Incidence, risk factors, and prognosis of stroke in people with type 1 diabetes

(1)

Folkhälsan Institute of Genetics Folkhälsan Research Center

Helsinki, Finland

Research Program for Clinical and Molecular Metabolism Faculty of Medicine, University of Helsinki

Helsinki, Finland Abdominal Center, Nephrology

University of Helsinki and Helsinki University Hospital Helsinki, Finland

Doctoral Program in Clinical Research Department of Medicine

University of Helsinki Helsinki, Finland

Incidence, risk factors, and prognosis of stroke in people with type 1 diabetes

STEFANIE HÄGG-HOLMBERG

ACADEMIC DISSERTATION

To be presented, with the permission of the Medical Faculty of the University of Helsinki, for public examination in Auditorium 2, Biomedicum Helsinki, Haartmaninkatu 8

on March 26^th, 2021, at 12 noon.

Helsinki 2021

(2)

Supervised by Docent Lena Thorn

Folkhälsan Institute of Genetics

Folkhälsan Research Center, Helsinki, Finland

Research Program for Clinical and Molecular Metabolism Faculty of Medicine

University of Helsinki

Helsinki, Finland

Department of General Practice and Primary Health Care University of Helsinki and Helsinki University Hospital

Helsinki, Finland

and

Professor Per-Henrik Groop Folkhälsan Institute of Genetics

Folkhälsan Research Center, Helsinki, Finland

Research Program for Clinical and Molecular Metabolism Faculty of Medicine

University of Helsinki

Helsinki, Finland

Abdominal Center, Nephrology

University of Helsinki and Helsinki University Hospital

Helsinki, Finland

(3)

Reviewed by Professor Päivi Korhonen Department of General Practice Turku University Hospital University of Turku

Turku, Finland

and

Docent Jussi Sipilä

Department of Clinical Neuroscience University of Turku

Turku, Finland

Opponent Professor Coen Stehouwer Department of Medicine University of Maastricht Maastricht, The Netherlands

(4)

The Faculty of Medicine uses the Urkund system (plagiarism recognition) to examine all doctoral dissertations.

,6%1ɺɸɹɺɶɲɶɲɸɲɳɴɹSDSHUEDFN ,6%1ɺɸɹɺɶɲɶɲɸɲɳɵɶ3') KWWSHWKHVLVKHOVLQNL¿

8QLJUD¿D2\

+HOVLQNLɳɱɳɲ

(5)

To Henrik, Lucas and Alva

“Nothing in life is to be feared, it is only to be understood.

Now is the time to understand more, so that we may fear less”

Marie Curie

(6)

(7)

ɸ

LIST OF ORIGINAL PUBLICATIONS

This thesis is based on the following publications:

I Hägg S, Thorn LM, Putaala J, Liebkind R, Harjutsalo V, Forsblom CM, Gordin D, Tatlisumak T, Groop PH; FinnDiane Study Group. Incidence of stroke according to presence of diabetic nephropathy and severe diabetic retinopathy LQSDWLHQWVZLWKW\SHɲGLDEHWHVDiabetes Careɳɱɲɴɴɷɵɲɵɱɵɲɵɷ

II Hägg S, Thorn LM, Forsblom CM, Gordin D, Saraheimo M, Tolonen N, Wadén J, Liebkind R, Putaala J, Tatlisumak T, Groop PH; FinnDiane Study Group.

'LɣHUHQWULVNIDFWRUSUR¿OHVIRULVFKHPLFDQGKHPRUUKDJLFVWURNHLQW\SHɲ diabetes. Stroke ɳɱɲɵɵɶɳɶɶɹɳɶɷɳ

,,, +lJJ+ROPEHUJ6'DKOVWU|P(+)RUVEORP&0+DUMXWVDOR9/LHENLQG5 Putaala J, Tatlisumak T, Groop PH, Thorn LM; FinnDiane Study Group. The UROHRIEORRGSUHVVXUHLQULVNRILVFKHPLFDQGKHPRUUKDJLFVWURNHLQW\SHɲ diabetes. Cardiovascular Diabetologyɳɱɲɺɲɹɹɹ

,9 +lJJ+ROPEHUJ67KRUQ/0)RUVEORP&0*RUGLQ'(ORQHQ1+DUMXWVDOR V, Liebkind R, Putaala J, Tatlisumak T, Groop PH; FinnDiane Study Group.

3URJQRVLV DQG LWV SUHGLFWRUV DIWHU LQFLGHQW VWURNH LQ SDWLHQWV ZLWK W\SH ɲ diabetes. Diabetes Careɳɱɲɸɵɱɲɴɺɵɲɵɱɱ

These publications are referred to in the text by their Roman numerals and have been reprinted with the kind permission of their copyright holders.

(12)

ɲɳ

ABBREVIATIONS

ɳɵK. ɳɵKRXUXULQDU\SRWDVVLXPH[FUHWLRQ ɳɵK1D ɳɵKRXUXULQDU\VRGLXPH[FUHWLRQ

AHT Antihypertensive treatment

BMI Body mass index

&.'(3, &KURQLF.LGQH\'LVHDVH(SLGHPLRORJ\&ROODERUDWLRQ

CT Computed tomography

DCCT/EDIC Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications

DN Diabetic nephropathy

eGDR Estimated glucose disposal rate H*)5 (VWLPDWHGJORPHUXODU¿OWUDWLRQUDWH (65' (QGVWDJHUHQDOGLVHDVH

FinnDiane Finnish Diabetic Nephropathy HbA_ɲF Glycosylated hemoglobin A_ɲF +'/ +LJKGHQVLW\OLSRSURWHLQ

Hilmo National Care Register for Health Care Hp Haptoglobin

HR Hazard ratio

KV&UHDFWLYHSURWHLQ +LJKVHQVLWLYLW\&UHDFWLYHSURWHLQ ,&' ,QWHUQDWLRQDO&ODVVL¿FDWLRQRI'LVHDVHV

ICH Intracerebral hemorrhage

JS Joint Statement criteria

.',*2 .LGQH\'LVHDVH,PSURYLQJ*OREDO2XWFRPHV

LACI Lacunar infarction

/'/ /RZGHQVLW\OLSRSURWHLQ

MRI Magnetic resonance imaging

NCEP National Cholesterol Education Program Adult Treatment Panel III criteria

1D.UDWLR 6RGLXPSRWDVVLXPUDWLR

PACI Partial anterior circulation infarct

Pittsburgh EDC Pittsburgh Epidemiology of Diabetes Complications 32&, 3RVWHULRUFLUFXODWLRQLQIDUFW

SAH Subarachnoid hemorrhage

SDR Severe diabetic retinopathy

TACI Total anterior circulation infarct

TIA Transient ischemic attack

UAER Urinary albumin excretion rate

:+5 :DLVWWRKLSUDWLR

(13)

ɲɴ

ABSTRACT

Background. ,QGLYLGXDOVZLWKW\SHɲGLDEHWHVKDYHDɶWRɳɱWLPHVKLJKHU ULVNRIVXɣHULQJDVWURNHZKHQFRPSDUHGZLWKERWKLQGLYLGXDOVZKRKDYHW\SHɳ diabetes and the general population. Such individuals also have a worse prognosis DIWHUVXɣHULQJDVWURNH<HWRQO\DIHZSULRUVWXGLHVKDYHLQYHVWLJDWHGWKHLQFLGHQFH and risk factors associated with stroke and its subtypes in individuals with type ɲGLDEHWHV)XUWKHUPRUHWKHSUHGLFWRUVRIVXUYLYDOIROORZLQJDVWURNHUHPDLQ unclear.

Aim. This study sought to examine the incidence and risk factors associated ZLWKVWURNHLQLQGLYLGXDOVZLWKW\SHɲGLDEHWHV,WDOVRVRXJKWWRHOXFLGDWHWKH prognosis and related predictors following an incident stroke in individuals with W\SHɲGLDEHWHV

Participants and methods. This study was conducted as part of the nationwide, multicenter FinnDiane Study, which aims to discover the genetic, HQYLURQPHQWDODQGFOLQLFDOULVNIDFWRUVDVVRFLDWHGZLWKPLFURDQGPDFURYDVFXODU FRPSOLFDWLRQVLQLQGLYLGXDOVZLWKW\SHɲGLDEHWHV7KHSRSXODWLRQIRU6WXGLHV ,,,DQG,9FRPSULVHGɵɱɹɴSDUWLFLSDQWVZLWKW\SHɲGLDEHWHVRIZKRPɲɵɺ KDGVXɣHUHGDQLQFLGHQWVWURNH7KHSRSXODWLRQIRU6WXG\,,,FRPSULVHGɵɲɱɶ SDUWLFLSDQWVZLWKW\SHɲGLDEHWHVRIZKRPɳɱɳKDGVXɣHUHGDQLQFLGHQWVWURNH

$OOIRXUVWXGLHVZHUHREVHUYDWLRQDOIROORZXSVWXGLHV$OOWKHLQFOXGHGSDUWLFLSDQWV were examined according to the same examination protocol. Individuals with W\SHɲGLDEHWHVZKRKDGVXɣHUHGDVWURNHZHUHLGHQWL¿HGWKURXJKWKH)LQQ'LDQH 6WXG\TXHVWLRQQDLUHVGHDWKFHUWL¿FDWHVDQGWKH1DWLRQDO&DUH5HJLVWHUIRU+HDOWK

&DUHDVEDVHGRQWKHWHQWKUHYLVLRQRIWKH,QWHUQDWLRQDO&ODVVL¿FDWLRQRI'LVHDVHV FRGHV,ɷɱ±,ɷɵ7KHSDUWLFLSDQWV¶VWURNHVZHUHFODVVL¿HGLQWRGLɣHUHQWVXEW\SHV EDVHGRQWKHLUPHGLFDO¿OHVDQGEUDLQLPDJHV

Results. The incidence of stroke and its subtypes (i.e., ischemic stroke, lacunar infarction, and hemorrhagic stroke) increased with the presence of both severe diabetic retinopathy and advancing diabetic nephropathy. A long duration of diabetes, poor glycemic control, high systolic blood pressure, a history of smoking, and lower insulin sensitivity were all found to be independent risk factors for ischemic stroke, while high systolic blood pressure and a lower body mass index were found to increase the risk of hemorrhagic stroke, along with severe diabetic retinopathy and diabetic nephropathy. The risk factors associated with lacunar infarctions were determined to be similar to those associated with ischemic stroke.

(14)

ɲɵ

$OOWKHGLɣHUHQWEORRGSUHVVXUHYDULDEOHVLHV\VWROLFEORRGSUHVVXUHGLDVWROLF blood pressure, mean arterial pressure, and pulse pressure) were found to be DVVRFLDWHGZLWKDQLQFUHDVHGULVNRIVWURNHLQLQGLYLGXDOVZLWKW\SHɲGLDEHWHV7KH risk of stroke increased in a linear fashion with increasing blood pressure, while QRHɣHFWRQWKHULVNRIVWURNHZDVLGHQWL¿HGLQUHODWLRQWRXULQDU\VRGLXPDQG potassium excretion. The overall likelihood of survival following an incident stroke ZDVIRXQGWREHSRRUZLWKDURXQGɶɴRISDUWLFLSDQWVKDYLQJGLHGGXULQJWKH PHDQIROORZXSSHULRGRIɴɵ\HDUV,VFKHPLFVWURNHZDVREVHUYHGWREHDVVRFLDWHG ZLWKDEHWWHUSURJQRVLVWKDQKHPRUUKDJLFVWURNHHVSHFLDOO\GXULQJWKH¿UVW\HDU following the stroke. The predictors of a worse outcome were found to be a stroke RIKHPRUUKDJLFRULJLQZRUVHQLQJNLGQH\IXQFWLRQDQGWKHSUHVHQFHRIHQGVWDJH renal disease.

Conclusions. ,QGLYLGXDOVZLWKW\SHɲGLDEHWHVZKRVXɣHUDVWURNHDUHJHQHUDOO\

of poorer health and have more diabetic complications, higher blood pressure, and ZRUVHJO\FHPLFFRQWUROWKDQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVZKRGRQRWVXɣHUD stroke. Both elevated systolic blood pressure and diabetic kidney disease represent important risk factors with regard to the development of stroke. The prognosis IROORZLQJDVWURNHLVSRRULQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVDQGWKHSUHVHQFHRI GLDEHWLFNLGQH\GLVHDVHKDVDVXEVWDQWLDOO\QHJDWLYHHɣHFWRQWKHLUSURJQRVLV,Q terms of the prevention and treatment of stroke, it is important to identify these KLJKULVNLQGLYLGXDOV7KLVFRXOGEHDFKLHYHGWKURXJKUHJXODUPHDVXUHPHQWVRI WKHEORRGSUHVVXUHDQGEORRGJOXFRVHOHYHOVRILQGLYLGXDOVZLWKW\SHɲGLDEHWHV in addition to screening for albuminuria.

(15)

ɲɶ

ABSTRAKT (ABSTRACT IN SWEDISH)

Bakgrund. 3HUVRQHUPHGW\SɲGLDEHWHVKDUHQɶ±ɳɱIDOGLJULVNI|UVWURNHMlP I|UWPHGSHUVRQHUPHGW\SɳGLDEHWHVVDPWSHUVRQHUXWDQGLDEHWHV3URJQRVHQ HIWHUHQVWURNHlURFNVnVlPUHYLGW\SɲGLDEHWHV7URWVGHWWD¿QQVGHWInVWXGLHU VRPXWUHGHULQFLGHQVRFKULVNIDNWRUHUI|UVWURNHYLGW\SɲGLDEHWHV'HWlURFNVn RNODUWYLONDIDNWRUHUVRPSnYHUNDUSURJQRVHQHIWHUHQVWURNHYLGW\SɲGLDEHWHV Studiens målsättningar. Målsättningen med denna avhandling var att ut UHGDLQFLGHQVHQVDPWULVNIDNWRUHUQDI|UVWURNHKRVSHUVRQHUPHGW\SɲGLDEHWHV Dessutom ville vi utreda vad prognosen är efter en stroke, samt vilka faktorer som påverkar den här prognosen.

