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| __NOTOC__
| | #Redirect [[Diabetes mellitus and COVID-19]] |
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| {{CMG}}; {{AE}}{{TAM}}
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| {{SK}} [[COVID-19-associated Diabetes Mellitus|New-onset Diabetes in COVID-19]] [[COVID-19-associated Diabetes Mellitus|Islet cell injury by SARS-CoV 2]]
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| To browse the complete page of COVID-19, [[COVID-19|Click here]].
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| ==Overview==
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| [[ACER2|ACE2 receptors]] in the [[Pancreas|endocrine pancreas]] serve the entrance for [[SARS-CoV-2|Severe acute respiratory syndrome coronavirus 2]] (SARS-CoV 2), which causes [[COVID-19|Corononavirus Disease 2019]] (COVID-19). Researchers in China observed [[COVID-19-associated diabetes mellitus|new-onset diabetes]] among [[SARS-CoV]] patients. Therefore in agreement with this, the [[SARS-CoV-2]] might enter [[pancreatic islets]] through binding to [[ACER2|ACE2]], and cause acute β-cell injury, leading to intense [[hyperglycemia]] and transient Type 2 [[Diabetes mellitus|Diabetes Mellitus]]. [[SARS-CoV-2|SARS-CoV 2]] can cause [[hyperglycemia]] by direct injuring of [[pancreatic beta cells]] and by downregulating [[ACER2|ACE2 receptors]] leading to unopposed [[Angiotensin|angiotensin II]], which may hinder [[insulin]] secretion
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| ==Historical Perspective==
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| * [[Diabetes mellitus]] is defined by [[insulin]] deficiency due to either diminished [[insulin]] release or end-organ [[insulin]] resistance.<ref name="KingAubert1998">{{cite journal|last1=King|first1=H.|last2=Aubert|first2=R. E.|last3=Herman|first3=W. H.|title=Global Burden of Diabetes, 1995-2025: Prevalence, numerical estimates, and projections|journal=Diabetes Care|volume=21|issue=9|year=1998|pages=1414–1431|issn=0149-5992|doi=10.2337/diacare.21.9.1414}}</ref>
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| * [[Diabetes]] is an umbrella term for conditions such as type I (T1DM) and type II (T2DM) [[diabetes mellitus]], [[gestational diabetes]], and [[maturity-onset diabetes of the young (MODY)]].<ref name="KingAubert1998">{{cite journal|last1=King|first1=H.|last2=Aubert|first2=R. E.|last3=Herman|first3=W. H.|title=Global Burden of Diabetes, 1995-2025: Prevalence, numerical estimates, and projections|journal=Diabetes Care|volume=21|issue=9|year=1998|pages=1414–1431|issn=0149-5992|doi=10.2337/diacare.21.9.1414}}</ref>
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| * Type 1 [[Diabetes Mellitus]] is caused by pancreatic β-cell failure or auto-immune destruction of the pancreatic β-cells. It generally presents in children and young adults.<ref name="KingAubert1998">{{cite journal|last1=King|first1=H.|last2=Aubert|first2=R. E.|last3=Herman|first3=W. H.|title=Global Burden of Diabetes, 1995-2025: Prevalence, numerical estimates, and projections|journal=Diabetes Care|volume=21|issue=9|year=1998|pages=1414–1431|issn=0149-5992|doi=10.2337/diacare.21.9.1414}}</ref>
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| * Type 2 [[Diabetes Mellitus]] (T2DM) is defined by [[insulin resistance]] and presents in adults. Family history, [[hypertension]], obesity, and [[dyslipidemia]] play a significant role in causing T2DM.<ref name="KingAubert1998">{{cite journal|last1=King|first1=H.|last2=Aubert|first2=R. E.|last3=Herman|first3=W. H.|title=Global Burden of Diabetes, 1995-2025: Prevalence, numerical estimates, and projections|journal=Diabetes Care|volume=21|issue=9|year=1998|pages=1414–1431|issn=0149-5992|doi=10.2337/diacare.21.9.1414}}</ref>
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| * Around 422 million individuals worldwide have diabetes, the dominant part living in low-and middle-income nations, and 1.6 million deaths are straightforwardly credited to [[diabetes]] every year. In the course of recent decades, a consistent rise has been observed in both the incidence and the prevalence.<ref>{{cite web |url=https://www.who.int/health-topics/diabetes#tab=tab_1 |title=Diabetes |format= |work= |accessdate=}}</ref>
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| * In China, in the year 2008, a study was done in which they compared 39 [[SARS-CoV]] patients with no previous history of diabetes, who never used steroids, with 39 matched healthy siblings.The results of the study revealed that 20 out of 39 [[SARS-CoV]] patients developed new-onset diabetes during the hospital stay. After 3 years of recovery from the SARS-CoV infection, only 5% of patients remained diabetic whereas blood sugar levels normalized in the rest of the patients with the infection recovery.<ref name="YangLin2009">{{cite journal|last1=Yang|first1=Jin-Kui|last2=Lin|first2=Shan-Shan|last3=Ji|first3=Xiu-Juan|last4=Guo|first4=Li-Min|title=Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes|journal=Acta Diabetologica|volume=47|issue=3|year=2009|pages=193–199|issn=0940-5429|doi=10.1007/s00592-009-0109-4}}</ref>
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| * ACE2 is the primary receptor For [[SARS-CoV]] spike protein. [[SARS-CoV-2|SARS-CoV]] causes infection by binding to ACE2 receptors on the target cells.<ref name="TurnerHiscox2004">{{cite journal|last1=Turner|first1=Anthony J|last2=Hiscox|first2=Julian A|last3=Hooper|first3=Nigel M|title=ACE2: from vasopeptidase to SARS virus receptor|journal=Trends in Pharmacological Sciences|volume=25|issue=6|year=2004|pages=291–294|issn=01656147|doi=10.1016/j.tips.2004.04.001}}</ref><ref name="LiMoore2003">{{cite journal|last1=Li|first1=Wenhui|last2=Moore|first2=Michael J.|last3=Vasilieva|first3=Natalya|last4=Sui|first4=Jianhua|last5=Wong|first5=Swee Kee|last6=Berne|first6=Michael A.|last7=Somasundaran|first7=Mohan|last8=Sullivan|first8=John L.|last9=Luzuriaga|first9=Katherine|last10=Greenough|first10=Thomas C.|last11=Choe|first11=Hyeryun|last12=Farzan|first12=Michael|title=Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus|journal=Nature|volume=426|issue=6965|year=2003|pages=450–454|issn=0028-0836|doi=10.1038/nature02145}}</ref> The study suggested, [[SARS-CoV]] may damage islets and cause acute [[insulin]] dependent [[diabetes mellitus]].<ref name="YangLin2009">{{cite journal|last1=Yang|first1=Jin-Kui|last2=Lin|first2=Shan-Shan|last3=Ji|first3=Xiu-Juan|last4=Guo|first4=Li-Min|title=Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes|journal=Acta Diabetologica|volume=47|issue=3|year=2009|pages=193–199|issn=0940-5429|doi=10.1007/s00592-009-0109-4}}</ref>
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| *In mid-April 2020, Finn Gnadt, an 18-year-old student from Kiel, Germany, learnt that he had been infected with the [[SARS-CoV-2|SARS-CoV-2 coronavirus]].
