Abstract
Aims
To determine if medium- and long-term blood glucose control as well as glycemic variability, which are known to be strong predictors of vascular complications, are associated with underlying cerebral small vessel disease (cSVD) in neurologically asymptomatic individuals with type 1 diabetes.
Methods
A total of 189 individuals (47.1% men; median age 40.0, IQR 33.0–45.2 years) with type 1 diabetes (median diabetes duration of 21.7, IQR 18.3–30.7 years) were enrolled in a cross-sectional retrospective study, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Glycated hemoglobin (HbA1c) values were collected over the course of ten years before the visit including a clinical examination, biochemical sampling, and brain magnetic resonance imaging. Markers of glycemic control, measured during the visit, included HbA1c, fructosamine, and glycated albumin.
Results
Signs of cSVD were present in 66 (34.9%) individuals. Medium- and long-term glucose control and glycemic variability did not differ in individuals with signs of cSVD compared to those without. Further, no difference in any of the blood glucose variables and cSVD stratified for cerebral microbleeds (CMBs) or white matter hyperintensities were detected. Neither were numbers of CMBs associated with the studied glucose variables. Additionally, after dividing the studied variables into quartiles, no association with cSVD was observed.
Conclusions
We observed no association between glycemic control and cSVD in neurologically asymptomatic individuals with type 1 diabetes. This finding was unexpected considering the large number of signs of cerebrovascular pathology in these people after two decades of chronic hyperglycemia and warrants further studies searching for underlying factors of cSVD.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
High blood glucose is a major risk factor for not only microvascular complications, but also cardiovascular disease in type 1 diabetes [1, 2]. Cardiovascular complications cause significant premature mortality in individuals with type 1 diabetes [3]. Despite the fact that type 1 diabetes increases the risk of stroke fourfold compared to non-diabetic individuals, this grim complication has been less studied than other cardiovascular consequences [4]. We observed recently that a third of neurologically asymptomatic individuals with type 1 diabetes showed signs of pathological cerebral small vessel disease (cSVD), however, virtually none among the healthy control subjects. Of the different manifestations, white matter hyperintensities (WMHs) were observed in 17% and cerebral microbleeds (CMBs) in 24% in our cohort comprised of individuals with type 1 diabetes and a mean age of 40.0 [5]. Our findings resemble those of the Pittsburgh EDC study reporting 33% of individuals with a mean age of 49.5 years showing signs of white matter hyperintensities (WMHs) in brain magnetic resonance imaging (MRI) [6]. As hemosiderin-sensitive sequences were not part of the MRI protocol in the Pittsburgh cohort CMBs could not be detected.
Notably, only few of the traditional risk factors were different in type 1 diabetes individuals with and without cSVDs. Blood pressure, a well-known risk factor for cSVD [7], was higher in both individuals with WMHs and CMBs compared to those without [5], and especially nocturnal hypertension was associated cSVD [8]. However, it is unlikely that the modestly higher blood pressure in individuals with cSVD compared to those with no cerebrovascular pathology would fully explain this finding [5]. Neither could we observe a difference in HbA1c at the time of the imaging study. This warrants further analysis of glycemic control in relation to cSVD in this type 1 diabetes cohort with more than two decades of hyperglycemia.
The aim of this study was to retrospectively determine whether medium- or long-term blood glucose control measured by different markers were associated with cSVD in neurologically asymptomatic individuals with type 1 diabetes. Additionally, we sought to investigate whether long-term glycemic fluctuations, known to predict vascular complications in this patient group, are predictive of cSVD.
Methods
This study was performed as part of the Finnish Diabetic Nephropathy (FinnDiane) Study, a nationwide multicenter study aiming to identify genetic, environmental, and clinical risk factors for micro- and macrovascular complications in type 1 diabetes [5]. A total of 191 individuals with type 1 diabetes were enrolled to the study. Two individuals were excluded due to missing clinical data. Thus, a total of 189 individuals with type 1 diabetes were included in the present study. Age span ranged between 18 and 50 years and the onset of diabetes was < 40 years. Individuals with renal replacement therapy, any clinical signs of cerebrovascular disease, or contraindications for MRI were excluded from this substudy. The study was carried out in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Helsinki and Uusimaa Hospital District. Each participant signed a written informed consent [5].
