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Increasing evidence has shown that small ubiquitin-like modifier (SUMO) modification plays an important role in metabolic regulation. We previously demonstrated that SUMO-specific protease 2 (SENP2) is involved in lipid metabolism in skeletal muscle and adipogenesis. In this study, we investigated the function of SENP2 in pancreatic β cells by generating a β cell-specific knockout (Senp2-βKO) mouse model. Glucose tolerance and insulin secretion were significantly impaired in the Senp2-βKO mice. In addition, glucose-stimulated insulin secretion (GSIS) was decreased in the islets of the Senp2-βKO mice without a significant change in insulin synthesis. Furthermore, islets of the Senp2-βKO mice exhibited enlarged mitochondria and lower oxygen consumption rates, accompanied by lower levels of S616 phosphorylated DRP1 (an active form of DRP1), a mitochondrial fission protein. Using a cell culture system of NIT-1, an islet β cell line, we found that increased SUMO2/3 conjugation to DRP1 due to SENP2 deficiency suppresses the phosphorylation of DRP1, which possibly induces mitochondrial dysfunction. In addition, SENP2 overexpression restored GSIS impairment induced by DRP1 knockdown and increased DRP1 phosphorylation. Furthermore, palmitate treatment decreased phosphorylated DRP1 and GSIS in β cells, which was rescued by SENP2 overexpression. These results suggest that SENP2 regulates mitochondrial function and insulin secretion at least in part by modulating the phosphorylation of DRP1 in pancreatic β cells.

Free fatty acids are converted to acyl-CoA by long-chain acyl-CoA synthetases (ACSLs) before entering into metabolic pathways for lipid biosynthesis or degradation. ACSL family members have highly conserved amino acid sequences except for their N-terminal regions. Several reports have shown that ACSL1, among the ACSLs, is located in mitochondria and mainly leads fatty acids to the β-oxidation pathway in various cell types. In this study, we investigated how ACSL1 was localized in mitochondria and whether ACSL1 overexpression affected fatty acid oxidation (FAO) rates in C2C12 myotubes. We generated an ACSL1 mutant in which the N-terminal 100 amino acids were deleted and compared its localization and function with those of the ACSL1 wild type. We found that ACSL1 adjoined the outer membrane of mitochondria through interaction of its N-terminal region with carnitine palmitoyltransferase-1b (CPT1b) in C2C12 myotubes. In addition, overexpressed ACSL1, but not the ACSL1 mutant, increased FAO, and ameliorated palmitate-induced insulin resistance in C2C12 myotubes. These results suggested that targeting of ACSL1 to mitochondria is essential in increasing FAO in myotubes, which can reduce insulin resistance in obesity and related metabolic disorders.

Background Most patients with low back pain prefer to ignore symptoms and avoid medical management because of incorrect perceptions about this condition. However, over 90% of patients with chronic low back pain are hardly unable to perform daily activities, with 50% reporting that their daily activities have been severely impeded. Purpose In this study, an individualized educational program was developed and implemented in a sample of Korean patients with chronic low back pain, and the effectiveness of this program was evaluated. Methods This study was conducted as a randomized controlled trial with outpatients (n = 43) in an orthopedic clinic. The Analysis, Design, Development, Implementation, and Evaluation model was applied to develop the educational program. The experimental group was provided with an educational booklet and contacted via biweekly personalized telephone and face-to-face counseling sessions. The control group was provided the educational booklet only. SAS Version 9.4 was used to analyze collected data using the χ2 test, t test, Fisher's exact test, Wilcoxon test, linear regression analysis, and Spearman partial correlation analysis. Results After 8 weeks, the experimental group demonstrated a significantly greater reduction in maximum, average, and current low back pain experienced within the immediately preceding 24 hours than the control group (p = .001, p = .002, and p = .014, respectively). In addition, daily living disability showed a greater reduction, and average back muscle strength showed a more significant improvement in the experimental group than in the control group (p = .001 and p = .035). The difference in medication adherence between the groups was not statistically significant (p = .089). The experimental group rated an average of 4.3 out of 5.0 points on the program satisfaction scale, indicating an 86% rate of satisfaction. Conclusions/implications for practice In this study, the individualized educational program was shown to be effective in helping alleviate symptoms in patients with chronic low back pain, decrease daily living disability, and improve average back muscle strength. It was further demonstrated that following up with expert medical staffs can motivate patients to incorporate the recommendations of the program into their daily routine, leading to higher patient satisfaction.

The adipose tissue is a key site regulating energy metabolism. One of the contributing factors behind this is browning of white adipose tissue (WAT). However, knowledge of the intracellular determinants of the browning process remains incomplete. By generating adipocyte-specific Senp2 knockout (Senp2-aKO) mice, here we show that SENP2 negatively regulates browning by de-conjugating small ubiquitin-like modifiers from C/EBPβ. Senp2-aKO mice are resistant to diet-induced obesity due to increased energy expenditure and heat production. Senp2 knockout promotes beige adipocyte accumulation in inguinal WAT by upregulation of thermogenic gene expression. In addition, SENP2 knockdown promotes thermogenic adipocyte differentiation of precursor cells isolated from inguinal and epididymal WATs. Mechanistically, sumoylated C/EBPβ, a target of SENP2, suppresses expression of HOXC10, a browning inhibitor, by recruiting a transcriptional repressor DAXX. These findings indicate that a SENP2-C/EBPβ-HOXC10 axis operates for the control of beige adipogenesis in inguinal WAT.