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| *Gnadt thought he had endured the infection unscathed, but days later, he started to feel worn out and exceedingly thirsty. In early May, he was diagnosed with [[Diabetes mellitus type 1|type 1 diabetes]], and his physician, Tim Hollstein at the University Hospital Schleswig-Holstein in Kiel, suggested that the sudden onset might be linked to the [[COVID-19|viral infection]].
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| *Hollstein suspected that the virus had destroyed his [[Pancreatic|β-cells]] because his blood didn’t contain the types of [[White blood cells|immune cells]] that typically damage the [[Islets of Langerhans|pancreatic islets]] where the β-cells live.<ref name="urlMounting clues suggest the coronavirus might trigger diabetes">{{cite web |url=https://www.nature.com/articles/d41586-020-01891-8 |title=Mounting clues suggest the coronavirus might trigger diabetes |format= |work= |accessdate=}}</ref>
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| *To browse the historical perspective of COVID-19, [[COVID-19 historical perspective|Click here]].
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| ==Classification==
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| * There is no established system for the classification of COVID-19-associated Diabetes.
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| * Future research is needed to provide a better understanding of the type of [[Diabetes]], [[SARS-CoV-2]] can cause. Whether [[SARS-CoV]] causes [[Diabetes mellitus type 1|T1DM]] or [[Diabetes mellitus type 2|T2DM]] or a new type of [[Diabetes]].
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| *To browse the classification of COVID-19, [[COVID-19 classification|Click here]].
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| ==Pathophysiology==
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| * [[Angiotensin-converting enzyme 2]] (ACE2) receptors expressed in the tissues that are highly involved in body metabolism. These tissues comprise of [[pancreatic beta cells]], [[adipose tissue]], [[small intestine]], and the [[kidneys]]. ACE2 receptors in the endocrine pancreas serve the entrance for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2), which causes Corononavirus Disease 2019 (COVID-19). <ref name="BornsteinDalan2020">{{cite journal|last1=Bornstein|first1=Stefan R.|last2=Dalan|first2=Rinkoo|last3=Hopkins|first3=David|last4=Mingrone|first4=Geltrude|last5=Boehm|first5=Bernhard O.|title=Endocrine and metabolic link to coronavirus infection|journal=Nature Reviews Endocrinology|volume=16|issue=6|year=2020|pages=297–298|issn=1759-5029|doi=10.1038/s41574-020-0353-9}}</ref>
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| * Expression of ACE2 receptors and effector protease TMPRSS2 in [[pancreas]] are associated with SARS-CoV 2 infection.<ref name="HoffmannKleine-Weber2020">{{cite journal|last1=Hoffmann|first1=Markus|last2=Kleine-Weber|first2=Hannah|last3=Schroeder|first3=Simon|last4=Krüger|first4=Nadine|last5=Herrler|first5=Tanja|last6=Erichsen|first6=Sandra|last7=Schiergens|first7=Tobias S.|last8=Herrler|first8=Georg|last9=Wu|first9=Nai-Huei|last10=Nitsche|first10=Andreas|last11=Müller|first11=Marcel A.|last12=Drosten|first12=Christian|last13=Pöhlmann|first13=Stefan|title=SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor|journal=Cell|volume=181|issue=2|year=2020|pages=271–280.e8|issn=00928674|doi=10.1016/j.cell.2020.02.052}}</ref>
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| * The pancreas consists of nine different cell types such as acinar cells, ductal cells, beta cells, alpha cells, mesenchymal cells, and [[Endothelium|endothelial cells]]. These pancreatic cells express both ACE2 and TMPRSS2. The expression of ACE2 in pancreatic alpha and beta cells is further proved by [[immunohistochemistry]]. Both beta cells that secrete insulin and alpha cells that secrete glucagon, stained positive for SARS-CoV 2 Spike protein and thus, it is postulated that [[SARS-CoV-2]] can infect pancreatic islet cells.<ref name="HoffmannKleine-Weber2020">{{cite journal|last1=Hoffmann|first1=Markus|last2=Kleine-Weber|first2=Hannah|last3=Schroeder|first3=Simon|last4=Krüger|first4=Nadine|last5=Herrler|first5=Tanja|last6=Erichsen|first6=Sandra|last7=Schiergens|first7=Tobias S.|last8=Herrler|first8=Georg|last9=Wu|first9=Nai-Huei|last10=Nitsche|first10=Andreas|last11=Müller|first11=Marcel A.|last12=Drosten|first12=Christian|last13=Pöhlmann|first13=Stefan|title=SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor|journal=Cell|volume=181|issue=2|year=2020|pages=271–280.e8|issn=00928674|doi=10.1016/j.cell.2020.02.052}}</ref>