All individuals were studied at the FinnDiane Research Center (Biomedicum) and the Medical Imaging Center at Helsinki University Hospital, both in Helsinki, Finland. Clinical visits included brain MRI scans, biochemical sampling, and a thorough clinical examination. The study visits and methods have been presented in greater detail before [5]. Briefly, brain MRI was performed with a 3.0 T scanner (Achieva; Philips, Best, the Netherlands). The images were assessed by an experienced neuroradiologist (JM) who was blinded to all clinical data. Markers of cSVD were rated per the standardized STRIVE criteria, including the assessment of WMHs (Fazekas scale used, with category ≥ 1 considered a significant burden), CMBs, and lacunar infarcts [9].
Measures of blood glucose control
To characterize medium-term glucose control, fructosamine (FA), and glycated albumin (GA), reflecting blood glucose during a time span of two to three weeks, were measured [10, 11]. Blood glycated hemoglobin (HbA1c), reflecting blood glucose control during a time span of one to two months, was measured using standardized assays in a central laboratory (Medix Laboratories, Espoo Finland) [12]. Three or more HbA1c values over the course of ten years before the visit (median count 16, IQR 10–23) were obtained in order to calculate overall mean HbA1c (HbA1c-meanoverall) for each individual to better delineate long-term glucose control. These values were collected from local laboratories using standardized methods (HPLC) with a normal range of 4–6%. Measurements of HbA1c visit-to-visit variability reflects long-term blood glucose fluctuations in a wider timespan of months to years [13]. To assess long-term blood glucose fluctuations HbA1c standard deviation (HbA1c-SD), HbA1c coefficient of variation (HbA1c-CV), and HbA1c average real variability (HbA1c-ARV) were calculated for each individual. To minimize any effect of a varying number of HbA1c values on long-term glucose variability, adjusted HbA1c standard deviation (HbA1c-adjSD) were defined for each individual. Of the individuals with type 1 diabetes, 44 had less than three HbA1c values available ten years before the visit, three had missing data on FA or GA and were excluded from the respective analyses.
Determination of glycated albumin (GA)
GA concentration was determined according to manufacturers' instructions using a competitive ELISA kit (Human glycated albumin ELISA Kit, CSB-E09599h, Cusabio, Wuhan, Hubei Province, China) [14]. Samples were diluted to 1:250 with the sample diluent buffer provided with the kit to achieve sample absorbance within the range of a standard curve. The absorbance was measured at 450 nm using a Synergy H1 hybrid multi-mode microplate reader (Biotek, Winooski, VT, USA). The amount of GA was determined by comparing with the known standard provided with the kit and expressed as nM/ml of GA present in human serum samples.
Determination of fructosamine (FA)
Serum FA levels were measured by colorimetric technique based on the ability of FA to reduce nitroblue tetrazolium (NBT) to tetrazinolyl radical NBT + , which further yields formation of colored formazan under alkaline condition [15]. The developed color intensity was measured at 540 nm and FA content was calculated using standard 1-deoxy-1 morpholino-D-fructose (0–3.2 mM/L).
Statistics
Statistical analyses were performed using IBM SPSS Statistics 26.0 (IBM, Armonk, NY). T-tests were used for parametric data and presented as means (± SD), and Mann–Whitney-U or Kruskal–Wallis tests for the nonparametric data presented as medians (interquartile range). The X2 test or Fisher’s exact tests were performed for categorical variables. HbA1c-adjSD was calculated according to the formula: \(\mathrm{SD}/\sqrt{[\mathrm{n}/(\mathrm{n}-1)]}\) [16, 17]. HbA1c-CV was calculated as the HbA1c (%) SD divided by the mean and multiplied by 100, result presented as a percentage and HbA1c-ARV as the average of the absolute differences between consecutive HbA1c (%) measurements [18]. The study individuals were divided into three groups based on the number of CMBs (zero, one to two, more than two) and into quartiles based on the HbA1c, FA, GA, HbA1c-meanoverall, HbA1c-SD, HbA1c-adjSD, HbA1c-CV, and HbA1c-ARV values. Bivariate (Pearson) correlation analysis was used to study correlations between HbA1c, FA, GA, and HbA1c-meanoverall. The threshold for statistical significance was set at p < 0.05.