Patienter och metoder. Den här avhandlingen är en del av den nationella PXOWLFHQWHUVWXGLHQ)LQQ'LDQHYDUVPnOlUDWWXWUHGDJHQHWLVNDPLOM|EHWLQJDGH RFKNOLQLVNDULVNIDNWRUHUI|UPLNURRFKPDNURYDVNXOlUDNRPSOLNDWLRQHUYLGW\S ɲGLDEHWHV3RSXODWLRQHQLVWXGLHUQD,,,RFK,9EHVWnUDYɵɱɹɴGHOWDJDUHPHG W\SɲGLDEHWHV$YGHVVDLQVMXNQDGHɲɵɺSHUVRQHULHQVWURNHI|UI|UVWDJnQJHQ XQGHUXSSI|OMQLQJVWLGHQ3RSXODWLRQHQLVWXGLH,,,EHVWnUDYɵɲɱɶGHOWDJDUHPHG W\SɲGLDEHWHVYDUDYɳɱɳLQVMXNQDGHLHQVWURNHI|UI|UVWDJnQJHQXQGHUXSS I|OMQLQJVWLGHQ$OODVWXGLHUQDlUHPSLULVNDXSSI|OMQLQJVVWXGLHU$OODLQNOXGHUDGH GHOWDJDUHJHQRPJLFNVDPPDXQGHUV|NQLQJVSURWRNROOYLD)LQQ'LDQHVWXGLHQ6W URNHLGHQWL¿HUDGHVIUnQ)LQQ'LDQHVWXGLHQVIUnJHIRUPXOlUG|GVFHUWL¿NDWVDPW det nationella vårdanmälningssystemet, baserat på den tionde upplagan av den ,QWHUQDWLRQHOODVWDWLVWLVNDNODVVL¿NDWLRQHQDYVMXNGRPDURFKUHODWHUDGHKlOVRSUR EOHP,&'NRGHUQD,ɷɱ,ɷɵ6WURNHNODVVL¿FHUDGHVLXQGHUJUXSSHUSnEDVHQDY patientjournaler samt radiologiska bilder på hjärnan.

Resultat.,QFLGHQVHQI|UVWURNHVDPWXQGHUW\SHUQDKMlUQLQIDUNWODNXQlULQIDUNW RFKKMlUQEO|GQLQJYDUK|JUHYLGDOOYDUOLJGLDEHWHVUHWLQRSDWLRFKGLDEHWHVQHIURSDWL ,QFLGHQVHQ|NDGHLWDNWPHGDWWGLDEHWHVQHIURSDWLQIUDPVNUHG/nQJGLDEHWHVGXUD WLRQGnOLJEORGVRFNHUEDODQVK|JWV\VWROLVNWEORGWU\FNU|NQLQJVEDNJUXQGRFKOnJ LQVXOLQNlQVOLJKHWYDUDOODVMlOYVWlQGLJDULVNIDNWRUHUI|UKMlUQLQIDUNWPHGDQK|JW systoliskt blodtryck och lågt kroppsmasseindex, tillsammans med diabetesnefro SDWLRFKGLDEHWHVUHWLQRSDWLVMlOYVWlQGLJW|NDGHULVNHQI|UKMlUQEO|GQLQJ'HVMlOY VWlQGLJDULVNIDNWRUHUQDI|UODNXQlULQIDUNWYDUGHVDPPDVRPI|UKMlUQLQIDUNW De olika blodtryckskomponenterna, dvs systoliskt blodtryck, diastoliskt blodtryck, SXOVWU\FNVDPWPHGHODUWlUWU\FNYDUDOODDVVRFLHUDGHPHGHQI|UK|MGULVNI|UVWURNH YLGW\SɲGLDEHWHV5LVNHQI|UVWURNH|NDGHOLQHlUWLWDNWPHGDWWEORGWU\FNHWVWHJ

(16)

ɲɷ

8WV|QGULQJHQDYQDWULXPRFKNDOLXPLXULQHQSnYHUNDGHLQWHULVNHQI|UVWURNH 3URJQRVHQHIWHUHQVWURNHYDUGnOLJɶɴDYGHOWDJDUQDGRJXQGHUXSSI|OMQLQJV WLGHQSnɴɵnU+MlUQLQIDUNWKDGHHQElWWUHSURJQRVlQKMlUQEO|GQLQJVSHFLHOOW XQGHUGHWI|UVWDnUHWHIWHUVWURNHQ+MlUQEO|GQLQJRFKI|UVlPUDGQMXUIXQNWLRQ VSHFLHOOWQMXUVMXNGRPLVOXWVNHGHWYDUULVNIDNWRUHUI|UHQVlPUHSURJQRV Slutsatser.3HUVRQHUPHGW\SɲGLDEHWHVVRPLQVMXNQDULHQVWURNHlULDOOPlQKHW VMXNDGHKDUPHUGLDEHWLVNDNRPSOLNDWLRQHURFKK|JUHEORGWU\FNVDPWVlPUH EORGVRFNHUEDODQVlQGHSHUVRQHUPHGW\SɲGLDEHWHVVRPLQWHInUHQVWURNH+|JW V\VWROLVNWEORGWU\FNVDPWGLDEHWLVNQMXUVMXNGRPlUYLNWLJDULVNIDNWRUHUI|UXSS NRPVWHQDYVWURNH3URJQRVHQHIWHUHQVWURNHlURFNVnGnOLJRFKI|UHNRPVWHQDY GLDEHWLVNQMXUVMXNGRPSnYHUNDUSURJQRVHQWLOOHQVWRUGHO)|UDWWI|UHE\JJDRFK LQOHGDYnUGDYVWURNHYLGW\SɲGLDEHWHVlUGHWGlUPHGYLNWLJWDWWLGHQWL¿HUDGHVVD K|JULVNSHUVRQHULWLG5HJHOEXQGHQXSSI|OMQLQJDYEORGWU\FNHWRFKEORGVRFNUHW VDPWVnOOQLQJI|UDOEXPLQXULlUGHYLNWLJDVWHUHGVNDSHQI|UDWWLGHQWL¿HUDGHVVD personer.

(17)

ɲɸ

TIIVISTELMÄ (ABSTRACT IN FINNISH)

Tausta.7\\SLQɲGLDEHWHVWDVDLUDVWDYLOODKHQNLO|LOOlRQɶ±ɳɱNHUWDLQHQULVNLVDL UDVWXDDLYRKDOYDXNVHHQYHUUDWWXQDW\\SLQɳGLDEHWHVWDVDLUDVWDYLLQKHQNLO|LKLQMD HLGLDEHHWLNRLKLQ+HLOOlRQP\|VKXRQRPSLHQQXVWHVDLUDVWHWXQDLYRKDOYDXNVHQ MlONHHQ7XWNLPXNVLDDLYRKDOYDXNVHQHVLLQW\Y\\GHVWlMDULVNLWHNLM|LVWlW\\SLQɲ diabeteksessa on tästä huolimatta vähän. Lisäksi aivohalvauksen jälkeisen ennus WHHVHHQYDLNXWWDYLDWHNLM|LWlW\\SLQɲGLDEHWHVWDVDLUDVWDYLOODKHQNLO|LOOlWXQQHWD Tavoitteet. 7lPlQYlLW|VNLUMDQWDYRLWWHHQDROLVHOYLWWllDLYRKDOYDXNVHQHVLLQW\

Y\\WWlMDULVNLWHNLM|LWlW\\SLQɲGLDEHWHVWDVDLUDVWDYLOODKHQNLO|LOOlVHNlVHOYHQWll mikä on aivohalvauksen jälkeinen ennuste ja mitkä tekijät tähän vaikuttavat.

Aineisto ja menetelmät.7lPlYlLW|VNLUMDRQRVD)LQQ'LDQHWXWNLPXVWDMRND on kansallinen monikeskustutkimus, jonka tavoitteena on selvittää geneettisiä, NOLLQLVLlMD\PSlULVW|OOLVLlULVNLHNLM|LWlPLNURMDPDNURYDVNXODDULVLLQOLLWlQQlLV VDLUDXNVLLQW\\SLQɲGLDEHWHNVHVVD2VDWXWNLPXVWHQ,,,MD,9QSRWLODVDLQHLVWR NRRVWXXɵɱɹɴW\\SLQɲGLDEHWHVWDVDLUDVWDYDVWDKHQNLO|VWlMRLVWDɲɵɺVDLUDVWXL HQVLPPlLVHHQDLYRKDOYDXNVHHQVHXUDQWDDLNDQD2VDWXWNLPXV,,,QSRWLODVDLQHLV WRNRRVWXXɵɲɱɶW\\SLQɲGLDEHWHVWDVDLUDVWDYDVWDKHQNLO|VWlMRLVWDɳɱɳVDLUDVWXL HQVLPPlLVHHQDLYRKDOYDXNVHHQVHXUDQWDDLNDQD.DLNNLRVDWXWNLPXNVHWRYDWHP SLLULVLlVHXUDQWDWXWNLPXNVLD.DLNNLWXWNLPXNVHHQRVDOOLVWXMDWWXWNLWWLLQVDPDOOD )LQQ'LDQHWXWNLPXVSURWRNROODOOD$LYRKDOYDXNVHWWXQQLVWHWWLLQ)LQQ'LDQHWXW kimuksen kyselylomakkeesta, kuolintodistuksista sekä kansallisesta Hoitoilmoi WXVUHNLVWHULVWlNDQVDLQYlOLVHQWDXWLOXRNLWXVWHQSHUXVWHHOOD,&'NRRGLW,ɷɱ,ɷɵ Aivohalvaukset luokiteltiin alaluokkiin sairaskertomusten ja aivojen radiologisten NXYDQWDPLVO|\G|VWHQSHUXVWHHOOD

Tulokset. Aivohalvauksen sekä alaluokkien (aivoinfarktit, lakunaariset infarktit MDDLYRYHUHQYXRGRWHVLLQW\Y\\VROLNRUNHDKHQNLO|LOOlMRLOODROLVDPDQDLNDLVHVWL diabeettinen retinopatia ja diabeteksen munuaistauti. Esiintyvyys oli sitä kor keampi, mitä vaikeampi diabeteksen munuaistauti oli. Pitkä diabeteksen kesto, huono verensokeritasapaino, korkea systolinen verenpaine, tupakointitausta ja KXRQRPSLLQVXOLLQLKHUNN\\VROLYDWDLYRLQIDUNWLQLWVHQlLVLlULVNLWHNLM|LWlNXQWDDV korkea systolinen verenpaine ja matala painoindeksi olivat diabeettisen retinopati DQMDGLDEHHWWLVHQPXQXDLVWDXGLQOLVlNVLDLYRYHUHQYXRGRQLWVHQlLVLlULVNLWHNLM|LWl Lakunaarisen infarktin riskitekijät olivat samat kuin aivoinfarktin riskitekijät.

.DLNNLHULOOLVHWYHUHQSDLQHNRPSRQHQWLWHOLV\VWROLQHQYHUHQSDLQHGLDVWROLQHQYH renpaine, keskiverenpaine ja pulssipaine lisäsivät riskiä sairastua aivohalvaukseen

(18)

ɲɹ

W\\SLQɲGLDEHWHNVHVVD$LYRKDOYDXNVHQULVNLQRXVLOLQHDDULVHVWLYHUHQSDLQHHQ nousun yhteydessä. Virtsaan erittyvä natrium ja kalium eivät vaikuttaneet aivo KDOYDXNVHQULVNLLQ(QQXVWHDLYRKDOYDXNVHQMlONHHQROLKHLNNRɶɴRVDOOLVWXMLVWD NXROLɴɵYXRGHQNHVNLPllUlLVHQVHXUDQWDDMDQDLNDQD$LYRLQIDUNWLLQVDLUDVWX neilla oli parempi ennuste verrattuna aivoverenvuotoon sairastuneilla, mikä nä kyi varsinkin ensimmäisen vuoden aikana aivohalvauksen jälkeen. Ennustetta huonontavat tekijät olivat aivoverenvuoto, heikentynyt munuaisten toiminta ja varsinkin loppuvaiheen diabeteksen munuaistauti.

Päätelmät. $LYRKDOYDXNVHHQ VDLUDVWXQHHW W\\SLQ ɲ GLDEHWHVWD VDLUDVWDYDW KHQNLO|WRYDW\OHLVHVWLVDLUDDPSLDNXLQW\\SLQɲGLDEHWHVWDVDLUDVWDYDWKHQNLO|W ilman aivohalvausta, ja heillä on enemmän diabeettisia komplikaatioita, korke DPSLYHUHQSDLQHVHNlKXRQRPSLYHUHQVRNHULWDVDSDLQR.RUNHDV\VWROLQHQYHUHQ SDLQHVHNlGLDEHWHNVHQPXQXDLVWDXWLRYDWWlUNHLWlDLYRKDOYDXNVHQULVNLWHNLM|LWl (QQXVWH VDLUDVWHWXQ DLYRKDOYDXNVHQ MlONHHQ RQ P\|V KHLNNR MD GLDEHWHNVHQ munuaistauti vaikuttaa ennusteeseen suuresti. Aivohalvauksen ennaltaehkäisyn MDKRLGRQNDQQDOWDRQHULWWlLQWlUNHllWXQQLVWDDQlPlNRUNHDQULVNLQKHQNLO|W 6llQQ|OOLQHQYHUHQSDLQHHQMDYHUHQVRNHULQVHXUDQWDVHNlDOEXPLQXULDQVHX ORQWDYLUWVDVWDRYDWWlUNHLPPlWYlOLQHHWQlLGHQKHQNLO|LGHQWXQQLVWDPLVHNVL

(19)

