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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EPatients with type 2 diabetes mellitus (T2DM) appear to have dysfunctional islet \u03b2 cells due to unknown mechanisms [Leahy JL and Pratley RE. \u003Cem\u003ETranslational Endo Metab\u003C\/em\u003E 2011]. Multiple new pharmacologic agents that are under development for the treatment of T2DM specifically target islet cells. This article discusses two signaling pathways in \u03b2 cells that may be important drug targets, the mechanisms underlying insulin resistance and potential drug targets, information on treating inflammation in adipose and skeletal tissues, as well as targeting mechanisms of glucose absorption and excretion in the treatment of T2DM.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EExclusive Article - For home page\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInsulin\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EExclusive Article - For home page\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInsulin\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EPatients with type 2 diabetes mellitus (T2DM) appear to have dysfunctional islet \u03b2 cells due to unknown mechanisms [Leahy JL and Pratley RE. \u003Cem\u003ETranslational Endo Metab\u003C\/em\u003E 2011]. Multiple new pharmacologic agents that are under development for the treatment of T2DM specifically target islet cells. Jack L. Leahy, MD, University of Vermont, Burlington, Vermont, USA, presented two signaling pathways in \u03b2 cells that may be important drug targets.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EDr. Leahy pointed out that there are several therapeutic targets within \u03b2 cells for the treatment of T2DM [Bailey CJ. \u003Cem\u003ELancet\u003C\/em\u003E 2012]. One target is an unsaturated medium- to long-chain free fatty acid receptor called GPR40 (also called FFAR1) that plays a role in free fatty acid-induced insulin secretion [Mancini AD, Poitout V. \u003Cem\u003ETrends Endocrinol Metab\u003C\/em\u003E 2013]. Studies have demonstrated decreased insulin secretion in GPR40 null mice compared with controls [Steneberg P et al. \u003Cem\u003ECell Metab\u003C\/em\u003E 2005; Kebede M et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2008]. Interestingly, GPR40 expression in human pancreas islet cells is decreased in patients with T2DM by up to 80%, when compared with controls [Del Guerra S et al. \u003Cem\u003ENutr Metab Cardiovasc Dis\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EDr. Leahy highlighted data from a Phase 2 trial in which 426 patients with T2DM were treated with the GPR40 agonist TAK-875, glimepiride, or placebo for 12 weeks [Burant CF et al. \u003Cem\u003ELancet\u003C\/em\u003E 2012]. Patients were counseled on diet and exercise and may or may not have been stable on metformin. A significant improvement in HbA1C levels was observed in patients who received TAK-875 or glimepiride, compared with those who received placebo (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). Patients treated with TAK-875 or glimepiride did not have improved insulin sensitivity or fasting glucagon levels. Additionally, treatment-related adverse events were similar among patients who received TAK-875 or placebo. However, a greater number of patients who received glimepiride demonstrated hypoglycemic events, as compared with those who received placebo or TAK-875.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/11\/4\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Effects of TAK-875, Glimepiride, and Placebo on Glycemia\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1526413006\u0022 data-figure-caption=\u0022Effects of TAK-875, Glimepiride, and Placebo on Glycemia\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/11\/4\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/11\/4\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/11\/4\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13901\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-5\u0022 class=\u0022first-child\u0022\u003EEffects of TAK-875, Glimepiride, and Placebo on Glycemia\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced from Burant CF et al. TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial. \u003Cem\u003ELancet\u003C\/em\u003E 21012;379(9824):1403\u20131411. With permission from Elsevier.