Results
Clinical characteristics
One hundred and eighty-nine individuals with type 1 diabetes were enrolled for this study, with demographics previously presented in greater detail [5]. Briefly, the median age of the individuals with type 1 diabetes was 40.0 (33.0–45.2) years, 47.1% were male and median diabetes duration was 21.7 (18.3–30.7) years. One individual had a history of an acute myocardial infarction, no other cardiovascular events were recorded. Mean systolic blood pressure was 130 ± 14 mmHg. Among cases, 31 (16.9%) had albuminuria, 20 (10.9%) microalbuminuria, and 11 (6.0%) macroalbuminuria. Sixty-six (34.9%) showed signs of cSVD, 45 (23.8%) had CMBs, 32 (16.9%) WMHs, and 4 (2.1%) lacunar infarcts. The overlap between these changes was eleven (5.8%) for CMBs and WMHs and two (1.1%) for both CMBs or WMHs and lacunar infarct. Examples of these MRI findings are presented in Fig. 1. Fifty-five (29.1%) of the individuals were on insulin pump treatment. Insulin pump treatment did not correlate with the presence of cSVD (data not shown). Median HbA1c, GA, and FA values during the visits were 8.1% (7.4–8.9%), (65.0 mmol/mol [57.0–73.0 mmol/mol]), 91.6 nM/ml (74.3–116.4 nM/ml), and 2.6 mM/l (2.4–3.0 mM/l), respectively. HbA1c-meanoverall, collected over the course of ten years before the visit (median count 16, IQR 10–23), were 8.1 ± 0.9% (65.4 ± 10.3 mmol/mol) (Table 1). Bivariate correlations between HbA1c, FA, GA, and HbA1c-meanoverall are presented in Supplementary Table 1. An association was observed between HbA1c vs. FA (p = 0.018) and HbA1c vs. HbA1c-meanoverall (p < 0.001). To overcome the possibility of bias by the number of HbA1c measurements we divided the study individuals into two groups, above and below median HbA1c count. The presence of cSVD were not different between the groups (24 [30.8%] vs. 29 [43.3%], p = 0.119).
Individuals with CMBs or WMHs had higher systolic blood pressure compared to those without CMBs or WMHs (135 \(\pm\) 17 mmHg vs. 129 \(\pm\) 13 mmHg, p = 0.011 for CMBs and 137 \(\pm\) 15 mmHg vs. 129 \(\pm\) 14 mmHg, p = 0.005 for WMHs). The presence of WMHs correlated also with age (45.0 [40.4–47.6] years vs. 38.6 [32.5–44.2] years, p < 0.001) and the presence of CMBs with albuminuria (13 [30.2%] vs. 18 [12.9%], p = 0.008). The other demographic variables were not associated with CMBs or WMHs.
Medium- and long-term blood glucose control and cSVD
HbA1c at the study visit did not correlate with the presence of cSVD (8.2% [7.6–8.9%], 66.0 mmol/mol [59.8–73.3 mmol/mol] vs. 8.0% [7.3–8.8%], 64.0 mmol/mol [56.0–73.0 mmol/mol], p = 0.259), CMBs, or WMHs in individuals with type 1 diabetes. GA and FA did not correlate with cSVD (97.2 [73.9–117.8] nM/ml vs. 89.6 [76.3–115.9] nM/ml, p = 0.704 for GA and 2.6 [2.4–2.9] mM/l vs. 2.5 [2.3–3.0] mM/l p = 0.587 for FA), CMBs, or WMHs in brain MRIs (Table 2). Furthermore, individuals with type 1 diabetes divided into quartiles based on their HbA1c, GA, and FA values showed no correlations with the presence on cSVD markers (Table 3). Neither did we observe associations between HbA1c, GA, and FA and the number of CMBs (Table 4).
