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AE Pontiroli, LD Monti, S Costa, PE Sandoli, A Pizzini, SB Solerte, E Mantovani, and PM Piatti

OBJECTIVES: To evaluate the frequency of impaired glucose tolerance (IGT) and of Type 2 diabetes mellitus (Type 2 DM) in siblings of patients with Type 2 DM, and to assess insulin release and insulin sensitivity in siblings with normal glucose tolerance (NGT), compared with NGT spouses of probands without family history of Type 2 DM. DESIGN AND METHODS: We evaluated 87 families including 103 Type 2 DM patients (87 probands), and we carried out an oral glucose tolerance test (OGTT) in 130 siblings and in 60 spouses. Among NGT subjects, 12 siblings and 16 spouses underwent a low-dose insulin-glucose infusion test (LDIGIT) to evaluate C-peptide release and insulin sensitivity. RESULTS: After the OGTT, 24 siblings were classified as having Type 2 DM, 31 as IGT, and only 14 spouses as IGT (P=0.0012 vs siblings). NGT siblings (n=75) showed higher insulin levels at 120 min than NGT spouses (n=46) at OGTT, in spite of identical blood glucose levels; at LDIGIT, NGT siblings secreted more C-peptide and showed a lower insulin sensitivity than NGT spouses. CONCLUSIONS: These data indicate that middle-aged siblings of probands with Type 2 DM have a high frequency of IGT and Type 2 DM, and that NGT siblings have increased insulin resistance and increased insulin secretion when compared with adequate controls.

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S. Platzer, H. Fill, G. Riccabona, J. Glatzl, J. Seidl, G. Cenderelli, M. Migliardi, H. Varetto, and A. Costa

(Acta endocr. (Kbh.) 85 (1977) 325–334)

The 4th line from the bottom on page 329 should read: than 20 μg/g creatinine = PBI 4.9 ± 0.9 μg/100 ml; urinary iodine more than 80 μg/g creatinine = PBI 5.0 ± 0.8 μg/100 ml).

The 4th line from above on page 331 should read:

statistically significant difference between normal and goitrous subject and there was also no valid correlation between iodine excretion and plasma TSH.

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S. Platzer, H. Fill, G. Riccabona, J. Glatzl, J. Seidl, G. Cenderelli, M. Migliardi, H. Varetto, and A. Costa

ABSTRACT

The whole population of Certosa (Karthaus) (altitude 1327 m), a little village in the Alto Adige province in Northern Italy, was studied regarding the incidence and pathophysiological data of endemic goitre. The study included 204 subjects: in 85 % of the whole population, and in 48 % of the school-children population from 6-14 years of age, thyroid enlargement and/or nodularity was found. The 24 h [131I]uptake was 48.6 ± 11.96; the grade "O" thyroids also showed an increased uptake. The region is poor in iodine; the mean iodine content of 55 samples of local drinking water was 0.81 ± 0.96 μg/I; the iodine content of several foodstuffs was definitely lower than those from Turin's markets. The mean iodine excretion in 60 samples of urine was 35.96 ± 22.4 μg/g creatinine. Urinary iodine excretion showed a linear negative correlation with [131I]uptake and did not correlate well with the presence or size of the goitre.

The mean values of PBI (6.12 ± 1.57 μg/100 ml) of T4 (7 ± 2.3 μg/100 ml), of T3 (121 ± 55.4 ng/100 ml) and of a free thyroxine index (ETR = 0.95), as well as of TSH (2.63 ± 1.9 μU/ml) were in the normal range. Grade III goitres had slightly lower hormonal values, and a somewhat elevated T3/(T4x100) ratio (0.19). Serum TSH levels showed no correlation with the presence or size of the goitre, radioiodine uptake, the urinary iodine excretion, and not always showed an inverse correlation with the peripheral thyroid hormone values. Urinary thiocyanate excretion (mean value 9.28 ± 2.96 mg/24 h) did not show any relation to the presence of goitre.