ɲɺ

1 INTRODUCTION

'LDEHWHVDɣHFWHGDURXQGɵɷɴPLOOLRQSHRSOHDJHGɳɱ±ɸɺ\HDUVZRUOGZLGHLQɳɱɲɺ and unfortunately, its incidence is still increasing. Indeed, it has been estimated WKDWE\ɳɱɵɶDVPDQ\DVɸɱɱPLOOLRQSHRSOHZLOOVXɣHUIURPWKLVFKURQLFGLVHDVH ɲ$URXQGɲɱRILQGLYLGXDOVZLWKGLDEHWHVVXɣHUIURPZKDWZDVIRUPDOO\NQRZQ DVFKLOGKRRGRQVHWGLDEHWHVZKLFKLVQRZUHIHUUHGWRDVW\SHɲGLDEHWHV7KLV PHDQV WKDW WKHUH DUH DSSUR[LPDWHO\ ɵɷ PLOOLRQ SHRSOH ZLWK W\SH ɲ GLDEHWHV ZRUOGZLGHɲɳ)LQODQGKDVRQHRIWKHKLJKHVWUDWHVRIW\SHɲGLDEHWHVLQWKH ZRUOGZLWKDOPRVWɶɴɱɱɱSHRSOHKDYLQJEHHQGLDJQRVHGZLWKW\SHɲGLDEHWHV E\WKHHQGRIɳɱɲɸɴ'LDEHWHVQRWRQO\DɣHFWVLQGLYLGXDOV¶EORRGJOXFRVHOHYHOV as it also results in other metabolic disturbances, such as disturbances in blood SUHVVXUHDQGOLSLGUHJXODWLRQZKLFKFDQOHDGWRFKURQLFPLFURDQGPDFURYDVFXODU FRPSOLFDWLRQV ɵ 'LDEHWLF QHSKURSDWK\ DQG GLDEHWLF UHWLQRSDWK\ DORQJ ZLWK diabetic neuropathy, represent the microvascular complications associated with diabetes. These chronic complications can have devastating consequences, including blindness and the need for dialysis treatment, kidney transplantations, DQG ORZHU H[WUHPLW\ DPSXWDWLRQV ɶ )XUWKHUPRUH WKH FRQVHTXHQFHV RI WKH macrovascular complications of diabetes and the resultant cardiovascular disease, ZKLFKPRVWO\PDQLIHVWVDVLVFKHPLFKHDUWGLVHDVHDQGVWURNHɶDUHVLPLODUO\

gruesome, leading to impaired quality of life and excessive mortality in those DɣHFWHGɷɸ$IWHULVFKHPLFKHDUWGLVHDVHVWURNHUHSUHVHQWVWKHVHFRQGOHDGLQJ FDXVHRIGHDWKZRUOGZLGHɹ,QɳɱɲɷDOPRVWɲɵPLOOLRQSHRSOHZRUOGZLGHVXɣHUHG DVWURNHɺ:KLOHWKHPRUWDOLW\UDWHDVVRFLDWHGZLWKVWURNHKDVGHFUHDVHGWKH QXPEHU RI VXUYLYRUV OLYLQJ ZLWK GLVDELOLWLHV WKDW DɣHFW WKHLU HYHU\GD\ OLIH KDV increased. Stroke is, therefore, the disease that most commonly results in disability DPRQJVXɣHUHUVɲɱ6WURNHLVXVXDOO\VXEFODVVL¿HGLQWRLVFKHPLFVWURNHZKLFKLV caused by the occlusion of the cerebral arteries, and hemorrhagic stroke, which is caused by the rupture of the cerebral blood vessels or aneurysms in the brain, DOWKRXJKERWKOHDGWRWKHREVWUXFWLRQRIWKHFHUHEUDOEORRGÀRZDQGGDPDJHWR WKHFHUHEUDOWLVVXHɲɲ,VFKHPLFVWURNHFDQEHIXUWKHUVXEFODVVL¿HGLQWRQRQ lacunar infarction (i.e., stroke due to the occlusion of the large arteries) and lacunar infarction (i.e., the occlusion of a single perforating artery, which causes OHVVVHYHUHGDPDJHZKHQFRPSDUHGZLWKQRQODFXQDULQIDUFWLRQɲɳ7KHGLYLVLRQ of stroke into strokes of ischemic or hemorrhagic origin is important because WKHUHDUHGLɣHUHQFHVLQWHUPVRIWKHSUHYHQWLRQDQGPDQDJHPHQWRIWKHVHWZR PDMRUVXEW\SHVɲɲ

'LDEHWHVLVFRQVLGHUHGWREHRQHRIWKHVWURQJHVWULVNIDFWRUVIRUVWURNHɲɴɲɵ +DYLQJW\SHɳGLDEHWHVLQFUHDVHVWKHULVNRIVWURNHE\XSWR¿YHWLPHVɲɶZKLOH

(20)

ɳɱ

WKHULVNFDQEHXSWRɳɱWLPHVKLJKHULQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVɲɷ ZKHQFRPSDUHGZLWKWKHJHQHUDOSRSXODWLRQ<HWGHVSLWHWKHKLJKULVNRIVWURNH LQLQGLYLGXDOVZLWKGLDEHWHVLQIRUPDWLRQRQVWURNHLQLQGLYLGXDOVZLWKW\SHɲ GLDEHWHVUHPDLQVVFDUFH2QO\DIHZVWXGLHVKDYHLQYHVWLJDWHGWKHLQFLGHQFHRI VWURNHLQWKRVHZLWKW\SHɲGLDEHWHVDQGGXHWRWKHVPDOOQXPEHURIVWURNHVLQ those studies, the incidence of the stroke subtypes (ischemic stroke, hemorrhagic VWURNHDQGODFXQDULQIDUFWLRQFRXOGQRWEHHOXFLGDWHGɲɴɲɸ7KHZD\LQZKLFK GLDEHWHVDɣHFWVWKHULVNRIODFXQDULQIDUFWLRQLVXQFOHDUKRZHYHUWKHUHVHHPV to be a link between chronic kidney disease, retinal microvascular changes, and ODFXQDU LQIDUFWLRQV HYHQ ZLWKRXW WKH SUHVHQFH RI GLDEHWHV ɲɹɲɺ *LYHQ WKDW FHUHEUDOVPDOOYHVVHOGLVHDVHLVDFRPPRQ¿QGLQJLQLQGLYLGXDOVZLWKGLDEHWHV ɳɱLWLVLPSRUWDQWWRVWXG\WKHHɣHFWRIGLDEHWLFPLFURYDVFXODUFRPSOLFDWLRQV RQWKHULVNRIVWURNHHVSHFLDOO\ODFXQDULQIDUFWLRQLQWKRVHZLWKW\SHɲGLDEHWHV

$VLGHIURPGLDEHWHVWKHRWKHUZHOONQRZQULVNIDFWRUVIRUVWURNHLQWKHJHQHUDO SRSXODWLRQLQFOXGHDQROGHUDJHK\SHUWHQVLRQVPRNLQJDQGDWULDO¿EULOODWLRQɳɲ ɳɴ,QLQGLYLGXDOVZLWKW\SHɳGLDEHWHVVLPLODUULVNIDFWRUVKDYHEHHQREVHUYHG ɳɵ$GGLWLRQDOO\WKHPHWDEROLFV\QGURPHDQGLWVFRPSRQHQWVKDYHEHHQIRXQG WRLQFUHDVHWKHULVNRIVWURNHHVSHFLDOO\LQLQGLYLGXDOVZLWKW\SHɳGLDEHWHVɳɶ ,QWKRVHZLWKW\SHɲGLDEHWHVWKHULVNIDFWRUVIRUVWURNHDSSHDUWRGLɣHUIURP WKHULVNIDFWRUVPHQWLRQHGDERYH,QIDFWLQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVD longer duration of diabetes, elevated systolic blood pressure, higher glycosylated hemoglobin A_ɲF (HbA_ɲFDQGRYHUWGLDEHWLFQHSKURSDWK\KDYHEHHQLGHQWL¿HGDV ULVNIDFWRUVIRUDQ\W\SHRIVWURNHɲɸ'LDEHWLFQHSKURSDWK\ZKLFKLVDIRUPRI FKURQLFNLGQH\GLVHDVHRFFXUVLQɳɱ±ɵɱRIDOOLQGLYLGXDOVZLWKGLDEHWHVɳɷ,W remains unclear how mildly decreased kidney function or moderately increased DOEXPLQXULDDɣHFWWKHULVNRIVWURNHDQGLWVVXEW\SHVLQLQGLYLGXDOVZLWKW\SHɲ GLDEHWHV0RUHRYHUWKHHɣHFWVRIGLDEHWLFUHWLQRSDWK\DQGRWKHUSRWHQWLDOULVN IDFWRUVRQVWURNHDQGLWVVXEW\SHVDOVRUHPDLQXQFOHDULQWKRVHZLWKW\SHɲGLDEHWHV Elevated blood pressure is one of the strongest risk factors for stroke among both WKHJHQHUDOSRSXODWLRQDQGWKRVHZLWKGLDEHWHVɳɲɳɵ7KHEORRGSUHVVXUHFDQ EHGHFRQVWUXFWHGLQWRGLɣHUHQWFRPSRQHQWVRIZKLFKWKHV\VWROLFEORRGSUHVVXUH represents the maximum pressure the blood exerts against the artery walls when the heart beats, while the diastolic blood pressure represents the minimum pressure. With age, the systolic blood pressure increases in a linear fashion, while the diastolic blood pressure starts to decrease, mainly due to reduced vascular FRPSOLDQFH7KHSXOVHSUHVVXUHUHSUHVHQWVWKHGLɣHUHQFHEHWZHHQWKHV\VWROLF and diastolic blood pressures. This component naturally increases with age due to the described changes in the systolic and diastolic blood pressures, and it can be XVHGDVDPHDVXUHPHQWRIDUWHULDOVWLɣQHVVɳɸ7KHSXOVHSUHVVXUHLVDSUHGLFWRU RIVWURNHLQWKHJHQHUDOSRSXODWLRQɳɹDOWKRXJKWKHHɣHFWWKDWLWDQGWKHRWKHU EORRGSUHVVXUHFRPSRQHQWVKDYHRQWKHULVNRIVWURNHLQLQGLYLGXDOVZLWKW\SHɲ

(21)

ɳɲ diabetes has not yet been studied. The risk of stroke increases in a linear fashion ZLWKLQFUHDVLQJEORRGSUHVVXUHLQWKHJHQHUDOSRSXODWLRQɳɲ,QWKRVHZLWKW\SH ɳGLDEHWHVKRZHYHUORZHUEORRGSUHVVXUHOHYHOVDOVRVHHPWRLQFUHDVHWKHULVNRI VWURNHHVSHFLDOO\LQLQGLYLGXDOVXQGHUWKHDJHRIɷɱɳɺ'HWHUPLQLQJZKHWKHU WKLVLVDOVRWKHFDVHLQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVUHTXLUHVIXUWKHUVWXGLHV

7KHPRUWDOLW\UDWHDVVRFLDWHGZLWKVWURNHLVKLJKZLWKPRUHWKDQɳɶRIWKRVH ZKRH[SHULHQFHDQLQFLGHQWVWURNHG\LQJZLWKLQD\HDUɴɱ$JHKHPRUUKDJLF stroke, the male sex, and diabetes all predict a higher mortality rate in the general SRSXODWLRQɴɲɴɳ,QDGGLWLRQSURWHLQXULDDQGGLDEHWLFQHSKURSDWK\VWURQJO\

SUHGLFW VHYHUH GLVDELOLW\ DQG D KLJK PRUWDOLW\ UDWH LQ LQGLYLGXDOV ZLWK W\SH ɳ GLDEHWHVɴɴɴɵ,QWKRVHZLWKW\SHɲGLDEHWHVWKHSURJQRVLVDIWHUDQLQFLGHQW stroke also appears to be poor. In the only prior study concerning this issue, more WKDQKDOIRIWKHUDWKHU\RXQJSDUWLFLSDQWVZLWKWKHPHDQDJHRIɵɱɳ\HDUVGLHG ZLWKLQ¿YH\HDUVDIWHUH[SHULHQFLQJDVWURNHɲɸ1HLWKHUWKHLPSDFWRIWKHVWURNH VXEW\SHVQRUWKHSUHGLFWRUVRIWKHSDUWLFLSDQWV¶SURJQRVLVZHUHHOXFLGDWHGLQWKDW study, meaning that further research is required.

(22)

ɳɳ

2 REVIEW OF THE LITERATURE

2.1 Diabetes mellitus

Diabetes mellitus is a chronic systemic disease characterized by elevated blood glucose levels (or hyperglycemia). This hyperglycemic condition may cause fatigue, excess urine production, systematic organ damage, and eventually, death.

For centuries, no treatment was available for diabetes, and it was not until the GLVFRYHU\RILQVXOLQE\3DXOHVFXLQɲɺɳɲDVZHOODVWKHVXEVHTXHQWH[WUDFWLRQDQG DGPLQLVWUDWLRQRIWKLVKRUPRQHE\%DQWLQJDQG%HVWLQɲɺɳɳWKDWWKHWUHDWPHQW RIGLDEHWHVZDVUHYROXWLRQL]HGɵ

2.1.1 Classiﬁcation of diabetes

7\SHɲDQGW\SHɳGLDEHWHV'LDEHWHVLVGH¿QHGDVDIDVWLQJSODVPDJOXFRVHRI

ɸɱPPROODWZRKRXUSODVPDJOXFRVHRIɲɲɲPPROOGXULQJDQRUDOJOXFRVH tolerance test, an HbA_ɲFRIɵɹPPROPRODQGRUDUDQGRPSODVPDJOXFRVHRI

ɲɲɲPPROOWKDWFDXVHVV\PSWRPVɴɶɴɷ'LDEHWHVQRWRQO\FDXVHVFKURQLF hyperglycemia and a carbohydrate imbalance, but also results in a disturbance LQOLSLGDQGSURWHLQPHWDEROLVP'LDEHWHVLVFDXVHGE\HLWKHULQVXOLQGH¿FLHQF\RU insulin resistance, or sometimes, a combination of the two. The two major types RIGLDEHWHVDUHW\SHɲZKLFKZDVIRUPHUO\NQRZQDVFKLOGKRRGRQVHWGLDEHWHV DQGW\SHɳZKLFKZDVIRUPHUO\NQRZQDVDGXOWRQVHWGLDEHWHV,QWKHFDVHRI W\SHɲGLDEHWHVDQDXWRLPPXQHDVVRFLDWHGSURFHVVOHDGVWRWKHGHVWUXFWLRQRIWKH LQVXOLQSURGXFLQJǃFHOOVLQWKHLVOHWVRI/DQJHUKDQVZLWKLQWKHSDQFUHDVWKHUHE\

OHDGLQJWRWRWDOLQVXOLQGH¿FLHQF\LQWKHLQGLYLGXDO7KHDɥLFWHGLQGLYLGXDOLVWKXV dependent on exogenous insulin for survival, and treatment with insulin is usually initiated immediately following diagnosis. Several genetic and environmental IDFWRUVKDYHEHHQIRXQGWREHDVVRFLDWHGZLWKWKHGHYHORSPHQWRIW\SHɲGLDEHWHV ZKLFKLVDOVRWKHFDVHZKHQLWFRPHVWRW\SHɳGLDEHWHVɴɸ

