The nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR-␥) is an important target in diabetes therapy, but its direct role, if any, in the restoration of islet function has remained controversial. To identify potential molecular mechanisms of PPAR-␥ in the islet, we treated diabetic or glucose-intolerant mice with the PPAR-␥ agonist pioglitazone or with a control. Treated mice exhibited significantly improved glycemic control, corresponding to increased serum insulin and enhanced glucose-stimulated insulin release and Ca 2؉ responses from isolated islets in vitro. This improved islet function was at least partially attributed to significant upregulation of the islet genes Irs1, SERCA, Ins1/2, and Glut2 in treated animals. The restoration of the Ins1/2 and Glut2 genes corresponded to a two-to threefold increase in the euchromatin marker histone H3 dimethyl-Lys4 at their respective promoters and was coincident with increased nuclear occupancy of the islet methyltransferase Set7/9. Analysis of diabetic islets in vitro suggested that these effects resulting from the presence of the PPAR-␥ agonist may be secondary to improvements in endoplasmic reticulum stress. Consistent with this possibility, incubation of thapsigargin-treated INS-1 ␤ cells with the PPAR-␥ agonist resulted in the reduction of endoplasmic reticulum stress and restoration of Pdx1 protein levels and Set7/9 nuclear occupancy. We conclude that PPAR-␥ agonists exert a direct effect in diabetic islets to reduce endoplasmic reticulum stress and enhance Pdx1 levels, leading to favorable alterations of the islet gene chromatin architecture.Type 2 diabetes mellitus results from a combination of insulin resistance and progressive islet dysfunction (46). In many individuals, ␤-cell failure may precede the clinical diagnosis of diabetes, and landmark studies such as the United Kingdom Prospective Diabetes Study have shown a continued decrement in ␤-cell function despite treatment intervention with sulfonylureas, metformin, and insulin (52). Thiazolidinediones are orally active agents used in the treatment of type 2 diabetes that act as agonists for the nuclear transcription factor peroxisome proliferator-activated receptor ␥ (PPAR-␥) (60). Although thiazolidinediones are classically thought to act as peripheral insulin sensitizers, there is growing evidence from studies of human and animal models that these agents may also act to preserve and/or enhance ␤-cell function in the setting of progressive type 2 diabetes and insulin resistance (3, 12). PPAR-␥ is known to be expressed in the pancreatic islet (8, 48), and PPAR-responsive elements have been identified in the promoters of genes involved in glucose-stimulated insulin secretion, including Glut2, Gck, and Pdx1 (16,21,26,27,33). Reports from studies of ␤-cell lines, rodent models of progressive type 2 diabetes, and humans at risk for type 2 diabetes suggest that PPAR-␥ agonist administration leads to preservation of islet mass and function (10,13,18,22,25,33,57,58).Whereas the studies noted ab...

BackgroundPeriprosthetic fracture following total knee arthroplasty (TKA) is usually associated with a traumatic event and typically treated with fracture fixation techniques. However, we report on a series of patients with early atraumatic condyle fractures that occurred as a result of insufficiency of the unloaded preoperative femoral condyle treated with delayed reconstruction.MethodsWe retrospectively reviewed a series of 7 patients who sustained femoral condyle fractures following TKA and evaluated risk factors for insufficiency.ResultsThere were 6 females and 1 male with an average age of 65.5 (range, 63-75) years and an average body mass index of 29.4 (range, 27-32). Fracture occurred on average 24.9 days from the index surgery and secondary to a low energy mechanism. Five patients had valgus alignment (mean, 15.2°) preoperatively and sustained fracture of the unloaded medial femoral condyle. Two patients had varus alignment (mean, 7.0°) preoperatively and both fractured the unloaded lateral condyle. One patient underwent early intervention requiring distal femoral replacement secondary to femoral bone loss. The remaining 6 patients underwent delayed surgery for an average of 6 weeks to allow for fracture healing followed by femoral component revision. At last follow-up (average, 48.5 months), 1 patient required a tibial component revision; however, no revision of the femoral component was required.ConclusionsEarly femoral condyle insufficiency fractures following TKA may be a risk in females with poor bone quality and preoperative valgus alignment. Delayed surgery and femoral component revision is a treatment strategy that prevented the need for other tertiary reconstruction.

