Volar Locking Plate or External Fixation With Optional Addition of K-Wires for Dorsally Displaced Distal Radius Fractures: A Randomized Controlled Study.

OBJECTIVES: To compare the outcomes after open reduction and fixation with a volar locking plate or external fixation with optional addition of K-wires in patients aged 50-74 years. DESIGN: Randomized controlled trial according to the Consolidated Standards of Reporting Trials criteria. SETTING: Single-center second-level trauma center in the capital of Sweden. PATIENTS: One hundred forty patients presenting with a dorsally displaced distal radius fracture were randomized to fixation with a volar locking plate (n = 70) or external fixation with optional addition of K-wires (n = 70). MAIN OUTCOME MEASUREMENT: The primary outcome was the Disability of the Arm, Shoulder, and Hand (DASH) at 12 months. EuroQol-5D, radiography, and recordings of complications were performed at 2 and 6 weeks and at 3 and 12 months. Patients were investigated for DASH, the Patient-Rated Wrist Evaluation, range of motion, and grip strength at 3 and 12 months. RESULTS: There were no significant differences between the groups in terms of DASH and Patient-Rated Wrist Evaluation at 3 months and 1 year (P > 0.05). EuroQol-5D was lower during the first 6 weeks in the external fixation group (P < 0.05), but the difference was no longer significant at 3 months. Radiographic restoration of alignment was better for the volar locking plate group in terms of volar tilt and radial length. The range of motion was equal in both groups except for radial deviation, which was better in the volar locking plate group at 1-year follow-up. The total rate of complications was equal for both groups. CONCLUSIONS: Volar plating and external fixation with optional addition of K-wires are 2 equally suitable treatment options for dorsally displaced distal radius fractures after low-energy trauma in a population aged 50-74 years. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

The impact of smoking on complications after operatively treated ankle fractures--a follow-up study of 906 patients.

OBJECTIVES: This study on patients with operatively treated ankle fractures aimed to investigate the impact of smoking on postoperative complications and especially deep wound infections. DESIGN: Cohort study with prospective follow-up. SETTING: University-associated teaching hospital with advanced trauma care. PATIENTS: A consecutive series of patients (n = 906) operatively treated for an acute ankle fracture during a 3-year period was identified. For the analysis, the patients were categorized as nonsmokers (n = 721) and smokers (n = 185). Data were collected from the department database and completed with a review of the patients' medical charts. MAIN OUTCOME MEASURES: Postoperative complications. RESULTS: Follow-up data at 6 weeks were available for 98.2% of the patients. Postoperative complications of any kind (30.1% versus 20.3%, P = 0.005) as well as deep wound infections (4.9% versus 0.8%, P < 0.001) were more common among smokers than nonsmokers. Multivariable analyses showed that smokers had six times higher odds of developing a deep infection compared with nonsmokers. A more complicated fracture, associated diabetes mellitus, and unsatisfactory operative fracture reduction also enhanced the risk of postoperative complications. CONCLUSIONS: We conclude that cigarette smoking increases the risk of postoperative complications in patients operatively treated for an ankle fracture. Smoking is a considerable risk factor. Therefore, physicians, nurses, and other healthcare professionals should strive to support patients to stop smoking while still under acute treatment.

Expression of the transcription factor 7-like 2 gene (TCF7L2) in human adipocytes is down regulated by insulin.

Variants in the TCF7L2 gene (transcription factor 7-like 2) have shown strong association with type 2 diabetes with two defined risk haplotypes, HapA and HapB(T2D). TCF7L2 may play a role in both glucose homeostasis and adipogenesis. Our aim was to characterize the TCF7L2 mRNA expression and regulation in human adipose tissue. We quantified TCF7L2 mRNA levels in cultured human adipocytes and in biopsies from visceral (VAT) and subcutaneous (SAT) adipose tissue from 38 obese non-diabetic subjects, using real-time PCR. The influence of haplotype and clinical traits on TCF7L2 mRNA levels were investigated. In vitro, insulin decreased TCF7L2 mRNA expression. This effect was attenuated in cells incubated with the free fatty acids palmitate or oleate. In vivo, we found significantly higher expression in SAT from more insulin resistant subjects. No correlations between TCF7L2 mRNA expression and obesity measures were observed. TCF7L2 expression was higher in VAT than in SAT and when stratifying for haplotype, this difference was seen in HapA carriers but not in non-HapA carriers. In conclusion, TCF7L2 mRNA levels in adipocytes are decreased by insulin and seem to increase in insulin resistant subjects and in HapA carriers.

Human SGBS cells - a unique tool for studies of human fat cell biology.

The human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cell strain provides a unique and useful tool for studies of human adipocyte biology. The cells originate from an adipose tissue specimen of a patient with SGBS. They are neither transformed nor immortalized, and provide an almost unlimited source due to their ability to proliferate for up to 50 generations with retained capacity for adipogenic differentiation. So far, the cells have been used for a number of studies on adipose differentiation, adipocyte glucose uptake, lipolysis, apoptosis, regulation of expression of adipokines, and protein translocation. The cells are efficiently differentiated in the presence of PPARgammaagonists and in the absence of serum and albumin. SGBS adipocytes respond to insulin stimulation by increasing glucose uptake several-fold (EC50 approximately 100 pmol/l), and by very effectively inhibiting (IC50 approximately 10 pmol/l) catecholamine-stimulated lipolysis.