7\SH ɳ GLDEHWHV LV FKDUDFWHUL]HG E\ D UHODWLYH LQVXOLQ GH¿FLHQF\ FDXVHG E\

ǃFHOOG\VIXQFWLRQDVZHOODVLQVXOLQUHVLVWDQFHZLWKLQWKHWDUJHWRUJDQV7\SH ɳGLDEHWHVLVPRUHFRPPRQO\DVVRFLDWHGZLWKREHVLW\DVHGHQWDU\OLIHVW\OHDQG DQROGHUDJHWKDQW\SHɲGLDEHWHVKRZHYHUWKHSUHYDOHQFHRIW\SHɳGLDEHWHV LVLQFUHDVLQJLQ\RXQJDGXOWVDQGFKLOGUHQ7\SHɳGLDEHWHVLV XVXDOO\WUHDWHG ZLWKRQHRUPRUHJOXFRVHORZHULQJDJHQWVDQGLQPDQ\FDVHVZLWKLQVXOLQDV ZHOOɴɸ5HFHQWO\DQHZPHDQVRIFODVVLI\LQJWKHGLɣHUHQWW\SHVRIGLDEHWHVKDV been proposed, which highlights the fact that diabetes is a heterogenous disease ZLWKGLɣHUHQWSKHQRW\SHVDQGGLɣHUHQWSURJQRVHV7KLVFODVVL¿FDWLRQLVEDVHG

(23)

ɳɴ RQLQVXOLQGH¿FLHQF\DQGUHVLVWDQFHWKHSUHVHQFHRIJOXWDPLFDFLGGHFDUER[\ODVH autoantibodies, metabolic derangements, and the age at onset. The intention EHKLQG WKLV QHZ FODVVL¿FDWLRQ LV WR DOORZ IRU WKH WDLORULQJ RI WUHDWPHQW WR WKH VSHFL¿FQHHGVRIWKHLQGLYLGXDOVZLWKLQHDFKJURXSɴɹ

2.1.2 Epidemiology of type 1 diabetes

7KHUHDUHFXUUHQWO\DSSUR[LPDWHO\ɵɷɱPLOOLRQSHRSOHZLWKGLDEHWHVZRUOGZLGH ɲ7\SHɳGLDEHWHVLVWKHPRVWFRPPRQW\SHDFFRXQWLQJIRUɹɶ±ɺɱRIDOOFDVHV ZKLOHDSSUR[LPDWHO\ɲɱRIFDVHVLQYROYHW\SHɲGLDEHWHVɲɳ,QOLJKWRIWKLV DSSUR[LPDWHO\ɵɷPLOOLRQSHRSOHZRUOGZLGHVXɣHUIURPW\SHɲGLDEHWHVPDNLQJ it one of the most common chronic autoimmune diseases in the world. Finland KDVWKHKLJKHVWLQFLGHQFHRIW\SHɲGLDEHWHVZRUOGZLGHɵɱɺɲɱɱɱɱɱSHU\HDULQ LQGLYLGXDOVXQGHUWKHDJHRIɲɶIROORZHGE\6DUGLQLDɴɸɹɲɱɱɱɱɱSHU\HDU7KH lowest incidence is found in China and Venezuela, which both have an incidence of ɱɲɲɱɱɱɱɱSHU\HDU,QFRQWUDVWWRRWKHUDXWRLPPXQHGLVHDVHVW\SHɲGLDEHWHV LVPRUHFRPPRQLQPHQɴɺ

7KHLQFLGHQFHRIW\SHɲGLDEHWHVZRUOGZLGHLQFUHDVHGUDSLGO\GXULQJWKHɳɱ^th FHQWXU\UHDFKLQJDSODWHDXLQWKHɲɺɹɱV$IWHUWKDWWKHLQFLGHQFHFRQWLQXHGWR ULVHHVSHFLDOO\LQ\RXQJFKLOGUHQXQGHUWKHDJHRIɲɱɵɱ6LQFHWKHEHJLQQLQJ RIWKHɳɲ^stFHQWXU\WKHLQFLGHQFHRIW\SHɲGLDEHWHVLQ)LQODQGKDVGHFUHDVHGLQ FKLOGUHQXQGHUWKHDJHRI¿YHZKLOHWKHLQFLGHQFHKDVUHPDLQHGWKHVDPHLQROGHU FKLOGUHQɵɲ7KHVSHFL¿FUHDVRQVIRUWKHLQFUHDVLQJLQFLGHQFHDUHQRWNQRZQ although several theories exist. For instance, better health care and the adjustment of insulin treatment, as well as other factors that promote health, have led to increased survival. Furthermore, the increased overall survival rate has given rise to increased genetic survival and the passing on of genes related to diabetes.

+RZHYHUDVPRUHQHZO\GLDJQRVHGFDVHVRIW\SHɲGLDEHWHVH[KLELWDUHGXFHG genetic predisposition toward the disease, other causes such as environmental IDFWRUVPXVWDOVROLHEHKLQGWKHLQFUHDVHɵɳ

2.1.3 Pathogenesis of type 1 diabetes

7KHSDWKRJHQHVLVRIW\SHɲGLDEHWHVLVQRW\HWIXOO\XQGHUVWRRGDOWKRXJKWKH interactions of genes, viral infections, and other environmental factors are all WKRXJKWWRSOD\DUROHLQWKHGLVHDVH¶VGHYHORSPHQWɴɸ7KHGLVHDVHFOXVWHUVZLWKLQ IDPLOLHVɵɴ0RUHVSHFL¿FDOO\LIWKHPRWKHUKDVW\SHɲGLDEHWHVWKHFXPXODWLYH ULVNRIWKHRɣVSULQJKDYLQJW\SHɲGLDEHWHVLVɶZKLOHWKHULVNLVɹLIWKHIDWKHULV DɣHFWHGɵɵ1RVLQJOHJHQHKDVEHHQIRXQGWRLQFUHDVHWKHULVNRIW\SHɲGLDEHWHV KRZHYHUGLɣHUHQWORFLKDYHEHHQDVVRFLDWHGZLWKWKHGLVHDVH2QHRIWKHPRVW ZHOONQRZQJHQHVDVVRFLDWHGZLWKW\SHɲGLDEHWHVLVSDUWRIWKHKXPDQOHXNRF\WH

(24)

ɳɵ

DQWLJHQFRPSOH[ɴɸ2WKHUJHQHWLFUHJLRQVKDYHDOVREHHQLGHQWL¿HGDQGPRVWRI WKHPDUHFRQQHFWHGWRIXQFWLRQVDɣHFWLQJWKHLPPXQHUHVSRQVHV\VWHPɵɶɵɷ

7KH H[DFW PHFKDQLVP EHKLQG WKH DXWRLPPXQH GHVWUXFWLRQ RI WKH ǃFHOOV within the pancreas (i.e., insulitis) remains unknown, although autoantibodies seem to play a role in activating the autoimmune response. Moreover, the triggers behind the autoimmune response in genetically prone individuals remain unclear.

ɴɸ%DFWHULDODQGYLUDOLQIHFWLRQVUHSUHVHQWRQHRIWKHPRVWZLGHO\GLVFXVVHG environmental factors responsible for the activation of autoantibody development.

,QSDUWLFXODU&R[VDFNLHYLUXV%ɲLVEHOLHYHGWRSOD\DVLJQL¿FDQWUROHLQWKLVɵɸ,Q accordance with this theory, a vaccine against this type of virus has been shown WREHSURWHFWLYHLQUHODWLRQWRWKHGHYHORSPHQWRIW\SHɲGLDEHWHVLQPLFHɵɹ

2WKHUHQYLURQPHQWDOULVNIDFWRUVWKDWDɣHFWWKHGHYHORSPHQWRIW\SHɲGLDEHWHV LQFOXGHSHULQDWDOIDFWRUVIRUH[DPSOHGHOLYHU\YLDFHVDUHDQVHFWLRQɵɺPDWHUQDO REHVLW\ɶɱDQGDKLJKELUWKZHLJKWɶɲ7KH³K\JLHQHK\SRWKHVLV´VXJJHVWVWKDW the decrease in infectious diseases that results from better hygiene, health, and medical conditions during childhood leads to the inadequate development of the LPPXQHV\VWHPDQGWKHUHIRUHWKHGHYHORSPHQWRIDXWRLPPXQHGLVHDVHVɶɳ This hypothesis is supported by the fact that the incidence of other autoimmune diseases, such as allergies and asthma, have increased as a result of the loss of SURWHFWLYHHQYLURQPHQWDOIDFWRUVɶɴ2WKHUHQYLURQPHQWDOIDFWRUVVXJJHVWHGWR WULJJHUWKHDXWRLPPXQHUHDFWLRQOHDGLQJWRW\SHɲGLDEHWHVLQFOXGHYLWDPLQ' GH¿FLHQF\ɶɵɶɶDQGFKDQJHVLQWKHJXWPLFURELRWDɶɷ

2.2 Chronic diabetic complications

7\SH ɲ GLDEHWHV VLPLODU WR WKH RWKHU IRUPV RI GLDEHWHV PD\ FDXVH FKURQLF complications. The hyperglycemic state and hypertension, among other things, DɣHFWWKHZDOOVRIWKHEORRGYHVVHOVHVSHFLDOO\WKHVPDOOEORRGYHVVHOVLQWKHUHWLQD NLGQH\VDQGQHUYHVɶɸ7KHFRPSOLFDWLRQVFDXVHGE\GLDEHWHVDQGK\SHUJO\FHPLD FDQEHGLYLGHGLQWRPLFURDQGPDFURYDVFXODUFRPSOLFDWLRQVGHSHQGLQJRQWKH VL]HVRIWKHDɣHFWHGEORRGYHVVHOV0DFURYDVFXODUFRPSOLFDWLRQVDɣHFWWKHODUJHU blood vessels, resulting in coronary heart disease, stroke, and lower extremity DUWHULDOGLVHDVH0LFURYDVFXODUFRPSOLFDWLRQVDVWKHQDPHVXJJHVWVDɣHFWWKH smaller blood vessels, and they comprise diabetic nephropathy, retinopathy, and QHXURSDWK\ɶ1RWRQO\GRWKHVHFKURQLFGLDEHWLFFRPSOLFDWLRQVUHVXOWLQDJUHDW EXUGHQRQWKHKHDOWKFDUHV\VWHPɶɹWKH\DOVROHDGWRH[FHVVLYHPRUWDOLW\ɸɶɺ DQGLPSDLUHGTXDOLW\RIOLIHLQLQGLYLGXDOVZLWKGLDEHWHVɷ

(25)

ɳɶ 2.2.1 Diabetic nephropathy

Terminology. The preferred terminology concerning the diabetic microvascular FRPSOLFDWLRQGLDEHWLFQHSKURSDWK\KDVFKDQJHGLQUHFHQW\HDUV$FFRUGLQJWR.LGQH\

'LVHDVH ,PSURYLQJ *OREDO 2XWFRPHV .',*2 DQ LQWHUQDWLRQDO RUJDQL]DWLRQ GHGLFDWHGWRGHYHORSLQJHYLGHQFHEDVHGJXLGHOLQHVUHJDUGLQJNLGQH\GLVHDVHWKLV FRPSOLFDWLRQVKRXOGQRZEHUHIHUUHGWRDVGLDEHWLFNLGQH\GLVHDVHɷɱ+RZHYHU at the time the studies included in this thesis were conducted, the preferred term was diabetic nephropathy, which is why diabetic kidney disease is referred to DVGLDEHWLFQHSKURSDWK\LQWKHSUHVHQWWKHVLV7KHWHUPLQRORJ\IRUWKHGLɣHUHQW stages of diabetic nephropathy, that is, microalbuminuria, macroalbuminuria, DQG HQGVWDJH UHQDO GLVHDVH KDV DOVR FKDQJHG ,QGHHG PLFURDOEXPLQXULD LV today referred to as moderately increased albuminuria, or albuminuria category

$ɳZKLOHPDFURDOEXPLQXULDLVUHIHUUHGWRDVVHYHUHO\LQFUHDVHGDOEXPLQXULDRU DOEXPLQXULDFDWHJRU\$ɴ0RUHRYHUDQRUPDODOEXPLQH[FUHWLRQUDWHLVUHIHUUHGWR DVQRUPDOWRPLOGO\LQFUHDVHGDOEXPLQXULDRUDOEXPLQXULDFDWHJRU\$ɲ$FFRUGLQJ WRWKHVHQHZJXLGHOLQHVWKHWHUPHQGVWDJHUHQDOGLVHDVHVKRXOGEHUHIHUUHGWR DVNLGQH\IDLOXUHɷɱ'XHWRWKHIDFWWKDWWKHROGWHUPLQRORJ\ZDVWKHSUHIHUUHG approach at the time the studies included in this thesis were conducted, the terms PLFURDOEXPLQXULDPDFURDOEXPLQXULDDQGHQGVWDJHUHQDOGLVHDVHZLOOEHXVHG throughout.

&ODVVL¿FDWLRQDQGSDWKRSK\VLRORJ\Diabetes is the most common cause RIFKURQLFNLGQH\GLVHDVHZRUOGZLGHɷɲ$OVRNQRZQDVGLDEHWLFQHSKURSDWK\

WKLVFRPSOLFDWLRQGHYHORSVLQɳɱ±ɵɱRIDOOLQGLYLGXDOVZLWKGLDEHWHVɳɷ,Q the case of diabetic nephropathy, the damaged kidneys lead to the loss of kidney function. The progression of diabetic nephropathy can eventually lead to complete kidney failure, leaving the individual in need of dialysis or a kidney transplant in order to survive. In diabetes, hyperglycemia and hypertension, among other FRPSOLFDWLRQVGDPDJHWKHVPDOOEORRGYHVVHOVRIWKHNLGQH\VVSHFL¿FDOO\WKH glomeruli, which represent the functional part of the kidneys. This leads to JORPHUXODUK\SHU¿OWUDWLRQZKLFKLVFOLQLFDOO\LQGLFDWHGE\SURWHLQRUDOEXPLQ OHDNDJHLQWRWKHXULQHRUDOEXPLQXULDɷɳ%DVHGRQWKHDPRXQWRIDOEXPLQ in the urine, diabetic nephropathy can be divided into four stages: a normal urinary albumin excretion rate (UAER), microalbuminuria, macroalbuminuria, DQGHQGVWDJHUHQDOGLVHDVHɷɴ$FFRUGLQJWRWKH.',*2JXLGHOLQHVWKHFXUUHQW corresponding terminology is normal to mildly increased albuminuria, moderately increased albuminuria, severely increased albuminuria, and kidney failure, UHVSHFWLYHO\ɷɱ

The development and progression of diabetic nephropathy usually takes decades.