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| * A recent experiement was conducted to study [[SARS-CoV-2]] tropism that is the cellular response to an external stimulus in human cells and organoids. Researchers infect human pluripotent stem cells (hPSC)-derived pancreatic endocrine cells with [[SARS-CoV-2]].<ref name="YangHan2020">{{cite journal|last1=Yang|first1=Liuliu|last2=Han|first2=Yuling|last3=Nilsson-Payant|first3=Benjamin E.|last4=Gupta|first4=Vikas|last5=Wang|first5=Pengfei|last6=Duan|first6=Xiaohua|last7=Tang|first7=Xuming|last8=Zhu|first8=Jiajun|last9=Zhao|first9=Zeping|last10=Jaffré|first10=Fabrice|last11=Zhang|first11=Tuo|last12=Kim|first12=Tae Wan|last13=Harschnitz|first13=Oliver|last14=Redmond|first14=David|last15=Houghton|first15=Sean|last16=Liu|first16=Chengyang|last17=Naji|first17=Ali|last18=Ciceri|first18=Gabriele|last19=Guttikonda|first19=Sudha|last20=Bram|first20=Yaron|last21=Nguyen|first21=Duc-Huy T.|last22=Cioffi|first22=Michele|last23=Chandar|first23=Vasuretha|last24=Hoagland|first24=Daisy A.|last25=Huang|first25=Yaoxing|last26=Xiang|first26=Jenny|last27=Wang|first27=Hui|last28=Lyden|first28=David|last29=Borczuk|first29=Alain|last30=Chen|first30=Huanhuan Joyce|last31=Studer|first31=Lorenz|last32=Pan|first32=Fong Cheng|last33=Ho|first33=David D.|last34=tenOever|first34=Benjamin R.|last35=Evans|first35=Todd|last36=Schwartz|first36=Robert E.|last37=Chen|first37=Shuibing|title=A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids|journal=Cell Stem Cell|year=2020|issn=19345909|doi=10.1016/j.stem.2020.06.015}}</ref>
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| * Researchers found when [[SARS-CoV-2]] infect pancreatic cells, it downregulates the pathways including calcium signaling pathways, [[glucagon]] signaling pathways of alpha cells, and metabolic pathways that assist in [[insulin]] secretion from [[Beta cell|pancreatic beta cells]].<ref name="YangHan2020">{{cite journal|last1=Yang|first1=Liuliu|last2=Han|first2=Yuling|last3=Nilsson-Payant|first3=Benjamin E.|last4=Gupta|first4=Vikas|last5=Wang|first5=Pengfei|last6=Duan|first6=Xiaohua|last7=Tang|first7=Xuming|last8=Zhu|first8=Jiajun|last9=Zhao|first9=Zeping|last10=Jaffré|first10=Fabrice|last11=Zhang|first11=Tuo|last12=Kim|first12=Tae Wan|last13=Harschnitz|first13=Oliver|last14=Redmond|first14=David|last15=Houghton|first15=Sean|last16=Liu|first16=Chengyang|last17=Naji|first17=Ali|last18=Ciceri|first18=Gabriele|last19=Guttikonda|first19=Sudha|last20=Bram|first20=Yaron|last21=Nguyen|first21=Duc-Huy T.|last22=Cioffi|first22=Michele|last23=Chandar|first23=Vasuretha|last24=Hoagland|first24=Daisy A.|last25=Huang|first25=Yaoxing|last26=Xiang|first26=Jenny|last27=Wang|first27=Hui|last28=Lyden|first28=David|last29=Borczuk|first29=Alain|last30=Chen|first30=Huanhuan Joyce|last31=Studer|first31=Lorenz|last32=Pan|first32=Fong Cheng|last33=Ho|first33=David D.|last34=tenOever|first34=Benjamin R.|last35=Evans|first35=Todd|last36=Schwartz|first36=Robert E.|last37=Chen|first37=Shuibing|title=A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids|journal=Cell Stem Cell|year=2020|issn=19345909|doi=10.1016/j.stem.2020.06.015}}</ref>
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| * Researchers further stained [[SARS-CoV-2]] infected hPSC-derived pancreatic endocrine cells with a cell apoptotic marker (CASP3). As a result of this staining, they found a large number of CASP3 cells in infected hPSC-derived pancreatic cells. This indicates that change in metabolic pathways of the [[pancreas]] is mainly due to cell apoptosis, trigger by [[SARS-CoV-2]]. This experiment suggest that when [[SARS-CoV-2]] binds to ACE2 in [[pancreas]], this will upregulate the genes responsible for apoptosis and downregulate the genes responsible for the cell survival. <ref name="YangHan2020">{{cite journal|last1=Yang|first1=Liuliu|last2=Han|first2=Yuling|last3=Nilsson-Payant|first3=Benjamin E.|last4=Gupta|first4=Vikas|last5=Wang|first5=Pengfei|last6=Duan|first6=Xiaohua|last7=Tang|first7=Xuming|last8=Zhu|first8=Jiajun|last9=Zhao|first9=Zeping|last10=Jaffré|first10=Fabrice|last11=Zhang|first11=Tuo|last12=Kim|first12=Tae Wan|last13=Harschnitz|first13=Oliver|last14=Redmond|first14=David|last15=Houghton|first15=Sean|last16=Liu|first16=Chengyang|last17=Naji|first17=Ali|last18=Ciceri|first18=Gabriele|last19=Guttikonda|first19=Sudha|last20=Bram|first20=Yaron|last21=Nguyen|first21=Duc-Huy T.|last22=Cioffi|first22=Michele|last23=Chandar|first23=Vasuretha|last24=Hoagland|first24=Daisy A.|last25=Huang|first25=Yaoxing|last26=Xiang|first26=Jenny|last27=Wang|first27=Hui|last28=Lyden|first28=David|last29=Borczuk|first29=Alain|last30=Chen|first30=Huanhuan Joyce|last31=Studer|first31=Lorenz|last32=Pan|first32=Fong Cheng|last33=Ho|first33=David D.|last34=tenOever|first34=Benjamin R.|last35=Evans|first35=Todd|last36=Schwartz|first36=Robert E.|last37=Chen|first37=Shuibing|title=A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids|journal=Cell Stem Cell|year=2020|issn=19345909|doi=10.1016/j.stem.2020.06.015}}</ref>
