Hypertriglyceridemia and hyperinsulinemia are potent inducers of endothelin-1 release in humans.

The purpose of the study was to evaluate fasting endothelin-1 levels in subjects with syndrome X, in subjects with insulinoma, and in normal subjects. The single and synergistic contributions of insulin and triglyceride levels to endothelin-1 release were studied in normal subjects. This was achieved by the evaluation of endothelin-1 levels in response to an insulin bolus combined with a euglycemic clamp (protocol A) and during intralipid (test 1) or saline (test 2) infusions lasting 360 min (protocol B). In protocol B, a euglycemic two-step hyperinsulinemic (25 and 125 mU x kg-1 x h-1) clamp was started at 120 min. Subjects with syndrome X showed significantly higher endothelin-1 levels than normal subjects and subjects with insulinoma (7.22 +/- 0.89 vs. 2.61 +/- 0.38 and 2.49 +/- 0.24 pg/ml, P < 0.01). After an insulin bolus, endothelin-1 levels peaked at 10 min (3.71 +/- 0.96 pg/ml). The incremental area of endothelin-1 was significantly higher after insulin than after a saline bolus. In test 1, an acute increase in triglyceride levels significantly enhanced endothelin-1 levels, with were further increased by the synergistic contribution of high insulin and triglyceride levels. In test 2, endothelin-1 release was achieved at high insulin levels but remained significantly lower than in test 1. In conclusion, subjects with syndrome X showed higher endothelin-1 levels than normal subjects and subjects with insulinoma. These levels were reproduced in normal subjects by a simultaneous increase in insulin and triglyceride levels.

Recombinant human TSH changes the multidisciplinary approach to patients with differentiated thyroid carcinoma. Two-year experience.

BACKGROUND: Recombinant human TSH (rhTSH) is available for monitoring differentiated thyroid carcinoma. rhTSH testing modifies the guidelines for this disease. METHODS: A 2-year experience with rhTSH on 27 consecutive patients with papillary cancer is reported. The aim of the study was to evaluate the sensitivity and specificity of thyroglobulin (Tg) after rhTSH in detecting residual thyroid cancer after primary therapies. Sensitivity and specificity of rhTSH testing were also compared with neck ultrasound (US) and whole-body scan (WBS). Favourable results were regarded as: Tg levels <1 microg/L after rhTSH, no US image indicative of thyroid tissue or suspect neck nodes, and negative WBS after (131)I and (99m)Tc-MIBI. RESULTS: Side effects were mild. Unfavourable baseline Tg levels were noted in 15% of patients with local or metastatic disease. After rhTSH testing, unfavourable Tg levels were noted in a further 17% of patients. After 12-24 months, Tg levels on rhTSH re-testing were favourable in 14 out of 17 patients evaluated and indicative of no disease progression in 1; in 2, they were still indicative of an unsatisfactory effect of further radioiodine therapy. No significant increase in a subunit (alphaSU) was noted after rhTSH administration. Sera from patients with hypothyroidism or collected on the day of TSH peak after rhTSH, showed isoform profiles of TSH (and alphaSU) similar to those found after focusing rhTSH. Agreement between rhTSH testing and neck US was found in 85% of patients. Agreement among rhTSH, neck US and (131)I and (99m)Tc-MIBI WBS was found in 46% of subjects. The specificity of rhTSH testing, neck US, (131)I and (99m)Tc-MIBI WBS was 95%, 84%, 89% and 53%, while sensitivity was 100%, 87%, 40% and 71%, respectively. CONCLUSIONS: Our data show that full bioactivity of TSH after rhTSH is indirectly suggested by the negligible increase in alphaSU after rhTSH and the similar pattern of TSH isoforms after rhTSH and hypothyroidism. Neck US is the most sensitive imaging technique in detecting local or neck node recurrence of the disease, while (99m)Tc-MIBI WBS is the least specific. After primary treatments for papillary thyroid carcinoma, rhTSH testing under L-T4 therapy and neck US may be regarded as first-line evaluations. Under L-T4 regimen, Tg levels lower than 1 microg/L after rhTSH testing seem to be the best index of normality on follow-up in patients with a history of thyroid papillary carcinoma. In these patients, diagnostic (131)I WBS seems to be unnecessary.

Circulating nitric oxide is modulated by recombinant human TSH administration during monitoring of thyroid cancer remnant.