Differences in HbA1c-meanoverall value, collected within ten years prior to the study visit, were not observed between those type 1 diabetes individuals with any signs of cSVD in their brain MRIs compared to those without (8.3 ± 1.0% [67.4 ± 11.2 mmol/mol] vs. 8.0 ± 0.9% [64.2 ± 9.5 mmol/mol], p = 0.141) (Table 2). This was also true when analyzing separately the cerebral changes CMBs and WMHs. We observed no associations between cumulative blood glucose values and cSVDs or the number of CMBs after dividing individuals with type 1 diabetes into quartiles based on the HbA1c-meanoverall (Tables 3 and 4).
Glycemic variability and cSVD
Long-term HbA1c variability, measured as HbA1c-SD (0.57% [0.42–0.78%] vs. 0.61% [0.44–0.81%], p = 0.655, HbA1c-adjSD (0.55% [0.40–0.73%] vs. 0.58% [0.43–0.78%], p = 0.771, HbA1c-CV (6.7% [5.5–8.7%] vs. 7.6% [5.7–9.9%], p = 0.245), and HbA1c-ARV (0.5 [0.4–0.6] vs. 0.5 [0.3–0.7], p = 0.953), did not correlate with the presence of cSVD. Similarly, no correlation was observed between glycemic variability and WMHs, CMBs, or the number of CMBs (Tables 2 and 4). After dividing the population into quartiles of HbA1c variability, no correlation was observed with the presence of cSVD, CMBs or WMHs observed in brain MRI (Table 3).
Discussion
The main finding of our study was that medium- and long-term blood glucose control and glycemic variability showed no association with cSVD in neurologically asymptomatic individuals with type 1 diabetes after two decades of chronic hyperglycemia. Our study results suggest that factors other than blood glucose control are central in the development of cSVD in type 1 diabetes.
Risk factors for cSVD, especially for CMBs, are scarcely studied in type 1 diabetes. The Pittsburgh EDC study reported no association between WMHs and chronic hyperglycemia measured as HbA1c [6]. Similar findings were reported in another cohort consisting of 114 individuals with type 1 diabetes [19]. Our findings are in concordance with these previous studies, further extending their observations by carefully characterizing blood glucose control as well as deepening the cerebrovascular phenotype. We measured cumulative blood glucose and glycemic variability after collecting HbA1c values over a course of ten years before the study visit. Furthermore, medium-term glucose control was estimated by adding two established glycemic markers, namely FA and GA, into the analyses. Lastly, in contrast to prior studies, CMBs being strongly associated with future strokes and mortality [20, 21] were identified from brain MRI scans in our study in contrast to only WMHs and lacunes in previous studies.
A third of the individuals in our population of neurologically asymptomatic individuals with type 1 diabetes showed signs of pathological cSVD. However, hardly any cerebrovascular changes were observed in the normoglycemic healthy control subjects. Only a few established clinical risk factors were different in individuals with and without cSVDs. Notably, differences in these risk factors, namely blood pressure and albuminuria, were only modestly explaining the cerebral findings [5]. It is, thus, surprising that variables reflecting blood glucose control at the time of the brain MRI study, cumulative blood glucose levels prior to the study, or blood glucose variability showed no associations with vascular pathology detected in brain MRI.
