ABSTRACT
Introduction: Type 1 diabetes has been linked to brain volume reductions as well as to cerebral small vessel disease (cSVD). This study concerns the relationship between normalized brain volumes (volume fractions) and cSVD, which has not been examined previously. Methods: We subjected brain magnetic resonance imaging studies of 187 adults of both sexes with Type 1 diabetes and 30 matched controls to volumetry and neuroradiological interpretation. Results: Participants with Type 1 diabetes had smaller thalami compared to controls without diabetes (p = 0.034). In subgroup analysis of the Type 1 diabetes group, having any sign of cSVD was associated with smaller cortical (p = 0.031) and deep gray matter volume fractions (p = 0.029), but a larger white matter volume fraction (p = 0.048). After correcting for age, the smaller putamen volume remained significant. Conclusions: We found smaller thalamus volume fractions in individuals with Type 1 diabetes as compared to those without diabetes, as well as reductions in brain volume fractions related to signs of cSVD in individuals with Type 1 diabetes.
Subject(s)
Brain , Cerebral Small Vessel Diseases , Diabetes Mellitus, Type 1 , Magnetic Resonance Imaging , Humans , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/diagnostic imaging , Cerebral Small Vessel Diseases/diagnostic imaging , Cerebral Small Vessel Diseases/pathology , Male , Female , Adult , Middle Aged , Brain/diagnostic imaging , Brain/pathology , Organ Size , Thalamus/diagnostic imaging , Thalamus/pathology , Case-Control Studies , Gray Matter/diagnostic imaging , Gray Matter/pathology , White Matter/diagnostic imaging , White Matter/pathologyABSTRACT
Individuals with type 1 diabetes (T1D) carry a markedly increased risk of stroke, with distinct clinical and neuroimaging characteristics as compared to those without diabetes. Using whole-exome or whole-genome sequencing of 1,051 individuals with T1D, we aimed to find rare and low-frequency genomic variants associated with stroke in T1D. We analysed the genome comprehensively with single-variant analyses, gene aggregate analyses, and aggregate analyses on genomic windows, enhancers and promoters. In addition, we attempted replication in T1D using a genome-wide association study (N = 3,945) and direct genotyping (N = 3,263), and in the general population from the large-scale population-wide FinnGen project and UK Biobank summary statistics. We identified a rare missense variant on SREBF1 exome-wide significantly associated with stroke (rs114001633, p.Pro227Leu, p-value = 7.30 × 10-8), which replicated for hemorrhagic stroke in T1D. Using gene aggregate analysis, we identified exome-wide significant genes: ANK1 and LRRN1 displayed replication evidence in T1D, and LRRN1, HAS1 and UACA in the general population (UK Biobank). Furthermore, we performed sliding-window analyses and identified 14 genome-wide significant windows for stroke on 4q33-34.1, of which two replicated in T1D, and a suggestive genomic window on LINC01500, which replicated in T1D. Finally, we identified a suggestively stroke-associated TRPM2-AS promoter (p-value = 5.78 × 10-6) with borderline significant replication in T1D, which we validated with an in vitro cell-based assay. Due to the rarity of the identified genetic variants, future replication of the genomic regions represented here is required with sequencing of individuals with T1D. Nevertheless, we here report the first genome-wide analysis on stroke in individuals with diabetes.
Subject(s)
Ankyrins , Diabetes Mellitus, Type 1 , Genetic Predisposition to Disease , Genome-Wide Association Study , Stroke , Whole Genome Sequencing , Adult , Female , Humans , Male , Middle Aged , Ankyrins/genetics , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/complications , Membrane Proteins/genetics , Polymorphism, Single Nucleotide , Regulatory Sequences, Nucleic Acid/genetics , Stroke/geneticsABSTRACT
BACKGROUND: Insulin resistance and chronic kidney disease are both associated with increased coronary artery disease risk. Many formulae estimating glucose disposal rate in type 1 diabetes infer insulin sensitivity from clinical data. We compare associations and performance relative to traditional risk factors and kidney disease severity between three formulae estimating the glucose disposal rate and coronary artery disease in people with type 1 diabetes. METHODS: The baseline glucose disposal rate was estimated by three (Williams, Duca, and Januszewski) formulae in FinnDiane Study participants and related to subsequent incidence of coronary artery disease, by baseline kidney status. RESULTS: In 3517 adults with type 1 diabetes, during median (IQR) 19.3 (14.6, 21.4) years, 539 (15.3%) experienced a coronary artery disease event, with higher rates with worsening baseline kidney status. Correlations between the three formulae estimating the glucose disposal rate were weak, but the lowest quartile of each formula was associated with higher incidence of coronary artery disease. Importantly, only the glucose disposal rate estimation by Williams showed a linear association with coronary artery disease risk in all analyses. Of the three formulae, Williams was the strongest predictor of coronary artery disease. Only age and diabetes duration were stronger predictors. The strength of associations between estimated glucose disposal rate and CAD incidence varied by formula and kidney status. CONCLUSIONS: In type 1 diabetes, estimated glucose disposal rates are associated with subsequent coronary artery disease, modulated by kidney disease severity. Future research is merited regarding the clinical usefulness of estimating the glucose disposal rate as a coronary artery disease risk factor and potential therapeutic target.