Background and purpose In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin. Methods The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo. Results We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice. Conclusions We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO.

In this study, trihydroxychalcone derivatives were synthesized and evaluated for their potential antidiabetic effects in a cell-culture system and a diabetic mouse model in vivo. Some of them increased fatty acid oxidation (FAO) in C2C12 myotubes without affecting the cell viability. In addition, some trihydroxychalcone derivatives, including chalcone 13, facilitated AMP-activated protein kinase (AMPK) activation. Chalcone 13 administration to high-fat diet (HFD)-induced diabetic mice improved glucose tolerance, increased muscle FAO, and reduced fat accumulation in the liver and skeletal muscles. These results suggest that some chalcone derivatives, particularly chalcone 13, might be potential therapeutic agents for the treatment of diabetes.

Spinal metastases from hepatocellular carcinoma (HCC) require high-dose irradiation for durable pain and tumor control. Stereotactic ablative body radiotherapy (SABR) enables the delivery of high-dose radiation. However, but vertebral compression fracture (VCF) can be problematic. The aim of his study is to evaluate the outcome and risk of VCF after SABR for spinal metastasis from HCC. We retrospectively reviewed 33 lesions in 42 spinal segments from 29 patients who received SABR with 1 fraction (16-20 Gy), or 3 fractions (18-45 Gy) from September 2009 to January 2015. The 1-year local control (LC) rate was 68.3%. Radiographic grade of cord compression (RGCC) was the only independent prognostic factor associated with LC (P = 0.007). The 1-year ultimate LC rate including the outcome of salvage re-irradiation was 87.2%. The pain response rate was 73.3% according to the categories of the International Bone Metastases Consensus Group. The 1-year VCF-free rate was 71.5%. Pre-existing VCF (P < 0.001) and only-lytic change (P = 0.017) were associated with a higher post-SABR VCF rate. One-third of post-SABR VCFs required interventions. SABR for spinal metastases from HCC provided efficacious LC, especially for lesions with RGCC ≤ II, and showed effective and durable pain relief. As VCF after SABR occurred frequently for vertebral segments with pre-existing VCF and only-lytic change, early preventive vertebroplasty is considerable for those high-risk vertebral segments.

OBJECTIVE There is a lack of evidence of how back muscle strength changes after lumbar fusion surgery and how exercise influences these changes. The aim of this study was to evaluate changes in back muscle strength after posterior lumbar interbody fusion (PLIF) and to measure the effects of a postoperative exercise program on muscle strength and physical and mental health outcomes. METHODS This prospective study enrolled 59 women (mean age 58 years) who underwent PLIF at 1 or 2 spinal levels. To assess the effects of a supervised lumbar stabilization exercise (LSE), the authors allocated the patients to an LSE (n = 26) or a control (n = 33) group. The patients in the LSE group performed the LSEs between 3 and 6 months postoperatively. Back extensor strength, visual analog scale (VAS) scores in back pain, and physical component summary (PCS) and mental component summary (MCS) scores on the 36-Item Short Form Health Survey were determined for the both groups. RESULTS Mean strength of the back muscles tended to slightly decrease by 7.5% from preoperatively to 3 months after PLIF (p = 0.145), but it significantly increased thereafter and was sustained until the last follow-up (38.1%, p < 0.001). The mean back muscle strength was similar in the LSE and control groups preoperatively, but it increased significantly more in the LSE group (64.2%) than in the control group (21.7%) at the last follow-up 12 months after PLIF (p = 0.012). At the last follow-up, decreases in back pain VAS scores were more significant among LSE group patients, who had a pain reduction on average of 58.2%, than among control group patients (reduction of 26.1%) (p = 0.013). The patients in the LSE group also had greater improvement in both PCS (39.9% improvement) and MCS (20.7% improvement) scores than the patients in the control group (improvement of 18.0% and 1.1%, p = 0.042 and p = 0.035, respectively). CONCLUSIONS After PLIF, strength in back muscles decreased until 3 months postoperatively but significantly increased after that period. The patients who regularly underwent postoperative LSE had significantly improved back strength, less pain, and less functional disability at 12 months postoperatively.