Raven's tests and physical data obtained from school-children in Alto Adige show some slight alteration in the distribution pattern when compared to normal populations.

It is concluded that iodine deficiency exists in the studied area, but that it is not always associated with goitre, and that other pathological factors must be involved in goitrogenesis. Goitre is not coupled with enhanced TSH serum levels.

The slight alteration in intellectual and somatic development in schoolchildren may possibly be related to iodine deficiency; other environmental or genetic factors, however, cannot be excluded.

Free access

S Corbetta, C Eller-Vainicher, M Frigerio, R Valaperta, E Costa, L Vicentini, A Baccarelli, P Beck-Peccoz, and A Spada

Objective

Primary hyperparathyroidism (PHPT) is often complicated by kidney stones. Hypercalciuria and urine oxalate excretion are considered risk factors for urolithiasis in PHPT as well as in idiopathic stone-formers. Recently, the anion-exchanger SLC26A6 has been involved in the oxalate metabolism.

Design and methods

We tested the hypothesis that the 206M polymorphic variant of SLC26A6 gene might contribute to the risk of kidney stones in PHPT. DNA samples from 145 PHPT patients and 129 age- and sex-matched healthy subjects were genotyped.

Results

The homozygous 206V genotype was the most frequent both in PHPT patients and controls (79.3 and 74.4%), while heterozygosity for the 206M allele was detected in 20.0 and 23.3% respectively. The homozygous 206M genotype was extremely rare, occurring in 0.7 and 2.3% of PHPT and healthy subjects respectively. In the PHPT cohort, the prevalence of urolithiasis did not differ between the V/V and V/M+M/M groups and urine oxalate excretions did not correlate with the genotype. Considering the subset of PHPT stone formers (n=74), calciuria was lower in V/M+M/M patients with respect to V/V stone-formers (4.40±1.88 vs 5.92±2.62 mg/kg per 24 h; mean±s.d., P=0.034). Finally, the SLC26A6 206M alleles were significantly related to the presence of hypertension (73.3 vs 47.8%), showing an OR of 4.8.

Conclusions

Though the SLC26A6 206M polymorphism did not correlate with kidney stone development in PHPT patients, PHPT stone-formers harbouring the M allele had a lower hypercalciuria. This observation and the high prevalence of hypertension associated with the 206M polymorphism need further investigation.

Free access

V Vanvooren, S Uchino, L Duprez, MJ Costa, J Vandekerckhove, J Parma, G Vassart, JE Dumont, J Van Sande, and S Noguchi

OBJECTIVE: Constitutively activating mutations of the thyrotropin receptor (TSHR) have been found in the majority of autonomously functioning thyroid nodules (AFTNs) in European patients. The reported frequency of these mutations varies among reports but amounts to 50-80%. To date, only one such mutation responsible for AFTNs has been identified in the Japanese population and the pathogenic role of such mutations in Japanese AFTNs has been questioned. In the present study, we evaluated the frequency of activating mutations in the TSHR and G(alpha)s in 10 Japanese AFTNs. DESIGN: Genomic DNA was extracted from fresh frozen tissue. The TSHR and the almost entire sequence of the gene coding for the alpha subunit of Gs have been amplified and sequenced. RESULTS: In sequence analysis, four mutations in the TSHR (T632A, I486M, M453T and L512R) were found. To complete our analysis, we searched mutations in the gene coding for the alpha subunit of Gs, in the samples negative for TSHR mutations. In one case a mutation (R201H) affecting GTPase activity was found. CONCLUSIONS: If we focus on the solitary nodules, we obtain the same mutation proportion as in European patients (70%). The absence of TSHR and G(alpha)s mutations in a significant proportion of autonomous adenomas in multinodular goiters suggests that other causes may also play a role in the genesis of these lesions.

