Type 2 Diabetes: Also a "Clock Matter"?

BACKGROUND: We investigated whether chronotype is associated with glycemic control, antidiabetic treatment, and risk of developing complications in patients with type 2 diabetes (T2DM). METHODS: The diabetologists filled out an online questionnaire on the Google Form platform to collect the following parameters of subjects with T2DM: body mass index (BMI), fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), diabetes history, antidiabetic treatment, diabetic complications, and chronotype categories. RESULTS: We enrolled 106 subjects with T2DM (M/F: 58/48; age: 63.3 ± 10.4 years; BMI: 28.8 ± 4.9 kg/m2). Thirty-five point eight% of the subjects showed a morning chronotype (MC), 47.2% an intermediate chronotype (IC), and 17% an evening chronotype (EC). EC subjects reported significantly higher HbA1c (p < 0.001) and FPG (p = 0.004) values, and higher prevalence of cardiovascular complications (CVC) (p = 0.028) and of subjects taking basal (p < 0.001) and rapid insulin (p = 0.01) compared to MC subjects. EC subjects reported significantly higher HbA1c (p < 0.001) and FPG (p = 0.015) than IC subjects. An inverse association was found between chronotype score, HbA1c (r = -0.459; p < 0.001), and FPG (r = -0.269; p = 0.05), remaining significant also after adjustment for BMI, age, and disease duration. CONCLUSIONS: EC is associated with higher prevalence of CVC and poorer glycemic control independently of BMI and disease duration in subjects with T2DM.

Preliminary results demonstrating the impact of Mediterranean diet on bone health.

BACKGROUND: Nutrition is an environmental factor affecting bone health. Nutrition is considered essential to achieve and maintain optimal bone mass. Mediterranean diet (MD) has shown to prevent bone disease. Aim of this study is to investigate the relationship between bone health status and adherence the MD. METHODS: Four-hundred eighteen healthy people (105 males and 313 females, age 50 ± 14 years) were recruited in the outdoor hospital of the "Campus Salute Onlus" held in Piazza del Plebiscito in Naples, October 17-20th 2013 and 09-11th October 2014. All subjects underwent clinical assessment, calcaneal quantitative ultrasound (QUS) scanner and PREvención con DIeta MEDiterránea (PREDIMED) questionnaire. RESULTS: Globally, prevalence of osteoporosis and osteopenia were 7.7 and 46.0%, respectively. The majority of subjects (60.5%) had an average score (score 6-9) of adherence to MD. The T-score showed positive correlation with PREDIMED score (r = 0.250, p < 0.001). The higher T-scores were positively associated with a higher consumption of extra-virgin olive oil (EVOO), vegetables, fruits, legumes, and fish and negatively associated with consumption of red meat. The higher T-scores were positively associated with the highest odds of PREDIMED scores (higher adherence) (OR 6.91, IC 6.27-7.61, p < 0.001). Multiple regression analysis models indicated that, among the single food items investigated, high T-score can be predicted by consumption of EVOO (p < 0.001), fish (p < 0.001) and fruit (p = 0.002) intake. A PREDIMED score of 3 was found to be predictive for a low T-score (α = 0.05, R-squared index = 0.417). CONCLUSIONS: The results demonstrate a positive correlation between bone health status and adherence to MD, suggesting that a high adherence to MD promotes bone health. The observations here reported confirmed that a specific dietary approach, such as MD, can represent a modifiable environmental factor for osteoporosis' prevention.

Testicular parenchymal abnormalities in Klinefelter syndrome: a question of cancer? Examination of 40 consecutive patients.