The failure modes, time to development, and clinical relevance are known to differ between proximal junctional kyphosis (PJK) and proximal junctional failure (PJF). However, there are no reports that study the risk factors of PJK and PJF separately. The aim of this study was to investigate the risk factors for PJK and PJF separately. A retrospective study of 160 consecutive patients who underwent a long instrumented fusion to the sacrum for adult spinal deformity with a minimum follow-up of 2 years was conducted. A separate survivorship analysis of PJK and PJF was performed using the Cox proportional hazards model for the 3 categorical parameters of surgical, radiographic, and patient factors. PJK developed in 27 patients (16.9%) and PJF in 29 patients (18.1%). The median survival time was 17.0 months for PJK and 3.0 months for PJF. Multivariate analyses revealed that a high body mass index was an independent risk factor for PJK (hazard ratio [HR] = 1.179), whereas the significant risk factors for PJF were older age, the presence of osteoporosis, the uppermost instrumented vertebra level at T11-L1, and a greater preoperative sagittal vertical axis (HR = 1.082, 6.465, 5.236, and 1.017, respectively). A large correction of sagittal deformity was shown to be a risk factor for PJF on univariate analyses, but not on multivariate analyses. PJK developed at a median of 17 months and PJF at a median of 3 months. A high body mass index was an independent risk factor for PJK, whereas older age, osteoporosis, uppermost instrumented vertebra level at the thoracolumbar junction, and greater preoperative sagittal vertical axis were risk factors for PJF. ASD, adult spinal deformityLL, lumbar lordosisPI, pelvic incidencePJF, proximal junctional failurePJA, proximal junctional anglePJK, proximal junctional kyphosisPT, pelvic tiltSVA, sagittal vertical axisTK, thoracic kyphosisUIV, uppermost instrumented vertebra.

This study aimed to assess the efficacy of allograft in 2-level anterior cervical discectomy and fusion (ACDF) with plate fixation by comparing its clinical and radiological outcomes to those of autograft. Thirty five patients with femur cortical allografts and 32 patients with tricortical iliac autografts were evaluated. All surgeries were performed by a single senior surgeon. During routine follow-up (at 3 months, 6 months, and annually after the surgery), the fusion rate, subsidence rate, and fused segmental lordosis angle were assessed by radiologic evaluation. Clinical outcomes were assessed using the visual analog scale (VAS), neck disability index (NDI) scores, and Odom criteria. This study was conducted using the results of the 2-year postoperative follow-up. Among 67 patients, 62 (92.5%) showed successful bone fusion at 2 years postoperatively: 91.4% (32/35) in the allograft group and 93.8% (30/32) in the autograft group. The fusion rate was 37.1% (13/35) in the allograft group and 68.8% (23/32) in the autograft group at 6 months and 68.5% (24/35) in the allograft group and 93.8% (30/32) in autograft group at 1 year. Eight (72.7%) of the remaining 11 patients with allograft achieved bone fusion without any intervention at the 2-year follow-up. The fusion was achieved faster in the autograft group than in the allograft group (P = .003). There was no significant difference in the subsidence rate or change in the fused segmental lordosis angle between the 2 groups; there was also no significant difference in clinical outcomes (NDI scores, VAS scores, Odom criteria) between the 2 groups. However, the intraoperative blood loss was significantly greater in the autograft group, and the operative time was also significantly longer in the autograft group (P < .001). In the autograft group, 6 patients (18.8%) had minor complications at the donor site. In 2-level ACDF with plate fixation, the radiologic and clinical outcomes of autograft and allograft were similar at 2-year follow-up, although fusion was observed earlier in the autograft group.

STUDY DESIGN A retrospective analysis. OBJECTIVE To evaluate the long-term clinical and radiographic outcomes and to investigate who achieved the successful outcomes after lumbar total disc replacement (TDR) using ProDisc II. SUMMARY OF BACKGROUND DATA There are few evidences regarding the long-term efficacy and safety of TDR. Furthermore, it has not been addressed which patients achieved good outcomes in long-term follow-up. METHODS Data at 1-, 2-, 5-, 7-year, and last follow-up were used for the analysis. According to the presence of combined pathologies, patients were categorized as groups A and B (presumed good and bad candidates, respectively). Clinical outcomes were evaluated using visual analog scale, Oswestry Disability Index, clinical success rate, and subjective satisfaction (four-point scale). Radiographic results included segmental range of motion. RESULTS Total study population was 54 patients with 69 segments with the average follow-up duration of 120.0 months. There were 39 patients in group A and 15 in group B. Visual analog scale and Oswestry Disability Index scores were improved significantly at all follow-up periods, reaching maximal improvement at the postoperative 2 years. Clinical success rate and satisfaction rate were significantly higher in group A (76.9% and 87.2%, respectively) than those in group B (40.0% and 60.0%, respectively) at the last follow-up. Five patients (9.3%) required revision fusion surgeries, and they are all in group B. The final segmental range of motion was well maintained in monosegmental TDR, but not in bisegmental TDR. CONCLUSION Lumbar TDR using Prodisc II showed the successful outcomes with the clinical success rate of 76.9% and the satisfaction rate of 87.2% when the patients were presumed as good candidate for TDR. However, the patients who had the combined pathologies showed suboptimal results with high risk of the revision surgeries. Thus, the strict patient selection process is mandatory for the successful outcomes. LEVEL OF EVIDENCE 4.