Free access

Xiaowen Liu, Ole-Petter R Hamnvik, Michael Petrou, Huizhi Gong, John P Chamberland, Costas A Christophi, Stefanos N Kales, David C Christiani, and Christos S Mantzoros

Objective

Lipocalin 2 (LCN2 or NGAL), a protein derived from neutrophils, macrophages, adipocytes, and other cells, has been proposed to be a link between obesity and insulin resistance (IR), but animal and cross-sectional human studies have revealed conflicting results. We studied the association of serum lipocalin 2 with anthropometric, metabolic, and cardiovascular risk markers in young healthy men cross-sectionally and, for the first time, prospectively after 2 years of follow-up, with and without adjustment for potential confounders including serum creatinine.

Design

Two hundred and seventy-two participants were randomly selected from the Cyprus Metabolism Study (1056 men, 18 years), of whom 93 subjects participated in the follow-up study 2 years after baseline assessment. Associations were also explored between total and free leptin levels (to serve as positive controls) and anthropometric metabolic variables.

Results

In the cross-sectional study, lipocalin 2 levels were marginally correlated in the unadjusted model with central fat distribution but not with body weight or total body fat mass. After adjusting for age, smoking, activity, body mass index, fat percentage, waist-to-hip ratio, and serum creatinine, no correlation was found with any cardiovascular risk factor. There was no correlation with the homeostasis model assessment of IR (HOMA-IR) at baseline. In the prospective analyses, baseline levels of lipocalin 2 were not predictive of any variables in unadjusted or adjusted models. As expected, total and free leptin were associated with anthropometric and metabolic variables both cross-sectionally and prospectively.

Conclusions

We demonstrate that lipocalin 2 is not an independent predictor of metabolic and cardiovascular risk factors in young men cross-sectionally or prospectively.

Free access

M G Teles, E B Trarbach, S D Noel, G Guerra-Junior, A Jorge, D Beneduzzi, S D Bianco, A Mukherjee, M T Baptista, E M Costa, M De Castro, B B Mendonça, U B Kaiser, and A C Latronico

Context

Loss-of-function mutations of the kisspeptin-1 receptor gene, KISS1R, have been identified in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH).

Objective

To investigate KISS1R defects in patients with absent or delayed puberty.

Patients

We investigated KISS1R gene defects in a cohort of 99 Brazilian patients with nIHH or constitutional delay of puberty (CDP).

Methods

The entire coding region of KISS1R was amplified by PCR followed by automatic sequencing. In addition, screening for KISS1R exonic deletions was performed by multiplex ligation-dependent probe amplification.

Results

One novel homozygous KISS1R mutation was identified in two siblings with nIHH. This variant was an insertion/deletion (indel) mutation characterized by the deletion of three nucleotides (GCA) at position −2 to −4, and by the insertion of seven nucleotides (ACCGGCT) at the same position, within the 3′ splice acceptor site of intron 2 of KISS1R. The brothers who carried this KISS1R mutation had no clinical evidence of pubertal development at the ages of 14 and 20 years. Computational analysis of this indel mutation predicted the generation of an abnormal protein. In addition, a new heterozygous KISS1R variant (p.E252Q) was identified in a male patient with sporadic nIHH. However, in vitro studies of this variant did not demonstrate functional impairment. Only known polymorphisms were identified in patients with CDP.

Conclusion

Loss-of-function mutations of KISS1R represents a rare cause of nIHH, and was absent in patients with CDP. We have described a novel KISS1R homozygous splice acceptor site mutation in the familial form of nIHH.

Free access

Maria T Vamvini, Konstantinos N Aronis, Grigorios Panagiotou, Joo Young Huh, John P Chamberland, Mary T Brinkoetter, Michael Petrou, Costas A Christophi, Stefanos N Kales, David C Christiani, and Christos S Mantzoros

Objective

Skeletal muscle is considered to be an endocrine organ that secretes a number of myokines including follistatin (FST), myostatin (MSTN), activin A, and the newly identified irisin. Irisin's biology and function exhibit similarities with the functions of the FST–MSTN–activin A axis. It remains unknown whether there is any interplay among these molecules. The aim of this study is to examine potential associations of irisin with the FST, MSTN, and activin A axis.