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| * ACE2 is the target receptor for both [[SARS-CoV-2|SARS-CoV]] and [[SARS-CoV-2]]. Researchers in China observed new-onset diabetes among [[SARS-CoV]] patients. Therefore in agreement with this, the [[SARS-CoV-2]] might enter [[pancreatic islets]] through binding to ACE2, and cause acute β-cell injury, leading to intense hyperglycemia and transient Type 2 [[Diabetes mellitus|Diabetes Mellitus]].<ref name="YangLin2009">{{cite journal|last1=Yang|first1=Jin-Kui|last2=Lin|first2=Shan-Shan|last3=Ji|first3=Xiu-Juan|last4=Guo|first4=Li-Min|title=Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes|journal=Acta Diabetologica|volume=47|issue=3|year=2009|pages=193–199|issn=0940-5429|doi=10.1007/s00592-009-0109-4}}</ref>
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| * ACE2 serves as the negative regulator of the Renin-Angiotensin System (RAS) mainly by converting Ang (angiotensin) I and Ang II into Ang 1-9 and Ang 1-7, respectively.<ref name="PatelZhong2016">{{cite journal|last1=Patel|first1=Vaibhav B.|last2=Zhong|first2=Jiu-Chang|last3=Grant|first3=Maria B.|last4=Oudit|first4=Gavin Y.|title=Role of the ACE2/Angiotensin 1–7 Axis of the Renin–Angiotensin System in Heart Failure|journal=Circulation Research|volume=118|issue=8|year=2016|pages=1313–1326|issn=0009-7330|doi=10.1161/CIRCRESAHA.116.307708}}</ref><ref name="WangGheblawi2020">{{cite journal|last1=Wang|first1=Kaiming|last2=Gheblawi|first2=Mahmoud|last3=Oudit|first3=Gavin Y.|title=Angiotensin Converting Enzyme 2: A Double-Edged Sword|journal=Circulation|year=2020|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.120.047049}}</ref> When [[SARS-CoV]] and [[SARS-CoV-2]] bind to ACE2 receptors, this will lead to the subsequent downregulation of surface ACE2 expression.<ref name="LiMoore2003">{{cite journal|last1=Li|first1=Wenhui|last2=Moore|first2=Michael J.|last3=Vasilieva|first3=Natalya|last4=Sui|first4=Jianhua|last5=Wong|first5=Swee Kee|last6=Berne|first6=Michael A.|last7=Somasundaran|first7=Mohan|last8=Sullivan|first8=John L.|last9=Luzuriaga|first9=Katherine|last10=Greenough|first10=Thomas C.|last11=Choe|first11=Hyeryun|last12=Farzan|first12=Michael|title=Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus|journal=Nature|volume=426|issue=6965|year=2003|pages=450–454|issn=0028-0836|doi=10.1038/nature02145}}</ref><ref name="WallsPark2020">{{cite journal|last1=Walls|first1=Alexandra C.|last2=Park|first2=Young-Jun|last3=Tortorici|first3=M. Alejandra|last4=Wall|first4=Abigail|last5=McGuire|first5=Andrew T.|last6=Veesler|first6=David|title=Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein|journal=Cell|volume=181|issue=2|year=2020|pages=281–292.e6|issn=00928674|doi=10.1016/j.cell.2020.02.058}}</ref><ref name="ZhouYang2020">{{cite journal|last1=Zhou|first1=Peng|last2=Yang|first2=Xing-Lou|last3=Wang|first3=Xian-Guang|last4=Hu|first4=Ben|last5=Zhang|first5=Lei|last6=Zhang|first6=Wei|last7=Si|first7=Hao-Rui|last8=Zhu|first8=Yan|last9=Li|first9=Bei|last10=Huang|first10=Chao-Lin|last11=Chen|first11=Hui-Dong|last12=Chen|first12=Jing|last13=Luo|first13=Yun|last14=Guo|first14=Hua|last15=Jiang|first15=Ren-Di|last16=Liu|first16=Mei-Qin|last17=Chen|first17=Ying|last18=Shen|first18=Xu-Rui|last19=Wang|first19=Xi|last20=Zheng|first20=Xiao-Shuang|last21=Zhao|first21=Kai|last22=Chen|first22=Quan-Jiao|last23=Deng|first23=Fei|last24=Liu|first24=Lin-Lin|last25=Yan|first25=Bing|last26=Zhan|first26=Fa-Xian|last27=Wang|first27=Yan-Yi|last28=Xiao|first28=Geng-Fu|last29=Shi|first29=Zheng-Li|title=A pneumonia outbreak associated with a new coronavirus of probable bat origin|journal=Nature|volume=579|issue=7798|year=2020|pages=270–273|issn=0028-0836|doi=10.1038/s41586-020-2012-7}}</ref> [[SARS-CoV-2]] differs from [[SARS-CoV]] by 380 amino acid substitutions and thus has a stronger binding affinity than [[SARS-CoV]], which explains the global impact of [[SARS-CoV-2]] than the previous [[SARS-CoV]] outbreak.<ref name="YanZhang2020">{{cite journal|last1=Yan|first1=Renhong|last2=Zhang|first2=Yuanyuan|last3=Li|first3=Yaning|last4=Xia|first4=Lu|last5=Guo|first5=Yingying|last6=Zhou|first6=Qiang|title=Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2|journal=Science|volume=367|issue=6485|year=2020|pages=1444–1448|issn=0036-8075|doi=10.1126/science.abb2762}}</ref><ref name="ShangYe2020">{{cite journal|last1=Shang|first1=Jian|last2=Ye|first2=Gang|last3=Shi|first3=Ke|last4=Wan|first4=Yushun|last5=Luo|first5=Chuming|last6=Aihara|first6=Hideki|last7=Geng|first7=Qibin|last8=Auerbach|first8=Ashley|last9=Li|first9=Fang|title=Structural basis of receptor recognition by SARS-CoV-2|journal=Nature|volume=581|issue=7807|year=2020|pages=221–224|issn=0028-0836|doi=10.1038/s41586-020-2179-y}}</ref>
