Chiara Mele

Vitamin D and Neurological Diseases: An Endocrine View

Vitamin D system comprises hormone precursors, active metabolites, carriers, enzymes, and receptors involved in genomic and non-genomic effects. In addition to classical bone-related effects, this system has also been shown to activate multiple molecular mediators and elicit many physiological functions. In vitro and in vivo studies have, in fact, increasingly focused on the “non-calcemic” actions of vitamin D, which are associated with the maintenance of glucose homeostasis, cardiovascular morbidity, autoimmunity, inflammation, and cancer. In parallel, growing evidence has recognized that a multimodal association links vitamin D system to brain development, functions and diseases. With vitamin D deficiency reaching epidemic proportions worldwide, there is now concern that optimal levels of vitamin D in the bloodstream are also necessary to preserve the neurological development and protect the adult brain. The aim of this review is to highlight the relationship between vitamin D and neurological diseases.

The impact of the metabolic phenotype on thyroid function in obesity

BackgroundObesity is known to promote mild hyperthyrotropinaemia by unknown metabolic mechanisms. This investigation aimed to explore the association between thyroid function and metabolic phenotype in euthyroid obese individuals. Retrospective, cross-sectional study. Tertiary care center.Methods952 euthyroid obese individuals referred to our Institution for obesity. Serum levels of TSH, FT4, glucose, insulin and HbA1c levels, lipid profile, liver function and proinflammatory indices were measured. Resting energy expenditure was assessed by indirect calorimetry and body composition by bioimpedance analysis.ResultsOn admission, 306 patients had previously diagnosed diabetes mellitus on treatment with metformin, while 113 patients were diagnosed with incident diabetes mellitus. Serum TSH levels were similar between metformin-treated diabetic subjects and metformin-untreated subjects, while FT4 was slightly but significantly higher in the former. Analysis stratified by TSH categories found no effect of metformin-treated diabetes mellitus on TSH levels. Interestingly, obese patients with incident diabetes showed lower TSH levels than normoglycaemic ones. In correlation studies on the whole dataset, an association related TSH to BMI and total cholesterol levels, which was lost upon adjustment for individual confounders. FT4 levels were found to be inversely related to BMI, insulin resistance and triglycerides, while being directly associated with HDL-cholesterol levels. These correlations remained unaltered after controlling for individual confounders. In multivariate linear regression analysis, TSH was associated with FT4, total cholesterol and BMI values. Significant predictors of FT4 were constituted by previously diagnosed diabetes mellitus, BMI, TSH and age.ConclusionsIn euthyroid obese subjects, FT4 seems more closely related than TSH levels to parameters of cardiometabolic risk. TSH levels did not differ between metformin-treated and untreated subjects, while they were lower in patients with incident diabetes mellitus compared to normoglycaemic ones.

Circulating angiopoietin-like 8 (ANGPTL8) is a marker of liver steatosis and is negatively regulated by Prader-Willi Syndrome

ANGPTL8 is a liver-derived protein related to insulin-sensitivity. Its relationship with obesity and liver function in Prader-Willi syndrome (PWS) is unknown. The present study investigated circulating ANGPTL8 in PWS and controls with common obesity, assessing its association to liver steatosis. For this purpose, 20 obese PWS and 20 controls matched for body mass index (BMI), sex and age underwent analysis of ANGPTL8 levels, glucose and lipid metabolism. Liver function tests and degree of liver steatosis by ultrasonography (US), fat-free mass (FFM) and fat mass (FM) by dual-energy x-ray absorptiometry (DEXA) were also assessed. In comparison to controls, obese PWS showed lower values of FFM (p < 0.0001) and higher FM (p = 0.01), while harbouring higher HDL cholesterol, lower triglycerides and OGTT-derived insulin levels, as well as a lower prevalence and severity of liver steatosis. With respect to obese controls, ANGPTL8 levels were significantly lower in PWS (p = 0.007) and overall correlated with transaminase levels and the severity of liver steatosis, as well as FFM (p < 0.05 for all). By a stepwise multivariable regression analysis, ANGPTL8 levels were independently predicted by PWS status (p = 0.01) and liver steatosis (p < 0.05). In conclusion, ANGPTL8 levels are lower in PWS than obese controls and are inversely associated with the severity of liver steatosis. Further studies should investigate the potential genetic basis for this observation.

