Sung-Kil Lim

Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone

OBJECTIVES: We investigated the effect of obesity on the serum levels of total and free IGF-1 and their relationship to the circulating levels of insulin and IGF binding proteins (IGFBPs) in age and sex-matched groups. SUBJECTS: The study included 43 obese subjects (ideal body weight; IBW>120%) and 45 controls (IBW<100%). All of the subjects were male. MEASUREMENT: Total IGF-1, free IGF-1, IGFBP-1, IGFBP-2, IGFBP-3, and insulin were measured in obese subjects and normal control subjects. RESULTS: No significant differences in the circulating levels of total and IGFBP-3 were observed between the obese and control groups. In contrast to total IGF-1, free IGF-1 in obese subjects was significantly increased compared to normal controls (P<0.05). Serum total and free IGF-1 were inversely correlated with age (r=−0.42, P=0.001, and −0.44, P=0.001). Fasting serum insulin concentrations were elevated in all the obese subjects (P<0.05) and positively correlated with IBW (r=0.57, P=0.001). The levels of serum GH and IGFBP-1 were suppressed in all the obese subjects (P<0.05). IGFBP-1 was inversely correlated with IBW (r=−0.51, P=0.001) and serum insulin concentrations (r=minus;0.48, P=0.001). The IGFBP-2 concentrations were also suppressed in obese subjects and inversely related to free IGF-1 (r=−0.48, P=0.001). Using multiple linear regression analysis, total IGF-1 and insulin concentrations were positively correlated (r=0.58, P=0.001) and free IGF-1 and IGFBP-1 concentrations were negatively correlated (r=−0.57, P=0.001). CONCLUSION: We confirmed that total IGF-1 and IGFBP-3 concentrations were not significantly different between the obese and control groups, despite GH hyposecretion in obesity. We also found that free IGF-1 concentrations were higher in obese subjects than in normal controls. It seems likely that overnutrition and chronic hyperinsulinaemia in obesity may alter this regulated growth response by insulin stimulation of IGF-1 production and suppression of hepatic IGFBP-1 and IGFBP-2 production, which may inhibit IGF-1 bioactivity.

miR-182 is a negative regulator of osteoblast proliferation, differentiation, and skeletogenesis through targeting FoxO1

Uncontrolled oxidative stress impairs bone formation and induces age‐related bone loss in humans. The FoxO family is widely accepted to play an important role in protecting diverse cells from reactive oxygen species (ROS). Activation of FoxO1, the main FoxO in bone, stimulates proliferation and differentiation as well as inhibits apoptosis of osteoblast lineage cells. Despite the important role of FoxO1, little is known about how FoxO1 expression in bone is regulated. Meanwhile, several recent studies reported that microRNAs (miRNAs) could play a role in osteoblast differentiation and bone formation by targeting various transcriptional factors. Here, we identified one additional crucial miRNA, miR‐182, which regulates osteoblastogenesis by repressing FoxO1 and thereby negatively affecting osteogenesis. Overexpression of miR‐182 in osteoblast lineage cells increased cell apoptosis and inhibited osteoblast differentiation, whereas in vivo overexpression of miR‐182 in zebrafish impaired bone formation. From in silico analysis and validation experiments, FoxO1 was identified as the target of miR‐182, and restoration of FoxO1 expression in miR‐182–overexpressing osteoblasts rescued them from the inhibitory effects of miR‐182. These results indicate that miR‐182 functions as a FoxO1 inhibitor to antagonize osteoblast proliferation and differentiation, with a subsequent negative effect on osteogenesis. To treat bone aging, an antisense approach targeting miR‐182 could be of therapeutic value.

Biopsy of Thyroid Nodules: Comparison of Three Sets of Guidelines

OBJECTIVE The purpose of this study was to compare the results with three sets of guidelines for fine-needle aspiration biopsy of thyroid nodules. MATERIALS AND METHODS A total of 1,398 nodules confirmed with fine-needle aspiration biopsy or surgery were included in the study. We compared the diagnostic value of three sets of guidelines for ultrasound findings that should lead to fine-needle aspiration biopsy of a nodule. According to the Kim criteria, a nodule should have at least one of the following findings: marked hypoechogenicity, irregular or microlobulated margins, microcalcifications, or length greater than width. According to the Society of Radiologists in Ultrasound, biopsy should be performed on a nodule 1 cm in diameter or larger with microcalcifications, 1.5 cm in diameter or larger that is solid or has coarse calcifications, and 2 cm in diameter or larger that has mixed solid and cystic components, and a nodule that has undergone substantial growth or is associated with abnormal cervical lymph nodes. According to the American Association of Clinical Endocrinologists, a hypoechoic nodule with at least one additional feature, such as irregular margins, length greater than width, and microcalcifications, should be biopsied. RESULTS For all nodules, the diagnostic accuracy of the Kim (area under the receiver operating characteristic curve [Az]=0.868) and American Association of Clinical Endocrinologists (Az=0.850) criteria was greater than that of the Society of Radiologists in Ultrasound criteria (Az=0.551). The number of nodules for which fine-needle aspiration biopsy was recommended (25.6%) was smallest with use of the American Association of Clinical Endocrinologists criteria, and the smallest number (7.3%) of missed malignant lesions was associated with use of the Kim criteria. The results did not change for the subgroup with nodules larger than 1 cm. CONCLUSION The Kim and American Association of Clinical Endocrinologists criteria are more accurate than the Society of Radiologists in Ultrasound criteria. The American Association of Clinical Endocrinologists guidelines are recommended for achieving high specificity, and the Kim criteria may be chosen for higher sensitivity.