Objective We investigated the effect and regulatory mechanism of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC) isolated from Cleistocalyx operculatus on metabolic parameters in myotubes, adipocytes and an obese mouse model. Materials and methods Myotubes and adipocytes were incubated with or without DMC. Glucose uptake, fatty acid oxidation, AMPK activation and adipocytes differentiation were investigated. To examine in vivo effect of DMC, 30 mg/kg/day DMC was administered by oral gavage for 2 weeks in high fat fed C57BL/6 male mice and intra-peritoneal glucose tolerance test was performed. In order to examine whether DMC directly activates AMPK, we performed cell free AMPK assay and surface plasmon resonance spectroscopy analysis. Result DMC increases glucose uptake and fatty acid oxidation (FAO) in myotubes. Also, DMC inhibits adipocyte differentiation in 3T3-L1 cells. Interestingly, DMC stimulates phosphorylation of AMP-dependent protein kinase (AMPK) alpha subunit (T172) by directly binding to AMPK, which results in the activation of AMPK. Furthermore, DMC binds AMPK with a higher affinity than AMP. When AMPK was knocked down, the stimulatory effect of DMC on FAO and its inhibitory effect on adipogenesis were abolished. These results suggest that the effects of DMC were primarily mediated by AMPK activation. In addition, treating mice fed a high fat diet with DMC improved glucose tolerance and significantly increased FAO of the muscles. Conclusion DMC, as a novel AMPK activator, shows anti-diabetic effects in cell culture systems, such as myotubes and adipocytes, and in a diet-induced obese mouse model.

OBJECT The aim of this study was to examine the results of microbiological cultures from local bone autografts used in posterior lumbar interbody fusion (PLIF) and to identify their association with postoperative spinal infection. METHODS The authors retrospectively evaluated cases involving 328 patients who had no previous spinal surgeries and underwent PLIF for degenerative diseases with a minimum 1-year follow-up. Local bone was obtained during laminectomy, and microbiological culture was performed immediately prior to bone grafting. The associations between culture results from local bone autografts and postoperative spinal infections were evaluated. RESULTS The contamination rate of local bone was 4.3% (14 of 328 cases). Coagulase-negative Staphylococcus (29%) was the most common contaminant isolated, followed by Streptococcus species and methicillin-sensitive Staphylococcus aureus. Of 14 patients with positive culture results, 5 (35.7%) had postoperative spinal infections and were treated with intravenous antibiotics for a minimum of 4 weeks. One of these 5 patients also underwent reoperation for debridement during this 4-week period. Regardless of the microbiological culture results, the infection rate after PLIF with local bone autograft was 2.4% (8 of 328 cases), with 5 (62.5%) of 8 patients showing positive results on autograft culture. CONCLUSIONS The incidence of contamination of local bone autograft during PLIF was considerable, and positive culture results were significantly associated with postoperative spinal infection. Special attention focused on the preparation of local bone for autograft and its microbiological culture will be helpful for the control of postoperative spinal infection.

Background: Expression of hepatic cholesterol 7α-hydroxylase (CYP7A1) is negatively regulated by orphan nuclear receptor small heterodimer partner (SHP). In this study, we aimed to find whether thyroid hormone regulates SHP expression by modulating the transcriptional activities of liver receptor homolog-1 (LRH-1). Methods: We injected thyroid hormone (triiodothyronine, T3) to C57BL/6J wild type. RNA was isolated from mouse liver and used for microarray analysis and quantitative real-time polymerase chain reaction (PCR). Human hepatoma cell and primary hepatocytes from mouse liver were used to confirm the effect of T3 in vitro. Promoter assay and electrophoretic mobility-shift assay (EMSA) were also performed using human hepatoma cell line. Results: Initial microarray results indicated that SHP expression is markedly decreased in livers of T3 treated mice. We confirmed that T3 repressed SHP expression in the liver of mice as well as in mouse primary hepatocytes and human hepatoma cells by real-time PCR analysis. LRH-1 increased the promoter activity of SHP; however, this increased activity was markedly decreased after thyroid hormone receptor β/retinoid X receptor α/T3 administration. EMSA revealed that T3 inhibits specific LRH1 DNA binding. Conclusion: We found that thyroid hormone regulates the expression of SHP mRNA through interference with the transcription factor, LRH-1.

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family and plays an important role in adipocyte differentiation, glucose homeostasis, and insulin sensitivity. Thiazolidinediones (TZDs), synthetic ligands of PPARγ, have been used for the treatment of diabetes mellitus for two decades. TZDs were expected to be amazing drugs not only for type 2 diabetes but also for metabolic syndrome and atherosclerotic vascular disease because they can reduce both insulin resistance and inflammation in experimental studies. However, serious unwanted effects pushed TZDs back to an optional second-tier drug for type 2 diabetes. Nevertheless, PPARγ is still one of the most important targets for the treatment of insulin resistance and diabetes mellitus, and novel strategies to modulate PPARγ activity to enhance its beneficial effects and reduce unwanted adverse effects are anticipated. Recent studies showed that post-translational modification (PTM) of PPARγ regulates PPARγ activity or stability and may be a novel way to optimize PPARγ activity with reduced adverse effects. In this review, we will focus on recent advances in PTM of PPARγ and the mechanisms regulating PPARγ function as well as in the development of PPARγ modulators or agonists.