During the administration of recombinant human TSH (rhTSH) to monitor differentiated thyroid carcinoma, mild side effects, such as nausea and headaches, often occur. The origin of these is not clear. Since changes in TSH and thyroid hormones can modulate some endothelial-derived factors, we aimed at testing whether rhTSH administration induces changes in nitric oxide. We studied 25 patients (56.6+/-12.6 yr) who had undergone thyroidectomy followed by ablative radioiodine for papillary thyroid cancer and who were under follow-up. While L-thyroxine therapy continued, thyroglobulin (Tg), TSH, free-T3, free-T4 and nitrite-plus-nitrate (NOx) concentrations were evaluated before and after rhTSH administration (0.9 mg i.m. on 2 consecutive days). Mean TSH showed a huge increase from baseline (0.1+/-0.0 mIU/l) to day 3 (216.3+/-17.5 mIU/l, p<0.001), which was not accompanied by changes in thyroid hormones. Mean baseline NOx levels were 12.6+/-1.2 micromoles/l and showed a significant increase on day 3 (20.1+/-1.2 micromoles/l, p<0.05 vs day 0), followed by progressive reduction from day 6 (18.1+/-2.8 micromoles/l) to day 9 (10.6+/-1.3 micromoles/l, p<0.05 vs day 0). There was a significant (p=0.04) correlation between the percentage increase in TSH and the percentage increase in NOx. On the other hand, increase in TSH did not correlate with the percentage decrease in NOx from day 6 to day 9. No correlation was noted between the increase in TSH or NOx and the occurrence or severity of the symptoms. Our study shows that, during rhTSH testing, circulating nitric oxide increases. This endothelial-derived factor might, in turn, mediate the occurrence of vasomotor headache and nausea in some particularly susceptible patients.

Three novel missense mutations in the glucokinase gene (G80S; E221K; G227C) in Italian subjects with maturity-onset diabetes of the young (MODY). Mutations in brief no. 162. Online.

The maturity-onset diabetes of the young (MODY), an autosomal dominant form of non-insulin dependent diabetes mellitus (NIDDM), is caused by mutations in the glucokinase (GK, MODY 2) and in the hepatocyte nuclear factor 1a (MODY 3) and 4a (MODY 1) genes. We have screened the glucokinase gene by the polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE) in fifteen subjects with clinical characteristics of MODY and one parent with NIDDM, impaired glucose tolerance or gestational diabetes. PCR products with abnormal mobility in DGGE were directly sequenced. We have identified four mutant alleles, three of them (G80S, E221K, G227C) are new missense mutations located in or near the region of the active site cleft of the enzyme. The mutations co-segregate with hyperglycemia in the families of the three probands, whose biochemical and clinical phenotype is similar to other individuals with MODY 2 mutations.

Effects of low-dose heparin infusion on arterial endothelin-1 release in humans.

BACKGROUND: The aim of this study was to evaluate the effect of low-dose heparin infusion on arterialized endothelin-1 (ET-1) release in the presence of fasting or high insulin levels in healthy humans. METHODS AND RESULTS: Eleven normal subjects underwent two tests in random order lasting 240 minutes. A primed (250 IU), continuous heparin (600 IU/h) infusion was performed in test 1; saline was infused in test 2 as control. At 120 minutes, a euglycemic hyperinsulinemic clamp (25 mU.kg-1.h-1) was started that lasted 2 hours in both tests. Two hours after heparin infusion (test 1), ET-1 levels decreased by 32% (3.52 +/- 0.60 to 3.02 +/- 0.73 pg/mL), while nitric oxide (NO) and forearm blood flow increased by 29% and 14%, respectively. During saline infusion, ET-1, nitric oxide, and forearm blood flow remained unchanged. There was a significant interaction between the effect of decreasing ET-1 levels and the heparin treatment (F, 4.06; df, 3.30; P < .01). The decrease in ET-1 levels was significantly correlated with the increase in forearm blood flow in test 1 (r = .74; P < .01) but not in test 2. During the heparin/insulin period, ET-1 increased by 25%, returning to fasting values; nitric oxide levels increased by 12%; and forearm blood flow remained unchanged. CONCLUSIONS: The present study showed that it is possible to decrease ET-1 levels by use of low-dose heparin infusion in humans. This effect seems mediated by a simultaneous increase in nitric oxide levels and is completely reversed by a mild increase in insulin concentrations.