Methods

Two observational studies were performed to evaluate the associations of irisin with the other three peptides. Study A included 150 healthy males aged 18.48±0.16 years with BMI 23.18±3.75 kg/m2. Fasting serum samples were used to measure the levels of the molecules of interest. Study B included 14 morbidly obese individuals, candidates for bariatric surgery, aged 53.14±8.93 years with BMI 50.18±10.63 kg/m2. Blood samples were obtained after an overnight fast. Eight out of the 14 participants consented to an optional thigh biopsy during their bariatric surgery. Using the above blood and tissue samples, we measured circulating levels and muscle mRNA of irisin, FST, MSTN, and activin A.

Results

We report that FNDC5 mRNA in muscle is positively correlated with FST mRNA expression in morbidly obese subjects (ρ=0.93, P<0.001). We also found that circulating irisin is positively correlated with FST circulating levels among lean subjects (ρ=0.17, P=0.05) while this association was suggestive among the obese (ρ=0.56, P=0.07).

Conclusion

The newly identified myokine irisin may be positively associated with FST at both the mRNA and circulating protein level.

Free access

E Setola, LD Monti, E Galluccio, A Palloshi, G Fragasso, R Paroni, F Magni, EP Sandoli, P Lucotti, S Costa, I Fermo, M Galli-Kienle, A Origgi, A Margonato, and P Piatti

OBJECTIVE: The purpose of this study was (a) to study whether a folate and vitamin B12 treatment, aimed at decreasing homocysteine levels, might ameliorate insulin resistance and endothelial dysfunction in patients with metabolic syndrome according to the National Cholesterol Education Program-Adult Treatment Panel-III criteria and (b) to evaluate whether, under these metabolic conditions, there is a relationship between hyperhomocysteinemia and insulin resistance. DESIGN AND METHODS: A double-blind, parallel, identical placebo-drug, randomized study was performed for 2 months in 50 patients. Patients were randomly allocated to two groups. In group 1, patients were treated with diet plus placebo for 2 months. In group 2, patients were treated with diet plus placebo for 1 month, followed by diet plus folic acid (5 mg/day) plus vitamin B12 (500 microg/day) for another month. RESULTS: In group 2, folate treatment significantly decreased homocysteine levels by 27.8% (12.2+/-1.2 vs 8.8+/-0.7 micromol/l; P<0.01). A significant decrement was observed for insulin levels (19.9+/-1.7 vs 14.8+/-1.6 microU/ml; P<0.01) accompanied by a 27% reduction in the homeostasis model assessment levels. A positive relationship was found between the decrement of homocysteine and insulin levels (r=0.60; P<0.002). In parallel, endothelial dysfunction significantly improved in the treated group, since post-ischemic maximal hyperemic vasodilation increased by 29.8% and cGMP by 13.6% while asymmetrical dimethylarginine levels decreased by 21.7%. On the contrary, in group 1 patients, treated with placebo, no changes were shown in any of the variables. CONCLUSIONS: Folate and vitamin B12 treatment improved insulin resistance and endothelial dysfunction, along with decreasing homocysteine levels, in patients with metabolic syndrome, suggesting that folic acid has several beneficial effects on cardiovascular disease risk factors.

Free access

Ana P M Canton, Sílvia S Costa, Tatiane C Rodrigues, Debora R Bertola, Alexsandra C Malaquias, Fernanda A Correa, Ivo J P Arnhold, Carla Rosenberg, and Alexander A L Jorge

Background

The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders.

Objective

To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause.

Patients and methods

A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature.

Results

In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation.

Conclusion

Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.