Transplantation of stem cell-derived insulin producing cells (IPCs) has been proposed as an alternative to islet transplantation for the treatment of diabetes mellitus. However, current IPC differentiation protocols are focused on generating functional cells from the pluripotent stem cells and tend to rely on multistep, long-term exposure to various exogenous factors. In this study, we addressed the observation that under stress, pancreatic β-cells release essential components that direct the differentiation of the bone marrow nucleated cells (BMNCs) into IPCs. Without any supplementation with known differentiation-inducing factors, IPCs can be generated from BMNCs by in vitro priming for 6 days with conditioned media (CM) from the β-cells. In vitro primed BMNCs expressed the β-cell-specific transcription factors, as well as insulin, and improved hyperglycemia and glucose intolerance after transplantation into the streptozotocin-induced diabetic mice. Furthermore, we have found that components of the CM which trigger the differentiation were enclosed by or integrated into micro particles (MPs), rather than being secreted as soluble factors. Identification of these differentiation-directing factors might enable us to develop novel technologies required for the production of clinically applicable IPCs.

Study design Prospective observational study. Summary of background data Tokuhashi score (TS) system was developed in 1990s and widely used for the prediction of survival in patients with spinal metastases. There were no reports about how accurately TS system predicts survival in the current practice. Objective To validate the accuracy of TS system using a recent series of the patients with metastatic spinal tumors, focusing on the primary tumor type. Methods Between January 2007 and March 2013, 145 patients who underwent surgical treatment for metastatic spinal tumors were followed up prospectively. The subjects were divided into 3 prognosis group according to TS system. The actual and predicted survivals were compared with calculate the accuracy rate. Results The mean age was 60.0 years. There were 96 male and 49 female patients. There are 106 patients in poor prognosis group (A), 30 in intermediate prognosis group (B), and 9 in good prognosis group (C). The overall accuracy to predict the survival time was 57.2%. The accuracy rate was especially poor in breast cancer (44.4%) and rectal cancer (42.9%). Forty-three patients (40.6%) in group A and 9 patients (30.0%) in group B survived longer than predicted. The mean survival time was 8.5, 18.1, and 41.6 months for group A, B, and C, respectively. Patients with rectal cancer showed poor survival profile than expected. Conclusions The accuracy of TS system was suboptimal (57.2%). The predicted survival time needs to be increased in response to the recent population's data. The score given to the rectal cancer subgroup should be lowered.

Mitochondrial dysfunction is associated with insulin resistance and diabetes. We previously showed that retinoid X receptor α (RXRα) played an important role in transcriptional regulation of oxidative phosphorylation (OXPHOS) genes in cells with mitochondrial dysfunction caused by mitochondrial DNA mutation. In this study, we investigated whether mitochondrial dysfunction induced by incubation with OXPHOS inhibitors affects insulin receptor substrate 1 (IRS1) mRNA and protein levels and whether RXRα activation or overexpression can restore IRS1 expression. Both IRS1 and RXRα protein levels were significantly reduced when C2C12 myotubes were treated with the OXPHOS complex inhibitors, rotenone and antimycin A. The addition of RXRα agonists, 9-cis retinoic acid (9cRA) and LG1506, increased IRS1 transcription and protein levels and restored mitochondrial function, which ultimately improved insulin signaling. RXRα overexpression also increased IRS1 transcription and mitochondrial function. Because RXRα overexpression, knock-down, or activation by LG1506 regulated IRS1 transcription mostly independently of mitochondrial function, it is likely that RXRα directly regulates IRS1 transcription. Consistent with the hypothesis, we showed that RXRα bound to the IRS1 promoter as a heterodimer with peroxisome proliferator-activated receptor δ (PPARδ). These results suggest that RXRα overexpression or activation alleviates insulin resistance by increasing IRS1 expression.

Mutation in HNF1B, the hepatocyte nuclear factor-1β (HNF-1β) gene, results in maturity-onset diabetes of the young (MODY) 5, which is characterized by gradual impairment of insulin secretion. However, the functional role of HNF-1β in insulin secretion and glucose metabolism is not fully understood. We identified a family with early-onset diabetes that fulfilled the criteria of MODY. Sanger sequencing revealed that a heterozygous P159L (CCT to CTT in codon 159 in the DNA-binding domain) mutation in HNF1B was segregated according to the affected status. To investigate the functional consequences of this HNF1B mutation, we generated a P159L HNF1B construct. The wild-type and mutant HNF1B constructs were transfected into COS-7 cells in the presence of the promoter sequence of human glucose transporter type 2 (GLUT2). The luciferase reporter assay revealed that P159L HNF1B had decreased transcriptional activity compared to wild-type (p < 0.05). Electrophoretic mobility shift assay showed reduced DNA binding activity of P159L HNF1B. In the MIN6 pancreatic β-cell line, overexpression of the P159L mutant was significantly associated with decreased mRNA levels of GLUT2 compared to wild-type (p < 0.05). However, INS expression was not different between the wild-type and mutant HNF1B constructs. These findings suggests that the impaired insulin secretion in this family with the P159L HNF1B mutation may be related to altered GLUT2 expression in β-cells rather than decreased insulin gene expression. In conclusion, we have identified a Korean family with an HNF1B mutation and characterized its effect on the pathogenesis of diabetes.