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-6\u0022\u003EDr. Leahy gave an example of identifying new therapeutic targets in well-studied signaling pathways in \u03b2 cells, such as the FoxO1 and PPAR-\u03b3 pathway in \u03b2 cells that is important for \u03b2 cell survival, function, metabolism, and response to incretin. Rats with hyperglycemia demonstrate reduced signaling through the FoxO1\/PPAR-\u03b3 pathway due to the potentially impaired translocation of FoxO1 from the nucleus to the cytoplasm [Gupta D et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2010]. Treatment of hyperglycemic rats with the DPP-4 inhibitor alogliptin appears to restore FoxO1\/PPAR-\u03b3 signaling [Gupta D et al. ADA 2013 (poster 2275)].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EAbd A. Tahrani, MD, PhD, University of Birmingham, Edgbaston, United Kingdom, discussed the mechanisms underlying insulin resistance and potential drug targets. Prof. Tahrani pointed out that the most important factor associated with insulin resistance is obesity; however, he noted that it is difficult to treat obesity. Targets for the treatment of insulin resistance include obesity and the mechanisms of insulin resistance such as inflammation, oxidative stress, lipotoxicity, and glucotoxicity, as well as targeting the insulin receptor and insulin post-receptor signaling.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EProf. Tahrani highlighted several drugs that target insulin resistance. The compounds demethylasterriquinone B1, compound 2, and D-410639 target insulin receptor activation [Zhang B et al. \u003Cem\u003EScience\u003C\/em\u003E 1999; Strowski MZ et al. \u003Cem\u003EEndocrinology\u003C\/em\u003E 2004; Tsai KW et al. \u003Cem\u003EJ Biomed Sci\u003C\/em\u003E 2009]. Some agents prolong phosphorylation of the \u03b2 subunit of the insulin receptor following insulin binding [Cohen P et al. \u003Cem\u003ENat Rev Mol Cell Biol\u003C\/em\u003E 2006], such as the agent TLK16998 [Manchem VP et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2001]. Other targets include interleukin-6 [Ridker PM et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2012], resveratrol [Ito-Nagahata T et al. \u003Cem\u003EBiosci Biotechnol Biochem\u003C\/em\u003E 2013], and inhibitor \u03ba-B kinase-\u03b2 inhibitors [Kamon J et al. \u003Cem\u003EBiochem Biophys Res Commun\u003C\/em\u003E 2004].\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EPostreceptor insulin signaling may also harbor potential targets for the treatment of insulin resistance. Prof. Tahrani highlighted signaling molecules within the insulin signaling pathway that may be ideal targets, such as inhibition of protein kinase C [Naruse K et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2006], promotion of phosphatidylinositol-3 kinase [Croze ML et al. \u003Cem\u003EBiochimie\u003C\/em\u003E 2013], inositol metabolites, inhibition of PTEN [Pal A et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012], and inhibition of inositol phosphatases.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EProf. Tahrani pointed out that nonpharmacologic interventions, such as weight loss, adequate sleep, and obstructive sleep apnea are also important to consider. For example, patients who were sleep restricted in a laboratory study had a significant decrease in glucose tolerance, acute insulin response to glucose, glucose effectiveness, and insulin sensitivity as compared with a well-rested state [Leproult R, Van Cauter E. \u003Cem\u003EEndocr Dev\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003ERobert R. Henry, MD, University of California, San Diego, La Jolla, California, USA, presented information on treating inflammation in adipose and skeletal tissues. Individuals that tend to accumulate adipose tissue in the visceral region are more likely to have inflammation in their adipose tissue. In addition, patients with T2DM have greater fat deposition in the visceral versus subcutaneous region, as compared with patients without diabetes.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EDr. Henry highlighted that adipose tissue produces chemicals called adipokines, which can have autocrine, paracrine, or endocrine signaling effects [Bl\u00fcher M. \u003Cem\u003EDiabetes Metab J\u003C\/em\u003E 2012]. As adiposity increases, the adipokines that are secreted become predominantly proinflammatory. A prevailing theory of a mechanism underlying insulin resistance in obesity is lipotoxicity [Johnson AM, Olefalsy JM. \u003Cem\u003ECell\u003C\/em\u003E 2013]. Excessive caloric intake can result in cellular stress and tissue inflammation, which can lead to insulin resistance [Odegaard JI, Chawla A. \u003Cem\u003EScience\u003C\/em\u003E 2013]. Ultimately, inflamed adipose tissue with some level of metabolic dysfunction demonstrates an altered milieu as compared with lean adipose tissue with normal metabolic function [Ouchi N et al. \u003Cem\u003ENat Rev Immunol\u003C\/em\u003E 2011]. Adipocytes that live in an inflamed tissue have reduced insulin action [Odegaard JI, Chawla A et