Relationships of urinary phyto‐oestrogen excretion to BMD in postmenopausal women

objective  Phyto‐oestrogens are plant compounds with both oestrogenic and anti‐oestrogenic properties. However, it is not known whether natural phyto‐oestrogens are beneficial or harmful in human osteoporosis. This study was performed to investigate the relationships between urinary phyto‐oestrogens and bone mineral density (BMD) in Korean postmenopausal women.

Low-dose growth hormone treatment combined with diet restriction decreases insulin resistance by reducing visceral fat and increasing muscle mass in obese type 2 diabetic patients

OBJECTIVE: To evaluate the effects of low-dose growth hormone (GH) therapy combined with diet restriction on changes in body composition and the consequent change in insulin resistance in newly-diagnosed obese type 2 diabetic patients.DESIGN: Double-blind and placebo-controlled trial of 25-kcal/kg IBW diet daily with GH (n = 9; rhGH, 0.15 IU/kg body weight/week) or placebo (n = 9) for 12 weeks.SUBJECTS: Eighteen newly-diagnosed obese type 2 diabetic patients (age 42–56 y, body mass index 28.1±2.7 kg/m2).MEASUREMENTS: Body composition and fat distribution parameters (by bioelectrical impedance analyzer and CT scans), serum IGF-1; serum glucose, insulin and free fatty acid (FFA) during oral glucose tolerance test (OGTT); HbA1c; serum lipid profiles; and glucose disposal rate (GDR) by euglycemic hyperinsulinemic clamp at baseline and after treatment.RESULTS: The fraction of body weight lost as fat lost was significantly greater (0.98±0.39 vs 0.52±0.32 kg/kg, P<0.05) and visceral fat area was decreased more in the GH-treated group compared to the placebo-treated group (27.9 vs 21.6%, P<0.05). Lean body mass and muscle area were reduced in the placebo-treated group, whereas an increase in both was observed in the GH-treated group. GDR the was significantly increased in only the GH-treated group (4.67±1.05 vs 6.95±0.91 mg/kg/min, P<0.05). The GH-induced increase in GDR was positively correlated with the decrease in the ratio of visceral fat area/muscle area (r = 0.588, P = 0.001). Serum glucose levels and insulin- and FFA-area under the curve during OGTT and HbA1c were significantly decreased after GH treatment. LDL-cholesterol level was decreased in only the GH-treated group.CONCLUSION: Low-dose GH treatment combined with dietary restriction resulted not only in a decrease of visceral fat but also in an increase of muscle mass with a consequent improvement of the insulin resistance observed in obese type 2 diabetic patients.

Oncogenic osteomalacia associated with mesenchymal tumour detected by indium‐111 octreotide scintigraphy

In a 40‐year‐old man who had suffered from vague and generalized bone pains for 7 years due to oncogenic osteomalacia, the causative tumour was finally detected by Indium‐111 octreotide scintigraphy. Some characteristics of the tumour associated with oncogenic osteomalacia, such as its size, growth rate, location and origin, often make the diagnosis difficult. However, the recent discovery of somatostatin receptors in mesenchymal tumours, which are the most common cause of oncogenic osteomalacia, has raised the possibility of early detection of this devastating disorder. Here, we report that radiolabelled octreotide scintigraphy has a potential role as a diagnostic tool in oncogenic osteomalacia. However, the exact role of somatostatin receptors in tumours associated with oncogenic osteomalacia still remains elusive.

Peripheral Effect of α-Melanocyte-stimulating Hormone on Fatty Acid Oxidation in Skeletal Muscle