The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study revealed WKDWPRUHWKDQɶɱRILQGLYLGXDOVZLWKW\SHɲGLDEHWHVGHYHORSPLFURDOEXPLQXULD

(26)

ɳɷ

ZLWKLQɴɱ\HDUVRIWKHLUGLDEHWHVGLDJQRVLV'LDEHWLFQHSKURSDWK\SURJUHVVHVLQ PDQ\LQGLYLGXDOVDVGHWHUPLQHGLQWKHVDPHVWXG\0RUHVSHFL¿FDOO\ɳɳRIWKRVH ZLWKW\SHɲGLDEHWHVGLHGDIWHUɴɱ\HDUVRIKDYLQJGLDEHWHVGXHWRWKHFRPSOLFDWLRQV RIHQGVWDJHUHQDOGLVHDVHɷɵ(DUO\LQWHUYHQWLRQDQGWUHDWPHQWUHGXFHWKHULVN of developing microalbuminuria and macroalbuminuria, thereby also reducing WKHULVNRIHQGVWDJHUHQDOGLVHDVHɷɶ7KHLQFLGHQFHRIGLDEHWLFQHSKURSDWK\

LQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVKDVIRUWXQDWHO\GHFUHDVHGRYHUWKHODVWIHZ decades due to improved treatment options and the early detection of albuminuria ɷɷɷɸ1RWDOORIWKRVHZKRGHYHORSDOEXPLQXULDSURJUHVVWRDVXEVHTXHQWVWDJH and the regression of this complication is also possible. In a study conducted DVSDUWRIWKH)LQQ'LDQH6WXG\ɳɴRIWKRVHZLWKERWKPLFURDOEXPLQXULDDQG macroalbuminuria regressed to a lower category of albuminuria, while the risk of developing cardiovascular complications in these individuals also diminished ɷɹ ,Q DGGLWLRQ QRW DOO GLDEHWHVUHODWHG NLGQH\ GLVHDVHV DUH DVVRFLDWHG ZLWK DOEXPLQXULD)RULQVWDQFHLQSHRSOHZLWKW\SHɳGLDEHWHVQRQDOEXPLQXULFUHQDO GLVHDVHLVSUHYDOHQWEHLQJREVHUYHGLQɴɺ±ɶɶRIDOOWKRVHZLWKFKURQLFNLGQH\

GLVHDVHɷɺɸɱZKLOHLQSHRSOHZLWKW\SHɲGLDEHWHVLWLVREVHUYHGLQRQO\ɲɷɸɲ Screening and diagnosis. The diagnosis of diabetic nephropathy is based on the amount of albumin in the urine. Screening for albuminuria is usually SHUIRUPHG WKURXJK WKH DQQXDO PHDVXUHPHQW RI WKH XULQDU\ DOEXPLQWR creatinine ratio from a random spot urine collection. Screening for albuminuria VKRXOGEHFRPPHQFHGɶ\HDUVDIWHUWKHGLDJQRVLVRIGLDEHWHVLQWKRVHZLWK W\SHɲGLDEHWHVDQGLPPHGLDWHO\DWWKHWLPHRIGLDJQRVLVLQWKRVHZLWKW\SHɳ GLDEHWHV$QRUPDOXULQDU\DOEXPLQWRFUHDWLQLQHUDWLRLVGH¿QHGDVɴɱPJJ ZKLOHDKLJKXULQDU\DOEXPLQH[FUHWLRQLVGH¿QHGDVɴɱPJJ)RUDGLDJQRVLV RI DOEXPLQXULD DQ LQFUHDVHG XULQDU\ DOEXPLQWRFUHDWLQLQH UDWLR VKRXOG EH VHHQLQWZRRXWRIWKUHHXULQHFROOHFWLRQVGXULQJDWKUHHWRVL[PRQWKSHULRG This is mainly due to confounding factors, such as infections, fever, strenuous exercise, congestive heart failure, and menstruation, which may cause transient DOEXPLQXULDZLWKRXWWKHSUHVHQFHRIGLDEHWLFQHSKURSDWK\7LPHGRUɳɵKRXUXULQH collections for the detection of albumin are also possible, although they require PRUHZRUNɸɳ7KH¿UVWVLJQRIGLDEHWLFQHSKURSDWK\LVPLFURDOEXPLQXULD,Q people with microalbuminuria, which is now referred to as moderately increased DOEXPLQXULDWKH8$(5LVɴɱDQGɴɱɱPJɳɵKRUɳɱDQGɳɱɱJPLQ 1RRWKHUV\PSWRPVDUHXVXDOO\SUHVHQWDWWKLVWLPH:KHQWKH8$(5H[FHHGV

ɴɱɱPJɳɵKRUɳɱɱJPLQWKHLQGLYLGXDOLVVDLGWRKDYHPDFURDOEXPLQXULDRU VHYHUHO\LQFUHDVHGDOEXPLQXULDɷɱɸɴ7KLVVWDJHLVFKDUDFWHUL]HGE\SURWHLQXULD KLJKEORRGSUHVVXUHɸɵDQGDQHYHQWXDOGHFOLQHLQNLGQH\IXQFWLRQɸɶ With WKHSURJUHVVLRQRIPDFURDOEXPLQXULDHQGVWDJHUHQDOGLVHDVHRUNLGQH\IDLOXUH ZLOOHYHQWXDOO\GHYHORS(QGVWDJHUHQDOGLVHDVHLVGH¿QHGDVXUHPLDDQGQRQ

(27)

ɳɸ H[LVWHQWNLGQH\IXQFWLRQDQGLWOHDYHVWKHDɣHFWHGLQGLYLGXDOGHSHQGHQWRQGLDO\VLV WUHDWPHQWRUUHQDOUHSODFHPHQWWKHUDS\ɸɶ$VSUHYLRXVO\PHQWLRQHGUHJUHVVLRQ EHWZHHQWKHGLɣHUHQWVWDJHVLVDOVRSRVVLEOHɷɹɸɷ

Another way to describe and grade diabetic kidney disease involves kidney IXQFWLRQ .LGQH\ IXQFWLRQ LV XVXDOO\ HVWLPDWHG XVLQJ IRUPXODH GHYHORSHG VSHFL¿FDOO\IRUWKLVSXUSRVHɸɸɸɺ7KHIRUPXODWKDWLVPRVWFRPPRQO\XVHG WRGD\IRUWKHHVWLPDWLRQRIWKHJORPHUXODU¿OWUDWLRQUDWHH*)5LVWKH&KURQLF .LGQH\'LVHDVH(SLGHPLRORJ\&ROODERUDWLRQ&.'(3,IRUPXODZKLFKLQFOXGHV WKHLQGLYLGXDO¶VVHUXPFUHDWLQLQHOHYHODJHVH[DQGHWKQLFLW\ɹɱ7KLVPHWKRG is considered to be more accurate than the other available methods because it HVWLPDWHVWKHJORPHUXODU¿OWUDWLRQUDWHUDWKHUWKDQWKHUDWHRIFUHDWLQLQHFOHDUDQFH ZKLFK RYHUHVWLPDWHV WKH JORPHUXODU ¿OWUDWLRQ UDWH 7KH H*)5 HVWLPDWHV WKH

¿OWUDWLRQFDSDFLW\RIWKHNLGQH\DQGWKHORZHUWKHYDOXHWKHSRRUHUWKHIXQFWLRQ :LWKWKLVPHWKRGNLGQH\IXQFWLRQLVFODVVL¿HGLQWRWKH¿YHVWDJHVRIFKURQLF NLGQH\GLVHDVH7DEOHɲ7RGD\WKHVWDJHVRIFKURQLFNLGQH\GLVHDVHVKRXOGQRW RQO\EHGH¿QHGDFFRUGLQJWRWKHH*)5EXWDOVRDFFRUGLQJWRWKHDOEXPLQXULD FDWHJRU\ɷɱDVVKRZQLQ7DEOHɲ

TABLE 1. Stages of chronic kidney disease according to the eGFR stage and level of albuminuria, adapted from the Kidney Disease: Improving Global Outcomes and American Diabetes Association guidelines (60,72), and including terminology used in this thesis.

CKD risk categories according to the CKD stage and albuminuria

Albuminuria Normal UAER Micro-

albuminuria

Macro- albuminuria Normal to

mildly increased

Moderately increased

Severely increased

CKD Stage eGFR

(mL/min/1.73 m²) < 30 mg t 30 and

< 300 mg t 300 mg

Stage 1 Normal or high t 90

Stage 2 Mildly decreased 60–89 Stage 3a Mildly to moderately

decreased 45–59

Stage 3b Moderately to mildly

decreased 30–44

Stage 4 Severely decreased 15–29 Stage 5 Kidney failure < 15

The white color depicts a low risk of CKD progression, the light grey color a moderately increased risk, the medium grey color a high risk, and the dark grey color a very high risk. eGFR = estimated glomerular ﬁltration rate, CKD = chronic kidney disease, UAER = urinary albumin excretion rate.

(28)

ɳɹ

Risk factors. Elevated blood glucose and high blood pressure, which are both FRPPRQLQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVDUHZHOONQRZQULVNIDFWRUVIRUWKH GHYHORSPHQWRIGLDEHWLFQHSKURSDWK\ɹɲɹɳ,QDGGLWLRQDQROGHUDJHɹɴDQGD ORQJHUGLDEHWHVGXUDWLRQɹɵDOVRLQFUHDVHWKLVULVN6PRNLQJLVDQLQGHSHQGHQW ULVNIDFWRUIRUWKHGHYHORSPHQWRIGLDEHWLFQHSKURSDWK\ɹɶDQGLWERWKDFFHOHUDWHV WKH ORVV RI UHQDO IXQFWLRQ DQG LQFUHDVHV PRUWDOLW\ LI HQGVWDJH UHQDO GLVHDVH GHYHORSVɹɷ3UHHFODPSVLDLVDOVRDVVRFLDWHGZLWKDQLQFUHDVHGULVNRIGLDEHWLF QHSKURSDWK\LQWKRVHZLWKW\SHɲGLDEHWHVɹɸ:KHQLWFRPHVWRG\VOLSLGHPLD ERWKDKLJKHUWRWDOFKROHVWHUROOHYHODQGDORZHUKLJKGHQVLW\OLSRSURWHLQ+'/

FKROHVWHUROOHYHOLQFUHDVHWKHULVNRIUHQDOLQVXɤFLHQF\LQLQGLYLGXDOVZLWKW\SHɲ GLDEHWHVɹɳ2EHVLW\LVDOVRDVVRFLDWHGZLWKDQLQFUHDVHGULVNRIWKHGHYHORSPHQW RIGLDEHWLFQHSKURSDWK\ɹɵɹɹ*HQGHUDSSHDUVWRSOD\DUROHZLWKWKHPDOH sex being found to increase the risk of the progression of diabetic nephropathy ɹɴ )XUWKHUPRUH WKHUH LV HYLGHQFH RI D JHQHWLF VXVFHSWLELOLW\ WR GHYHORSLQJ GLDEHWLF QHSKURSDWK\ ɹɺ ,Q WKRVH ZLWK W\SH ɲ GLDEHWHV WKH GLDEHWLF PLFUR and macrovascular complications cluster within individuals, and the presence of diabetic retinopathy generally precedes the development of diabetic nephropathy ɺɱ

Treatment. When it comes to managing diabetic nephropathy, annual screening for albuminuria is highly important. If, or when, microalbuminuria and diabetic nephropathy develop, the focus should be on treating the risk factors mentioned above. Intensive treatment and lowering both the blood glucose concentration DQG EORRG SUHVVXUH VKRXOG EH WKH ¿UVW LQWHUYHQWLRQV DSSOLHG ɸɳ $ VWULFWHU UHJLPHQRIJO\FHPLFFRQWUROVKRXOGUHGXFHWKHULVNRIGHYHORSLQJERWKPLFURDQG PDFURDOEXPLQXULDɺɲ+LJKV\VWROLFDQGGLDVWROLFEORRGSUHVVXUHVDFFHOHUDWHWKH development of diabetic nephropathy, and aggressive blood pressure treatment leads to the recovery of the kidneys, diminishes the need for dialysis treatment or kidney transplantation, and reduces the mortality rate linked to renal failure ɺɳ$QJLRWHQVLQFRQYHUWLQJHQ]\PHLQKLELWRUVRUDQJLRWHQVLQUHFHSWRUEORFNHUV have been shown to not only protect the kidneys and reduce the risk of the progression of diabetic nephropathy, but also to lower the cardiovascular risk associated with this complication, leading to them being the agents of choice when WUHDWLQJEORRGSUHVVXUHLQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVɺɴɺɵ+RZHYHULI neither hypertension nor albuminuria are present, these agents will not prevent WKH GHYHORSPHQW RI GLDEHWLF QHSKURSDWK\ ɺɶ 7KH EORRG SUHVVXUH WDUJHW LQ LQGLYLGXDOVZLWKRXWDOEXPLQXULDLVɲɵɱɺɱPP+JZKLOHLQWKRVHZKRKDYH GHYHORSHGPLFURDOEXPLQXULDWKHWDUJHWLVɲɴɱɹɱPP+Jɺɷ

,IHQGVWDJHUHQDOGLVHDVHGHYHORSVWKHNLGQH\VDUHQRORQJHUDEOHWR¿OWUDWH urine, which leaves the individual in need of dialysis treatment or transplantation.