Individuals with type 1 diabetes have a markedly increased risk for cardiovascular morbidity and mortality compared to the healthy population [22]. We have previously shown that HbA1c is an independent risk factor for ischemic but not for hemorrhagic stroke [23]. Similarly, intensive diabetes therapy reduced a pooled cardiovascular disease (CVD) end-point consisting of nonfatal myocardial infarction, stroke and death by 57 percent in the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications (EDIC) Study [2]. It may well be that CVD outcomes in these longitudinal studies were partly secondary to diabetic kidney disease (DKD), a strong risk factor for cerebrovascular disease, whereas 83.1% of the participants in our study, showed no signs of DKD. This raises the question whether the detrimental effect of hyperglycemia on the cerebrovascular bed is mediated via diabetic microvascular complications, and kidney disease in particular.
Glycemic variability has been suggested to cause cellular damage in different organs, particularly via oxidative stress [24]. We have shown long-term glucose variability, measured as SD of longitudinal HbA1c values, to predict incident of microalbuminuria, progression of renal disease, and cardiovascular disease events in type 1 diabetes [13]. Similar findings were reported in another study, where HbA1c variability predicted retinopathy, nephropathy, and cardiac autonomic neuropathy in adolescents with type 1 diabetes [25]. The DCCT Study reported HbA1c variability to contribute to the development of retinopathy and nephropathy, whereas short-term glucose variability did not predict the development of these complications [16, 26, 27]. Previous reports showed no strong association of FA with severity of hemiparesis and predicted stroke outcome in general population with brain infarction of the carotid territory [28] and in individuals with cerebral hemorrhage at an early stage of their illness [29]. Also, GA has shown different impact on stroke outcomes being associated with only large artery atherosclerosis but not with small vessel occlusion and cardioembolism in diabetic individuals with acute ischemic stroke [30]. However, other study reported association of GA with early neurological deterioration in prediabetic individuals with acute ischemic stroke [31]. Reflecting short-term glycemia, FA and GA levels can be affected by acute blood glucose change, albumin turnover or metabolism [32] and therefore reflects its variability in a disease specific manner. These observations and present findings suggest that an abnormal level of glycemic biomarkers reflect metabolic illness but does not exacerbate an acute manifestation of cerebrovascular changes. Future studies are needed to investigate whether short-term glucose control and variability contribute to the risk of cSVD, especially CMBs in type 1 diabetes.
High blood glucose is the main driver of diabetic retinopathy, another form of cerebrovascular disease, in type 1 diabetes [33]. It is thus of interest that the number of CMBs has earlier been shown to be higher in individuals with type 1 diabetes and severe diabetic retinopathy [34]. Similarly, the prevalence of WMHs and/or lacunes has been shown to correlate with diabetic retinopathy in type 2 diabetes [35]. We did also observe an association between CMBs and diabetic retinal disease [36]. This association was, however, independent of HbA1c reflecting the strong relationship between blood glucose and diabetic retinal disease. The findings that the blood glucose levels were associated with diabetic retinopathy albeit not cSVD raises the question, whether the mechanisms of the adverse effects of hyperglycemia on the central nervous system could be different from those in the retina. It may well be that changes in multiple metabolic factors induced by diabetes contribute differently to the abnormalities in the cerebral and the retinal vasculature. Further studies on potential metabolic changes in our cohort are now ongoing to address this question.
It is of note that the glucose levels on both sides of the blood brain barrier, namely blood and cerebrospinal fluid, may not be identical. Important regulators are involved in this delicate balance such as glucose transporters (GLUTs) to maintain the continuous high glucose and energy demands of the brain [37, 38]. Mechanistic studies are warranted to give an answer whether GLUTs could explain these findings. Interestingly, poorly controlled diabetes mellitus can cause a variety of adverse effects on brain function and metabolism via both low and high blood glucose levels [37]. These blood glucose alterations in diabetes mellitus can affect cerebral neurotransmitter metabolism, cerebral blood flow, and blood–brain barrier [37, 39]. Particularly dysfunction of the blood–brain barrier has been suggested to relate to intracerebral hemorrhage and the presence of CMBs [40]. Whether a damaged blood–brain barrier explains the number of CMBs in our cohort is not known. Neither if such changes could be caused by a poor glycemic control.
