DENSITA¿ MINERALE OSSEA, QUALITA¿ DELL¿OSSO E RISCHIO DI FRATTURA NEL DIABETE MELLITO TIPO 2:RUOLO DELL¿ASSE IPOTALAMO-IPOFISI-SURRENE EDELLA SENSIBILITA¿ AI GLUCOCORTICOIDI

Introduzione: Nel Diabete Mellito di tipo 2 (T2D) vi \ue8 un aumento del rischio di frattura vertebrale (VFx). L\u2019asse ipotalamo-ipofisi-surrene (HPA) sembra attivato nel T2D scompensato e la sensibilit\ue0 ai glucocorticoidi (GC) sembra influenzare la densit\ue0 minerale ossea (DMO) nei soggetti con osteoporosi. Obiettivo: Valutare il ruolo dell\u2019asse HPA e della sensibilit\ue0 ai GC, mediante i polimorfismi (SNPs) BclI e N363S del recettore GC e l\u2019attivit\ue0 della 11\u3b2idrossisteroidodeidrogenasi tipo 2, (11HSD2) sulla DMO, VFx e qualit\ue0 dell\u2019osso valutata mediante il Trabecular Bone Score, (TBS), in donne con T2D compensato in menopausa. Materiali/metodi: in 92 donne con T2D (emoglobina glicata 6.7\ub11.2%) e 92 controlli, paragonabili per et\ue0, sesso, BMI, abbiamo valutato: 1) metabolismo calcio-fosforo, livelli ACTH, cortisoluria 24h (CLU), cortisone (CoLU) su urine 24h, cortisolo dopo 1 mg desametasone h 23 (1mgDST); 2) attivit\ue0 del 11HSD2 (rapporto CLU/CoLU), SNPs di BclI e N363S; 3) DMO (Z-score, lombare, LS e collo femorale, FN) e TBS (Z-score) mediante DXA e VFx mediante morfometria. Risultati: Le pazienti con T2D hanno mostrato, rispetto ai controlli, VFx aumentate (34.8 vs 19.6 %, rispettivamente, p=0.031) e DMO maggiore (LS 0.81\ub10.47 vs 0.17\ub11.32, p=0.002; FN 0.63\ub10.99 vs 0.04\ub10.94, p=0.000), mentre TBS, attivit\ue0 HPA e 11HSD2, e prevalenza degli SNPs di BclI e N363S sono risultate paragonabili. Le pazienti con T2D e VFx hanno mostrato un\u2019aumentata frequenza dello SNPs N363S in eterozigosi (15.6%) e DMO e TBS minori rispetto a quelle senza VFx (3.3%, p=0.047), ma simili secrezione di cortisolo, attivit\ue0 11HSD2 e frequenza dello SNP BclI. Lo stesso \ue8 risultato nei soggetti di controllo. Le VFx sono risultate associate al T2D (OR=2.6, 95%CI 1.2-5.5, p=0.015) ed allo SNP N363S in eterozigosi (OR=8.5, 95%CI 2.3-31.1, p=0.01). Conclusioni: Nel T2D compensato la prevalenza di VFx \ue8 aumentata e, come nella popolazione generale, sembra associata ad un\u2019aumentata sensibilit\ue0 ai GC.Introduction: Patients affected by type 2 diabetes (T2D) are at increased risk of vertebral fractures (VFx). At the same time, there is evidence of activated hypothalamus-pituitary-adrenal (HPA) axis in T2D, and an increased glucocorticoid (GC) sensitivity seems to have a negative impact on bone mineral density (BMD) in osteoporosis. Objectives: To evaluate the association between HPA axis activity and GC sensitivity, measured by single nucleotide polymorphisms (SNPs) BclI, N363S of GC receptor and by activity of 11HSD2, with BMD, VFx and bone quality, evaluated with Trabecular Bone Score (TBS), in T2D postmenopausal women. Material/methods: We recruited 92 T2D women (HbA1c 6.7\ub11.2%) and 92 age- and BMI-matched controls. The following parameters were evaluated in all subjects: 1) calcium-phosphorus metabolism, ACTH, urine free cortisol 24h (UFC), urine free cortisone 24h (UFCo), serum cortisol after overnight 1 mg dexamethasone (1mgDST); 2) activity of 11HSD2 (ratio UFC/UFCo), SNPs of BclI, N363S; 3) BMD (Z-score, lumbar spine, LS, femoral neck, FN), TBS (Z-score) with DXA and VFx with radiography. Results: T2D subjects had increased prevalence of VFx (34.8 vs 19.6 %, respectively, p=0.031) in presence of increased BMD (LS 0.81\ub10.47 vs 0.17\ub11.32, p=0.002; FN 0.63\ub10.99 vs 0.04\ub10.94, p=0.000), in comparison to controls. There were no differences in TBS, HPA parameters, 11HSD2 activity, prevalence of BclI and N363S SNPs between groups. T2D patients with VFx had reduced levels of FN BMD, TBS and increased prevalence of the N363S SNPs (15.6%), compared to T2D ones without VFx. No differences were found in HPA parameters, 11HSD2 activity, prevalence of the BclI SNPs. The same pattern was seen in controls. In logistic regression analysis VFx were associated with T2D (OR=2.6, 95%CI 1.2-5.5, p=0.015) and N363S SNPs (OR=8.5, 95%CI 2.3-31.1, p=0.01) Conclusions: In subjects with and without T2D the presence of VFx is associated with increased GC sensitivity