To study the peripheral effects of melanocortin on fuel homeostasis in skeletal muscle, we assessed palmitate oxidation and AMP kinase activity in α-melanocyte-stimulating hormone (α-MSH)-treated muscle cells. After α-MSH treatment, carnitine palmitoyltransferase-1 and fatty acid oxidation (FAO) increased in a dose-dependent manner. A strong melanocortin agonist, NDP-MSH, also stimulated FAO in primary culture muscle cells and C2C12 cells. However, [Glu6]α-MSH-ND, which has ample MC4R and MC3R agonistic activity, stimulated FAO only at high concentrations (10–5 m). JKC-363, a selective MC4R antagonist, did not suppress α-MSH-induced FAO. Meanwhile, SHU9119, which has both antagonistic activity on MC3R and MC4R and agonistic activity on both MC1R and MC5R, increased the effect of α-MSH on FAO in both C2C12 and primary muscle cells. Small interference RNA against MC5R suppressed the α-MSH-induced FAO effectively. cAMP analogues mimicked the effect of α-MSH on FAO, and the effects of both α-MSH and cAMP analogue-mediated FAO were antagonized by a protein kinase A inhibitor (H89) and a cAMP antagonist ((Rp)-cAMP). Acetyl-CoA carboxylase activity was suppressed by α-MSH and cAMP analogues by phosphorylation through AMP-activated protein kinase activation in C2C12 cells. Taken together, these results suggest that α-MSH increases FAO in skeletal muscle, in which MC5R may play a major role. Furthermore, these results suggest that α-MSH-induced FAO involves cAMP-protein kinase A-mediated AMP-activated protein kinase activation.

Expression and Regulation of Osteoprotegerin in Adipose Tissue

Purpose Osteoprotegerin (OPG), a potent inhibitor of osteoclastic bone resorption, has a variety of biological functions that include anti-inflammatory effects. Adipocytes and osteoblasts share a common origin, and the formation of new blood vessels often precedes adipogenesis in developing adipose tissue microvasculature. We examined whether OPG is secreted from adipocytes, therefore contributing to the prevention of neovascularization and protecting the vessels from intimal inflammation and medial calcification. Materials and Methods The mRNA expression of OPG and receptor activator of NF-κB ligand (RANKL) was measured in differentiated 3T3L1 adipocytes and adipose tissues. Results OPG mRNA expression increased with the differentiation of 3T3L1 adipocytes, while RANKL expression was not significantly altered. OPG mRNA was expressed at higher levels in white adipose tissue than in brown adipose tissue and was most abundant in the epididymal portion. In differentiated 3T3L1 adipocytes, Rosiglitazone and insulin reduced the OPG/RANKL expression ratio in a dose- and time-dependent manner. In contrast, tumor necrosis factor-α (TNF-α) increased the expression of both OPG and RANKL in a time-dependent manner. The OPG/RANKL ratio was at a maximum two hours after TNF-α treatment and then returned to control levels. Furthermore, OPG was abundantly secreted into the media after transfection of OPG cDNA with Phi C31 integrase into 3T3L1 cells. Conclusion Our results indicate that OPG mRNA is expressed and regulated in the adipose tissue. Considering the role of OPG in obesity-associated inflammatory changes in adipose tissue and vessels, we speculate that OPG may have both a protective function against inflammation and anti-angiogenic effects on adipose tissue.

Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia

Objective  ACTH‐independent macronodular adrenal hyperplasia (AIMAH) is a rare and unusual cause of Cushings syndrome, characterized by bilateral nodular adrenocortical hyperplasia and hypersecretion of cortisol. Familial AIMAH has rarely been reported. Recently, the aberrant expression of adrenal receptors for various ligands in AIMAH patients has become important in explaining the pathogenesis of AIMAH. In this study, we present the cases of two sisters who were affected with AIMAH.

Analysis of adrenal masses by 18F-FDG positron emission tomography scanning

This study aimed to analyse the characteristics of adrenal masses visible in the computerised tomography (CT) scans which have been also evaluated by 2‐[18F]fluoro‐2‐deoxy‐D‐glucose positron emission tomography (18F‐FDG PET), and to characterise the features of 18F‐FDG PET scans associated with various adrenal endocrine tumours, especially benign functional tumours. 18F‐FDG PET scans of 105 patients with adrenal masses on the CT scan were analysed. Positive uptakes in the 18F‐FDG PET scans were seen in 60 malignant tumours (54 metastasic lesions, six primary adrenal cancers) and seven benign tumours. The positive predictive value of 18F‐FDG PET imaging to characterise an adrenal mass as a malignant tumour was 90%; the corresponding negative predictive value to rule out malignancy was also 90%. Benign adrenal tumours were smaller than that of malignant lesions (p < 0.05). The mean standardised uptake value max (SUVmax) of the metastatic lesions [8.4 ± 6.5 (μCi/g)/μCi/kg] was significantly higher than that of the benign adrenal tumours [2.4 ± 1.2 (μCi/g)/μCi/kg, p < 0.001]. Examination of only the primary adrenal lesions revealed that all adrenocortical carcinomas, two of three cases of pheochromocytomas, three of five neuroblastomas and two of four cases of primary aldosteronism showed positive 18F‐FDG uptake. In conclusion, for patients presenting adrenal masses with a high probability of malignancy, 18F‐FDG PET can be used to differentiate malignant from benign adrenal lesions. However, the 18F‐FDG PET uptake did not show an always consistent pattern for endocrine tumours, which was probably due to the variability inherent in 18F‐FDG uptake. This study suggests that 18F‐FDG PET scanning can offer supporting data to localise and characterise adrenal tumours.