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| * ACE2 is the negative regulator of the Renin-Angiotensin system (RAS) and has protective benefits against many diseases and complications. [[SARS-CoV-2]] binds to ACE2 receptors, this blocks all the protective benefits of the ACE2 pathway and shifts the cascade back to ACE/Ang II/AT1R-pathway, increasing Ang II, decreasing ACE2 and Ang-( 1-7)<ref name="GheblawiWang2020">{{cite journal|last1=Gheblawi|first1=Mahmoud|last2=Wang|first2=Kaiming|last3=Viveiros|first3=Anissa|last4=Nguyen|first4=Quynh|last5=Zhong|first5=Jiu-Chang|last6=Turner|first6=Anthony J.|last7=Raizada|first7=Mohan K.|last8=Grant|first8=Maria B.|last9=Oudit|first9=Gavin Y.|title=Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System|journal=Circulation Research|volume=126|issue=10|year=2020|pages=1456–1474|issn=0009-7330|doi=10.1161/CIRCRESAHA.120.317015}}</ref><ref name="D’ArdesBoccatonda2020">{{cite journal|last1=D’Ardes|first1=Damiano|last2=Boccatonda|first2=Andrea|last3=Rossi|first3=Ilaria|last4=Guagnano|first4=Maria Teresa|last5=Santilli|first5=Francesca|last6=Cipollone|first6=Francesco|last7=Bucci|first7=Marco|title=COVID-19 and RAS: Unravelling an Unclear Relationship|journal=International Journal of Molecular Sciences|volume=21|issue=8|year=2020|pages=3003|issn=1422-0067|doi=10.3390/ijms21083003}}</ref> as shown in the figure.
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| [[File:COVID-19 associated Diabetes.PNG|600px|center]]
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| * Inhibition of '''RAS(Angiotensin→Ang1→Ang2→AT1R)''' protects pancreatic β-cells from oxidative stress-related tissue damage, therefore improves [[insulin]] synthesis and secretion.<ref name="GrankvistMarklund1981">{{cite journal|last1=Grankvist|first1=K|last2=Marklund|first2=S L|last3=Täljedal|first3=I B|title=CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse|journal=Biochemical Journal|volume=199|issue=2|year=1981|pages=393–398|issn=0264-6021|doi=10.1042/bj1990393}}</ref>Hyperactivity of [[RAS]] works in contrast. In '''[[adipose tissue]]''', Ras decreases insulin sensitivity, decreases glucose uptake. In '''[[Pancreas|pancreatic tissue]]''', it decreases [[insulin]] secretion, increases islet [[oxidative stress]] and [[fibrosis]], decrease perfusion.<ref name="BindomLazartigues2009">{{cite journal|last1=Bindom|first1=Sharell M.|last2=Lazartigues|first2=Eric|title=The sweeter side of ACE2: Physiological evidence for a role in diabetes|journal=Molecular and Cellular Endocrinology|volume=302|issue=2|year=2009|pages=193–202|issn=03037207|doi=10.1016/j.mce.2008.09.020}}</ref>
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| [[File:RAS.PNG|600px|center]]
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| * In an experimental trial, pressor doses of Ang-II were given to healthy human subjects. As a result, researchers observed suppression of basal, pulsatile, and glucose-stimulated [[insulin]] release.<ref name="FliserSchaefer1997">{{cite journal|last1=Fliser|first1=Danilo|last2=Schaefer|first2=Franz|last3=Schmid|first3=Daniela|last4=Veldhuis|first4=Johannes D.|last5=Ritz|first5=Eberhard|title=Angiotensin II Affects Basal, Pulsatile, and Glucose-Stimulated Insulin Secretion in Humans|journal=Hypertension|volume=30|issue=5|year=1997|pages=1156–1161|issn=0194-911X|doi=10.1161/01.HYP.30.5.1156}}</ref>This loss of [[insulin]] release is supposed to be the contributing factor in the development of [[Diabetes mellitus type 2|T2DM]].<ref name="Gerich2002">{{cite journal|last1=Gerich|first1=J. E.|title=Is Reduced First-Phase Insulin Release the Earliest Detectable Abnormality in Individuals Destined to Develop Type 2 Diabetes?|journal=Diabetes|volume=51|issue=Supplement 1|year=2002|pages=S117–S121|issn=0012-1797|doi=10.2337/diabetes.51.2007.S117}}</ref>
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| * SARS-CoV 2 can cause [[hyperglycemia]] by direct injuring of [[pancreatic beta cells]]<ref name="YangLin2009">{{cite journal|last1=Yang|first1=Jin-Kui|last2=Lin|first2=Shan-Shan|last3=Ji|first3=Xiu-Juan|last4=Guo|first4=Li-Min|title=Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes|journal=Acta Diabetologica|volume=47|issue=3|year=2009|pages=193–199|issn=0940-5429|doi=10.1007/s00592-009-0109-4}}</ref> and by downregulating ACE2 receptors leading to unopposed [[Angiotensin|angiotensin II]], which may hinder [[insulin]] secretion.<ref name="CarlssonBerne1998">{{cite journal|last1=Carlsson|first1=P.-O.|last2=Berne|first2=C.|last3=Jansson|first3=L.|title=Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats|journal=Diabetologia|volume=41|issue=2|year=1998|pages=127–133|issn=0012-186X|doi=10.1007/s001250050880}}</ref>
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| *To browse the pathophysiology of COVID-19, [[COVID-19 pathophysiology|Click here]].
