presented here involved performing a randomized placebo-controlled crossover study with danaparoid sodium in diabetic patients with overt proteinuria. The aim of the study was to evaluate the effect on proteinuria and safety/tolerability. Nine patients completed the study, without major side effects; the crossover study consisted of two 6-wk periods of treatment with 750 anti-Xa units danaparoid sodium subcutaneously once-daily or placebo. Following danaparoid sodium, significant declines of both albuminuria and proteinuria were found. After danaparoid sodium, the albumin excretion ratio standardized for urinary creatinine reduced with 17% in comparison with an increase of 23% after placebo (95% confidence interval of the difference,-75.9-3.9%; P = 0.03). The percentage change of the urinary protein excretion corrected for urinary creatinine differed at 8 wk significantly between both treatment arms (P = 0.001). Additional parameters for safety as hematological, hemostasis, biochemical parameters, and fundusphotography did not show any clinically significant difference for both groups. Only two patients had minor skin hematomas at the injection site while using danaparoid sodium. In conclusion, the supplementation was found to be feasible and was not associated with side effects. A significant decline of proteinuria was found. More prospective dose-finding and long-term studies must be performed to see whether danaparoid sodium could not only induce a reduction of proteinuria but also halt the progression of renal disease.

Recovery of serum calcium concentrations following acute hypocalcemia in patients with osteoporosis on long-term oral therapy with the bisphosphonate pamidronate.

Bisphosphonates, synthetic compounds that are taken up preferentially by the skeleton and that suppress bone resorption, are currently used in the management of patients with osteoporosis. Long-term uninterrupted administration of low oral doses is the preferred mode of treatment in current clinical trials with newer bisphosphonates. These compounds have, however, a long residence time in the skeleton, and there is no information about their long-term effects on blood calcium homeostasis. We examined the effect of long-term therapy with oral bisphosphonate on blood calcium homeostasis following an acute hypocalcemic stimulus. Twenty patients with vertebral osteoporosis (10 untreated controls and 10 treated with oral pamidronate, 150 mg/day for at least 5 yr) were given intravenous infusions of sodium EDTA, and the concentrations of calcium and PTH in blood were followed for 24 h. Serum calcium concentrations decreased similarly in both groups (maximum decrease 0.21 mmol/L and 0.22 mmol/L, respectively). The recovery of serum calcium concentrations was identical in both groups, and all patients had normal concentrations at 24 h. Plasma PTH increased to a peak of 17.3 +/- 2.5 pmol/L in the control group and to 17.0 +/- 3.1 pmol/L in the pamidronate-treated patients. During the whole study period, there was no difference in either the peak PTH response or in the recovery of plasma PTH values between the two groups. However, when only PTH responses between 60 min and 24 h were examined, there were differences between the two groups. Plasma PTH values, although strictly within the normal range, were significantly higher in the pamidronate-treated patients (P = 0.001). There were no differences in the calcemic responses during this period. Further, there were no detectable changes in immunoreactive PTH-related protein in either group after the EDTA infusions. In conclusion, our study showed that longterm therapy with oral pamidronate does not affect the calcemic response to an acute hypocalcemic stimulus in patients with osteoporosis.

Effects of hypoxia and atrial natriuretic peptide on aldosterone secretion in healthy subjects.

