Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion.

CONTEXT: Although adrenal incidentalomas (AIs) are associated with a high prevalence of cardiovascular risk (CVR) factors, it is not clear whether patients with nonfunctioning AI (NFAI) have increased CVR. OBJECTIVE: Our objective was to investigate CVR in patients with NFAI. DESIGN AND SETTING: This case-control study was performed in a tertiary general hospital. SUBJECTS: SUBJECTS included 60 normotensive euglycemic patients with AI and 32 healthy controls (C) with normal adrenal imaging. MAIN OUTCOME MEASURES: All participants underwent adrenal imaging, biochemical and hormonal evaluation, and the following investigations: 1) measurement of carotid intima-media thickness (IMT) and flow-mediated dilatation, 2) 2-hour 75-gram oral glucose tolerance test and calculation of insulin resistance indices (homeostasis model assessment, quantitative insulin sensitivity check, and Matsuda indices), 3) iv ACTH stimulation test, 4) low-dose dexamethasone suppression test, and 5) NaCl (0.9%) post-dexamethasone saline infusion test. RESULTS: Based on cutoffs obtained from controls, autonomous cortisol secretion was documented in 26 patients (cortisol-secreting AI [CSAI] group), whereas 34 exhibited adequate cortisol and aldosterone suppression (NFAI group). IMT measurements were higher and flow-mediated vasodilatation was lower in the CSAI group compared with both NFAI and C and in the NFAI group compared with C. The homeostasis model assessment index was higher and quantitative insulin sensitivity check index and Matsuda indices were lower in the CSAI and NFAI groups compared with C as well as in CSAI compared with the NFAI group. The area under the curve for cortisol after ACTH stimulation was higher in the CSAI group compared with the NFAI group and C and in the NFAI group compared with C. In the CSAI group, IMT correlated with cortisol, urinary free cortisol, and cortisol after a low-dose dexamethasone suppression test, whereas in the NFAI group, IMT correlated with area under the curve for cortisol after ACTH stimulation and urinary free cortisol. CONCLUSIONS: Patients with CSAI without hypertension, diabetes, and/or dyslipidemia exhibit adverse metabolic and CVR factors. In addition, NFAIs are apparently associated with increased insulin resistance and endothelial dysfunction that correlate with subtle but not autonomous cortisol excess.

Studies of insulin resistance in patients with clinical and subclinical hyperthyroidism.

OBJECTIVE: Although clinical hyperthyroidism (HR) is associated with insulin resistance, the information on insulin action in subclinical hyperthyroidism (SHR) is limited. DESIGN AND METHODS: To investigate this, we assessed the sensitivity of glucose metabolism to insulin in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes) in 12 euthyroid subjects (EU), 16 patients with HR, and 10 patients with SHR. RESULTS: HR and SHR patients displayed higher postprandial glucose levels (area under the curve, AUC(0)(-)(300) 32,190±1067 and 31,497±716,mg/dl min respectively) versus EU (27,119±1156 mg/dl min, P<0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC(0)(-)(300) 11,020±985 and 9565±904 mU/l min respectively) compared with EU subjects (AUC(0)(-)(300) 7588±743 mU/l min, P<0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81±0.3 and 2.43±0.38 respectively) compared with EU subjects (1.27±0.16, P<0.05), while Matsuda and Belfiore indices were decreased in HR (4.21±0.41 and 0.77±0.05 respectively, P<0.001) and SHR patients (4.47±0.33 and 0.85±0.05 respectively, P<0.05 versus EU (7.76±0.87 and 1 respectively). At 100 µU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8±7 mean fluorescence intensity (MFI)) and SHR patients (522.2±25 MFI) compared with EU subjects (407±18 MFI, P<0.01 and P<0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8±5%) versus EU subjects (61.26±10%, P<0.05). CONCLUSIONS: Insulin-stimulated glucose transport in isolated monocytes of patients with HR was decreased compared with EU subjects. Insulin resistance was comparable in patients with both HR and SHR.

Studies of insulin resistance in patients with clinical and subclinical hypothyroidism.