Background A prolonged-release formulation of oxycodone/naloxone has been shown to be effective in European populations for the management of chronic moderate to severe pain. However, no clinical data exist for its use in Korean patients. The objective of this study was to assess efficacy and safety of prolonged-release oxycodone/naloxone in Korean patients for management of chronic moderate-to-severe pain. Methods In this multicenter, single-arm, open-label, phase IV study, Korean adults with moderate-to-severe spinal disorder-related pain that was not satisfactorily controlled with weak opioids and nonsteroidal anti-inflammatory drugs received prolonged-release oral oxycodone/naloxone at a starting dose of 10/5 mg/day (maximum 80/40 mg/day) for 8 weeks. Changes in pain intensity and quality of life (QoL) were measured using a numeric rating scale (NRS, 0-10) and the Korean-language EuroQol-five dimensions questionnaire, respectively. Results Among 209 patients assessed for efficacy, the mean NRS pain score was reduced by 25.9% between baseline and week 8 of treatment (p < 0.0001). There was also a significant improvement in QoL from baseline to week 8 (p < 0.0001). The incidence of adverse drug reactions was 27.7%, the most common being nausea, constipation, and dizziness; 77.9% of these adverse drug reactions had resolved or were resolving at the end of the study. Conclusions Prolonged-release oxycodone/naloxone provided significant and clinically relevant reductions in pain intensity and improved QoL in Korean patients with chronic spinal disorders. (ClinicalTrials.gov identifier: NCT01811238).

Objective Autophagy is suppressed in skeletal muscle and the liver with insulin resistance induced by a high-fat diet. Autophagy is essential for maintaining mitochondrial function, and dysfunctional mitochondria are associated with insulin resistance. As carnitine treatment is well known to improve insulin resistance by promoting mitochondrial function, we investigated if carnitine affects autophagy in the skeletal muscle of a high-fat diet-induced rodent model of obesity. Results After 6 weeks on a high-fat diet (48 kcal% fat), mice developed glucose intolerance, and the gastrocnemius muscle showed a decrease in insulin signaling and mitochondrial function, which was reversed after carnitine (100 mg/kg/day) treatment by oral gavage for 2 weeks. Swollen mitochondria with destroyed cristae were observed in the skeletal muscle of high-fat diet-fed mice but were not there after carnitine treatment. High-fat diet decreased LC3B-II, a marker of autophagosome formation, and increased sequestosome 1 (SQSTM1), expression of which was reversed after carnitine treatment. In C2C12 myotubes, prolonged treatment with palmitate suppressed autophagy, which was relieved by carnitine treatment. However, the induction of autophagy by carnitine in C2C12 myotubes was not observed after knock-down of peroxisome proliferator-activated receptor γ (PPARγ), which is known to regulate autophagy. Conclusion We conclude that the removal of dysfunctional mitochondria by induction of autophagy through PPARγ may be a novel mechanism by which carnitine improves insulin resistance and mitochondrial dysfunction in obesity.

Background The long-term results of heterotopic ossification (HO) following lumbar total disc replacement (TDR) and the corresponding clinical and radiological outcomes are unclear. Purpose This study aimed to report the long-term results of HO following lumbar TDR and to analyze the clinical and radiological outcomes. Study Design/Setting A retrospective case review was performed for the consecutive patients who underwent lumbar TDR. Patient Sample The study included 48 patients (60 segments) who underwent lumbar TDR. Outcome Measures The time and location of HO development, segmental range of motion (ROM) of index level, the visual analog scale (VAS), and the Oswestry Disability Index (ODI) were analyzed. Methods Forty-eight patients (60 segments) were divided into HO and non-HO groups, and radiographs were used to measure the time and location of HO development. We compared segmental ROM between two groups using flexion-extension radiographs. Clinical outcomes were assessed using the VAS and the ODI. Furthermore, the segmental ROM, VAS, and ODI scores of each HO class were compared with those of the non-HO group. Results The mean follow-up duration was 104.4 months. Heterotopic ossification was detected in 30 of 60 segments following lumbar TDR, and HO progression was noted in six segments. The mean segmental ROM was significantly lower in the HO group than in the non-HO group. The mean VAS and ODI scores were not significantly different between the two groups. Segmental ROM was significantly lower in the class III and IV of the HO group than in the non-HO group. The VAS and ODI scores were not significantly different among the different classes. Conclusions We found that the incidence of HO is the highest within 12 months after lumbar TDR, and the incidence might increase 5 years after surgery. Furthermore, HO progressed over time. Segmental ROM was decreased in the HO groups; however, the limitation in motion might have little clinical influence.