To evaluate the inhibitory effect of hypoxia and atrial natriuretic peptide (ANP) on aldosterone secretion, 11 healthy male subjects were infused with 5 ng.kg-1 x min-1 ANP or placebo. The subjects were exposed in a stepwise fashion to incremental hypobaric hypoxia, which decreased arterial oxygen saturation to 79 +/- 2% in the placebo and 84 +/- 2% in the ANP condition (P < 0.05). In the placebo condition, the plasma ANP concentration increased from 13.8 +/- 1.0 to 19.6 +/- 2.3 pmol/l (P < 0.01) at the lowest barometric pressure. Plasma renin activity did not change, whereas the plasma aldosterone levels increased consequent to the increase of plasma adrenocorticotropic hormone (ACTH). Continuous infusion of ANP increased the plasma levels twofold (P < 0.001) and the level of guanosine 3',5'-cyclic monophosphate threefold (P < 0.001). However, the plasma aldosterone concentrations were not different in the two experimental conditions. Administration of supplementary oxygen significantly decreased ACTH to baseline values (P < 0.01) together with a decrease in aldosterone. Free water clearance (P = 0.05) but not sodium excretion (P = NS) increased during continuous ANP infusion. The data indicate that the aldosterone secretion in hypoxia is not inhibited by (patho)physiological plasma ANP levels. The inhibition of aldosterone secretion may well be explained by a direct effect of hypoxia on the adrenal cells. ACTH is a major stimulus of aldosterone secretion in hypoxia, which overrides the natriuretic effect of ANP.

The influence of serotonergic neurotransmission on pituitary hormone release in obese and non-obese females.

It has been suggested that a defect in hypothalamic serotonergic neurotransmission may be partly responsible for the impaired pituitary hormone release in obese subjects. In this study we investigated basal serum pituitary hormone concentrations and pituitary hormone release in response to the sequential injection of four hypothalamic releasing hormones before and after a seven-day course of fluoxetine, which inhibits serotonin re-uptake by presynaptic neurons and acts specifically in the brain. Ten obese women (body mass index (BMI) 35.6 +/- 1.0 kg/m2) and nine women of normal weight (BMI 22.9 +/- 0.9 kg/m2) were studied in the early and mid-follicular phases of the menstrual cycle. Basal concentrations of pituitary hormones were measured at 09.00. Subsequently 200 micrograms of TRH and 100 micrograms of CRH, GnRH and GHRH were injected intravenously. The pituitary hormone response was measured at regular intervals until 180 min after the four injections. The experiment was repeated after a seven-day course of 60 mg fluoxetine orally. We found the basal concentrations of prolactin (PRL) and growth hormone to be significantly lower in obese subjects than in the normal controls. Basal concentrations of ACTH, beta-endorphin, TSH, LH and FSH in the two groups were comparable. Releasing hormone-induced responses in the two groups were not significantly different. Administration of fluoxetine "restored" the basal PRL concentrations in obese subjects. It did not affect the other basal hormone concentrations. Furthermore, fluoxetine treatment reduced TRH-induced TSH release in both normal and obese subjects. It did not influence the other releasing hormone-induced responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian and pulsatile thyrotropin release in treated acromegalics.

We studied the 24-h TSH profiles of 16 treated male acromegalic patients (age range 26-68 yr) in clinical and biochemical remission. Eight had undergone transsphenoidal surgery, the others surgery and pituitary irradiation. Blood samples were taken at 20-min intervals; circadian rhythms were established by cosinor analysis, pulsatile release with the Cluster programme. All patients, except one irradiated subject, were euthyroid. TSH reserve was diminished preoperatively in 7 subjects and at the time of the profile study in 10 subjects, one of whom was biochemically hypothyroid. A significant circadian rhythm was present in 14 subjects and absent in the hypothyroid patient. The acrophase occurred at 2.46 +/- 0.51 h in nonirradiated patients and at 3.37 +/- 0.38 h in irradiated patients (NS). About 10 TSH pulses/24 h (range 6-13) were detected; there was no significant difference between irradiated and non-irradiated patients. With cross-correlation techniques synchronous release of TSH and PRL was demonstrated in 7 out of 8 nonirradiated patients in contrast to only 2 of the irradiated patients. This study demonstrates a qualitatively normal TSH secretion pattern for treated acromegalic patients, but the absolute TSH levels are clearly low compared with published data on normal subjects. The present findings can be explained by a diminished TSH cell mass; in addition radiation therapy causes a disturbance at the hypothalamic level, as indicated by the loss of synchronism between TSH and PRL release.