The failure of metabolic tissues to appropriately respond to insulin ("insulin resistance") is an early marker in the pathogenesis of type 2 diabetes. Protein phosphorylation is central to the ...adipocyte insulin response, but how adipocyte signaling networks are dysregulated upon insulin resistance is unknown. Here we employ phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults causing insulin resistance, we observe a marked rewiring of the insulin signaling network. This includes both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying dysregulated phosphosites common to multiple insults reveals subnetworks containing non-canonical regulators of insulin action, such as MARK2/3, and causal drivers of insulin resistance. The presence of several bona fide GSK3 substrates among these phosphosites led us to establish a pipeline for identifying context-specific kinase substrates, revealing widespread dysregulation of GSK3 signaling. Pharmacological inhibition of GSK3 partially reverses insulin resistance in cells and tissue explants. These data highlight that insulin resistance is a multi-nodal signaling defect that includes dysregulated MARK2/3 and GSK3 activity.
Quantitative measurements of the electric near-field distribution of star-shaped gold nanoparticles have been performed by femtosecond laser ablation. Measurements were carried out on and off the ...plasmon resonance. A detailed comparison with numerical simulations of the electric fields is presented. Semi-quantitative agreement is found, with slight systematic differences between experimentally observed and simulated near-field patterns close to strong electric-field gradients. The deviations are attributed to carrier transport preceding ablation.
Rapid wound closure is important after arthroplasty procedures to prevent postoperative complications. Platelets are rich in growth factors and leukocytes contribute to innate immunity. We ...hypothesized that topical leukocyte platelet‐rich plasma (L‐PRP) derived from the blood of patients would be beneficial to wound healing. In this randomized controlled trial, patients subjected to elective total hip arthroplasty (THA) were assigned by concealed allocation either L‐PRP application onto the sutured fascia or no application (control) after the THA intervention. In addition, all patients received 1.5 g protein/kg, 5 g L‐arginine, 500 mg vitamin C and 44 mg zinc daily over the 4‐week postoperative period to obtain optimal nutrition. The primary endpoint was complete healing of the skin incision. The secondary endpoints were blood transfusions, length of hospital stay, pain and wound infections. Sixteen patients in the L‐PRP group and 17 patients in the control group completed the trial. L‐PRP treatment accelerated complete wound healing after 3 weeks (seven in the L‐PRP group vs. zero in the control group, p = 0.003) and after 4 weeks (12 in the L‐PRP group vs. six in the control group, p = 0.037). No postoperative superficial wound infections occurred within 4 weeks, and there were no significant differences in the other secondary outcomes. L‐PRP generated in 10 sex‐matched healthy volunteers revealed increased concentrations of platelets (5.8‐fold) and leukocytes (2.3‐fold) compared with those in whole blood. Furthermore, the concentration of keratinocyte mitogen epidermal growth factor in L‐PRP (380 ± 130 pg/ml, mean ± SD) was higher (p < 0.001) than that in serum (130 ± 26 pg/ml). In conclusion, a single intraoperative local application of L‐PRP promoted wound healing after THA, possibly mediated by EGF receptor agonists.
A two-particle model is proposed which enables the assessment of particle-particle interactions in large, sparse arrays of randomly distributed plasmonic metal nanoparticles of arbitrary geometry in ...inhomogeneous environments. The two-particle model predicts experimentally observed peak splittings in the extinction cross section spectrum for randomly distributed gold nanocones on a TiO
:Er
thin film with average center-to-center spacings of 3-5 diameters. The main physical mechanism responsible is found to be interference between the incident field and the far-field component of the single-particle scattered field which is guided along the film.
