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.

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 (1.97G0.22) and SHO (1.99G0.13) versus EU (1.27G0.16, P!0.05), while Matsuda index was decreased in HO (3.89G0.36) and SHO (4.26G0.48) versus EU (7.76G0.87, P!0.001), suggesting insulin resistance in both fasting and post-glucose state. At 100 mU/ml insulin: i) GLUT4 levels on the monocyte plasma membrane were decreased in both HO (215G19 mean fluorescence intensity, MFI) and SHO (218G24 MFI) versus EU (270G25 MFI, PZ0.03 and 0.04 respectively), and ii) glucose transport rates in monocytes from HO (481G30 MFI) and SHO (462G19 MFI) were decreased versus EU (571G15 MFI, PZ0.04 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.

International audienceOsteoporosis has been recently recognized as a severe comorbidity factor in hemophilia. However, its pathogenesis is still obscure. We evaluated the incidence of osteoporosis in 90 hemophilia patients and investigated possible correlations with clinical and laboratory data. Out of the 90 patients, 80 (89%) had severe hemophilia, and 35 (38.9%) were human immunodeficiency virus (HIV)-positive. Hemophilic arthropahty was assessed using World Federation of Hemophilia clinical score and Petterson radiological score. Bone mineral density of the lumbar spine (LS) and femoral neck (FN) were measured using dual-energy X-ray absortiometry. Bone turnover was evaluated by the measurement of: (1) bone resorption markers [N-terminal cross-linking telopeptide of collagen type I (NTX), C-terminal cross-linking telopeptide of collagen type I (CTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], (2) bone formation markers [bone-alkaline phosphatase (bALP) and osteocalcin], and (3) osteoclast stimulators (receptor activator of nuclear factor-κB ligand, osteoprotegerin, and tumor necrosis factor-alpha). Osteopenia or osteoporosis was observed in 86% and 65% of the patients in FN and LS, respectively. Osteoporosis was more common among HIV-positive patients in both FN (65.3% vs 41.6%;  = 0.007) and LS (17.86% vs 5.41%,  = 0.004). The severity of osteoporosis in FN correlated with the patients' total clinical and radiological score ( = 0.001). Hemophilia patients showed increased osteoclastic activity (significant increase of TRACP-5b, NTX, and CTX), which was not accompanied by a comparable increased bone formation (reduced osteocalcin and borderline increase of bALP). In multivariate analysis, HIV infection ( = 0.05) and total clinical score ( = 0.001) were independent risk factors for osteoporosis development. We conclude that there is a high prevalence of osteoporosis among hemophiliacs, which is related to the severity of arthropathy and is enhanced by HIV infection. We report for the first time a high bone resorption that seems not to be balanced by a comparable bone formation

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.

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 190G1067 and 31 497G716 mg/dl min respectively) versus EU (27 119 G1156 mg/dl min, P!0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC 0-300 11 020G985 and 9565G904 mU/l min respectively) compared with EU subjects (AUC 0-300 7588G743 mU/l min, P!0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81G0.3 and 2.43G0.38 respectively) compared with EU subjects (1.27 G0.16, P!0.05), while Matsuda and Belfiore indices were decreased in HR (4.21G0.41 and 0.77G0.05 respectively, P!0.001) and SHR patients (4.47G0.33 and 0.85G0.05 respectively, P!0.05 versus EU (7.76G0.87 and 1 respectively). At 100 mU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8G7 mean fluorescence intensity (MFI)) and SHR patients (522.2G25 MFI) compared with EU subjects (407G18 MFI, P!0.01 and P!0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8G5%) versus EU subjects (61.26G10%, 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.