Klinefelter syndrome (KS) is a hypergonadotropic hypogonadism characterized by a 47, XXY karyotype. The risk of testicular cancer in KS is of interest in relation to theories about testicular cancer etiology generally; nevertheless it seems to be low. We evaluated the need for imaging and serum tumor markers for testicular cancer screening in KS. Participants were 40 consecutive KS patients, enrolled from December 2009 to January 2013. Lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and beta-human chorionic gonadotrophin subunit (ß-HCG) serum levels assays and testicular ultrasound (US) with color Doppler, were carried out at study entry, after 6 months and every year for 3 years. Abdominal magnetic resonance (MR) was performed in KS when testicular US showed micro-calcifications, testicular nodules and cysts. Nearly 62% of the KS had regular testicular echotexture, 37.5% showed an irregular echotexture and 17.5% had micro-calcifications and cysts. Eighty seven percent of KS had a regular vascular pattern, 12.5% varicocele, 12.5% nodules <1 cm, but none had nodules >1 cm. MR ruled out the diagnosis of cancer in all KS with testicular micro calcifications, nodules and cysts. No significant variations in LDH, AFP, and ß-HCG levels and in US pattern have been detected during follow-up. We compared serum tumor markers and US pattern between KS with and without cryptorchidism and no statistical differences were found. We did not find testicular cancer in KS, and testicular US, tumor markers and MR were, in selected cases, useful tools for correctly discriminating benign from malignant lesions.

Cardiovascular abnormalities in Klinefelter syndrome.

BACKGROUND: Several epidemiological studies have demonstrated an increased mortality from cardiovascular causes in patients with Klinefelter Syndrome (KS). Little information is available about the nature of the underlying cardiovascular abnormalities. Aim of the study was to investigate exercise performance, left ventricular architecture and function, vascular reactivity, and carotid intima-media thickness in a group of patients with KS. MATERIALS AND METHODS: Sixty-nine patients with KS and 48 age-matched controls participated in our population-controlled study. Forty-eight Klinefelter subjects were on testosterone treatment at the time of the investigation while 21 were naive and underwent a complete Doppler echocardiographic examination, a cardiopulmonary exercise test as well as a vascular study including measures of carotid intima-media thickness and endothelial function with flow-mediated dilation of the brachial artery. Patients with KS on testosterone therapy (n=48) were also matched against a population of men with treated secondary hypogonadism (n=21). RESULTS: Patients with KS exhibited a wide array of cardiovascular abnormalities including left ventricular diastolic dysfunction, reduced maximal oxygen consumption (p<0.01), increased intima-media thickness (p<0.05) (-34% and +42% vs. controls, respectively) and a high prevalence of chronotropic incompetence (55% of patients, p<0.01). No significant difference was found between treated and untreated KS in variance with men treated for secondary hypogonadism. CONCLUSION: Left ventricular diastolic dysfunction, impaired cardiopulmonary performance, chronotropic incompetence, and increased intima-media thickness suggest that cardiovascular abnormalities are a common finding in KS that is not reversed by testosterone replacement therapy and may represent the pathophysiological underpinnings of the increased risk of dying from heart disease.

Upregulation of endocrine gland-derived vascular endothelial growth factor in papillary thyroid cancers displaying infiltrative patterns, lymph node metastases, and BRAF mutation.

BACKGROUND: Endocrine gland-derived vascular endothelial growth factor (Prok1) and prokineticin 2 (Prok2) are involved in the organ-specific regulation of angiogenesis, which is a crucial step toward cancer progression in most tumors, including those of thyroid gland. The oncogene BRAF V600E mutation is associated with poor clinical outcome of papillary thyroid cancer (PTC) and can independently predict its recurrence. DESIGN: Our hypothesis was that Prok1 and Prok2 expression levels associated with BRAF mutations can be prognostic factors for PTC outcome. Prok1 and Prok2 were examined in PTC, a cell line derived from a human PTC (designated FB-2), euthyroid multinodular goiter (MNG), Graves' disease (GD), and contralateral normal thyroid (NT) tissues from PTC cases. We evaluated BRAF mutation and its relationship with Prok1 expression pattern in PTC. METHODS: We studied Prok1 and Prok2 mRNAs by real-time polymerase chain reaction and BRAF mutation by mutant allele-specific polymerase chain reaction amplification. Formalin-fixed, paraffin-embedded blocks of PTC and NT were used for the immunohistochemical determination of Prok1 using anti-endocrine gland vascular endothelial growth factor primary antibody. RESULTS: Prok1 and Prok2 transcripts were both present in thyroid tissues, and Prok1 was differentially expressed in PTC compared to MNG, GD, and NT. Prok1 mRNA levels were very low in NT and MNG and significantly higher in PTC, FB-2, and GD (p<0.05). Prok1 protein was almost undetectable in NT but was highly expressed in all PTC samples having an infiltrative pattern of growth and lymph node metastases ( p<0.05). Further, the expression of Prok1 in PTC was associated with 60% of the samples being positive for the BRAF mutation ( p<0.05). CONCLUSIONS: We found that Prok1 is significantly increased in PTC, and its expression in PTC is related to BRAF mutation. These results suggest that Prok1 could be a new useful marker for thyroid cancer progression. Prok1 therefore could also be a potential target for novel therapeutic strategies, although the lack of functional data suggests caution against generalization of this assumption

