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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.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\u003EDiabetes has a devastating systemic impact on those who suffer from it, including a 2- to 4-fold increase in cardiovascular events and stroke, nontraumatic lower extremity amputations, end-stage renal disease, and blindness in working age adults. These outcomes underscore the importance of identifying novel pathways that lead to late diabetic complications.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHyperglycemia\/Hypoglycemia\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EDiabetes has a devastating systemic impact on those who suffer from it, including a 2- to 4-fold increase in cardiovascular events and stroke, nontraumatic lower extremity amputations, end-stage renal disease, and blindness in working age adults. These outcomes underscore the importance of identifying novel pathways that lead to late diabetic complications. Prof. Dr. Angelika Bierhaus, Department of Medicine I and Clinical Chemistry, University Hospital, Heidelberg, Germany, reviewed the latest research and hypotheses on novel pathways.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ERisk for complications may be due, in part, to shortcomings in HbA1C. Recent clinical studies show that HbA1C and the duration of disease only explain approximately 11% of the risk of diabetic microvascular complications. The remaining 89% of the risk most likely reflects the fact that HbA1C fails to fully capture the elements of glycemia that determine risk [Lachin JM et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2008].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EAccording to Dr. Prof. Bierhaus, HbA1C reflects time-averaged mean glucose only\u2014it does not mirror any other elements independently of glycemia that might determine risk. This leads to the Diabetes Paradox\u2014that hyperglycemia is necessary for the development of late diabetic complications\u2014but average blood glucose HbA1C only explains a small percentage of complications.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003ESkriver et al. [\u003Cem\u003EDiabetologia\u003C\/em\u003E 2010] studied a subtype of patients who were phenotypically at high risk of developing diabetes but currently had normal glucose tolerance (NGT). The primary aim was to assess whether HbA1C added prognostic information in relation to all-cause mortality in people with normal NGT and high risk of type 2 diabetes.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003ECompared with individuals with NGT and HbA1C \u0026lt;6%, adjusted hazard ratios were 1.21 (95% CI, 0.95 to 1.56) for those with NGT and HbA1C between 6.0% and 6.5%; 2.48 (95% CI, 1.23 to 4.99) for individuals with NGT and HbA1C \u22656.5%; and 1.73 (95% CI, 1.40 to 2.13) for those with type 2 diabetes. The authors concluded that HbA1C levels in patients with NGT and a high risk of diabetes were clearly associated with increased risk of all-cause mortality [Skriver MV et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EProf. Dr. Bierhaus and colleagues have found that a focus not only on hyperglycemia but also on the balance between excess metabolite formation and reduced metabolite detoxification not only lends itself to an explanation of the \u201cdiabetic paradox\u201d but also provides new therapeutic approaches to the as-yet unsolved problem of late diabetic complications.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EData indicate that the level of risk for complications is determined by glucose-dependent activation mechanisms and independent inactivation mechanisms. Proposed major independent mechanisms of hyperglycemia-induced tissue damage include increases in polyol pathway flux, hexosamine pathway, and protein kinase C activation, leading to increased formation of advanced glycation endproducts (AGEs) and activation of the AGE\/receptor for advanced glycation endproducts (RAGE) axis. Loss of renal function is reduced by blockade\/absence of RAGE [Wendt TM et al. \u003Cem\u003EAm J Pathol\u003C\/em\u003E 2003].\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EMultiple independent inactivation mechanisms could be implicated in late diabetic complications, including a novel pathway in which small reactive molecules directly reduce neuronal blood flow and induce hyperalgesia. This finding might provide a new concept for therapeutic options in treating pain [Bierhaus A et al. In revision].\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2011 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\/11\/11\/31.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_openurl.js?nzmyje\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}