7KLVPD\RFFXULQDVPDQ\DVɸRILQGLYLGXDOVZLWKLQɴɱ\HDUVRIWKHGLDJQRVLVRI

(29)

ɳɺ W\SHɲGLDEHWHVLQ)LQODQGɷɷ'LDO\VLVWUHDWPHQWOLPLWVWKHOLIHRIWKHLQGLYLGXDO DQGERWKFDUGLRYDVFXODUPRUELGLW\ɺɸDQGDOOFDXVHPRUWDOLW\ɶɺDUHJUHDWO\

LQFUHDVHGLQFDVHVRIHQGVWDJHUHQDOGLVHDVH. For those who are eligible, renal WUDQVSODQWDWLRQOHDGVWRLPSURYHGVXUYLYDOZKHQFRPSDUHGZLWKGLDO\VLVɺɹ,Q LQGLYLGXDOVZLWKW\SHɲGLDEHWHVVLPXOWDQHRXVSDQFUHDVNLGQH\WUDQVSODQWDWLRQ may be possible, resulting in the individual having restored kidney function DQG QRUPDO LQVXOLQ SURGXFWLRQ )XUWKHUPRUH VXUYLYDO DIWHU SDQFUHDVNLGQH\

transplantation is substantially better than survival after kidney transplantation DORQHɺɺ

2.2.2 Diabetic retinopathy

&ODVVL¿FDWLRQDQGSDWKRSK\VLRORJ\ In addition to being the most common microvascular complication of diabetes, diabetic retinopathy is the leading cause RI EOLQGQHVV DPRQJ DGXOWV LQ GHYHORSHG FRXQWULHV ɲɱɱ 'LDEHWLF UHWLQRSDWK\

LV FODVVL¿HG LQWR WKH GLɣHUHQW VWDJHV RI QRQSUROLIHUDWLYH DQG SUROLIHUDWLYH UHWLQRSDWK\ZLWKWKHSUROLIHUDWLYHIRUPEHLQJWKHVLJKWWKUHDWHQLQJVWDJHWKDW UHTXLUHVWUHDWPHQWɲɱɲ$QRWKHUIRUPRIGLDEHWLFUHWLQRSDWK\LVPDFXODUHGHPD or diabetic maculopathy, which is caused by the thickening of the retina in the PDFXODUUHJLRQ7KLVFDQEHSUHVHQWLQERWKQRQSUROLIHUDWLYHDQGSUROLIHUDWLYH UHWLQRSDWK\DQGLWUHSUHVHQWVDPDMRUWKUHDWWRWKHLQGLYLGXDO¶VYLVLRQɲɱɳ7KH DJHVWDQGDUGL]HGSUHYDOHQFHRIDQ\W\SHRIGLDEHWLFUHWLQRSDWK\LVɳɶLQWKRVH ZLWKW\SHɳGLDEHWHVZKLOHLQWKRVHZLWKW\SHɲGLDEHWHVWKHSUHYDOHQFHLVDVKLJK DVɸɸ)RUSUROLIHUDWLYHGLDEHWLFUHWLQRSDWK\WKHFRUUHVSRQGLQJSHUFHQWDJHVDUH ɴDQGɴɴUHVSHFWLYHO\ɲɱɴ2IDOOWKHLQGLYLGXDOVZLWKW\SHɲGLDEHWHVZKR GHYHORSGLDEHWLFUHWLQRSDWK\ɶ±ɲɱZLOOORVHWKHLUYLVLRQɲɱɵ

7KH¿UVWVLJQRIGLDEHWLFUHWLQRSDWK\LVWKHVZHOOLQJRIWKHVPDOOEORRGYHVVHOV in the retina, or microaneurysms. As the complication progresses, intraretinal hemorrhages and cotton wool spots appear, while the blood vessels that nourish the retina may lose the ability to transport blood. In proliferative diabetic UHWLQRSDWK\LVFKHPLDLQGXFHGQHRYDVFXODUL]DWLRQGHYHORSVLQWKHUHWLQD7KHVH new blood vessels are fragile, and they have a tendency to bleed. Vision loss occurs partly due to this. Furthermore, the development of the new blood vessels leads to WKHDFFRPSDQ\LQJ¿EURXVWLVVXHGLVWRUWLQJWKHUHWLQD0RUHRYHUWKHLQGLYLGXDO¶V central vision can be impaired by the macular edema caused by increased vascular SHUPHDELOLW\DQGWKHORVVRIFDSLOODU\SHUIXVLRQɲɱɲɲɱɶ

Risk factors. Diabetic retinopathy is closely associated with the duration of GLDEHWHV ,Q D VWXG\ E\ <DXet al, no risk of developing proliferative diabetic UHWLQRSDWK\ZDVVHHQLQWKRVHZLWKW\SHɲGLDEHWHVGXULQJWKH¿UVWɲɱ\HDUVDIWHU WKHGLDJQRVLVRIGLDEHWHV+RZHYHULIWKHGXUDWLRQZDVPRUHWKDQɲɱ\HDUVWKHULVN

(30)

ɴɱ

LQFUHDVHGDOPRVWVHYHQIROGɲɱɴ1H[WWRWKHGLDEHWHVGXUDWLRQSRRUJO\FHPLF FRQWUROLVDPDMRUULVNIDFWRUIRUWKHGHYHORSPHQWRIGLDEHWLFUHWLQRSDWK\ɲɱɷ7KH Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) showed that intensive treatment of the blood glucose decreased the risk of the progression of diabetic retinopathy by more than ɸɱɲɱɸ$VLQWKHFDVHRIGLDEHWLFQHSKURSDWK\K\SHUWHQVLRQLQFUHDVHVWKHULVN RIGLDEHWLFUHWLQRSDWK\ɲɱɹ,QLQGLYLGXDOVZLWKW\SHɲGLDEHWHVORZHULQJWKH EORRGSUHVVXUHUHGXFHVWKHLQFLGHQFHɲɱɺDQGSURJUHVVLRQRIGLDEHWLFUHWLQRSDWK\

ɲɱɷ$OWKRXJKQRWDVVWURQJDVWKHULVNIDFWRUVPHQWLRQHGHDUOLHUG\VOLSLGHPLD DOVRLQFUHDVHVWKHULVNRIGLDEHWLFUHWLQRSDWK\ɲɱɷ6PRNLQJKDVEHHQDVVRFLDWHG ZLWK GLDEHWLF UHWLQRSDWK\ LQ D FURVVVHFWLRQDO VWXG\ ɲɲɱ KRZHYHU QR VXFK DVVRFLDWLRQ KDV EHHQ IRXQG LQ SURVSHFWLYH VWXGLHV ɲɱɷɲɲɲ 0RUHRYHU WKHUH seems to be a genetic predisposition toward diabetic retinopathy. As observed in the same study, the severity of diabetic retinopathy is closely associated with the VHYHULW\RIGLDEHWLFQHSKURSDWK\ɲɲɳ

Screening, diagnosis, and treatment. Diabetic retinopathy is diagnosed by means of fundus photography or ophthalmoscopy. Screenings are performed regularly in individuals with diabetes in order to identify those who are at ULVNRIGHYHORSLQJVLJKWWKUHDWHQLQJFKDQJHVɸɳ7KURXJKUHJXODUVFUHHQLQJV HDUO\GHWHFWLRQDQGWKHWUHDWPHQWRIGLDEHWLFUHWLQRSDWK\XSWRɺɹRIYLVXDO ORVVGXHWRWKLVFRPSOLFDWLRQFDQEHSUHYHQWHGɲɲɴ6FUHHQLQJVLQWKRVHZLWK W\SHɲGLDEHWHVVKRXOGEHLQLWLDWHGZLWKLQ¿YH\HDUVRIRQVHWDQGLIQRVLJQVRI UHWLQRSDWK\DUHSUHVHQWVXEVHTXHQWVFUHHQLQJVVKRXOGEHSHUIRUPHGHYHU\ɲ±ɳ

\HDUVɸɳ*RRGJO\FHPLFFRQWURODQGWKHSUHYHQWLRQRIPRGL¿DEOHULVNIDFWRUV such as hypertension and dyslipidemia are key to the prevention and treatment RIGLDEHWLFUHWLQRSDWK\ɲɱɲɲɲɵ+RZHYHUWKHRYHUO\VZLIWORZHULQJRIWKHEORRG glucose concentrations in those who have already developed retinopathy may H[DFHUEDWHWKHUHWLQRSDWK\LWVHOIɲɲɶ:KHQSUROLIHUDWLYHGLDEHWLFUHWLQRSDWK\

develops, retinal laser treatment is required to mitigate vision disturbances and SUHYHQWYLVLRQORVVɲɲɷ

2.2.3 Diabetic neuropathy

As the most common of all the neuropathies worldwide, diabetic neuropathy GHYHORSV LQ ɶɱ RI DOO LQGLYLGXDOV ZLWK DQ\ W\SH RI GLDEHWHV ɲɲɸ 7KH K\SHUJO\FHPLFVWDWHLVWKRXJKWWRDɣHFWWKHQHUYHVWKURXJKFDXVLQJGHP\HOLQDWLRQ DQG WKH GHJHQHUDWLRQ RI D[RQV ɲɲɹ 'LVWDO V\PPHWULF SRO\QHXURSDWK\ LV WKH most common form, and its symptoms include numbness, tingling and burning sensations, pain, weakness, loss of sensation, and loss of proprioception. The symptoms usually start distally in the lower extremities, before moving up to the

(31)

ɴɲ PRUHSUR[LPDOSDUWVRIWKHOLPEVDQGHYHQWXDOO\DOVRDɣHFWLQJWKHXSSHUOLPEV ɲɲɸ7KHPRVWLPSRUWDQWULVNIDFWRUVIRUGLDEHWLFQHXURSDWK\DUHWKHGXUDWLRQRI GLDEHWHVDQGSRRUJO\FHPLFFRQWUROɲɲɺ

Another form of diabetic neuropathy is autonomic neuropathy, which involves GLVWXUEDQFHVLQWKHV\PSDWKHWLFDQGSDUDV\PSDWKHWLFQHUYRXVV\VWHPVɲɲɸ 7KHV\PSWRPVFDQEHGLYLGHGLQWRGLɣHUHQWRUJDQIXQFWLRQVRIZKLFKWKHPRVW dangerous are the cardiovascular symptoms. These consist of resting tachycardia DQGRUWKRVWDWLFK\SRWHQVLRQLQDGGLWLRQWRVLOHQWP\RFDUGLDOLQIDUFWLRQɲɳɱ 2WKHUV\PSWRPVLQFOXGHJDVWURSDUHVLVG\VSKDJLDEODGGHUG\VIXQFWLRQVH[XDO G\VIXQFWLRQDQGGLɤFXOW\UHFRJQL]LQJK\SRJO\FHPLDɲɲɸɲɳɱ7KHWUHDWPHQWRI diabetic neuropathy focuses on improving glycemic control and pain management, DQGUHJXODUH[HUFLVHLVHQFRXUDJHGɲɲɸɲɲɹ

2.2.4 Cardiovascular disease and macrovascular complications

Epidemiology of cardiovascular disease and coronary heart disease.

In comparison to microvascular disease, macrovascular disease has been studied WRDOHVVHUH[WHQWLQWKRVHZLWKW\SHɲGLDEHWHVHVSHFLDOO\ZKHQLWFRPHVWRWKH GLɣHUHQWKDUGFDUGLRYDVFXODUHQGSRLQWV,QPRVWVWXGLHVLQYROYLQJLQGLYLGXDOVZLWK W\SHɲGLDEHWHVWKHFDUGLRYDVFXODUHYHQWVLHFRURQDU\KHDUWGLVHDVHVWURNHDQG lower extremity artery disease) are pooled into a common cardiovascular endpoint termed cardiovascular disease. This macrovascular complication contributes to DOPRVWɷɱRIDOOGHDWKVLQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVDQGZLWKDGLDEHWHV GXUDWLRQRIPRUHWKDQɳɱ\HDUVɲɳɲ)XUWKHUPRUHHYHQWKRXJKWKHPRUWDOLW\UDWH DQGWKHLQFLGHQFHRIHQGVWDJHUHQDOGLVHDVHKDYHGHFOLQHGRYHUUHFHQWGHFDGHV in these individuals, the incidence of coronary heart disease has remained UHODWLYHO\KLJKDQGXQFKDQJHGɲɳɳ7KHULVNRIFDUGLRYDVFXODUGLVHDVHDULVHV ɲɱ±ɲɶ\HDUVHDUOLHULQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVZKHQFRPSDUHGZLWKWKH JHQHUDOSRSXODWLRQ0HQZLWKW\SHɲGLDEHWHVKDYHDIRXUIROGKLJKHUULVNRIPDMRU FDUGLRYDVFXODUGLVHDVHZKLOHWKHULVNIRUZRPHQLVDOPRVWHLJKWIROGKLJKHUZKHQ FRPSDUHGZLWKWKHJHQHUDOSRSXODWLRQɲɳɴ6RHGHPDK0XWKXet al found that the KLJKHVWUHODWLYHULVNRIFDUGLRYDVFXODUGLVHDVHRFFXUVLQ\RXQJZRPHQZLWKW\SHɲ GLDEHWHVXQGHUWKHDJHRIɶɶ\HDUVZKHQFRPSDUHGZLWKZRPHQZLWKRXWGLDEHWHVRI WKHVDPHDJHZKLFKGHPRQVWUDWHVWKDWWKHSURWHFWLYHUROHRISUHPHQRSDXVHVHHQ LQWKHJHQHUDOSRSXODWLRQGRHVQRWH[LVWLQWKRVHZLWKW\SHɲGLDEHWHVɲɳɴɲɳɵ Microvascular complications, cardiovascular disease, and all- cause mortality. When compared with individuals who have a normal UAER, microalbuminuria, the mildest form of diabetic nephropathy, doubles the risk RI FRURQDU\ KHDUW GLVHDVH DQG FDUGLRYDVFXODU PRUWDOLW\ LQ WKRVH ZLWK W\SH ɲ diabetes, although it must be recognized that confounding factors were not taken

(32)

