study protocols were approved by the mayo clinic and olmsted medical center institutional review boards . criteria for type 2 diabetes were 1 ) treatment ( oral antidiabetic agents , insulin ) or 2 ) fasting blood glucose > 126 mg / dl on two separate occasions or 3 ) a physician diagnosis , using information from participant medication bottles and from the participant medical record ( 3 ) . individuals who only met the latter two criteria were considered as having type 2 diabetes without treatment ; they had very mild disease ( median glycosylated hemoglobin [ hba1c ] was 5.8% [ range 5.16.7% ] ) . diabetes - related complications were defined as self - reported physician - diagnosed diabetic nephropathy , retinopathy , or neuropathy ( 3 ) . demographic factors were assessed by interview , and vascular risk factors ( hypertension , coronary heart disease , and dyslipidemia ) were assessed from the medical record . height and weight were measured , and apolipoprotein ( apoe ) 4 genotyping was performed . cognitive status was evaluated by a nurse , a neurologist , and by cognitive testing for a diagnosis of cognitively normal , mci , or dementia as previously described ( 7 ) . mri studies were performed on a 3-t system ( signa ; ge healthcare , waukesha , wi ) , with an eight - channel phased - array head coil and a fluid - attenuated inversion recovery sequence ( 8) . a trained technician assessed presence of white matter hyperintensities ( wmhs ) , hemispheric cortical infarctions ( > 10 mm ) , and subcortical infarctions ( lacunar infarctions in the central gray or capsular region or in the hemispheric white matter ; areas > 3 mm , dark in the center , bright rim , and not a perivascular space ) as previously described ( 9 ) . we compared subcortical infarctions ( present or absent ) in case subjects and control subjects using logistic regression methods with adjustment for age , sex , years of education , and apoe 4 allele carrier status ( model 1 ) and with additional adjustment for potential confounders or covariates ( model 2 ) . mri studies were performed on a 3-t system ( signa ; ge healthcare , waukesha , wi ) , with an eight - channel phased - array head coil and a fluid - attenuated inversion recovery sequence ( 8) . a trained technician assessed presence of white matter hyperintensities ( wmhs ) , hemispheric cortical infarctions ( > 10 mm ) , and subcortical infarctions ( lacunar infarctions in the central gray or capsular region or in the hemispheric white matter ; areas > 3 mm , dark in the center , bright rim , and not a perivascular space ) as previously described ( 9 ) . we compared subcortical infarctions ( present or absent ) in case subjects and control subjects using logistic regression methods with adjustment for age , sex , years of education , and apoe 4 allele carrier status ( model 1 ) and with additional adjustment for potential confounders or covariates ( model 2 ) . consistent with the matched case - control design , the distributions of age ( median 79 years ) , sex ( 41% female ) , years of education ( median 12 years ) , and apoe 4 allele carrier status ( 26% ) were similar in case subjects and control subjects . case subjects ( vs. control subjects ) had a higher frequency of hypertension ( 94 vs. 68% ; p < 0.01 ) , bmi > 30 kg / m ( 33 vs. 21% ; p = 0.03 ) , coronary heart disease ( 40 vs. 27% ; p = 0.04 ) , dyslipidemia ( 88 vs. 70% ; p = < 0.001 ) , and median hba1c levels ( 6.0 vs. 5.0% ; p < 0.01 ) but did not differ from control subjects in the frequency of smoking ( 57 vs. 56% ; p = 0.86 ) , mci ( 25 vs. 22% ; p = 0.49 ) , or wmh ( 15 vs. 16 cm ; p = 0.86 ) . of the 90 subjects with subcortical infarctions , 55 subjects had one , 20 had two , and 5 had three to nine subcortical infarctions detected . the frequency of subcortical infarctions was higher in case subjects ( 39% ) than in control subjects ( 29% ; odds ratio [ or ] 1.59 [ 95% ci 0.912.75 ] ; p = 0.10 ) . compared with control subjects , the or was elevated for case subjects without treatment for type 2 diabetes , case subjects with diabetes - related complications , and case subjects diagnosed with type 2 diabetes in late life ( table 1 ) . hypertension was not associated with subcortical infarctions , and there was no interaction of hypertension with type 2 diabetes . association of type 2 diabetes and diabetes - related measures with subcortical infarctions * * case subjects were matched to control subjects without type 2 diabetes by age , sex , and years