The Asp727Glu polymorphism in the TSH receptor is associated with insulin resistance in healthy elderly men

BACKGROUND: Variations in thyroid function within the normal range are associated with differences in metabolism and body composition. For instance, TSH is positively associated with body mass index (BMI). This could be due to alterations in thyroid hormone activity, or to direct effects of TSH, as the TSH receptor (TSHR) is also expressed in adipose tissue. The TSHR-Asp727Glu polymorphism is associated with lower serum TSH levels in vivo. In this study, we analysed whether serum thyroid parameters and the TSHR-Asp727Glu polymorphism were associated with glucose metabolism and insulin resistance. In addition, we analysed the Thr92Ala polymorphism in the type 2 deiodinase (D2), which was recently associated with insulin resistance. METHODS: Genotypes were determined in a population of 349 elderly men (age 77.7 +/- 3.5 years), for whom serum thyroid parameters and data on insulin resistance, such as fasting blood glucose, serum insulin and homeostasis model assessment (HOMA) values, were available. RESULTS: In nondiabetic, euthyroid subjects, TSH was positively associated with leptin levels, whereas FT4 and rT3 were significantly negatively correlated with insulin and HOMA. Carriers of the TSHR-Glu727 allele had a significantly higher glucose (P = 0.01), insulin (P = 0.001), glycated haemoglobin (HbA1c) (P = 0.002), HOMA (P = 0.001) and leptin (P = 0.008). The D2-Ala(92) allele showed a trend towards higher levels of insulin (P = 0.07) and a higher HOMA (P = 0.09). CONCLUSION: In this population of nondiabetic elderly men, serum thyroid parameters and the TSHR-Asp727Glu polymorphism were associated with relative insulin resistance. Our study suggests that genetic variation in TSHR plays a role in insulin resistance and thereby influences glucose metabolism.     

Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment

OBJECTIVE: To assess whether the addition of metformin to gonadotrophin ovulation induction in insulin-resistant, normogonadotrophic, anovulatory women alters ovarian responsiveness to exogenous FSH. DESIGN: Placebo-controlled double-blind assessment in an academic hospital. RESULTS: After a progestagen withdrawal bleeding, patients were randomised for either metformin (n = 11) or placebo (n = 9) treatment. In cases of absent ovulation, exogenous FSH was subsequently administered to induce ovulation. Only during metformin treatment did body mass index and androgen (androstenedione and testosterone) levels decrease, whereas FSH and LH levels increased significantly. In the metformin group, a single patient ovulated before the initiation of exogenous FSH. Significantly more monofollicular cycles and lower preovulatory oestradiol concentrations were observed in women receiving FSH with metformin compared with FSH alone. CONCLUSIONS: Metformin co-treatment in a group of insulin-resistant, normogonadotrophic, anovulatory patients resulted in normalization of the endocrine profile and facilitated monofollicular development during the FSH induction of ovulation.     

Central administration of antiserum to vasoactive intestinal peptide delays and reduces luteinizing hormone and prolactin surges in ovariectomized, estrogen-treated rats

The present study investigated the role of hypothalamic VIP in the regulation of the LH and PRL surge using immunoneutralization of endogenous VIP in mature ovariectomized (OVX), estradiol benzoate (EB)-treated female Wistar rats. We compared the effect of intracerebroventricular (i.c.v.) injections of a VIP antiserum (VIP-Ab) with that of saline (Ctr) on LH and PRL profiles in two separate groups of rats following two subcutaneous EB injections on days 8 and 9 after OVX. VIP-Ab or Ctr injections were given during the second half of the dark period, i.e. at 22:00 h (day 9), and, in addition, the following morning, i.e. at 08:00 h (day 10), just before the expected onset of the LH surge. Hourly blood samples were collected between 09:00 and 18:00 h on day 10. In addition, we studied the reproducibility of EB-induced LH and PRL surges and compared the effect of Ctr and VIP-Ab treatment on sequential surges in individual OVX females, i.e. 10 and 23 days after OVX, using each animal as its own control. Although we observeda large variation in the height and timing of LH and PRL peak levels between EB-treated females, the characteristics of successive surges of individual rats were highly reproducible. This reproducibility suggests that differences in functioning of the suprachiasmatic nucleus as well as in the response of the hypothalamus to steroid feedback largely explain the normal variation in hormone responses between rats. The VIP-Ab treatment resulted in a significant delay in the time course and a strong reduction of the magnitude of the afternoon LH and PRL surge. When analyzed within individual females, the effect of VIP-Ab treatment was even more pronounced due to a reduction in variability when each animal was used as its own control. These results suggest that hypothalamic VIP is an important regulator of both the timing and the magnitude of the EB-induced LH and PRL surge in the OVX rat, and suggest that its role may be stimulatory in this respect.     