ɴɳ

LQWRDFFRXQWLQWKHUHOHYDQWVWXGLHVɲɳɴɲɳɶ0DFURDOEXPLQXULDDQGGLDEHWLF QHSKURSDWK\VLJQL¿FDQWO\DɣHFWWKHULVNRIKDUGFDUGLRYDVFXODUHYHQWV,QIDFW LQGLYLGXDOVZLWKGLDEHWLFQHSKURSDWK\KDYHDWHQIROGKLJKHUULVNRIVXɣHULQJIURP coronary heart disease and stroke when compared with those without nephropathy ɲɳɷ'LDEHWLFQHSKURSDWK\DOVRDɣHFWVFDUGLRYDVFXODUPRUWDOLW\%RUFK-RKQVRQ et alIRXQGDQDOPRVWɵɱIROGKLJKHUULVNRIFDUGLRYDVFXODUPRUWDOLW\LQLQGLYLGXDOV ZLWKW\SHɲGLDEHWHVDQGGLDEHWLFQHSKURSDWK\ZKHQFRPSDUHGZLWKWKRVHZLWKRXW diabetic nephropathy. A particularly concerning fact is that the highest mortality UDWHVZHUHVHHQLQ\RXQJLQGLYLGXDOVEHWZHHQWKHDJHVRIɳɷDQGɵɶɲɳɸ*URRS et al found that the presence and the severity of chronic kidney disease increase WKHULVNRIDOOFDXVHPRUWDOLW\LQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVɶɺ6LPLODU UHVXOWVZHUHIRXQGLQWKH3LWWVEXUJK('&6WXG\ɲɳɹ$VVHHQLQWKHVHVWXGLHV WKHULVNRIDOOFDXVHPRUWDOLW\LVWKUHHWRVL[IROGKLJKHULIPLFURDOEXPLQXULDLV SUHVHQWQLQHWRɲɴIROGKLJKHULQWKHSUHVHQFHRIPDFURDOEXPLQXULDDQGɲɹWR ɴɱIROGKLJKHULQWKHFDVHRIHQGVWDJHUHQDOGLVHDVHɶɺɲɳɹ)XUWKHUPRUHWKH UHODWLRQVKLSEHWZHHQWKHH*)5DQGPRUWDOLW\VKRZVDUHYHUVH-VKDSHGFXUYH ZKHUHE\ERWKDORZH*)5XQGHUɷɱPOPLQɲɸɴP^ɳDQGDKLJKH*)5RYHUɲɳɱ POPLQɲɸɴP^ɳLQFUHDVHWKHPRUWDOLW\UDWHLQWKRVHZLWKW\SHɲGLDEHWHVɶɺ

Even though renal dysfunction is one of the strongest predictors of mortality LQWKRVHZLWKW\SHɲGLDEHWHVDUHFHQWVWXG\IRXQGWKDWLQGLYLGXDOVZLWKDQRUPDO 8$(5DQGW\SHɲGLDEHWHVDOVRIDFHDKLJKHUULVNRIPRUWDOLW\ZKHQFRPSDUHGZLWK the general population, mainly due to acute diabetes complications and ischemic KHDUWGLVHDVHɲɳɺ7KHRWKHUPLFURYDVFXODUFRPSOLFDWLRQVIRXQGLQWKRVHZLWK W\SHɲGLDEHWHVKDYHQRWVKRZQVLPLODUO\VWURQJUHODWLRQVKLSVZLWKFDUGLRYDVFXODU disease. Diabetic retinopathy increases the risk of coronary heart disease when WKHLQGLYLGXDO¶VDJHDQGGXUDWLRQRIGLDEHWHVDUHFRQVLGHUHGEXWQRWLIGLDEHWLF nephropathy is also present. The same is true for neuropathy. No independent associations between these two microvascular complications and coronary heart disease have been found, partly due to the strong relationship with diabetic QHSKURSDWK\DVZHOODVRWKHUGLDEHWHVUHODWHGULVNIDFWRUVɲɴɱ

Other risk factors for cardiovascular disease. As mentioned above, blood SUHVVXUHFDQEHGLYLGHGLQWRGLɣHUHQWYDULDEOHVQDPHO\V\VWROLFEORRGSUHVVXUH GLDVWROLF EORRG SUHVVXUH SXOVH SUHVVXUH DQG PHDQ DUWHULDO SUHVVXUH $V ¿UVW revealed in the Framingham Heart Study, the systolic blood pressure, among all the blood pressure components, has the strongest association with cardiovascular GLVHDVHLQWKHJHQHUDOSRSXODWLRQɲɴɲ8QVXUSULVLQJO\WKHV\VWROLFEORRGSUHVVXUH is an independent risk factor for coronary heart disease in individuals with type ɲ GLDEHWHV ɲɴɱɲɴɳ :LWK UHJDUG WR WKH SXOVH SUHVVXUH WKLV EORRG SUHVVXUH FRPSRQHQWFDQEHFRQVLGHUHGDPHDVXUHPHQWRIDUWHULDOVWLɣQHVVDQGLWXVXDOO\

ULVHVZLWKDJHɲɴɴ7KHSXOVHSUHVVXUHLVDQLQGHSHQGHQWULVNIDFWRUIRUFRURQDU\

(33)

ɴɴ heart disease despite the elevated systolic blood pressure seen in the general SRSXODWLRQɲɴɵ,QLQGLYLGXDOVZLWKW\SHɲGLDEHWHVDQGUHQDOGLVHDVHWKHSXOVH SUHVVXUHLVDSUHGLFWRURILQFLGHQWFDUGLRYDVFXODUHYHQWVɲɴɶ

Elevated HbA_ɲF LV DQ LQGHSHQGHQW ULVN IDFWRU IRU ERWK QRQIDWDO DQG IDWDO FDUGLRYDVFXODU HYHQWV LQ WKRVH ZLWK W\SH ɲ GLDEHWHV ɲɴɷɲɴɸ 7KH ULVN RI coronary heart disease increases in a linear fashion with higher blood glucose FRQFHQWUDWLRQVDQGIRUHYHU\ɲXQLWLQFUHDVHLQ+E$_ɲF, the risk of coronary KHDUWGLVHDVHLQFUHDVHVE\ɴɱɲɴɷ,QWKHZHOONQRZQ'&&7(',&VWXGLHV the intensive treatment of the glucose level during the DCCT in individuals with W\SHɲGLDEHWHVUHGXFHGWKHULVNRIDQ\FDUGLRYDVFXODUHYHQWE\ɵɳDQGRIIDWDO FDUGLRYDVFXODUGLVHDVHE\ɶɸ0RUHRYHUWKHHɣHFWSHUVLVWHGIRU\HDUVDIWHUWKH DCCT study ended. The observed risk reduction was mostly attributable to the improved glucose levels during the DCCT, and it was sustained for a prolonged WLPHDOWKRXJKWKHGLɣHUHQFHLQJOXFRVHFRQWUROEHWZHHQWKHJURXSVGLVDSSHDUHG ɲɴɹ

In terms of the diabetes duration and the risk of coronary heart disease in LQGLYLGXDOVZLWKW\SHɲGLDEHWHVWKHUHVXOWVDUHVRPHZKDWFRQWUDGLFWRU\6RPH VWXGLHV KDYH IRXQG HYLGHQFH WKDW D GLDEHWHV GXUDWLRQ RI PRUH WKDQ ɳɱ \HDUV LQGHSHQGHQWO\LQFUHDVHVWKHULVNRIFRURQDU\KHDUWGLVHDVHɲɴɷɲɴɺZKLOHRWKHU VWXGLHVKDYHIRXQGQRVXFKDVVRFLDWLRQɲɴɱ

,Q PHQ ZLWK W\SH ɲ GLDEHWHV D KLJKHU ZDLVWWRKLS UDWLR :+5 ZKLFK LV indicative of obesity, increases the risk of coronary heart disease, although no VLPLODUDVVRFLDWLRQKDVEHHQIRXQGLQZRPHQɲɴɱ7KHPHWDEROLFV\QGURPH LQFUHDVHVWKHULVNRIFDUGLRYDVFXODUGLVHDVHLQERWKWKHJHQHUDOSRSXODWLRQɲɵɱ DQGWKRVHZLWKW\SHɳGLDEHWHVɲɵɲ,QLQGLYLGXDOVZLWKW\SHɲGLDEHWHVWKH metabolic syndrome increases the risk of cardiovascular disease as well as the ULVNRIERWKFDUGLRYDVFXODUDQGGLDEHWHVUHODWHGPRUWDOLW\ɲɵɳ7KHUHLVDOVR evidence of an association between insulin resistance and the risk of coronary KHDUWGLVHDVHLQWKRVHZLWKW\SHɲGLDEHWHVɲɵɴ

While dyslipidemia is a strong risk factor for both cardiovascular disease and FRURQDU\KHDUWGLVHDVHLQWKHJHQHUDOSRSXODWLRQɲɵɵDQGWKRVHZLWKW\SHɳ GLDEHWHVɲɵɶWKHUHVXOWVDUHQRWFOHDUZLWKUHJDUGWRW\SHɲGLDEHWHV)RUUHVWet al IRXQGWKDWORZ+'/FKROHVWHUROOHYHOVLQGHSHQGHQWO\LQFUHDVHWKHULVNRIFRURQDU\

KHDUWGLVHDVHɲɴɳZKLOH6RHGHPDK0XWKXet alIRXQGQRVXFKDVVRFLDWLRQɲɴɱ Instead, higher fasting triglyceride levels were found to be modestly associated ZLWKDQLQFUHDVHGULVNRIFRURQDU\KHDUWGLVHDVHɲɴɱ,QDGGLWLRQKLJKHU+'/

cholesterol levels were seen to linearly decrease the risk of coronary heart disease LQPHQZLWKW\SHɲGLDEHWHVZKLOHLQZRPHQZLWKW\SHɲGLDEHWHVD-VKDSHG phenomenon is seen, meaning that the risk of coronary heart disease starts to LQFUHDVHDJDLQZLWKDQ+'/FKROHVWHUROOHYHOEHQHDWKɱɺPPROOɲɵɷ

(34)

ɴɵ

2.3 Stroke

6WURNHZDVGH¿QHGE\WKH:RUOG+HDOWK2UJDQL]DWLRQLQWKHɲɺɸɱVDVDVXGGHQORVV of neurological function due to a disruption to the blood circulation in the brain WKDWSHUVLVWVIRUɳɵKRXUVRUORQJHUɲɵɸ,QDQXSGDWHGGH¿QLWLRQWKHWHUPEUDLQ has been replaced with the term central nervous system. In addition to the brain, WKHXSGDWHGGH¿QLWLRQLQFOXGHVWKHVSLQDOFRUGDQGWKHUHWLQDOFHOOV0RUHRYHU WKHIRFXVLVRQWLVVXHGDPDJHUDWKHUWKDQWKHWLPHOLPLWRIɳɵKRXUVIRUWKH V\PSWRPVWRSHUVLVWɲɵɹ6WURNHLVWKHVHFRQGOHDGLQJFDXVHRIGHDWKZRUOGZLGH DIWHULVFKHPLFKHDUWGLVHDVHɹDQGLWLVDOVRRQHRIWKHPRVWFRPPRQGLVHDVHV FDXVLQJGLVDELOLW\ZRUOGZLGHɲɱ,QɳɱɲɷDOPRVWɲɵPLOOLRQSHRSOHZRUOGZLGH VXɣHUHGDQLQFLGHQWVWURNHɺ

2.3.1 Classiﬁcation and pathophysiology of stroke

Ischemic stroke.6WURNHLVFODVVL¿HGLQWRWZRPDMRUVXEJURXSVQDPHO\LVFKHPLF DQGKHPRUUKDJLFVWURNHɲɵɺ7KHPDMRULW\WKDWLVDSSUR[LPDWHO\ɸɶRIDOO VWURNHVDUHRILVFKHPLFRULJLQ,VFKHPLFVWURNHFDQEHIXUWKHUFODVVL¿HGLQWRQRQ lacunar or lacunar stroke based on the mechanism leading to the stroke (i.e., WKH72$67FODVVL¿FDWLRQV\VWHPɲɶɱWKHORFDWLRQRIWKHVWURNHɲɶɲRUWKH phenotypic characteristics of the clinical stroke syndrome and the radiological IHDWXUHV ɲɳ 7KH 72$67 FODVVL¿FDWLRQ V\VWHP GLYLGHV LVFKHPLF VWURNH LQWR

¿YH FDWHJRULHV ODUJH DUWHU\ DWKHURVFOHURVLV GXH WR HPEROXV RU WKURPERVLV FDUGLRHPEROLVP VPDOOYHVVHO RFFOXVLRQ LH ODFXQDU LQIDUFWLRQ VWURNH RI RWKHUGHWHUPLQHGFDXVHDQGVWURNHRIXQGHWHUPLQHGFDXVHɲɶɱ%DPIRUGet alSUHVHQWHGDFODVVL¿FDWLRQV\VWHPZLWKIRXUVXEJURXSVQDPHO\WRWDODQWHULRU circulation infarcts (TACI), partial anterior circulation infarcts (PACI), posterior FLUFXODWLRQLQIDUFWV32&,DQGODFXQDULQIDUFWLRQV/$&,ɲɶɲ3DQWRQLet al FODVVL¿HGLVFKHPLFVWURNHLQWRWZRVXEJURXSVQRQODFXQDULHODUJHYHVVHOVWURNH mainly due to either atherosclerosis of the carotid artery or cardioembolism) or ODFXQDU LH FDXVHG E\ WKH RFFOXVLRQ RI D VLQJOH SHUIRUDWLQJ DUWHU\ ɲɳ 7KH GLɣHUHQWFODVVL¿FDWLRQPHWKRGVDUHVHWRXWLQ7DEOHɳ

(35)

ɴɶ

TABLE 2. Classiﬁcation of ischemic stroke

TOAST ⁽¹⁵⁰⁾ Large artery

atherosclerosis Cardioembolism

Stroke of determined

cause

Stroke of undetermined

cause

Small-vessel occlusion BAMFORD

et al ⁽¹⁵¹⁾

Total anterior circulation infarcts (TACI)

Partial anterior circulation infarcts

(PACI)

Posterior circulation infarcts

(POCI)

Lacunar infarcts (LACI) PANTONI

et al⁽¹²⁾ Non-lacunar stroke Lacunar stroke

Classiﬁcation of ischemic stroke based on pathophysiology (TOAST), location (Bamford et al), and phenotype (Pantoni et al).