al. \u003Cem\u003EScience\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EA recent study demonstrated that treatment with salsalate, a tumor necrosis factor-\u03b1 inhibitor, resulted in a significant decrease in white blood cell count, neutrophil count, and lymphocyte count over a 48-week period [Goldfine AB et al. \u003Cem\u003EDiabetalogia\u003C\/em\u003E 2013]. In addition, salsalate treatment caused a reduction in nuclear factor kappa-light chain enhancer (NF-\u03baB) activity in visceral adipose tissue, compared with placebo, after 12 weeks of treatment. Importantly, NF-\u03baB is a major player in inflammatory signaling pathways [Reilly SM et al. \u003Cem\u003ENat Med\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EInflammation of skeletal muscle is increased in obese patients compared with lean patients, as measured by macrophage infiltration and, as body mass index increases, so does the macrophage content of skeletal muscle [Varma V et al. \u003Cem\u003EAm J Physiol Endocrinol Metab\u003C\/em\u003E 2009]. However, other studies have suggested that this finding may be due to cross-contamination by adipose tissue that is found within skeletal tissue [Tam CS et al. \u003Cem\u003EObesity\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EBernard Zinman, CM, MD, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada, discussed targeting mechanisms of glucose absorption and excretion in the treatment of T2DM. The alpha-glucosidase inhibitors [AGI] are a drug class that modifies glucose absorption by inhibiting the breakdown of carbohydrates in the upper intestine. Interestingly the AGIs also modify the secretion of gastrointestinal (GI) peptides like GLP1 but have modest efficacy. However, the tolerability of AGI is a major problem and their widespread acceptance in the United States has been limited by frequent GI side effects, such as diarrhea, flatulence, and abdominal distention.\u003C\/p\u003E\u003Cp id=\u0022p-16\u0022\u003EA new strategy focuses on targeting the sodium glucose cotransporter-2 (SGLT-2), which is an important mechanism responsible for the filtered glucose to be reabsorbed in the proximal tuble of the kidney. Nonetheless the capacity of the two transporters, SGLT-1 [high-affinity, low-capacity] and SGLT-2 [low-affinity, high-capacity] to reabsorb glucose is limited; therefore, excess blood glucose levels above \u223c180 mg\/dL causes glucose to remain in the urine filtrate [Gerich JE et al. \u003Cem\u003EDiabetic Med\u003C\/em\u003E 2010]. However, in patients with poorly controlled diabetes there is an adaptive response whereby SGLT-2 is upregulated so that reabsorption of glucose is increased. Thus SGLT-2 inhibitors reduce glucose reabsorption in the kidney and with resultant glucosuria [increased urinary glucose]. Several SGLT-2 inhibitors that have shown promising results in clinical trials include empagliflozin [Hach T et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2013], canagliflozin (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E) [Schernthaner G et al. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2013], and dapagliflozin [FDA. Dapagliflozin Advisory Committee Meeting. \u003Ca href=\u0022http:\/\/www.fda.gov\/downloads\/AdvisoryCommittees\/CommiitteesMeetingMaterials\/Drugs\/EndocrinologicandMetabolicDrugsAdvisoryCommittee\/UCM264314.pdf\u0022\u003Ehttp:\/\/www.fda.gov\/downloads\/AdvisoryCommittees\/CommiitteesMeetingMaterials\/Drugs\/EndocrinologicandMetabolicDrugsAdvisoryCommittee\/UCM264314.pdf\u003C\/a\u003E. Published July 19, 2011].\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/11\/4\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Effect of Canagliflozin Versus Sitagliptin on HbA1C Levels\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1526413006\u0022 data-figure-caption=\u0022Effect of Canagliflozin Versus Sitagliptin on HbA1C Levels\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/11\/4\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/11\/4\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/11\/4\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13902\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-17\u0022 class=\u0022first-child\u0022\u003EEffect of Canagliflozin Versus Sitagliptin on HbA1C Levels\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced from Schernthaner G et al. Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea: A 52-week randomized trial. \u003Cem\u003EDiabetes Care\u003C\/em\u003E 2013;36(4):908\u2013913. With permission from the American Diabetes Association.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/13\/11\/4.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nznqi2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznqi2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}