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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\u003EFrom 1986 to 2002, sleep apnea affected \u0026gt;100 million individuals worldwide [WHO; Chronic Respiratory Diseases]. Apneas lead to periodic desaturation of O2 in arterial blood. In severe cases, O2 saturation drops to nearly 50%, and the frequency of apneas can reach as many as 60 to 90 episodes per hour. This article discusses the effects of intermittent hypoxia on glucose homeostasis.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ESleep Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInsulin\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERenal Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EFrom 1986 to 2002, sleep apnea affected \u0026gt;100 million individuals worldwide [WHO; Chronic Respiratory Diseases]. Recurrent apneas are characterized by transient cessation of breathing (approximately 10 to 30 seconds), due either to obstruction of the upper airways or to disturbances in respiratory rhythm generation (central apneas). Apneas lead to periodic desaturation of O\u003Csub\u003E2\u003C\/sub\u003E in arterial blood. In severe cases, O\u003Csub\u003E2\u003C\/sub\u003E saturation drops to nearly 50%, and the frequency of apneas can reach as many as 60 to 90 episodes per hour. Nanduri R. Prabhakar, PhD, University of Chicago, Chicago, Illinois, USA, discussed the effects of intermittent hypoxia on glucose homeostasis.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ESleep apnea is associated with myocardial infarctions, stroke, and other comorbidities, as well as altered glucose homeostasis and type 2 diabetes mellitus (T2DM). Despite a large body of evidence of epidemiological and clinical evidence that suggests that sleep-disordered breathing is an independent risk factor for the development of T2DM, the underlying pathogenesis of altered glucose metabolism in sleep apnea remains to be determined [Pallayova M et al. \u003Cem\u003EMed Hypotheses\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003ENotwithstanding the previously proposed causal pathways that link sleep apnea with T2DM through increased insulin resistance and\/or deterioration in insulin sensitivity, there is a paucity of information on sleep apnea-related alterations in pancreatic \u03b2-cell function [Palloyava M et al. \u003Cem\u003EMed Hypothesis\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EAn examination of the effects of intermittent hypoxia on glucose homeostasis and pancreatic \u03b2-cell function in animal models showed that intermittent hypoxia increases basal plasma insulin levels but without a corresponding decrease in glucose levels, indicating insulin resistance. Hypoxia impairs glucose-stimulated insulin secretion as well. Evidence also suggests that hypoxia affects pancreatic \u03b2-cells, decreasing insulin content through insulin synthesis and\/or processing of proinsulin to insulin. Intermittent hypoxia downregulates prohormone convertase 1, with an ensuing decrease in the processing of proinsulin to insulin [Palloyava M et al. \u003Cem\u003EMed Hypothesis\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EConsiderable evidence indicates elevated reactive oxygen species (ROS) levels in patients who experience chronic intermittent hypoxia (CIH) is a consequence of recurrent apneas. The role of mitochondrial ROS in \u03b2-cell function is related to molecular mechanisms, including hypoxia-inducible transcription factor, with its constitutive and O\u003Csub\u003E2\u003C\/sub\u003E subunits. Hypoxia-inducible factor 1 (HIF-1) mediates intermittent hypoxia-induced ROS generation via normoxia (NOX) upregulation [Prabhakar NR et al. \u003Cem\u003EAntioxid Redox Signal\u003C\/em\u003E 2007].\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EPathophysiological Role of Hypoxia in Diabetic Nephropathy\u003C\/h2\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EChronic kidney disease (CKD) is a common complication of, and risk factor for, mortality for type 1 diabetes. The presence and severity of CKD remain the major determinants of excess mortality that is associated with type 1 diabetes.\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EHypoxia is an important pathogenic factor in many renal diseases, including diabetic nephropathy. Deficiency of endogenous H\u003Csub\u003E2\u003C\/sub\u003EO may contribute to their pathogenesis by compromising medullary oxygenation [PH Groop et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2009].\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EAerobic exercise that is conducted during hemodialysis sessions contributes to the improvement of physical capacity and control of hypertension in patients with CKD. Data show a significant increase in the distance walked during the 6-minute walk test from 509\u00b191.9 m to 555\u00b1105.8 m after exercise and a significant reduction in systolic blood pressure (151\u00b118.4 mm Hg to 143\u00b114.7 mm Hg), diastolic blood pressure (94\u00b110.5 mm Hg to 91\u00b19.6 mm Hg), and average arterial pressure (114\u00b113.0 mm Hg to 109\u00b1 11.4 mm Hg) [Henrique DM et al. \u003Cem\u003EArq Bras Cardiol\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EIntensive therapy effectively delays the onset and slows the progression of diabetic nephropathy in patients with type 1 diabetes [The Diabetes Control and Complications Trial Research Group. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 1993]. The Diabetes Control and Complications Trial (DCCT) demonstrated the benefits of intensive treatment of diabetes in reducing glycemic levels and slowing the progression of diabetic nephropathy.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EThe DCCT cohort was examined annually for another 8 years as part of the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. The persistent beneficial effects on albumin excretion and the reduced incidence of hypertension 7 to 8 years after the end of the DCCT suggest that previous intensive treatment of diabetes with near-normal glycemia during the DCCT had an extended benefit in delaying progression of diabetic nephropathy (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Writing Team for the Diabetes Control and Complications Trial\/Epidemiology of Diabetes Interventions and Complications Research Group. \u003Cem\u003EJAMA\u003C\/em\u003E 2003].\u003C\/p\u003E\n         \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\/11\/11\/23\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Persistent Beneficial Effects of EDIC\/DCCT.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1811846495\u0022 data-figure-caption=\u0022Persistent Beneficial Effects of EDIC\/DCCT.\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\/11\/11\/23\/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\/11\/11\/23\/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\/11\/11\/23\/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\/12498\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-12\u0022 class=\u0022first-child\u0022\u003EPersistent Beneficial Effects of EDIC\/DCCT.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from PH Groop, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EKoh et al. [\u003Cem\u003ENephrology (Carlton)\u003C\/em\u003E 2011] found that both male and female diabetes subjects with microalbuminuria have elevated urine albumin-to-creatinine ratios (uACR) 1 hour postexercise (87.8, \u221224.3\u2013199.4 \u0026amp; 6.7, 2.1\u201311.3). The authors concluded that exercise increased uACR estimation in normoalbuminuric subjects with diabetes, with a larger effect in females. It remains unknown whether exercise unmasks early diabetic nephropathy in normoalbuminuric subjects.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EBlunted baroreflex sensitivity (BRS), typical of type 1 diabetes, is caused by a higher degree of tissue hypoxia in diabetes. Bernardi et al. [\u003Cem\u003EDiabetologia\u003C\/em\u003E 2011] found that BRS increases after administration of oxygen in type 1 diabetes (p\u0026lt;0.05; \u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E). The increased response to oxygen suggests a preexisting condition of tissue hypoxia that functionally restrains parasympathetic activity in patients with type 1 diabetes. Autonomic abnormalities can be partially or temporarily reversed by functional maneuvers, such as slow breathing, and oxygen administration through enhancement of parasympathetic activity and\/or correction of tissue hypoxia.\u003C\/p\u003E\n         \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\/11\/11\/23\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022BRS Increase After O2 Administration in Type 1Diabetes.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1811846495\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;BRS Increase After O\u0026amp;lt;sub\u0026amp;gt;2\u0026amp;lt;\/sub\u0026amp;gt; Administration in Type 1Diabetes.\u0026amp;lt;\/div\u0026amp;gt;\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\/11\/11\/23\/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\/11\/11\/23\/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\/11\/11\/23\/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\/12500\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-15\u0022 class=\u0022first-child\u0022\u003EBRS Increase After O\u003Csub\u003E2\u003C\/sub\u003E Administration in Type 1Diabetes.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from PH Groop, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EChronic hypoxia induces sequential abnormalities in oxygen metabolism in the kidneys of individuals with diabetes. Identification of these abnormalities improves our understanding of therapeutic benefits that can be achieved with antihypertensive agents, the control of hyperglycemia and\/or hyperinsulinemia, and the dietary correction of obesity [Miyata T, de Strihou CY. \u003Cem\u003ENat Rev Nephrol\u003C\/em\u003E 2010]. According to Miyata and de Strihou, HIF has a key role in the body\u0027s defense against hypoxia. The activity of HIF is modulated by propyl hydroxylase 4\u2014oxygen sensors whose inhibition may prove to be therapeutic.\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EIn conclusion, Prof. Groop reminded attendees that patients with diabetes are hypoxic; the defense mechanisms to cope with hypoxia are impaired in diabetes; hypoxia leads to abnormalities in the autonomic and vascular functions that precede diabetic complications; regular exercise is a natural mode of treatment to cope with hypoxia; and there are new promising medications to fight hypoxia that are already under development.\u003C\/p\u003E\n      \u003C\/div\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\/23.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?nzmy2q\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?nzmy2q\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}