OBJECTIVE: Although clinical hypothyroidism (HO) is associated with insulin resistance, there is no information on insulin action in subclinical hypothyroidism (SHO). DESIGN AND METHODS: To investigate this, we assessed the sensitivity of glucose metabolism to insulin both in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes with flow cytometry) in 21 euthyroid subjects (EU), 12 patients with HO, and 13 patients with SHO. RESULTS: All three groups had comparable plasma glucose levels, with the HO and SHO having higher plasma insulin than the EU (P<0.05). Homeostasis model assessment index was increased in HO (1.97+/-0.22) and SHO (1.99+/-0.13) versus EU (1.27+/-0.16, P<0.05), while Matsuda index was decreased in HO (3.89+/-0.36) and SHO (4.26+/-0.48) versus EU (7.76+/-0.87, P<0.001), suggesting insulin resistance in both fasting and post-glucose state. At 100 microU/ml insulin: i) GLUT4 levels on the monocyte plasma membrane were decreased in both HO (215+/-19 mean fluorescence intensity, MFI) and SHO (218+/-24 MFI) versus EU (270+/-25 MFI, P=0.03 and 0.04 respectively), and ii) glucose transport rates in monocytes from HO (481+/-30 MFI) and SHO (462+/-19 MFI) were decreased versus EU (571+/-15 MFI, P=0.04 and 0.004 respectively). CONCLUSIONS: In patients with HO and SHO: i) insulin resistance was comparable; ii) insulin-stimulated rates of glucose transport in isolated monocytes were decreased due to impaired translocation of GLUT4 glucose transporters on the plasma membrane; iii) these findings could justify the increased risk for insulin resistance-associated disorders, such as cardiovascular disease, observed in patients with HO or SHO.

IGF-I increases the recruitment of GLUT4 and GLUT3 glucose transporters on cell surface in hyperthyroidism.

OBJECTIVE: In hyperthyroidism, tissue glucose disposal is increased to adapt to high energy demand. Our aim was to examine the regulation of glucose transporter (GLUT) isoforms by IGF-I in monocytes from patients with hyperthyroidism. DESIGN AND METHODS: Blood (20 ml) was drawn from 21 healthy and 10 hyperthyroid subjects. The abundance of GLUT isoforms on the monocyte plasma membrane was determined in the absence and presence of IGF-I (0.07, 0.14, and 0.7 nM) using flow cytometry. Anti-CD14-phycoerythrin monocional antibody was used for monocyte gating. GLUT isoforms were determined after staining the cells with specific antisera to GLUT3 and GLUT4. RESULTS: In monocytes from the euthyroid subjects, IGF-I increased the abundance of GLUT3 and GLUT4 on the monocyte surface by 25 and 21% respectively (P<0.0005 with repeated measures ANOVA). Hyperthyroidism increased the basal monocyte surface GLUT3 and GLUT4; in these cells, IGF-I had a marginal but highly significant effect (P=0.003, with repeated measures ANOVA) on GLUT3 (11%) and GLUT4 (10%) translocation on the plasma membrane. CONCLUSIONS: In hyperthyroidism: 1) basal abundance of GLUT3 and GLUT4 on the plasma membrane is increased and 2) the sensitivity of the recruitment of GLUT3 and GLUT4 transporters on the plasma membrane in response to IGF-I is increased. These findings may contribute to the understanding of the mechanism by which hyperthyroidism increases glucose disposal in peripheral tissues.

Bone mineral density of both genders in Type 1 diabetes according to bone composition.

AIMS: This study is an investigation of the impact of Type 1 diabetes on bone mineral density (BMD) with regard to bone composition. MATERIAL AND METHODS: Thirty male and 30 premenopausal female patients with Type 1 diabetes (IDD) were retrospectively compared with an equal number of healthy individuals, matched on a person-to-person basis and to the reference population mean. BMD was measured at the L2-L4 vertebrae and femoral neck (FN) by dual energy X-ray absorptiometry (DXA). RESULTS: BMD absolute values were significantly lower in the diabetic than in the healthy males at vertebrae and FN (P<.05). The vertebral BMD values of diabetic women did not significantly differ, whereas those of FN were significantly lower compared with those of the healthy participants. FN age-adjusted BMD values (Z scores) were significantly lower than those of the healthy persons and the population reference mean in both genders (P=.01, <.001 for males and <.01 for females), whereas regarding the vertebrae, only in the diabetic males (P<.05 and <.01 respectively). The percentages of osteopenia and osteoporosis were significantly higher in the male compared to the female diabetic patients (P<.001). No significant correlations existed between the BMD values and diabetes duration, glycosylated hemoglobin (HbA1c) concentration, or age of diabetes onset. Similar results were obtained when applying stepwise multiple regression analysis to explain the BMD value variance. CONCLUSIONS: Young males with Type 1 diabetes exhibit significantly lower BMD values of trabecular and mixed cortical-trabecular bone, compared with matched healthy persons. Premenopausal females with Type 1 diabetes present significantly lower BMD values of mixed bone only. Blood glucose control and diabetes duration do not appear to influence BMD behavior.