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| ==Causes==
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| *[[SARS-CoV-2]] can cause COVID-19-associated [[diabetes mellitus]] by two mechanisms:
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| :* Direst damage of [[Beta-cells|pancreatic beta-cells]] by [[SARS-CoV-2|SARS-CoV 2]] <ref name="YangLin2009">{{cite journal|last1=Yang|first1=Jin-Kui|last2=Lin|first2=Shan-Shan|last3=Ji|first3=Xiu-Juan|last4=Guo|first4=Li-Min|title=Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes|journal=Acta Diabetologica|volume=47|issue=3|year=2009|pages=193–199|issn=0940-5429|doi=10.1007/s00592-009-0109-4}}</ref>
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| :* Downregulation of [[ACER2|ACE2]] by [[SARS-CoV-2|SARS-CoV 2]] shift the cascade to the [[Renin-angiotensin system|ACE/AngII/AT1R pathway]] which further leads to decrease [[insulin]] release and [[islet cell]] oxidative damage.<ref name="CarlssonBerne1998">{{cite journal|last1=Carlsson|first1=P.-O.|last2=Berne|first2=C.|last3=Jansson|first3=L.|title=Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats|journal=Diabetologia|volume=41|issue=2|year=1998|pages=127–133|issn=0012-186X|doi=10.1007/s001250050880}}</ref>
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| *To browse the causes of COVID-19, [[COVID-19 causes|Click here]].
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| ==Differentiating COVID-19-associated diabetes mellitus from other Diseases==
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| * For more information on COVID-19-associated diabetes mellitus differential diagnosis [[COVID-19-associated diabetes mellitus differential diagnosis|click here]].
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| *To browse the differential diagnosis of COVID-19, [[COVID-19 differential diagnosis|Click here]].
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| ==Epidemiology and Demographics==
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| * There is not enough data available on incidence and prevalence of COVID-19-associated Diabetes Mellitus.
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| * To browse the epidemiology and Demographics of [[Diabetes mellitus|Diabetes Mellitus]]. [[Diabetes mellitus|Click here]].
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| * To browse the epidemiology and demographics of COVID-19, [[COVID-19 epidemiology and demographics|Click here]].
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| ==Risk Factors==
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| * There are no established risk factors for COVID-19-associated Diabetes.
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| * To browse the risk factors for different types of [[Diabetes mellitus|Diabetes Mellitus]], [[Diabetes mellitus|Click here]].
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| * To browse the risk factors of COVID-19 [[COVID-19 risk factors|clicking here]].
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| ==Screening==
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| * There is insufficient evidence to recommend routine screening for COVID-19-associated Diabetes.
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| * To browse the screening performed for [[Diabetes mellitus|Diabetes Mellitus]], [[Diabetes mellitus|Click here]].
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| * To browse the screening performed for COVID-19, [[COVID-19 screening|Click here]].
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| ==Natural History, Complications, and Prognosis==
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| ===Natural History===
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| *A high [[Blood sugar|blood sugar level]] can cause several symptoms, including:<ref name="urlDiabetes: MedlinePlus Medical Encyclopedia">{{cite web |url=https://medlineplus.gov/ency/article/001214.htm |title=Diabetes: MedlinePlus Medical Encyclopedia |format= |work= |accessdate=}}</ref>
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| **[[Blurred vision|Blurry vision]]
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| **[[Polydipsia|Excess thirst]]
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| **[[Fatigue]]
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| **[[Polyuria|Frequent urination]]
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| **[[Hunger]]
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| **[[Weight loss]]
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| ===Complications===
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| *After many years, diabetes can lead to serious health problems:<ref name="urlDiabetes: MedlinePlus Medical Encyclopedia">{{cite web |url=https://medlineplus.gov/ency/article/001214.htm |title=Diabetes: MedlinePlus Medical Encyclopedia |format= |work= |accessdate=}}</ref>
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| **Blindness
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| **'''Infection:''' Feet and skin can develop sores and infections. After a long time, foot or leg may need to be amputated. Infection can also cause pain and itching in other parts of the body.
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| **'''High blood pressure and cholesterol:''' Diabetes may make it harder to control blood pressure and cholesterol. This can lead to a heart attack, stroke, and other problems. It can become harder for blood to flow to legs and feet.