This study evaluated the characteristics of a newly developed 3-dimensional printed mesh structure titanium spacer and its efficacy for posterior lumbar interbody fusion. Posterior lumbar interbody fusion with this spacer was performed at 53 segments (40 patients; mean age, 64 years; range, 51–73 years). Data were collected prospectively. Radiographic characteristics were analyzed with changes in interbody height, instability of the segments, formation of bone bridges around the implants, and pseudarthrosis, as determined by dynamic radiographs and postoperative computed tomography scans. Clinical outcomes were evaluated with the visual analog scale for the low back and extremities, the Oswestry Disability Index, and the 36-Item Short Form Survey. Radiographically, preoperative anterior and posterior interbody height was significantly increased immediately postoperatively ( P P Orthopedics. 2017; 40(5):e880–e885.]

Study design Retrospective analysis. Purposes To introduce the mini-open lateral approach for the anterior lumbar interbody fusion (ALIF), and to investigate the advantages, technical pitfalls and complications by providing basic knowledge on extreme lateral interbody fusion (XLIF) or direct lumbar interbody fusion (DLIF). Overview of literature Recently, minimally invasive lateral approach for the lumbar spine is revived and receiving popularity under the name of XLIF or DLIF by modification of mini-open method when using the sequential tubular dilator and special expandable retractor system. Methods Seventy-four patients who underwent surgery by the mini-open lateral approach from September 2000 to April 2008 with various disease entities were included. Blood losses, operation times, incision sizes, postoperative time to mobilization, length of hospital stays, technical problems and complications were all analyzed. Results The blood losses and operation times of patients who underwent simple ALIF were 61.2 mL and 86 minutes for one level, 107 mL and 106 minutes for two levels, 250 mL and 142.8 minutes for three levels, and 400 mL and 190 minutes for four levels of fusion. The incision sizes were on average 4.5 cm for one level, 6.3 cm for two levels, 8.5 cm for three levels and 10.0 cm for four levels of fusion. The complications were retroperitoneal hematoma (2 cases), pneumonia (1 case) and transient lumbosacral plexus palsy (3 cases). Conclusions Trials of mini-open lateral approach would be helpful before the trial of XLIF or DLIF. However, special attention is required for complications such as transient lumbosacral plexus palsy.

Early graft loss in islet transplantation means that a large amount of donor islets is required. Endothelial cells and endothelial colony-forming cells (ECFCs) have been reported to improve instant blood-mediated inflammatory reaction (IBMIR) in vitro. In this study, we examined if ECFC-coated porcine islets would prevent early graft loss in vivo. Human ECFCs were prepared from cord blood and cocultured with islets to make composite grafts. Diabetic nude mice underwent intraportal transplantation. Blood glucose levels were monitored, and morphological examination of the grafts along with analysis of the components of IBMIR and inflammatory reaction were performed with the liver tissues. The ECFC-coated islets significantly decreased blood glucose levels immediately after transplantation compared to the uncoated islets. Composite ECFC islet grafts were observed in the liver sections, associated with a more insulin+ area compared to that of the uncoated group within 48 h after transplantation. Deposition of CD41a, C5b-9, and CD11b+ cells was also decreased in the ECFC-coated group. Expression of porcine HMGB1 and mouse TNF-α was increased in the transplantated groups compared to the sham operation group, with a trend of a decreasing trend across the uncoated group, the ECFC-coated group, and the sham group. We demonstrated that the composite ECFC porcine islets transplanted into the portal vein of nude mice improved early graft loss and IBMIR in vivo.

Background Chronic exposure to elevated levels of free fatty acids contributes to pancreatic β-cell dysfunction. Although it is well known that metformin induces cellular energy depletion and a concomitant activation of AMP-activated protein kinase (AMPK) through inhibition of the respiratory chain, previous studies have shown inconsistent results with regard to the action of metformin on pancreatic β-cells. We therefore examined the effects of metformin on pancreatic β-cells under lipotoxic stress. Methods NIT-1 cells and mouse islets were exposed to palmitate and treated with 0.05 and 0.5 mM metformin. Cell viability, glucose-stimulated insulin secretion, cellular adenosine triphosphate, reactive oxygen species (ROS) levels and Rho kinase (ROCK) activities were measured. The phosphorylation of AMPK was evaluated by Western blot analysis and mRNA levels of endoplasmic reticulum (ER) stress markers and NADPH oxidase (NOX) were measured by real-time quantitative polymerase chain reaction analysis. Results We found that metformin has protective effects on palmitate-induced β-cell dysfunction. Metformin at a concentration of 0.05 mM inhibits NOX and suppresses the palmitate-induced elevation of ER stress markers and ROS levels in a AMPK-independent manner, whereas 0.5 mM metformin inhibits ROCK activity and activates AMPK. Conclusion This study suggests that the action of metformin on β-cell lipotoxicity was implemented by different molecular pathways depending on its concentration. Metformin at a usual therapeutic dose is supposed to alleviate lipotoxic β-cell dysfunction through inhibition of oxidative stress and ER stress.