Subject(s)
Biomarkers , Blood Glucose , Coronary Artery Disease , Diabetes Mellitus, Type 1 , Insulin Resistance , Humans , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Coronary Artery Disease/epidemiology , Coronary Artery Disease/diagnosis , Coronary Artery Disease/blood , Male , Female , Adult , Incidence , Middle Aged , Risk Assessment , Time Factors , Blood Glucose/metabolism , Biomarkers/blood , Finland/epidemiology , Longitudinal Studies , Risk Factors , Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/diagnosis , Prognosis , Predictive Value of Tests , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/physiopathology , Renal Insufficiency, Chronic/blood , Kidney/physiopathology , Insulin/blood , Insulin/therapeutic use , Young Adult , Severity of Illness IndexABSTRACT
BACKGROUND: As the retina is suggested to mirror the brain, we hypothesized that diabetic retinopathy and macular edema are indicative of stroke risk in type 1 diabetes and sought to assess this association in individuals with type 1 diabetes. METHODS: We included 1,268 adult FinnDiane Study participants with type 1 diabetes (age 38.7 ± 11.8 years, 51.7% men vs. 48.3% women, and 31.5% had diabetic kidney disease), data on baseline diabetic retinopathy severity, and first stroke during our observational follow-up. Retinopathy was graded by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and macular edema as clinically significant (CSME) or not. Strokes identified from registries were confirmed from medical files. Adjusted hazard ratios (HR) for stroke by retinopathy severity and CSME were calculated by Cox models adjusted for clinical confounders, including diabetic kidney disease. RESULTS: During median 18.0 (14.1-19.3) follow-up years, 130 strokes (96 ischemic, 34 hemorrhagic) occurred. With no-very mild (ETDRS 10-20) retinopathy as reference, the adjusted HR for stroke was 1.79 (95%CI 1.02-3.15) in non-proliferative (ETDRS 35-53), and 1.69 (1.02-2.82) in proliferative (ETDRS 61-85) retinopathy. Corresponding adjusted HR for ischemic stroke was 1.68 (0.91-3.10) in non-proliferative and 1.35 (0.77-2.36) in proliferative retinopathy. The adjusted HR for hemorrhagic stroke was 2.84 (0.66-12.28) in non-proliferative and 4.31 (1.16-16.10) in proliferative retinopathy. CSME did not increase HR for any stroke type after adjustment for clinical confounders (data not shown). CONCLUSIONS: Stroke incidence increases with the severity of diabetic retinopathy independently of comorbid conditions, including diabetic kidney disease.
Subject(s)
Diabetes Mellitus, Type 1 , Diabetic Retinopathy , Macular Edema , Severity of Illness Index , Humans , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/complications , Diabetic Retinopathy/epidemiology , Diabetic Retinopathy/diagnosis , Female , Male , Macular Edema/epidemiology , Macular Edema/diagnosis , Incidence , Adult , Middle Aged , Risk Factors , Time Factors , Finland/epidemiology , Risk Assessment , Registries , Ischemic Stroke/epidemiology , Ischemic Stroke/diagnosis , Stroke/epidemiology , Stroke/diagnosis , Hemorrhagic Stroke/epidemiology , Hemorrhagic Stroke/diagnosisABSTRACT
OBJECTIVES: A third of asymptomatic individuals with type 1 diabetes (T1D) show signs of cerebrovascular disease in brain MRI. These signs associate with advanced stages of diabetic retinal disease, but not in mild or moderate retinopathy. We aimed to evaluate a wider spectrum of retinal changes by exploring the relationship between quantitative measures of retinal vessel parameters (RVP) and cerebrovascular changes in T1D. METHODS: We included 146 neurologically asymptomatic individuals with T1D [51% women, median age 40 (33.0-45.1) years] and 24 healthy, sex-matched and age-matched controls. All individuals underwent a clinical and biochemical work-up and brain MRI, which was evaluated for cerebral microbleeds (CMBs), white matter hyperintensities, and lacunar infarcts. RVPs, including central retinal arteriole (CRAE) and central retinal vein (CRVE) equivalents and the ratio of the two variables (arteriovenous ratio, AVR) were assessed quantitatively by a computer-assisted method (IVAN software, version 3.2.6) from fundus images. RESULTS: Among T1D participants, those with CMBs had a lower arteriovenous ratio (AVR) compared with those without CMBs ( P â=â0.023). AVR was inversely associated with the amount of CMBs ( r â=â-0.063, P â=â0.035). CMB prevalence was higher in those with AVR below the median (31%) compared with above the median (16%, P â<â0.001), and this difference was significant also after individuals with only no-to-mild retinopathy were included (28 vs. 16%, P â=â0.005). A correlation between blood pressure and CRAE ( r â=â-0.19, P â=â0.025) appeared among those with T1D. CONCLUSION: Regardless of the severity of diabetic retinopathy, AVR is associated with the existence of CMBs in T1D.