TXNIP regulates peripheral glucose metabolism in humans.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. METHODS AND FINDINGS: We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. CONCLUSIONS: TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.

Adipose triglyceride lipase and hormone-sensitive lipase are the major enzymes in adipose tissue triacylglycerol catabolism.

The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol lipases. In this study, we demonstrate that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown in in vitro assays and in organ cultures of murine white adipose tissue (WAT). To differentiate between ATGL- and HSL-specific activities in cytosolic preparations of WAT and to determine the relative contribution of these TG hydrolases to the lipolytic catabolism of fat, mutant mouse models lacking ATGL or HSL and a mono-specific, small molecule inhibitor for HSL (76-0079) were used. We show that 76-0079 had no effect on TG catabolism in HSL-deficient WAT but, in contrast, essentially abolished free fatty acid mobilization in ATGL-deficient fat. CGI-58, a recently identified coactivator of ATGL, stimulates TG hydrolase activity in wild-type and HSL-deficient WAT but not in ATGL-deficient WAT, suggesting that ATGL is the sole target for CGI-58-mediated activation of adipose lipolysis. Together, ATGL and HSL are responsible for more than 95% of the TG hydrolase activity present in murine WAT. Additional known or unknown lipases appear to play only a quantitatively minor role in fat cell lipolysis.

Characterization of the transcriptional and functional effects of fibroblast growth factor-1 on human preadipocyte differentiation.

We recently established that fibroblast growth factor (FGF)-1 promotes adipogenesis of primary human preadipocytes (phPA). In the current report, we have characterized the adipogenic effects of FGF-1 in phPA and also in a human PA strain derived from an individual with Simpson-Golabi-Behmel syndrome (SGBS PA), which exhibit an intrinsic capacity to differentiate with high efficiency. In further studies, we compared these models with the well-characterized murine 3T3-L1 preadipocyte cell line (3T3-L1 PA). FGF-1 up-regulated the adipogenic program in phPA, with increased expression of peroxisome proliferator-activated receptor-gamma in confluent PA prior to induction of differentiation and increased expression of adipocyte markers during differentiation. Moreover, phPA differentiated in the presence of FGF-1 were more insulin responsive and secreted increased levels of adiponectin. FGF-1 treatment of SGBS PA further enhanced differentiation. For the most part, the adipogenic program in phPA paralleled that observed in 3T3-L1 PA; however, we found no evidence of mitotic clonal expansion in the phPA. Finally, we investigated a role for extracellular regulated kinase 1/2 (ERK1/2) in adipogenesis of phPA. FGF-1 induced robust phosphorylation of ERK1/2 in early differentiation and inhibition of ERK1/2 activity significantly reduced phPA differentiation. These data suggest that FGF-1 treated phPA represent a valuable in vitro model for the study of adipogenesis and insulin action and indicate that ERK1/2 activation is necessary for human adipogenesis in the absence of mitotic clonal expansion.

Variation in the adiponutrin gene influences its expression and associates with obesity.

Adiponutrin is one of three recently identified adipocyte lipases. Surprisingly, these proteins also retain transacylase activity, a hitherto unknown pathway of triacylglycerol synthesis in the adipocytes. This may enable them to participate in both anabolic and catabolic processes. The adiponutrin gene (ADPN) is downregulated by fasting and upregulated by refeeding, suggesting a role in lipogenesis. Experiments in human adipocytes confirmed that the gene is upregulated in response to insulin in a glucose-dependent fashion. Obese subjects had increased levels of subcutaneous and visceral abdominal adipose tissue ADPN mRNA. Visceral ADPN mRNA expression was correlated to measures of insulin sensitivity (fasting insulin and homeostasis model assessment). We also studied genetic variation in ADPN and its relation to obesity, lipolysis, and mRNA expression. Two ADPN polymorphisms showed association with obesity. Carriers of the obesity-associated variants showed a lesser increase in the levels of adipose tissue ADPN mRNA and an increased basal lipolysis. Our results suggest that obese subjects that are insulin resistant and/or carriers of the obesity-associated ADPN alleles fail to upregulate the gene and that upregulation of adiponutrin may be an appropriate response to orchestrate energy excess.

Carbazates as potent inhibitors of hormone-sensitive lipase.

The central role of adipose tissue hormone-sensitive lipase in regulating fatty acid metabolism makes it a potential pharmacological target for the prevention of peripheral insulin resistance in obese, prediabetic and diabetic individuals. The synthesis of a new series of carbazates is presented. Modification of the phenolic 4-position in a series of 1,2,3,4-tetrahydroisoquinoline and morpholine derived carbazates, yielded inhibitors of the catalytic activity of this enzyme with nanomolar potency.

Inhibition of death-receptor mediated apoptosis in human adipocytes by the insulin-like growth factor I (IGF-I)/IGF-I receptor autocrine circuit.