This study aimed at deriving a lordosis predictive equation using the pelvic incidence and to establish a simple prediction method of lumbar lordosis for planning lumbar corrective surgery in Asians.Eighty-six asymptomatic volunteers were enrolled in the study. The maximal lumbar lordosis (MLL), lower lumbar lordosis (LLL), pelvic incidence (PI), and sacral slope (SS) were measured. The correlations between the parameters were analyzed using Pearson correlation analysis. Predictive equations of lumbar lordosis through simple regression analysis of the parameters and simple predictive values of lumbar lordosis using PI were derived.The PI strongly correlated with the SS (r = 0.78), and a strong correlation was found between the SS and LLL (r = 0.89), and between the SS and MLL (r = 0.83). Based on these correlations, the predictive equations of lumbar lordosis were found (SS = 0.80 + 0.74 PI (r = 0.78, R (2) = 0.61), LLL = 5.20 + 0.87 SS (r = 0.89, R (2) = 0.80), MLL = 17.41 + 0.96 SS (r = 0.83, R (2) = 0.68). When PI was between 30° to 35°, 40° to 50° and 55° to 60°, the equations predicted that MLL would be PI + 10°, PI + 5° and PI, and LLL would be PI - 5°, PI - 10° and PI - 15°, respectively.This simple calculation method can provide a more appropriate and simpler prediction of lumbar lordosis for Asian populations. The prediction of lumbar lordosis should be used as a reference for surgeons planning to restore the lumbar lordosis in lumbar corrective surgery.

The objective of this study is to investigate whether F-box only protein 9 (FBXO9), an ubiquitination E3 ligase, has a functional role in adipocyte differentiation. Expression of FBXO9 was compared between obese mice and control lean mice using real-time PCR. Also, expression pattern of FBXO9 was monitored during 3T3-L1 adipocyte differentiation. FBXO9 was highly expressed in obese mice, and increased in the early stages of adipogenesis. To verify a functional role of FBXO9 in adipogenesis, FBXO9 was knocked down using transfection of siRNAs against FBXO9 into 3T3-L1 cells during the induction of adipogenesis. Knockdown of FBXO9 in early stage of adipogenesis almost completely inhibited adipogenesis, and CCAAT/enhancer binding protein β (C/EBPβ) levels were significantly reduced. However, the cells stably expressing C/EBPβ were fairly differentiated into adipocytes in the FBXO9 knockdown condition. These results suggest that FBXO9 is required for adipocyte differentiation, and C/EBPβ plays a role in the effect of FBXO9 on adipogenesis.

Many studies regarding spinal sagittal alignment were focused mainly on above-hip structures, not considering the knee joint. Knee-spine syndrome was proposed earlier, but the mechanism of this phenomenon has not been revealed. The aim of the study was to demonstrate how spinopelvic alignment and sagittal balance change in response to simulated knee flexion in normal non-diseased population.Thirty young male were enrolled in the study cohort. Two motion-controlled knee braces were used to simulate knee flexion of 0°, 15°, and 30° settings. Whole spine and lower extremity lateral radiographs were taken at each knee setting of 0°, 15°, and 30° flexion. Spinal and pelvic parameters were measured, including two angular parameters, femoropelvic angle (FPA) and femoral tilt angle (FTA).The following equation can be made; PT (pelvic tilt) = FPA + FTA. The mean values of FPA and lumbar lordosis decreased significantly at 15° and 30° knee settings compared to the parameters at the 0° knee setting, while the mean values of pelvic tilt and sacral slope rarely changed. Results also showed FTA was not correlated with PT, but strongly correlated with FPA (R = -0.83, p 0.01).The knee flexion resulted in decrease of lumbar lordosis without a significant change of pelvic posture in non-diseased population group.

Thyroid-stimulating hormone (TSH) receptor is expressed in extrathyroidal tissues such as hepatocytes, adipocytes, and skeletal muscle, which suggests a possible novel role of TSH in various metabolic processes in extrathyroidal tissues independent of thyroid hormones. We investigated whether TSH has any effects on glucose tolerance and insulin sensitivity in the skeletal muscle using diet-induced obesity (DIO) mouse models and rodent skeletal muscle cells. TSH improved glucose tolerance in DIO mice and this was associated with an improvement of skeletal muscle insulin sensitivity resulting from the increased expression of insulin receptor substrate (IRS)-1 protein and mRNA therein. TSH significantly increased both basal and insulin-stimulated glucose transport in rat L6 myotubes and increased the expression of IRS-1 protein and mRNA in these cells as well. TSH also stimulated Irs1 promoter activation; this stimulation was abolished by protein kinase A (PKA) inhibition using H89 or by mutation of the cAMP-response element site located at -1155 to -875 bp of the Irs1 promoter region, supporting a novel role of TSH activated-cAMP/PKA/CREB signaling in the regulation of Irs1 expression. In conclusion, TSH improves insulin sensitivity in skeletal muscle by increasing Irs1 gene expression. This regulatory effect is mediated by a PKA-CREB-dependent pathway.