The ability of metabolically active tissues to increase glucose uptake in response to insulin is critical to whole-body glucose homeostasis. This report describes the Dual Tracer Test, a robust ...method involving sequential retro-orbital injection of 14C2-deoxyglucose (14C2DG) alone, followed 40 min later by injection of 3H2DG with a maximal dose of insulin to quantify both basal and insulin-stimulated 2DG uptake in the same mouse. The collection of both basal and insulin-stimulated measures from a single animal is imperative for generating high-quality data since differences in insulin action may be misinterpreted mechanistically if basal glucose uptake is not accounted for. The approach was validated in a classic diet-induced model of insulin resistance and a novel transgenic mouse with reduced GLUT4 expression that, despite ubiquitous peripheral insulin resistance, did not exhibit fasting hyperinsulinemia. This suggests that reduced insulin-stimulated glucose disposal is not a primary contributor to chronic hyperinsulinemia. The Dual Tracer Test offers a technically simple assay that enables the study of insulin action in many tissues simultaneously. By administering two tracers and accounting for both basal and insulin-stimulated glucose transport, this assay halves the required sample size for studies in inbred mice and demonstrates increased statistical power to detect insulin resistance, relative to other established approaches, using a single tracer. The Dual Tracer Test is a valuable addition to the metabolic phenotyping toolbox.
A new method for dose regularization in optimization-based proximity-effect-correction is proposed. In contrast to the commonly adopted approach of adding penalty terms to the objective function, a ...modified scheme is demonstrated where dose regularization is achieved via filtering and projection techniques.
The resulting dose patterns are simple and two-toned, and can thus readily be applied in production. Furthermore, existing extensions developed in the context of topology optimization that build on top of the filtering framework, such as robust optimization and strict length scale control, can be adopted directly. The validity of the scheme is assessed in experiments, where the resolvable feature size of the considered 30 kV electron-beam lithography system is decreased from around 100 nm to a few tens of nm. A Python implementation of the scheme is made freely available.
Despite the fact that genes and the environment are known to play a central role in islet function, our knowledge of how these parameters interact to modulate insulin secretory function remains ...relatively poor. Presently, we performed ex vivo glucose-stimulated insulin secretion and insulin content assays in islets of 213 mice from 13 inbred mouse strains on chow, Western diet (WD), and a high-fat, carbohydrate-free (KETO) diet. Strikingly, among these 13 strains, islets from the commonly used C57BL/6J mouse strain were the least glucose responsive. Using matched metabolic phenotyping data, we performed correlation analyses of isolated islet parameters and found a positive correlation between basal and glucose-stimulated insulin secretion, but no relationship between insulin secretion and insulin content. Using in vivo metabolic measures, we found that glucose tolerance determines the relationship between ex vivo islet insulin secretion and plasma insulin levels. Finally, we showed that islet glucose-stimulated insulin secretion decreased with KETO in almost all strains, concomitant with broader phenotypic changes, such as increased adiposity and glucose intolerance. This is an important finding as it should caution against the application of KETO diet for beta-cell health. Together these data offer key insights into the intersection of diet and genetic background on islet function and whole body glucose metabolism.
Thirteen strains of mice on chow, Western diet, and high-fat, carbohydrate-free (KETO), correlating whole body phenotypes to ex vivo pancreatic islet functional measurements, were used. The study finds a huge spectrum of functional islet responses and insulin phenotypes across all strains and diets, with the ubiquitous C57Bl/6J mouse exhibiting the lowest secretory response of all strains, highlighting the overall importance of considering genetic background when investigating islet function. Ex vivo basal and stimulated insulin secretion are correlated in the islet, and KETO imparts widescale downregulation of islet insulin secretion.
The large-diameter metal-on-metal hip prostheses were expected to have low wear and reduced dislocation rate compared to the traditional metal-on-polyethylene implants. We compare 2 such prostheses, ...the ReCap resurfacing implant and the M2a-Magnum stemmed implant, with the C2a ceramic-on-ceramic stemmed implant as to clinical performance, serum concentrations of prosthesis metals, and the durability of the implants in a randomized, controlled clinical trial at 7 years of follow-up.
All included patients had osteoarthritis. Preoperatively, the size of the implants was estimated from a magnetic resonance imaging (MRI) scan. Follow-up data included serum cobalt and chromium concentrations, Oxford and Harris Hip Scores, leg press and abduction force, 6-minute walk distance, WOMAC and SF-36 self-assessment scores, and from the 7th postoperative year also ultrasonography (US) examination of the soft tissue adjacent to the implant as well as MRI with metal artifact reduction sequence (MARS-MRI) when indicated.
