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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 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:COVID 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]]''':'''As a result of high blood sugar, feet and skin can develop sores and infections.
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| :*[[High blood pressure|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]]''':''' High blood sugar can damage the nerves, causing [[pain]], tingling, and [[Paresthesia|numbness]].
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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 transplantation|kidney transplant]].
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| :*[[Immune dysfunction|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. [[Diabetic ketoacidosis]] 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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