Bone Health in Type 1 Diabetes: Where We Are Now and How We Should Proceed

Type 1 diabetes (T1D) is autoimmune disease with chronic hyperglycaemic state. Besides diabetic retinopathy, nephropathy, and neuropathy, T1D is characterized by poor bone health. The reduced bone mineralization and quality/strength, due to hyperglycemia, hypoinsulinemia, autoimmune inflammation, low levels of insulin growth factor-1 (IGF-1), and vitamin D, lead to vertebral/hip fractures. Young age of T1D manifestation, chronic poor glycemic control, high daily insulin dose, low BMI, reduced renal function, and the presence of complications can be helpful in identifying T1D patients at risk of reduced bone mineral density. Although risk factors for fracture risk are still unknown, chronic poor glycemic control and presence of diabetic complications might raise the suspicion of elevated fracture risk in T1D. In the presence of the risk factors, the assessment of bone mineral density by dual-energy X-ray absorptiometry and the search of asymptomatic vertebral fracture by lateral X-ray radiography of thorax-lumbar spine should be recommended. The improvement of glycemic control may have a beneficial effect on bone in T1D. Several experiments showed promising results on using anabolic pharmacological agents (recombinant IGF-1 and parathyroid hormone) in diabetic rodents with bone disorder. Randomized clinical trials are needed in order to test the possible use of bone anabolic therapies in humans with T1D

Bone Health in Type 1 Diabetes: Where We Are Now and How We Should Proceed

Type 1 diabetes (T1D) is autoimmune disease with chronic hyperglycaemic state. Besides diabetic retinopathy, nephropathy, and neuropathy, T1D is characterized by poor bone health. The reduced bone mineralization and quality/strength, due to hyperglycemia, hypoinsulinemia, autoimmune inflammation, low levels of insulin growth factor-1 (IGF-1), and vitamin D, lead to vertebral/hip fractures. Young age of T1D manifestation, chronic poor glycemic control, high daily insulin dose, low BMI, reduced renal function, and the presence of complications can be helpful in identifying T1D patients at risk of reduced bone mineral density. Although risk factors for fracture risk are still unknown, chronic poor glycemic control and presence of diabetic complications might raise the suspicion of elevated fracture risk in T1D. In the presence of the risk factors, the assessment of bone mineral density by dual-energy X-ray absorptiometry and the search of asymptomatic vertebral fracture by lateral X-ray radiography of thorax-lumbar spine should be recommended. The improvement of glycemic control may have a beneficial effect on bone in T1D. Several experiments showed promising results on using anabolic pharmacological agents (recombinant IGF-1 and parathyroid hormone) in diabetic rodents with bone disorder. Randomized clinical trials are needed in order to test the possible use of bone anabolic therapies in humans with T1D