Acute Vitamin D3 Supplementation in Severe Obesity: Evaluation of Multimeric Adiponectin

Obesity predisposes to vitamin D deficiency (VDD) and glucose abnormalities. It is currently debated if vitamin D administration may improve glucose homeostasis by interacting with modulators of insulin sensitivity, such as adiponectin and its oligomers. In a 4-week inpatient study on a metabolic rehabilitation program, consisting of individualized caloric restriction and aerobic physical exercise in obese subjects with VDD, we assessed the acute effects of 600,000 IU cholecalciferol given per os VD group, 12 subjects; body mass index (BMI) 42.7 ± 1.3 kg/m2) or placebo per os (PL group, 12 subjects, BMI 39.8 ± 0.9 kg/m2) on high (HWM-A), medium (MMW-A), and low molecular weight adiponectin (LMW-A), as quantified by western immunoblot (WIB) and ELISA. During the 4-week study, dieting promoted a similar magnitude of weight loss in VD and PL groups. Compared to the PL group, cholecalciferol administration increased 25(OH)Vit D levels (p < 0.001) and promoted a significant increase of HMW-A expression analyzed by WIB (p = 0.02). In parallel, a significant decrease of leptin/HMW-A ratio (p < 0.05), a biomarker of metabolic homeostasis, was observed. During the study, changes of MMW-A and LMW-A occurred independently of cholecalciferol administration, and were likely explained by weight loss. At odds with these findings, the ELISA assessment of adiponectin oligomers showed no modifications in the VD group or PL group. Current findings suggest that acute cholecalciferol administration selectively modifies HMW-A and the leptin/HMW-A ratio.

Baseline glucose homeostasis predicts the new onset of diabetes during statin therapy: A retrospective study in real life

OBJECTIVEWe evaluated the risk of altered glucose levels and new-onset diabetes (NOD) associated with statins according to glucose levels at baseline in a population treated for dyslipidemia on primary prevention for >5 years. DESIGN. The retrospective study included 308 subjects (265 on statins and 43 controls on diet) with a follow-up of 5–15 years. The cohort was classified according to glucose tolerance at both baseline and follow-up.RESULTSThe cumulative incidence of NOD was 13.6% (9.3% in controls and 13.5% in treated patients). NOD was diagnosed after 3.4±1.8 years. In the group with normal glucose levels at baseline, a family history of diabetes (OR: 3.4, 95% CI 1.3–8.9), BMI >30 kg/m2 (OR: 8.5, 95% CI 2.0–35.8), treatment with thiazide (OR: 21.9, 95% CI 1.2–384.2) and no alcohol consumption (OR: 0.3, 95% CI 0.1–0.8) reduced the risk of developing altered glucose levels or NOD. No effects of statins were seen. In the group with altered glucose levels at baseline, hypertension (OR: 5.0, 95% CI 1.0–25.3) and hypertriglyceridemia (OR: 3.5, 95% CI 1.0–11.8) increased the risk of remaining with altered glucose levels or developing NOD. Treatment with statins (OR: 7.5, 95% CI 1.5–37.4), in particular atorvastatin, was associated with an increased risk. In the whole population, statin therapy (OR: 4.0, 95% CI 1.1–14.1, p<0.020), and in particular simvastatin and atorvastatin, was associated with increased risk of altered glucose levels or NOD. Patients who developed or maintained altered glucose levels or NOD had a poor metabolic phenotype at baseline.CONCLUSIONSStatins were associated with an increased risk of NOD or altered glucose levels, mainly in subjects with altered glucose levels before the beginning of therapy. Poor metabolic phenotype and unhealthy behaviors or family history of diabetes contributed to that risk.