Recent studies in rodent models suggest that liver X receptors (LXRs) may play an important role in the maintenance of glucose homeostasis and islet function. To date, however, no studies have comprehensively examined the role of LXRs in human islet biology. Human islets were isolated from non-diabetic donors and incubated in the presence or absence of two synthetic LXR agonists, TO-901317 and GW3965, under conditions of low and high glucose. LXR agonist treatment enhanced both basal and stimulated insulin secretion, which corresponded to an increase in the expression of genes involved in anaplerosis and reverse cholesterol transport. Furthermore, enzyme activity of pyruvate carboxylase, a key regulator of pyruvate cycling and anaplerotic flux, was also increased. Whereas LXR agonist treatment up-regulated known downstream targets involved in lipogenesis, we observed no increase in the accumulation of intra-islet triglyceride at the dose of agonist used in our study. Moreover, LXR activation increased expression of the genes encoding hormone-sensitive lipase and adipose triglyceride lipase, two enzymes involved in lipolysis and glycerolipid/free fatty acid cycling. Chronically, insulin gene expression was increased after treatment with TO-901317, and this was accompanied by increased Pdx-1 nuclear protein levels and enhanced Pdx-1 binding to the insulin promoter. In conclusion, our data suggest that LXR agonists have a direct effect on the islet to augment insulin secretion and expression, actions that should be considered either as therapeutic or unintended side effects, as these agents are developed for clinical use.The liver X receptors (LXRs), 2 LXR␣ (NR1H3), and LXR␤ (NR1H2) are members of the nuclear hormone receptor superfamily and function to integrate lipid metabolic and inflammatory signaling (1). Upon binding to oxysterol ligands and heterodimerization with retinoid X receptors, LXRs bind to conserved LXR-responsive elements in target genes to regulate their expression. LXRs augment lipogenesis through transcriptional up-regulation of the genes encoding sterol regulatory binding-protein 1c (SREBP-1c), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD). They also function to regulate reverse cholesterol transport through the induction of genes encoding the ATP binding cassette transporters (ABCs) (2, 3). Furthermore, LXRs contribute to the regulation of innate immunity and have anti-inflammatory effects that are mediated through repression of several downstream targets of NF-B (nuclear factor light chain-enhancer of activated B cells) (4, 5).In addition to these well described effects on lipid metabolism and inflammation, LXRs also appear to play a role in the maintenance of glucose homeostasis. Oral administration of synthetic LXR agonists to diabetic rodent models, including obese db/db mice and Zucker fatty rats, results in improved glucose tolerance (6, 7). These effects of LXR agonists appear to arise in part from actions on insulin-sensitive tissues, as LXRs have been shown to enhance...

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Biceps tenodesis maintains the cosmetic appearance and length-tension relationship of the biceps with an associated predictable clinical outcome compared with tenotomy. Arthroscopic suprapectoral techniques are being developed to avoid the disadvantages of the open subpectoral approach. This study biomechanically compared 3 arthroscopic suprapectoral biceps tenodesis techniques performed with a suture anchor with lasso loop technique, an interference screw, and a compressive rivet. For a total of 15 randomized paired tests, 15 pairs of human cadaveric shoulders were used to test 1 technique vs another 5 times with 3 customized setups. Biomechanical testing was performed with an electromechanical testing system. The tendon was preloaded with 10 N and cyclically loaded at 0 to 40 N for 50 cycles. Load to failure testing was performed at 1 mm/s until failure occurred. The compressive rivet, interference screw, and suture anchor with lasso loop had mean load to failure of 97.1 N, 146.4 N, and 157.6 N, respectively. The difference in ultimate strength between the suture anchor with lasso loop and the compressive rivet was statistically significant (P=.04). No significant differences were found between the suture anchor with lasso loop and the interference screw (P=.93) or between the interference screw and the rivet (P=.10). When adjusted for sex, the load to failure overall among the 3 constructs was not significantly different. All 3 techniques had a different predominant mechanism of failure. The suture anchor with lasso loop showed superior load to failure compared with the compressive rivet. The minimum load to failure required to achieve clinically reliable biceps tenodesis is unknown. [Orthopedics. 2017; 40(6):e1009-e1016.].