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

Prevalence of subclinical contributors to low bone mineral density and/or fragility fracture

Objective: The prevalence of subclinical contributors to low bone mineral density (BMD) and/or fragility fracture is debated. We evaluated the prevalence of subclinical contributors to low BMD and/or fragility fracture in the presence of normal 25-hydroxyvitamin D (25OHVitD) levels. Design: Prospective observational study. Methods: Among 1095 consecutive outpatients evaluated for low BMD and/or fragility fractures, 602 (563 females, age 65.4G10.0 years) with apparent primary osteoporosis were enrolled. A general chemistry profile, phosphate, 25OHVitD, cortisol after 1-mg overnight dexamethasone suppression test, antitissue transglutaminase and endomysial antibodies and testosterone (in males) were performed. Serum and urinary calcium and parathyroid hormone levels were also evaluated after 25OHVitD levels normalization. Vertebral deformities were assessed by radiograph. Results: In total, 70.8% of patients had low 25OHVitD levels. Additional subclinical contributors to low BMD and/or fragility fracture were diagnosed in 45% of patients, with idiopathic hypercalciuria (IH, 34.1%) and primary hyperparathyroidism (PHPT, 4.5%) being the most frequent contributors, apart from hypovitaminosis D. Furthermore, 33.2% of IH and 18.5% of PHPT patients were diagnosed only after 25OHVitD levels normalization. The subclinical contributors to low BMD and/or fragility fracture besides hypovitaminosis D were associated inversely with age (odds ratio (OR) 1.02, 95% CI 1-1.04, PZ0.04) and BMI (OR 1.1, 95% CI 1.05-1.17, PZ0.0001) and directly with fragility fractures (OR 1.89, 95% CI 1.31-2.73, PZ0.001), regardless of BMD. Conclusions: Subclinical contributors to low BMD and/or fragility fracture besides hypovitaminosis D are present in more than 40% of the subjects with apparent primary osteoporosis. Hypovitaminosis D masks a substantial proportion of IH and PHPT patients

Bilateral and unilateral adrenal incidentalomas : biochemical and clinical characteristics

Objective: The possible different prevalence of arterial hypertension (AH), type 2 diabetes mellitus (T2DM), dyslipidaemia (DL) and vertebral fractures (FX) between patients with bilateral and unilateral adrenal incidentalomas (BAI and UAI, respectively) with and without subclinical hypercortisolism (SH) is unknown. In this study we compared the prevalence of AH, T2DM, DL and FX in BAI and UAI patients in relation to SH. Design: Prospective study. Methods: In 175 UAI and 38 BAI patients, we evaluated BMI, spinal and femoral bone mineral density (LS and FN BMD, respectively) and the presence of AH, T2DM, DL and FX. SH was diagnosed in the presence of R2 of the following: urinary free cortisol levels O193 nmol/24 h, serum cortisol levels after 1 mg dexamethasone suppression test O83 nmol/l or ACTH levels !2.2 pmol/l. Results: Age, BMI and cortisol secretion were comparable, while FN BMD was lower in BAI than in UAI patients (K0.45G0.86 vs 0.09G1.07, PZ0.004). The prevalence of SH, AH, T2DM, and DL was comparable, while the prevalence of FX was higher in BAI than in UAI (52.6 vs 28%, PZ0.007). The presence of FX was associated with BAI (odds ratio (OR) 2.6, 95% confidence interval (95% CI) 1.2\u20135.6, PZ0.016), after adjusting for SH (OR 1.77, 95% CI 0.85\u20133.7, PZ0.12), BMI (OR 1.06, 95% CI 0.98\u20131.13, PZ0.1), age (OR 1.07, 95% CI 1.04\u20131.11, PZ0.0001) and LS BMD (OR 1.31, 95% CI 1.03\u20131.67, PZ0.03). Conclusion: BAI patients have an increased FX risk than UAI ones. Further studies should investigate the causes of bone involvement in BAI patients

Vitamin D and sleep regulation: Is there a role for vitamin D?