CDKN1B V109G polymorphism a new prognostic factor in sporadic medullary thyroid carcinoma.

CONTEXT: CDKN1B encodes the cyclin-dependent kinase inhibitor p27Kip1 and is mutated in multiple endocrine neoplasia-like syndromes. CDKN1B also harbors single nucleotide polymorphisms; the T/G transversion at nucleotide 326 (the V109G variant) has been reported to be protective in breast, hereditary prostate, and pancreatic tumors. Association of CDNK1B mutations or polymorphisms with sporadic medullary thyroid carcinoma (MTC) has not been investigated yet. OBJECTIVE AND DESIGN: We screened germline DNA from 84 patients affected by sporadic MTC and 90 healthy age- and gender-matched controls for CDKN1B mutations or polymorphisms by PCR amplification and sequencing of the amplicons. We also tested all germline and 50 tumor tissue DNA for RET proto-oncogene mutations. Computed tomography, ultrasound scans, and serum calcitonin were carried out before surgery and during the follow-up and associated with CDKN1B polymorphism and disease remission. RESULTS: The T/G transversion at nucleotide 326 was the only DNA variation detected. The overall frequency of the T/G and G/G alleles in combination was 46.4%. This variant (V109G) was correlated with post-operative calcitonin levels in the normal range and biochemical remission. Conversely, the wild-type (T/T) allele was associated with post-operative calcitonin levels above normal and a higher risk to develop clinical recurrence and distant metastases. Somatic RET mutations were significantly associated with a more aggressive behavior especially in wild-type allele-bearing patients. CONCLUSIONS: Collectively, in sporadic MTC, the CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker.

Effects of somatostatin analog SOM230 on cell proliferation, apoptosis, and catecholamine levels in cultured pheochromocytoma cells.

Surgery is the primary therapy for pheochromocytoma (PHEO), a catecholamine-producing tumor. Benign and malignant PHEO could develop recurrences, and the intraoperative risk of recurrent PHEO is an important unresolved issue. Non-surgical treatments of PHEO recurrence would therefore better prepare patients for reintervention as well as provide them with palliative management. We investigated the effects of the new somatostatin analog (pasireotide) SOM230 versus octreotide (OCT) in primary PHEO cell cultures (Pheo-c). Pheo-c from six benign surgical samples were set up and characterized by immunocytochemistry. Real-time PCR, using both PHEO tissues and Pheo-c, showed different levels of somatostatin receptor(1-5) mRNA expression. Cells treated with various doses of OCT or SOM230 for 48 and 72 h were analyzed to assess their effects on cell proliferation and apoptosis and catecholamine levels. Even if reduction of cell viability was observed in Pheo-c treated for 48 h with either OCT or SOM230 and this effect increased after 72 h, a more significant inhibition of cell growth as well as a significantly higher induction of apoptosis was seen in Pheo-c treated with SOM230 versus OCT. In particular, apoptosis in Pheo-c was detected after 48 h and was associated with increased expression and activation of caspase-3 and cleaved poly(ADP-ribose) polymerase. OCT 10(-6) M and SOM230 10(-7) M significantly reduced catecholamine levels. Our results indicate that while both OCT and SOM230 modulate cell growth and apoptosis and catecholamine levels in Pheo-c through specific receptors, SOM230 is more effective. This improves our knowledge on the mechanism of SOM230 action in PHEO and supports a possible therapeutic use in benign PHEO recurrence.