Disappearance of a growth hormone secreting macro adenoma during long-term somatostatin analogue administration and recurrence following somatostatin withdrawal.

Acromegaly is caused by excessive growth hormone secretion, usually from a pituitary adenoma. The use of somatostatin analogues as primary or adjunctive therapy has been widely applied in the management of acromegaly. We are aware of only three reported cases of complete shrinkage of a pituitary adenoma after long-term analogue administration. However in these cases, the reduction in the dimension of the adenoma was obtained with the everyday use of somatostatin analogues and not with the newer longer acting formulations. We report a patient in whom long term (62 months) lanreotide-L.A.R administration resulted in complete disappearance of a growth hormone secreting pituitary macroadenoma, followed by recurrence of the adenoma six months post therapy discontinuation.

Bone remodeling.

The skeleton is a metabolically active organ that undergoes continuous remodeling throughout life. Bone remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized. The remodeling cycle consists of three consecutive phases: resorption, during which osteoclasts digest old bone; reversal, when mononuclear cells appear on the bone surface; and formation, when osteoblasts lay down new bone until the resorbed bone is completely replaced. Bone remodeling serves to adjust bone architecture to meet changing mechanical needs and it helps to repair microdamages in bone matrix preventing the accumulation of old bone. It also plays an important role in maintaining plasma calcium homeostasis. The regulation of bone remodeling is both systemic and local. The major systemic regulators include parathyroid hormone (PTH), calcitriol, and other hormones such as growth hormone, glucocorticoids, thyroid hormones, and sex hormones. Factors such as insulin-like growth factors (IGFs), prostaglandins, tumor growth factor-beta (TGF-beta), bone morphogenetic proteins (BMP), and cytokines are involved as well. As far as local regulation of bone remodeling is concerned, a large number of cytokines and growth factors that affect bone cell functions have been recently identified. Furthermore, through the RANK/receptor activator of NF-kappa B ligand (RANKL)/osteoprotegerin (OPG) system the processes of bone resorption and formation are tightly coupled allowing a wave of bone formation to follow each cycle of bone resorption, thus maintaining skeletal integrity.

Bone density patterns after normal and premature menopause.

OBJECTIVES: The investigation of the effect of time and type of menopause on bone mineral density (BMD) at different ages. METHODS: Five hundred and fourteen women, who had never received any hormonal substitution were studied in a cross-sectional design: 177 with normal (NMP), 210 with surgical (SUMP) and 127 with premature natural (EMP) menopause. Age at menopause was 49.1+/-3.9, 38.3+/-4.7 and 38.1+/-4.2 years (mean+/-1 S.D.), respectively. BMD was measured at L2-L4 vertebrae and proximal femur by the DEXA method. RESULTS: EMP women presented significantly lower vertebral BMD than NMP women in the 45-55-years segments (P<0.001), but did not differ from SUMP women. This group exhibited lower vertebral BMD than NMP between 45 and 50 years (P<0.001). Regarding femoral neck, EMP women exhibited lower values than SUMP in the 45-50 and 55-65 age segments (P<0.001) whereas SUMP women presented significantly higher BMD values than NMP women after 55 years of age (P<0.001). The percentages of women with vertebral BMD (T-score values) in the osteoporotic range were significantly greater in EMP compared with either NMP or SUMP groups (both P<0.001) whereas in femoral neck lower in SUMP than the other two categories. CONCLUSIONS: Women with either natural or surgical premature menopause exhibit lower BMD of trabecular bone compared with normal menopause women at the age segments 45-55 and 45-50, respectively. However, surgical menopause women exceed normal menopause women in their mixed bone BMD values after 60 years as well as premature natural menopause women at almost all age segments.