Our study does not go without limitations. We had serial A1c values from ten years enabling us to assess both cumulative blood glucose control and blood glucose variability. The cross-sectional retrospective nature of the study should, however, be taken into account. Our study had no data regarding short-term glucose control such as time in range (TIR) or variability measured from continuous glucose monitoring systems (CGMS), leaving this interesting topic open for future studies. The number of participants and HbA1c measurements, reflecting long-term blood glucose levels and fluctuations, is limited and this may have an effect on the statistical power to detect differences between the groups. A larger cohort would have enabled greater statistical power. It is, however, improbable that this would markedly have changed the results considering the consistence of the observations. The strengths of this study are the standardized imaging and clinical assessment, as well as the strong phenotypic data.
Conclusion
We observed no association between medium- and long-term blood glucose control and long-term glycemic variability and cSVD in neurologically asymptomatic individuals with type 1 diabetes. This finding was unexpected considering the large number of signs of cerebrovascular pathology in these people after two decades of chronic hyperglycemia and warrants further studies searching for underlying factors of cSVD.
Availability of data and materials
The database is available for all FinnDiane researchers.
References
The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329 (14):977–986
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group (2005) Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353 (25):2643–2653
Groop PH, Thomas MC, Moran JL et al (2009) The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 58(7):1651–1658. https://doi.org/10.2337/db08-1543
Janghorbani M, Hu FB, Willett WC et al (2007) Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses’ Health Study. Diabetes Care 30(7):1730–1735. https://doi.org/10.2337/dc06-2363
Thorn LM, Shams S, Gordin D et al (2019) Clinical and MRI features of cerebral small-vessel disease in type 1 diabetes. Diabetes Care 42(2):327–330. https://doi.org/10.2337/dc18-1302
Nunley KA, Ryan CM, Orchard TJ et al (2015) White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes. Neurology 84(20):2062–2069
Meissner A (2016) Hypertension and the brain: a risk factor for more than heart disease. Cerebrovasc Dis 42(3–4):255–262. https://doi.org/10.1159/000446082
Eriksson MI, Gordin D, Shams S et al (2020) Nocturnal blood pressure is associated with cerebral small-vessel disease in type 1 diabetes. Diabetes care 43(8):e96–e98. https://doi.org/10.2337/dc20-0473
Wardlaw JM, Smith EE, Biessels GJ et al (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12(8):822–838. https://doi.org/10.1016/s1474-4422(13)70124-8
Nansseu JR, Fokom-Domgue J, Noubiap JJ et al (2015) Fructosamine measurement for diabetes mellitus diagnosis and monitoring: a systematic review and meta-analysis protocol. BMJ Open 5(5):e007689. https://doi.org/10.1136/bmjopen-2015-007689
Roohk HV, Zaida AR (2008) A review of glycated albumin as an intermediate glycation index for controlling diabetes. J Diabetes Sci Technol 2:1114–1121
Wright LA, Hirsch IB (2017) Metrics beyond hemoglobin A1C in diabetes management: time in range, hypoglycemia, and other parameters. Diabetes Technol Ther 19(S2):S16–S26. https://doi.org/10.1089/dia.2017.0029
Waden J, Forsblom C, Thorn LM et al (2009) A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropathy in patients with type 1 diabetes. Diabetes 58(11):2649–2655. https://doi.org/10.2337/db09-0693
Rhode H, Muckova P, Buchler R et al (2019) A next generation setup for pre-fractionation of non-denatured proteins reveals diverse albumin proteoforms each carrying several post-translational modifications. Sci Rep 9(1):11733. https://doi.org/10.1038/s41598-019-48278-y