The relationship between resting energy expenditure and thyroid hormones in response to short-term weight loss in severe obesity

Background Regulating thermogenesis is a major task of thyroid hormones (THs), and involves TH-responsive energetic processes at the central and peripheral level. In severe obesity, little is known on the relationship between THs and resting energy expenditure (REE) before and after weight loss. Methods We enrolled 100 euthyroid subjects with severe obesity who were equally distributed between genders. Each was examined before and after completion of a 4-wk inpatient multidisciplinary dieting program and subjected to measurement of thyroid function, REE, fat-free mass (FFM, kg) and percent fat mass (FM). Results Baseline REE was lower than predicted in 70 obese patients, and overall associated with BMI, FFM and FM but not thyroid-related parameters. By the study end, both BMI and REE decreased (5.5% and 4.1%, p<0.001 vs. baseline) and their percent changes were significantly associated (p<0.05), while no association related percent changes of REE and FFM or FM. Individually, REE decreased in 66 and increased in 34 patients irrespective of gender, BMI and body composition. Weight loss significantly impacted TSH (-6.3%), FT3 (-3.3%) and FT4 levels (3.9%; p<0.001 for all). By the study end, a significant correlation became evident between REE and FT4 (r = 0.42, p<0.001) as well as FT3 (r = 0.24, p<0.05). In stepwise multivariable regression analysis, however, neither THs nor body composition entered the regression equation for REE response to weight loss. Conclusions In severe obesity, short-term weight loss discloses a positive relationship between REE and THs.

AN ITALIAN SURVEY OF COMPLIANCE WITH MAJOR GUIDELINES FOR L-THYROXINE OF PRIMARY HYPOTHYROIDISM

OBJECTIVE The adherence by endocrinologists to guideline regarding levothyroxine (LT4) therapy and the compliance of patients may impact the management of hypothyroidism. The aim of this study was to compare the adherence of Italian endocrinologists to the ATA/AACE and ETA guidelines on the management of newly diagnosed primary hypothyroidism and to validate the Italian version of the Morisky-Green Medical Adherence Scale-8 (MMAS-8) questionnaire as applied to the evaluation of the adherence of patients with hypothyroidism to LT4 treatment. METHODS This was an observational, longitudinal, multicenter, cohort study, involving 12 Italian Units of Endocrinology. RESULTS The study enrolled 1,039 consecutive outpatients (mean age 48 years; 855 women, 184 men). The concordance of Italian endocrinologists with American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) and European Thyroid Association (ETA) recommendations was comparable (77.1% and 71.7%) and increased (86.7 and 88.6%) after the recommendations on LT4 dose were excluded, considering only the remaining recommendations on diagnosis, therapy, and follow-up. The MMAS-8 was filled out by 293 patients. The mean score was 6.71 with 23.9% low (score <6), 38.6% medium (6 to <8), 37.5% highly (= 8) adherers; the internal validation coefficient was 0.613. Highly adherent patients were not more likely to have good control of hypothyroidism compared with either medium (69% versus 72%, P = .878) or low (69% versus 43%, P = .861) adherers. CONCLUSION Clinical management of hypothyroidism in Italy demonstrated an observance of international guidelines by Italian endocrinologists. Validation of the Italian version of the MMAS-8 questionnaire provides clinicians with a reliable and simple tool for assessing the adherence of patients to LT4 treatment. ABBREVIATIONS AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; EDIPO = Endotrial SIE: DIagnosis and clinical management of Primitive hypothyrOidism in Italy; eCRF = electronic case report form; ETA = European Thyroid Association; fT3 = free triiodothyronine; fT4 = free thyroxine; LT4 = levothyroxine; MMAS-8 = Morisky-Green Medical Adherence Scale-8; PH = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; US = ultrasonography.