One hundred fifty-two hips in 146 patients were included. The serum cobalt and chromium concentrations were significantly higher for the 2 metal-on-metal prostheses than for the ceramic-on-ceramic, with the M2a-Magnum as the highest. No significant difference was found between the groups concerning physical performance measurements and scores as well as dislocations and prosthesis survival. Five revisions were done and concerned all groups, for reasons of pain, high serum cobalt and chromium concentrations, cystic fluid collection around the joint, and infection. Metal concentrations, US, and MARS-MRI contributed to the decision making regarding prosthesis revision.
Metal concentrations were significantly higher for the metal-on-metal prostheses than for the ceramic-on-ceramic. The clinical performance was good in all 3 prosthesis groups. Metal concentrations, US, and MARS-MRI findings were of use to identify hips needing revision.
ID Number in ClinicalTrials.gov PRS: NCT00284674
Purpose
Elevated levels of serum metal ions can be found in some patients with metal-on-metal (MoM) hip replacements. This study seeks to identify whether there is a significant association between ...the contact patch to rim distance (CPRD) and the anterior center edge angle (ACEA), respectively, and serum cobalt (Co) and chromium (Cr) levels in patients treated with unilateral MoM hip replacements by using standing anteroposterior and false profile view radiographs.
Methods
This is a retrospective analysis on 53 patients with either unilateral ReCap or M2a-Magnum MoM hip replacements operated in 2006 or 2007. Univariate linear regression and multivariable linear regression (MLR) analyses were performed using the CPRD and ACEA along with risk factors for elevated serum levels of Co and Cr previously suggested in the literature as explanatory variables. Serum Co and Cr were measured using inductively coupled plasma mass spectrometry.
Results
The MLR model showed that the same three variables (gender, CPRD and ACEA) were significantly associated with serum levels of both Co and Cr explaining approximately half of the variation. A univariate analysis showed a polynomial association between both anteversion angle and the ACEA with serum levels of Co and Cr. The vertex of the polynomial function was located at approximately 20° and 40°, respectively.
Conclusion
Gender, CPRD and ACEA are independently associated with serum levels of Co and Cr. Both ACEA and anteversion angles have optimae associated with low serum metal levels which may be useful for post-surgery evaluation of cup positioning.
Skeletal muscle and adipose tissue insulin resistance are major drivers of metabolic disease. To uncover pathways involved in insulin resistance, specifically in these tissues, we leveraged the ...metabolic diversity of different dietary exposures and discrete inbred mouse strains. This revealed that muscle insulin resistance was driven by gene-by-environment interactions and was strongly correlated with hyperinsulinemia and decreased levels of ten key glycolytic enzymes. Remarkably, there was no relationship between muscle and adipose tissue insulin action. Adipocyte size profoundly varied across strains and diets, and this was strongly correlated with adipose tissue insulin resistance. The A/J strain, in particular, exhibited marked adipocyte insulin resistance and hypertrophy despite robust muscle insulin responsiveness, challenging the role of adipocyte hypertrophy per se in systemic insulin resistance. These data demonstrate that muscle and adipose tissue insulin resistance can occur independently and underscore the need for tissue-specific interrogation to understand metabolic disease.
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•Gene-by-environment interactions drive tissue insulin action•Adipose insulin resistance is dissociated from systemic insulin resistance•Large adipocytes strongly associate with adipose insulin resistance•Muscle insulin resistance correlates with hyperinsulinemia and decreased glycolysis
Using a diverse panel of mouse strains, Nelson et al. reveal that muscle insulin resistance is most closely linked to levels of circulating insulin and muscle glycolytic enzymes. Intriguingly, certain strains had enlarged fat cells and adipose insulin resistance, but completely healthy muscle insulin response, showing tissue-specific progression toward metabolic disease.
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