Baker JR, Metcalf PA, Johnson RN, Newman D, Rietz P (1985) Use of protein-based standards in automated colorimetric determinations of fructosamine in serum. Clin Chem 31(9):1550–1554
Kilpatrick ES, Rigby AS, Atkin SL (2006) The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care 29(7):1486–1490. https://doi.org/10.2337/dc06-0293
Shen Y, Zhou J, Shi L et al (2021) Association between visit-to-visit HbA1c variability and the risk of cardiovascular disease in patients with type 2 diabetes. Diabetes Obes Metab 23(1):125–135. https://doi.org/10.1111/dom.14201
Sheng C-S, Tian J, Miao Y et al (2020) Prognostic significance of long-term HbA1c variability for all-cause mortality in the ACCORD trial. Diabetes Care 43(6):1185–1190. https://doi.org/10.2337/dc19-2589
Weinger K, Jacobson AM, Musen G et al (2008) The effects of type 1 diabetes on cerebral white matter. Diabetologia 51(3):417–425. https://doi.org/10.1007/s00125-007-0904-9
Akoudad S, Portegies ML, Koudstaal PJ et al (2015) Cerebral microbleeds are associated with an increased risk of stroke: the rotterdam study. Circulation 132(6):509–516. https://doi.org/10.1161/CIRCULATIONAHA.115.016261
Charidimou A, Shams S, Romero JR et al (2018) Clinical significance of cerebral microbleeds on MRI: a comprehensive meta-analysis of risk of intracerebral hemorrhage, ischemic stroke, mortality, and dementia in cohort studies (v1). Int J Stroke 13(5):454–468. https://doi.org/10.1177/1747493017751931
Schofield J, Ho J, Soran H (2019) Cardiovascular risk in type 1 diabetes mellitus. Diabetes Ther 10(3):773–789. https://doi.org/10.1007/s13300-019-0612-8
Hägg S, Thorn LM, Forsblom CM et al (2014) Different risk factor profiles for ischemic and hemorrhagic stroke in type 1 diabetes mellitus. Stroke 45(9):2558–2562. https://doi.org/10.1161/STROKEAHA.114.005724
Ceriello A, Monnier L, Owens D (2019) Glycaemic variability in diabetes: clinical and therapeutic implications. Lancet Diabetes Endocrinol 7(3):221–230. https://doi.org/10.1016/s2213-8587(18)30136-0
Virk SA, Donaghue KC, Cho YH et al (2016) Association between HbA1c variability and risk of microvascular complications in adolescents with type 1 diabetes. J Clin Endocrinol Metab 101(9):3257–3263. https://doi.org/10.1210/jc.2015-3604
Kilpatrick ES, Rigby AS, Atkin SL (2008) A1C variability and the risk of microvascular complications in type 1 diabetes: data from the diabetes control and complications trial. Diabetes Care 31(11):2198–2202. https://doi.org/10.2337/dc08-0864
Kilpatrick ES, Rigby AS, Atkin SL (2009) Effect of glucose variability on the long-term risk of microvascular complications in type 1 diabetes. Diabetes Care 32(10):1901–1903. https://doi.org/10.2337/dc09-0109
Chmielewska B, Hasiec T, Belniak-Legieć E (1996) Value of glucose, glycosylated hemoglobin and fructosamine in blood of patients with ischemic cerebral infarction without diabetes during the early stage of the disease. Ann Univ Mariae Curie Sklodowska Med 51:61–68
Chmielewska B, Hasiec T, Belniak-Legieć E (1995) The concentration of glucose, glycosylated hemoglobin and fructosamine in blood of patients with cerebral hemorrhage in the acute stage of the disease. Ann Univ Mariae Curie Sklodowska Med 50:123–130
Lee SH, Jang MU, Kim Y et al (2020) Effect of prestroke glycemic variability estimated glycated albumin on stroke severity and infarct volume in diabetic patients presenting with acute ischemic stroke. Front Endocrinol (Lausanne) 11:230. https://doi.org/10.3389/fendo.2020.00230
Lee SH, Kim Y, Park SY, Kim C, Kim YJ, Sohn JH (2021) Pre-stroke glycemic variability estimated by glycated albumin is associated with early neurological deterioration and poor functional outcome in prediabetic patients with acute ischemic stroke. Cerebrovasc Dis 50(1):26–33. https://doi.org/10.1159/000511938