Background: Vitamin D exerts multiple pleiotropic effects beyond its role in calcium-phosphate metabolism. Growing evidence suggests an association between hypovitaminosis D and sleep disorders, thus increasing the interest in the role of this vitamin in the regulatory mechanisms of the sleep-wake cycle. Objective: The study aimed to explore and summarize the current knowledge about the role of vitamin D in sleep regulation and the impact of vitamin D deficiency on sleep disorders. Methods: The main regulatory mechanisms of vitamin D on sleep are explained in this study. The literature was scanned to identify clinical trials and correlation studies showing an association between vitamin D deficiency and sleep disorders. Results: Vitamin D receptors and the enzymes that control their activation and degradation are expressed in several areas of the brain involved in sleep regulation. Vitamin D is also involved in the pathways of production of Melatonin, the hormone involved in the regulation of human circadian rhythms and sleep. Furthermore, vitamin D can affect sleep indirectly through non-specific pain disorders, correlated with alterations in sleep quality, such as restless legs syndrome and obstructive sleep apnea syndrome. Conclusions: Vitamin D has both a direct and an indirect role in the regulation of sleep. Although vitamin D deficiency has been associated to sleep disorders, there is still scant evidence to concretely support the role of vitamin D supplementation in the prevention or treatment of sleep disturbances; indeed, more intervention studies are needed to better clarify these aspects

The activity of 11β-hydroxysteroid dehydrogenase type 2 enzyme and cortisol secretion in patients with adrenal incidentalomas

In adrenal incidentaloma (AI) patients, beside the cortisol secretion, a different 11\u3b2-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity, measurable by 24-h urinary cortisol/cortisone ratio (R-UFF/UFE) (the higher R-UFF/UFE the lower HSD11B2 activity), could influence the occurrence of the subclinical hypercortisolism (SH)-related complications (hypertension, type 2 diabetes, obesity). We evaluated whether in AI patients, UFF levels are associated to UFE levels, and the HSD11B2 activity to the complications presence. In 156 AI patients (93F, age 65.2 \ub1 9.5 years), the following were measured: serum cortisol after 1 mg-dexamethasone test (1 mg-DST), ACTH, UFF, UFE levels, and R-UFF/UFE (by liquid chromatography\u2013tandem mass spectrometry), the latter was also evaluated in 63 matched-controls. We diagnosed SH (n = 22) in the presence of 652 among ACTH 83 nmol/L. Patients showed higher UFF levels and R-UFF/UFE than controls (75.9 \ub1 43.1 vs 54.4 \ub1 22.9 nmol/24 h and 0.26 \ub1 0.12 vs 0.20 \ub1 0.07, p < 0.005, respectively) but comparable UFE levels (291 \ub1 91.1 vs 268 \ub1 61.5, p = 0.069). The R-UFF/UFE was higher in patients with high (h-UFF, n = 28, 0.41 \ub1 0.20) than in those with normal (n-UFF, 0.22 \ub1 0.10, p < 0.005) UFF levels and in patients with SH than in those without SH (0.30 \ub1 0.12 vs 0.25 \ub1 0.12, p = 0.04). UFF levels were associated with R-UFF/UFE (r = 0.849, p < 0.001) in n-UFF, but not in h-UFF patients. Among h-UFF patients, the complications prevalence was not associated with R-UFF/UFE values. In AI patients, the UFF increase is not associated with a UFE increase. The HSD11B2 activity is inversely associated with UFF levels in n-UFF patients but not in h-UFF patients, and it is not associated with the SH complications