$VWKHWHUPVVXJJHVWODFXQDUVWURNHDQGFHUHEUDOVPDOOYHVVHOGLVHDVHLQFOXGH stroke due to damage to the cerebral small arteries, veins, arterioles, and capillaries that leads to either ischemia (manifesting as white matter lesions or ODFXQDULQIDUFWLRQVRUKHPRUUKDJHGXHWRPLFUREOHHGVɲɳ&HUHEUDOVPDOOYHVVHO GLVHDVHLVEHOLHYHGWREHWKHFDXVHRIDFXWHLVFKHPLFVWURNHLQɲɷ±ɳɲRIDOOVWURNHV ɲɶɳɲɶɴ&HUHEUDOVPDOOYHVVHOGLVHDVHLVFDXVHGE\DWKHURVFOHURVLVLQWKHVPDOO EORRG YHVVHOV WKH DFFXPXODWLRQ RI DP\ORLG SODTXHV LQÀDPPDWRU\ GLVRUGHUV RUYHQRXVFROODJHQRVLVɲɳ7KHFOLQLFDOPDQLIHVWDWLRQVRIERWKFHUHEUDOVPDOO vessel disease and lacunar strokes are less severe when compared with those of ODUJHYHVVHOVWURNHKRZHYHUWKH\DUHDVVRFLDWHGZLWKFRJQLWLYHLPSDLUPHQWDQG GHPHQWLDɲɶɵ$QH[DPSOHRIDQLVFKHPLFVWURNHDVFDSWXUHGRQDPDJQHWLF UHVRQDQFHLPDJH05,LVVKRZQLQ)LJXUHɲ$

Figure 1A. Magnetic resonance image of a large cerebral infarction with hemorrhagic transformation, which is visible as the white area.

(36)

ɴɷ

Hemorrhagic stroke. The two major hemorrhagic stroke subtypes are LQWUDFHUHEUDO KHPRUUKDJH DQG VXEDUDFKQRLG KHPRUUKDJH ɲɶɶ ,QWUDFHUHEUDO KHPRUUKDJH ,&+ DFFRXQWV IRU ɲɱ±ɲɶ RI DOO VWURNHV ɲɶɷ DQG LW LV GH¿QHG as bleeding into the brain parenchyma, which in some cases also extends into WKH YHQWULFOHV ɲɶɸ ,&+ FDQ HLWKHU EH SULPDU\ RU VHFRQGDU\ GHSHQGLQJ RQ WKH XQGHUO\LQJ FDXVH RI WKH KHPRUUKDJH ɲɶɷ 3ULPDU\ ,&+ ZKLFK DFFRXQWV IRU ɸɹ±ɹɹ RI DOO WKH FDVHV RI LQWUDFHUHEUDO KHPRUUKDJH LV FDXVHG E\ WKH spontaneous rupture of the small blood vessels due to hypertension or cerebral DP\ORLGDQJLRSDWK\ɲɶɶ6HFRQGDU\,&+LVFDXVHGE\WKHUXSWXUHRIYDVFXODU malformations, of which arteriovenous malformations, cavernous angiomas, and DQHXU\VPVDUHWKHPRVWFRPPRQɲɶɷɲɶɹ7KHRWKHUPRUHPLQRUFDXVHVRI secondary ICH include trauma to the head, tumors in the brain parenchyma, coagulopathy due to drug use or hemostatic/hematologic disorders, toxins (e.g., FRFDLQH RU WKH KHPRUUKDJLF WUDQVIRUPDWLRQ RI LVFKHPLF VWURNH ɲɲɲɶɷɲɶɺ )LJXUHɲ%LOOXVWUDWHVDQ,&+DVVKRZQRQDFRPSXWHGWRPRJUDSK\&7LPDJH

Figure 1B. Computed tomography image of an intracerebral hemorrhage, which is visible as the dense white area.

Subarachnoid hemorrhage (SAH), the other hemorrhagic stroke subtype, accounts IRUDSSUR[LPDWHO\ɶRIDOOVWURNHV2IDOOWKH6$+ɹɶDUHFDXVHGE\WKHUXSWXUH RIVDFFXODUDQHXU\VPVLQWKHVXEDUDFKQRLGVSDFHɲɲ,QWKHJHQHUDOSRSXODWLRQ WKHUHPDLQGHURI6$+DUHFDXVHGE\LQÀDPPDWLRQLQWKHFHUHEUDODUWHULHVGLɣHUHQW coagulopathies (i.e., drug use or hemostatic/hematologic disorders), brain tumors, RUWR[LQVɲɷɱɲɷɲ$OWKRXJKERWK,&+DQG6$+DUHFRQVLGHUHGWREHVXEW\SHV RIKHPRUUKDJLFVWURNHWKHLUHWLRORJ\GLɣHUVDQGWKH\DUHFRQVLGHUHGWREHWZR

(37)

ɴɸ GLɣHUHQWNLQGVRIVWURNHɲɵɹ+RZHYHUWKH)LQQ'LDQH6WXG\VKRZHGWKDW6$+

LQLQGLYLGXDOVZLWKW\SHɲGLDEHWHVGLɣHUIURP6$+LQWKHJHQHUDOSRSXODWLRQ ZLWKWKHPDMRULW\EHLQJRIQRQDQHXU\VPDORULJLQPLPLFNLQJWKHPLFURYDVFXODU origin found in the case of ICH. Thus, the mechanisms and risk factors for these VWURNHVXEW\SHVDSSHDUWREHUDWKHUVLPLODULQWKHSUHVHQFHRIGLDEHWHVɲɷɳ Transient ischemic attack. A preliminary form of stroke is a transient LVFKHPLFDWWDFNRU7,$ZKLFKLVGH¿QHGDVDEULHIIRFDOORVVRIQHXURORJLFDO IXQFWLRQWKRXJKWWREHFDXVHGE\ORFDOLVFKHPLDWKDWODVWVIRUOHVVWKDQɳɵKRXUV ,QWKHFDVHRID7,$WKHLVFKHPLDLQWKHEUDLQLVFRQ¿QHGWRDVPDOODUHDSHUIXVHG E\DVSHFL¿FDUWHU\ɲɷɴ7KLVGH¿QLWLRQKDVKRZHYHUEHHQTXHVWLRQHGVLQFH in many cases brain injury has been visible on the MRI of individuals with the classical symptoms of a TIA. Therefore, it has been proposed that a TIA should EHGH¿QHGDVD³EULHIHSLVRGHRIQHXURORJLFDOG\VIXQFWLRQFDXVHGE\IRFDOEUDLQ or retinal ischemia, with clinical symptoms typically lasting less than one hour, DQGZLWKRXWHYLGHQFHRIDFXWHLQIDUFWLRQ´ɲɷɵ,UUHVSHFWLYHRIWKHLQFRQFOXVLYH GH¿QLWLRQDOFULWHULDD7,$VKRXOGQRWEHLJQRUHGDVWKLVFRQGLWLRQLVFRQVLGHUHG WREHDULVNIDFWRUIRUVWURNHɲɷɶɲɷɷ

Pathophysiology of ischemic stroke. Ischemic stroke can be caused by thrombosis or embolus of the arteries, hypoperfusion, or venous thrombosis, which DOOOHDGWRDFRPSURPLVHGEORRGVXSSO\WRWKHEUDLQɲɷɸ$WKHURVFOHURVLVFDXVHV the majority of such changes, and the development of atherosclerosis continues IRUGHFDGHVEHIRUHFOLQLFDOO\VLJQL¿FDQWFKDQJHVDUHVHHQɲɷɹ7KHGHYHORSPHQW of atherosclerosis begins with foam cells accumulating on the inside of the blood YHVVHOZDOOVWKHUHE\OHDGLQJWRIDWW\VWUHDNVɲɷɺ$VWKH\HDUVJRE\WKRVHIDWW\

streaks enlarge when extracellular lipids, such as cholesterol and lipoproteins, are R[LGL]HGDQGDFFXPXODWHDWWKLVVLWHLQWKHEORRGYHVVHOZDOOVɲɸɱ6XFKFKDQJHV to the vascular walls usually develop at the branching points of the blood vessels, DVWKHVHDUHDVDUHH[SRVHGWRVKHDUVWUHVVɲɷɺ)XUWKHUFKDQJHVWRWKHEORRG vessel walls include the development of atherosclerotic plaques, that is, the lipid FRUHEHFRPHVFRYHUHGZLWKVPRRWKPXVFOHFHOOVDQGFROODJHQɲɸɱ7KHSODTXHV may continue to grow and eventually occlude the blood vessel lumen, leading to thrombosis and the occlusion of either the large blood vessels or single perforating arteries. The plaques may also rupture, thereby causing emboli and occlusion. The formation of atherosclerotic plaques also weakens the blood vessel walls, which may lead to the formation of aneurysms or hemorrhage into the cerebral tissue ZKHQWKHSODTXHVUXSWXUHɲɸɱɲɸɲ

In the case of extracranial carotid artery disease, the atherosclerotic plaques are formed mainly in the bifurcation area of the large carotid arteries that supply EORRGÀRZWRWKHEUDLQɲɸɳ7KHSODTXHVPD\FDXVHVWHQRVLVZKLFKOHDGVWR

(38)

ɴɹ

H[WHQVLYHGLVUXSWHGFHUHEUDOEORRGSHUIXVLRQDVH[SODLQHGDERYHɲɸɱɲɸɲ7KH plaques can also rupture, thereby leading to emboli and the occlusion of smaller DUWHULHVORFDWHGPRUHGLVWDOO\ɲɸɳ,UUHJXODUOLSLGULFKSODTXHVZLWKQHFURWLF FRUHVDUHHVSHFLDOO\SURQHWRUXSWXUHɲɸɴ7KHXVHRIOLSLGORZHULQJDJHQWVLQ LQGLYLGXDOVZLWKFDURWLGDUWHU\VWHQRVLVGLPLQLVKHVWKHVL]HDQGLQÀDPPDWLRQRI WKHSODTXHVSRWHQWLDOO\OHDGLQJWRDGLPLQLVKHGULVNRIVWURNHɲɸɵ

In terms of cardioembolic stroke, the thrombi or emboli formed in the cavities of the heart travel to the cerebral vasculature, where they cause the obstruction RIWKHFHUHEUDOEORRGÀRZɲɶɱ$WULDO¿EULOODWLRQFDXVHVWKHG\VIXQFWLRQRIWKH cardiac endothelium and disturbs the coagulation cascade, which promotes WKURPEXVIRUPDWLRQɲɸɶ7KHSULPDU\SDWKRORJLFFKDQJHVHHQLQWKHFDVHRIDWULDO

¿EULOODWLRQLVWKHIRUPDWLRQRI¿EURVLVDQGWKHGLODWLRQRIWKHDWULXPɲɸɷ7KH left atrium has a tubular structure with an appendage, and it is the formation of WKLVDSSHQGDJHWKDWHQKDQFHVWKHIRUPDWLRQRIEORRGFORWVɲɸɸ$WULDO¿EULOODWLRQ DOVROHDGVWRGHFUHDVHGEORRGÀRZIURPWKHDWULXP7RJHWKHUZLWKDQHQODUJHG DQGG\VIXQFWLRQDOOHIWDWULXPWKLVOHDGVWRDQDFWLYDWHGLQWUDYDVFXODUFRDJXODWLRQ

¿EULQRO\VLVFDVFDGHDQGWKHIRUPDWLRQRIEORRGFORWVɲɸɹ)XUWKHUPRUHDWULDO

¿EULOODWLRQDOVRFDXVHVWKHUHOHDVHRIWKHLQÀDPPDWRU\DQGKHPRVWDWLFPDUNHUV WKDWSURPRWHFRDJXODWLRQɲɸɺ7KHREVWUXFWLRQRIWKHFHUHEUDOEORRGÀRZGXHWR these thrombi causes similar damage to the cerebral tissue as seen in the case of DWKHURVFOHURVLVɲɸɱɲɸɲ

7KHGLVUXSWLRQRIWKHFHUHEUDOEORRGÀRZGDPDJHVWKHEUDLQ$VWKHFHUHEUDO tissue is dependent on the continuous supply of oxygen due to the lack of a UHVSLUDWRU\ UHVHUYH LW LV SDUWLFXODUO\ YXOQHUDEOH WR LVFKHPLD ɲɷɸ 7KH ODFN RIR[\JHQLQLWLDWHVDQLVFKHPLFFDVFDGHOHDGLQJWRDODFNRIHQHUJ\ɲɹɱ7KH ODFNRIHQHUJ\FDXVHVWKHDSRSWRVLVRIQHXURQVDQLQÀDPPDWRU\UHVSRQVHWKH SKDJRF\WRVLVRIGDPDJHGWLVVXHDQGGDPDJHWRWKHEORRGEUDLQEDUULHUZKLFK causes cerebral edema and damage to the cerebral tissue ɲɸɲɲɹɱ7KHGDPDJHG tissue can be divided into the ischemic core, in which irreversible damage has occurred, and the surrounding penumbra, in which tissue salvation is feasible if the oxygen supply is restored. This penumbra is the primary target of the WUHDWPHQWRIVWURNHɲɹɲ

Pathophysiology of hemorrhagic stroke. Similar to ischemic stroke, hemorrhagic stroke causes hypoxia to the cerebral tissue due to the pressure RI WKH H[SDQGLQJ KHPDWRPD DV ZHOO DV WKH GLVUXSWHG YDVFXODU VXSSO\ ɲɹɳ )XUWKHUPRUHWKHUHOHDVHGEORRGKDVWR[LFHɣHFWVRQWKHFHUHEUDOWLVVXHZKLFK FDXVHVDQLQÀDPPDWRU\UHDFWLRQZKHUHE\WKHLQÀDPPDWRU\FHOOVDQGPHGLDWRUVRI WKHLPPXQHV\VWHPLQMXUHWKHFHUHEUDOWLVVXHɲɹɴ,IWKHEOHHGLQJFRQWLQXHVWKH LQFUHDVHGLQWUDFHUHEUDOSUHVVXUHPD\IXUWKHUUHVWULFWWKHFHUHEUDOEORRGÀRZɲɹɳ As previously described, ICH is generally caused by hypertensive arteriolosclerosis,

Incidence, risk factors, and prognosis of stroke in people with type 1 diabetes

Incidence, risk factors, and prognosis of stroke in people with type 1 diabetes

STEFANIE HÄGG-HOLMBERG

To Henrik, Lucas and Alva

“Nothing in life is to be feared, it is only to be understood.

Now is the time to understand more, so that we may fear less”

Marie Curie

CONTENTS

LIST OF ORIGINAL PUBLICATIONS

ABBREVIATIONS

ABSTRACT

ABSTRAKT (ABSTRACT IN SWEDISH)

TIIVISTELMÄ (ABSTRACT IN FINNISH)

1 INTRODUCTION

2 REVIEW OF THE LITERATURE

2.1 Diabetes mellitus

2.2 Chronic diabetic complications

2.3 Stroke