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| **'''Neuropathy:''' Nerves in the body can get damaged, causing pain, tingling, and numbness. Because of nerve damage, one could have problems digesting the food. One could feel weakness or have trouble going to the bathroom. Nerve damage can make it harder for men to have an erection.
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| **'''Nephropathy:''' High blood sugar and other problems can lead to kidney damage. Kidneys may not work as well as they used to. They may even stop working so that one needs dialysis or a kidney transplant.
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| **'''Immune Dysfunction:''' Immune system can weaken, which can lead to frequent infections.<ref name="urlDiabetes: MedlinePlus Medical Encyclopedia">{{cite web |url=https://medlineplus.gov/ency/article/001214.htm |title=Diabetes: MedlinePlus Medical Encyclopedia |format= |work= |accessdate=}}</ref>
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| ===Prognosis===
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| *There is not enough data available on the prognosis of SARS-CoV-2 induced [[Diabetes mellitus|Diabetes Mellitus]]. Based on the data of SARS-CoV induced diabetes, the overall prognosis is good.
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| * In China, in the year 2008, a study was done in which they compared 39 [[SARS-CoV]] patients with no previous history of diabetes, who never used steroids, with 39 matched healthy siblings. The results of the study revealed that 20 out of 39 [[SARS-CoV]] patients developed new-onset diabetes during the hospital stay. After 3 years of recovery from the [[Coronavirus|SARS-CoV]] infection, only 5% of patients remained diabetic whereas [[Blood sugar|blood sugar levels]] normalized in the rest of the patients with the infection recovery.<ref name="YangLin2009">{{cite journal|last1=Yang|first1=Jin-Kui|last2=Lin|first2=Shan-Shan|last3=Ji|first3=Xiu-Juan|last4=Guo|first4=Li-Min|title=Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes|journal=Acta Diabetologica|volume=47|issue=3|year=2009|pages=193–199|issn=0940-5429|doi=10.1007/s00592-009-0109-4}}</ref>
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| *To browse the natural history, complications, and prognosis of COVID-19, [[COVID-19 natural history, complications and prognosis|Click here]].
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| ==Diagnosis==
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| ===Diagnostic Study of Choice===
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| *Diagnostic study of choice for diabetes mellitus is fasting plasma glucose (FPG). According to the American Diabetes Association (ADA) criteria, diabetes mellitus is diagnosed with FPG ≥126 mg/dL (7.0 mmol/L). <ref name="pmid25126259">{{cite journal |vauthors=Nguyen Q, Nguyen L, Felicetta J |title=Evaluation and management of diabetes mellitus |journal=Am Health Drug Benefits |volume=1 |issue=8 |pages=39–48 |date=October 2008 |pmid=25126259 |pmc=4106505 |doi= |url=}}</ref><ref name="pmid18165335">{{cite journal |vauthors= |title=Standards of medical care in diabetes--2008 |journal=Diabetes Care |volume=31 Suppl 1 |issue= |pages=S12–54 |date=January 2008 |pmid=18165335 |doi=10.2337/dc08-S012 |url=}}</ref><ref>{{cite journal|title=2. Classification and Diagnosis of Diabetes:Standards of Medical Care in Diabetes—2018|journal=Diabetes Care|volume=41|issue=Supplement 1|year=2017|pages=S13–S27|issn=0149-5992|doi=10.2337/dc18-S002}}</ref>
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| *To browse the diagnostic study of choice of COVID-19, [[COVID-19 diagnostic study of choice|Click here]].
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| ===History and Symptoms===
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| *According to a recent case report of [[Diabetic ketoacidosis|Diabetic ketoacidoses]] precipitated by [[COVID-19]] in a patient with newly diagnosed [[diabetes mellitus]]. He was a previously healthy man presented with 1-week history of:
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| **Fever (38.5 °C)
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| **[[Nausea and vomiting|Vomiting,]]
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| **[[Polydipsia]] (intense thirst)
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| **[[Polyuria]] (production of abnormally large volumes of dilute urine)<ref name="CheeNg2020">{{cite journal|last1=Chee|first1=Ying Jie|last2=Ng|first2=Shereen Jia Huey|last3=Yeoh|first3=Ester|title=Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus|journal=Diabetes Research and Clinical Practice|volume=164|year=2020|pages=108166|issn=01688227|doi=10.1016/j.diabres.2020.108166}}</ref>
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| *To browse the history and symptoms of COVID-19, [[COVID-19 history and symptoms|Click here]].
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| ===Physical Examination===
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| * Mildly [[Tachycardia|tachycardic]]
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| * Kusmmaul's breathing was not observed.<ref name="CheeNg2020">{{cite journal|last1=Chee|first1=Ying Jie|last2=Ng|first2=Shereen Jia Huey|last3=Yeoh|first3=Ester|title=Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus|journal=Diabetes Research and Clinical Practice|volume=164|year=2020|pages=108166|issn=01688227|doi=10.1016/j.diabres.2020.108166}}</ref>
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| *To browse the physical examination of COVID-19, [[COVID-19 physical examination|Click here]].