Adipose tissue mass is reflected by the volume and the number of adipocytes and is subject to homeostatic regulation involving cell death mechanisms. In this study we have investigated the mechanisms of apoptosis in human preadipocytes and adipocytes that may play a role in the regulation of adipose tissue mass. We found that death receptors (CD95, TNF-related apoptosis-inducing ligand receptors 1 and 2, and TNF receptor 1) are expressed in human fat cells and that apoptosis can be induced by specific ligands. Sensitivity to apoptosis could be stimulated by an inhibitor of biosynthesis. In addition, inhibition of auto-/paracrine action of IGF-I dramatically sensitizes human adipocytes for death ligand-induced apoptosis. Phosphoinositide 3-kinase and, to a weaker extent, p38 MAPK are involved in IGF-I-mediated survival. IGF-I protects human fat cells from apoptosis by maintaining the expression of antiapoptotic proteins, Bcl-x(L) and Fas-associated death domain-like IL-1-converting enzyme inhibitory protein. In conclusion, we identified mechanisms of apoptosis induction in human fat cells. We furthermore demonstrate that human fat cells protect themselves from apoptosis by IGF-I in an auto-/paracrine manner.

IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors.

Insulin and growth hormone (GH) induce mitogenic and metabolic signals in cells, GH either directly or indirectly via IGF-I production. We have studied a spontaneous murine T-cell lymphoma (LB cells) devoid of IGF-1 receptors in which proliferation is maintained by insulin [Int. J. Cancer 50 (1992) 80], and show that GH is more potent than insulin, with both GH and insulin dose-response curves for thymidine incorporation being bell-shaped. Binding showed somatogenic rather than lactogenic GH receptors. Insulin stimulated phosphorylation of the insulin receptor and of a 160-kDa protein, identified as the IRS-4 protein. This phosphorylated IRS-4 associated with PI3-kinase, which was activated along with the downstream p70(S6) kinase, whereas the Ras-MAPK pathway was not. Using selective inhibitors, the PI3-kinase, but not p70(S6) kinase or MEK, was found to be involved in insulin-stimulated DNA synthesis. GH induced tyrosine phosphorylation of IRS-4 and nuclear translocation of STAT5. The LB cells constitute a new model for studying GH and insulin signalling without interference of IGF-1 receptors.

FOXC2 mRNA Expression and a 5' untranslated region polymorphism of the gene are associated with insulin resistance.

The human transcription factor FOXC2 has recently been shown to protect against diet-induced insulin resistance in transgenic mice. We investigated the expression of FOXC2 in fat and muscle and performed a genetic analysis in human subjects. FOXC2 mRNA levels were increased in visceral compared with subcutaneous fat from obese subjects (12 +/- 4-fold; P = 0.0001), and there was a correlation between whole-body insulin sensitivity and FOXC2 mRNA levels in visceral fat (fS-insulin R = -0.64, P = 0.01, and homeostasis model assessment of insulin resistance [HOMA-IR] R = -0.68, P = 0.007) and skeletal muscle (fS-insulin R = -0.57, P = 0.03, and HOMA-IR R = -0.55, P = 0.04). Mutation screening of the FOXC2 gene identified a common polymorphism in the 5' untranslated region (C-512T). The T allele was associated with enhanced insulin sensitivity (HOMA-IR P = 0.007) and lower plasma triglyceride levels in females (P = 0.007). Also, the higher expression of FOXC2 in visceral than in subcutaneous fat was restricted to subjects homozygous for the T allele (P = 0.03 vs. P = 0.7). Our data suggest that increased FOXC2 expression may protect against insulin resistance in human subjects and that genetic variability in the gene may influence features associated with the metabolic syndrome.

Induction of adipocyte differentiation by a thiazolidinedione in cultured, subepidermal, fibroblast-like cells of an infant with congenital generalized lipodystrophy.

Congenital generalized lipodystrophy (CGL) is characterized by the absence of adipose tissue from birth due to a hypothetical differentiation block. The genetic causes of CGL are still not completely understood. Subepidermal, fibroblast-like cells were prepared from the sc tissue of an infant with CGL. Preadipocytes from sc adipose tissue and foreskin fibroblasts from three healthy patients, respectively, were used as controls. Adipose differentiation was induced in cultured cells by exposure to 10 nM insulin, 200 pM T(3), 1 microM cortisol, and 2 microM rosiglitazone. Under these conditions 42% of the subepidermal, fibroblast-like CGL cells developed into mature adipocytes. Adipogenic differentiation was dependent on rosiglitazone. The differentiation rate was comparable in cultures of preadipocytes from control patients maintained under the same conditions (53%, 38%, and 20%). In contrast, foreskin fibroblasts did not differentiate into adipocytes. Morphological changes in CGL cells during differentiation were associated with the expression of fat cell-specific mRNAs (PPARgamma, leptin, and glut-4). In addition, these cells revealed characteristic features of mature adipocytes, such as lipogenesis or leptin secretion. Taken together, we show that adipocyte precursor cells were present in subepidermal tissue of a patient with CGL and were able to differentiate into adipocytes in the presence of a thiazolidinedione. These findings strongly support clinical trials with thiazolidinediones in patients with CGL.