Risk of malignancy in thyroid incidentalomas detected by (18)f-fluorodeoxyglucose positron emission tomography: a systematic review

Background: The expanding use of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) has led to the identification of increasing numbers of patients with an incidentaloma in the thyroid gland. We aimed to review the proportion of incidental thyroid cancers found by (18)F-FDG PET or PET/computed tomography imaging. Methods: Studies evaluating thyroid carcinomas discovered incidentally in patients or healthy volunteers by (18)F-FDG PET were systematically searched in the PubMed database from 2000 to 2011. The main exclusion criteria were known thyroid disease, lack of assigned diagnoses, investigation of diffuse uptake only, or investigation of patients with head and neck cancer, or cancer in the upper part of the thorax. Results: Twenty-two studies met our criteria comprising a total of 125,754 subjects. Of these, 1994 (1.6%) had unexpected focal hypermetabolic activity, while 999 of 48,644 individuals (2.1%) had an unexpected diffuse hypermetabolic activity in the thyroid gland. A diagnosis was assigned in 1051 of the 1994 patients with a focal uptake, 366 of whom (34.8%) had thyroid malignancy. Likewise, a diagnosis was assigned in 168 of 999 patients with a diffuse uptake, 7 of whom (4.4%) had thyroid malignancy. In the eight studies reporting individual maximum standardized uptake values (SUV(max)), the mean SUV(max) was 4.8 (standard deviation [SD] 3.1) and 6.9 (SD 4.7) in benign and malignant lesions, respectively (p<0.001). Conclusions: Incidentally found thyroid nodules, using (18)F-FDG PET, are at high risk of harboring malignancy if uptake is focal. SUV are significantly higher in malignant than in benign nodules. The pronounced inhomogeneity and other shortcomings of the studies are discussed.     

Multiple genetic loci within 11p15 defined by Beckwith-Wiedemann syndrome rearrangement breakpoints and subchromosomal transferable fragments.

Beckwith-Wiedemann syndrome (BWS) involves fetal overgrowth and predisposition to a wide variety of embryonal tumors of childhood. We have previously found that BWS is genetically linked to 11p15 and that this same band shows loss of heterozygosity in the types of tumors to which children with BWS are susceptible. However, 11p15 contains > 20 megabases, and therefore, the BWS and tumor suppressor genes could be distinct. To determine the precise physical relationship between these loci, we isolated yeast artificial chromosomes, and cosmid libraries from them, within the region of loss of heterozygosity in embryonal tumors. Five germ-line balanced chromosomal rearrangement breakpoint sites from BWS patients, as well as a balanced chromosomal translocation breakpoint from a rhabdoid tumor, were isolated within a 295- to 320-kb cluster defined by a complete cosmid contig crossing these breakpoints. This breakpoint cluster terminated approximately 100 kb centromeric to the imprinted gene IGF2 and 100 kb telomeric to p57KIP2, an inhibitor of cyclin-dependent kinases, and was located within subchromosomal transferable fragments that suppressed the growth of embryonal tumor cells in genetic complementation experiments. We have identified 11 transcribed sequences in this BWS/tumor suppressor coincident region, one of which corresponded to p57KIP2. However, three additional BWS breakpoints were > 4 megabases centromeric to the other five breakpoints and were excluded from the tumor suppressor region defined by subchromosomal transferable fragments. Thus, multiple genetic loci define BWS and tumor suppression on 11p15.     

Improvement of fecal fat excretion after addition of omeprazole to pancrease in cystic fibrosis is related to residual exocrine function of the pancreas

Pancreatic function tests were performed in 11 adult cystic fibrosis (CF) patients with a fecal fat excretion of more than 10% during treatment with pancrease 2 capsules three times a day. These tests included urinary p-aminobenzoic acid (PABA) excretion, fasting serum trypsin and pancreatic polypeptide (PP), and glucose and insulin in fasting and postprandial serum. Subsequently, the patients entered a double-blind placebo-controlled crossover study to assess the effect of gastric acid inhibition by 20 mg omeprazole on fecal fat excretion. Adjunct therapy with omeprazole resulted in a reduction of fecal fat excretion in patients with residual pancreatic function. This improvement showed significant positive correlations with urinary PABA excretion and the increase in serum PP after the meal (P<0.02 and P<0.05), but not with the other parameters studied. Therefore, the addition of omeprazole to pancrease is most successful in CF patients with residual pancreatic function, determined by urinary PABA excretion or incremental PP.     

Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam Study

Aims/hypothesis

Previous literature documents controversial results for the impact of dehydroepiandrosterone (DHEA) in glucose metabolism. We aimed to assess the associations between serum levels of DHEA and its main derivatives DHEA sulphate (DHEAS) and androstenedione, as well as the ratio of DHEAS to DHEA, and risk of type 2 diabetes.

Methods

We used data on serum levels of DHEA, DHEAS and androstenedione from 5189 middle-aged and elderly men and women from the prospective population-based Rotterdam Study. Type 2 diabetes was defined as a fasting blood glucose ≥7.0 mmol/l or a non-fasting blood glucose ≥11.1 mmol/l.

Results

During a median follow-up of 10.9 years, 643 patients with incident type 2 diabetes were identified. After adjusting for age, sex, cohort, fasting status, fasting glucose and insulin, and BMI, both serum DHEA levels (per 1 unit natural log-transformed, HR 0.76, 95% CI 0.67, 0.87) and serum DHEAS levels (per 1 unit natural log-transformed, HR 0.82, 95% CI 0.73, 0.92) were inversely associated with risk of type 2 diabetes in the total population. Further adjustment for alcohol, smoking, physical activity, prevalent cardiovascular disease, serum total cholesterol, use of lipid-lowering medications, systolic BP, treatment for hypertension, C-reactive protein, oestradiol and testosterone did not substantially affect the association between DHEA and incident type 2 diabetes (per 1 unit natural log-transformed, HR 0.80, 95% CI 0.65, 0.99), but abolished the association between DHEAS and type 2 diabetes. Androstenedione was not associated with risk of type 2 diabetes, nor was DHEAS to DHEA ratio.

Conclusions/interpretation

DHEA serum levels might be an independent marker of type 2 diabetes.