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| ===Laboratory Findings===
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| {| class="wikitable"
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| |+Laboratory findings in a patient with COVID-19-associated diabetes mellitus<ref name="pmid32339533">{{cite journal| author=Chee YJ, Ng SJH, Yeoh E| title=Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus. | journal=Diabetes Res Clin Pract | year= 2020 | volume= 164 | issue= | pages= 108166 | pmid=32339533 | doi=10.1016/j.diabres.2020.108166 | pmc=7194589 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32339533 }} </ref>
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| !Investigation
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| !Result
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| !Reference Range
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| |-
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| |[[Venous]] [[glucose]] (mmol/L)
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| |39.7
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| | –
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| |-
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| |[[Arterial blood gas]]
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| |-
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| |[[pH]] (mmHg)
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| |7.28
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| |7.25–7.35
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| |-
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| |[[Bicarbonate]] (mmol/L)
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| |12
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| |22–28
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| |-
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| |[[pCO2]] (mmHg)
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| |25
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| |35–45
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| |-
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| |[[Sodium]] (mmol/L)
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| |128
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| |135–145
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| |-
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| |[[Chloride]] (mmol/L)
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| |86
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| |95–110
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| |-
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| |[[Anion gap]]
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| |30
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| |8–16
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| |-
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| |[[Ketones]] (mmol/L)
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| |6.4
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| |<0.6
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| |-
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| |[[Creatinine]] (umol/L)
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| |95
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| |67–112
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| |-
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| |Glycated hemoglobin (%)
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| |14.2
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| | –
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| |}<br />
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| *[[COVID-19|COVID-19 infection]] can cause [[ketosis]] and [[ketoacidosis]].<ref name="LiWang2020">{{cite journal|last1=Li|first1=Juyi|last2=Wang|first2=Xiufang|last3=Chen|first3=Jian|last4=Zuo|first4=Xiuran|last5=Zhang|first5=Hongmei|last6=Deng|first6=Aiping|title=
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| COVID
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| ‐19 infection may cause ketosis and ketoacidosis
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| |journal=Diabetes, Obesity and Metabolism|year=2020|issn=1462-8902|doi=10.1111/dom.14057}}</ref>When the body doesn’t make enough [[insulin]] to break down sugar, it uses [[Ketone|ketones]] as an alternative source of fuel.<ref>{{cite web |url=https://www.nature.com/articles/d41586-020-01891-8 |title=Mounting clues suggest the coronavirus might trigger diabetes |format= |work= |accessdate=}}</ref>
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| *To browse the laboratory findings of COVID-19, [[COVID-19 laboratory findings|Click here]].
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| *To browse the diagnosis of [[Diabetes mellitus]], [[Diabetes mellitus|Click here]].
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| ===Electrocardiogram===
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| * There are no [[electrocardiographic]] findings of COVID-19 associated Diabetes Mellitus.
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| * To browse the electrocardiogram findings of COVID-19, [[COVID-19 electrocardiogram|click here]].<br />
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| ===X-ray===
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| *There are no X-ray findings of COVID-19-associated diabetes mellitus.
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| * To view the x-ray finidings of COVID-19, [[COVID-19 x ray|click here]].<br />
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| ===Echocardiography or Ultrasound===
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| *There are no echocardiography/ultrasound findings associated with [[COVID-19]]-associated diabetes mellitus.
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| * To browse the [[echocardiography]] findings of [[COVID-19]], [[COVID-19 echocardiography and ultrasound|Click here]].
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| ===CT Scan===
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| *There are no CT scan findings associated with [[COVID-19]]-associated diabetes mellitus.
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| *To browse the CT Scan findings of [[COVID-19]], [[COVID-19 CT scan|Click here]].
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| ===MRI===
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| *There are no MRI findings associated with COVID-19-associated diabetes mellitus.
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| * To browse the MRI findings of COVID-19, [[COVID-19 MRI|Click here]].
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| ===Other Diagnostic Studies===
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| *Fasting plasma glucose (FPG) test
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| *HbA1C or A1C test
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| *Random plasma glucose (RPG) test<ref name="urlDiabetes Tests & Diagnosis | NIDDK">{{cite web |url=https://www.niddk.nih.gov/health-information/diabetes/overview/tests-diagnosis#diagnosediabetes |title=Diabetes Tests & Diagnosis | NIDDK |format= |work= |accessdate=}}</ref>
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| ==Treatment==
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| ===Medical Therapy===
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| *A 37-year-old, previously healthy man diagnosed with [[COVID-19]]-associated diabetes mellitus. The patient received 6 L of [[intravenous fluids]] and [[Insulin|intravenous insulin infusion]] in the first 24 h. Serum electrolytes were closely monitored. [[Diabetes]] resolved the following day and he was transitioned to [[Insulin|subcutaneous insulin therapy]].<ref name="pmid32339533">{{cite journal| author=Chee YJ, Ng SJH, Yeoh E| title=Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus. | journal=Diabetes Res Clin Pract | year= 2020 | volume= 164 | issue= | pages= 108166 | pmid=32339533 | doi=10.1016/j.diabres.2020.108166 | pmc=7194589 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32339533 }} </ref>
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| *To browse the treatment of Diabetes Mellitus, [[Diabetes mellitus|Click here]].
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| ===Primary Prevention===
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| *Keeping an ideal body weight and an active lifestyle may prevent or delay the start of [[diabetes]]. If overweight, losing just 5% of body weight can reduce the risk.<ref name="urlDiabetes: MedlinePlus Medical Encyclopedia">{{cite web |url=https://medlineplus.gov/ency/article/001214.htm |title=Diabetes: MedlinePlus Medical Encyclopedia |format= |work= |accessdate=}}</ref>
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| ===Secondary Prevention===
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| * Getting better control over your [[blood sugar]], [[cholesterol]], and [[blood pressure]] levels help reduce the risk for [[Nephropathy|kidney disease]], [[eye disease]], [[nervous system disease]], [[Heart attack (patient information)|heart attack]], and [[stroke]].<ref name="urlDiabetes: MedlinePlus Medical Encyclopedia">{{cite web |url=https://medlineplus.gov/ency/article/001214.htm |title=Diabetes: MedlinePlus Medical Encyclopedia |format= |work= |accessdate=}}</ref>
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| *To browse the medical therapy of COVID-19, [[COVID-19 medical therapy|Click here]].
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| ==References==
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| {{reflist|2}}
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