of education . model 1 includes adjustment for age , sex , years of education ( as a continuous variable ) , and apoe 4 allele carrier status to account for any residual confounding . model 2 includes model 1 variables in addition to hypertension , dyslipidemia , coronary heart disease , bmi , and smoking . when we examined associations with subcortical infarctions as an ordinal variable ( 0 , 1 , and 2 ) , the magnitude of the associations were attenuated but remained in the same direction as in the table . with subjects without type 2 diabetes as the references groups , the estimates for model 1 are as follows : oral antidiabetic agents ( or 1.03 [ 95% ci 0.512.08 ] ; p = 0.93 ) , insulin use ( 1.64 [ 0.584.61 ] ; p = 0.35 ) ; without treatment ( 2.03 [ 0.914.53 ] ; p = 0.08 ) ; without diabetes - related complications ( 1.03 [ 0.472.27 ] ; p = 0.95 ) and with complications ( 1.68 [ 0.903.13 ] ; p = 0.10 ) ; age at diagnosis < 65 years ( 1.10 [ 0.442.75 ] ; p = 0.84 ) and 65 years ( 1.52 [ 0.842.74 ] ; p = 0.16 ) ; short duration of diabetes ( 0.93 [ 0.451.94 ] ; p = 0.86 ) ; < 8 years ( 1.94 [ 1.003.74 ] ; p = 0.05 ) . when restricted to case subjects only , the or of subcortical infarctions was elevated in case subjects without treatment ( or 2.34 [ 95% ci 0.846.54 ] ; p = 0.10 ) , case subjects treated with insulin ( 1.51 [ 0.435.26 ] ; p = 0.52 ) compared with case subjects treated with oral antidiabetic agents ( reference group ) , case subjects with complications versus no complications ( 1.75 [ 0.615.05 ] ; p = 0.30 ) , case subjects with diagnosis at aged 65 years versus aged < 65 years ( 1.75 [ 0.615.05 ] ; p = 30 ) , and case subjects with shorter versus longer duration of diabetes ( 2.61 [ 1.016.75 ] ; p = 0.05 ) . in this elderly sample , subjects with untreated type 2 diabetes , diabetes - related complications , and later age at diagnosis were more likely to have subcortical infarctions . untreated type 2 diabetes may contribute to subclinical microvascular disease and undetected large vessel atherosclerotic disease ( 10 ) . in a stroke registry , type 2 diabetes was associated with multiple lacunar infarctions ( 11 ) . insulin treatment , a marker for disease severity , has been associated with micro- and macrocerebrovascular disease including subcortical infarctions ( 12 ) . the present findings are consistent with a role of subcortical infarctions as a mediator of cognitive impairment in patients with type 2 diabetes . the nonsignificant association for insulin - treated diabetes may be due to survival bias and underrepresentation of subjects with insulin - treated diabetes in our study , given the increased risk of mortality and stroke in subjects with severe diabetes or to limited power due to small numbers . consistent with our study , type 2 diabetes was associated with an increased risk of lacunar infarctions in the honolulu - asia aging study ( 6 ) , the utrecht diabetic encephalopathy study ( 13 ) , and the cardiovascular health study ( 14 ) . in contrast , others have not found associations of type 2 diabetes with lacunar infarctions ( 15 ) or have observed associations with wmh ( 13 ) . potential limitations of our study include the cross - sectional design , potential nonparticipation bias , underrepresentation of subjects with early onset of diabetes , and inadequate power to assess associations of type 2 diabetes with cortical infarctions . in summary , our findings suggest that untreated type 2 diabetes , diabetes - related complications , and insulin treatment are associated with subcortical infarctions .
objectiveto investigate the association of type 2 diabetes with subcortical infarctions.research design and methodswe investigated this association in subjects with type 2 diabetes ( case subjects ; n = 93 ) and without type 2 diabetes ( control subjects ; n = 186 ) , matched by age , sex , and years of education . 
 participants were a subset of the mayo clinic study of aging ( median age 79 years ) who had undergone magnetic resonance imaging.resultsthe frequency of subcortical infarctions was 39% in case subjects and 29% in control subjects ( odds ratio 1.59 [ 95% ci 0.912.75 ] ) . 
 the association was stronger in case subjects without treatment ( 2.60 [ 1.116.08 ] ) and in case subjects with diabetes - related complications ( 1.96 [ 1.023.74 ] ) compared with control subjects.conclusionsthese findings suggest that untreated type 2 diabetes and type 2 diabetes with complications are associated with subcortical infarctions .