Rabbani N, Thornalley PJ (2021) Protein glycation - biomarkers of metabolic dysfunction and early-stage decline in health in the era of precision medicine. Redox Biol 42:101920. https://doi.org/10.1016/j.redox.2021.101920
Hainsworth DP, Bebu I, Aiello LP et al (2019) Risk factors for retinopathy in type 1 diabetes: the DCCT/EDIC study. Diabetes Care 42(5):875–882. https://doi.org/10.2337/dc18-2308
Woerdeman J, van Duinkerken E, Wattjes MP et al (2014) Proliferative retinopathy in type 1 diabetes is associated with cerebral microbleeds, which is part of generalized microangiopathy. Diabetes Care 37(4):1165–1168. https://doi.org/10.2337/dc13-1586
Sanahuja J, Alonso N, Diez J et al (2016) Increased burden of cerebral small vessel disease in patients with type 2 diabetes and retinopathy. Diabetes Care 39(9):1614–1620. https://doi.org/10.2337/dc15-2671
Eriksson MI, Summanen P, Gordin D et al (2021) Cerebral small-vessel disease is associated with the severity of diabetic retinopathy in type 1 diabetes. BMJ Open Diabetes Res Care. https://doi.org/10.1136/bmjdrc-2021-002274
McCall AL (2004) Cerebral glucose metabolism in diabetes mellitus. Eur J Pharmacol 490(1–3):147–158. https://doi.org/10.1016/j.ejphar.2004.02.052
Patching SG (2017) Glucose transporters at the blood-brain barrier: function, regulation and gateways for drug delivery. Mol Neurobiol 54(2):1046–1077. https://doi.org/10.1007/s12035-015-9672-6
Prasad S, Sajja RK, Naik P, Cucullo L (2014) Diabetes mellitus and blood-brain barrier dysfunction: an overview. J Pharmacovigil 2(2):125. https://doi.org/10.4172/2329-6887.1000125
Freeze WM, Jacobs HIL, Schreuder F et al (2018) Blood-brain barrier dysfunction in small vessel disease related intracerebral hemorrhage. Front Neurol 9:926. https://doi.org/10.3389/fneur.2018.00926
Acknowledgements
The authors deeply acknowledge the technical assistance of Anna Sandelin, Jaana Tuomikangas, and Mira Korolainen. They also thank Pentti Pölönen, HUS Medical Imaging Center, Helsinki University Hospital, for performing the MRI scans.
Funding
Open Access funding provided by University of Helsinki including Helsinki University Central Hospital. The FinnDiane study was supported by grants from Folkhälsan Research Foundation, Academy of Finland (316664), Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation (NNF OC0013657), Sigrid Juselius Foundation, Päivikki and Sakari Sohlberg Foundation, Finnish Foundation for Cardiovascular Research, and by governmental research funding. D.G. was supported by Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Medical Society of Finland (Finska Läkaresällskapet), Dorothea Olivia, Karl Walter and Jarl Walter Perklén’s Foundation, Päivikki and Sakari Sohlberg Foundation, Sigrid Juselius Foundation, the University of Helsinki (Clinical Researcher stint), and the Academy of Finland (UAK1021MRI). T.T. has received research funding from University of Gothenburg, Sahlgrenska University Hospital, European Union, Sigrid Juselius Foundation, and Wennerström Foundation. None of the funding bodies had any role in the study design; collection, analysis, or interpretation of data; writing of the manuscript; or the decision to submit the manuscript for publication.
Author information
Authors and Affiliations
Consortia
Contributions
JI, KA, VH, CF, RL, TT, LMT, P–HG, SS, JM, JP, and DG contributed to the study design and acquisition of data, as well as the interpretation of data. JI, KA, VH, JM, JP, and DG had the main responsibility for analyzing data and writing the first draft of the paper. JI, KA, VH, CF, RL, TT, LMT, P–HG, SS, JM, JP, and DG critically revised the manuscript. P–HG is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Corresponding author
Ethics declarations
Conflict of interest
D.G. Lecture or advisory honoraria: AstraZeneca, Boehringer Ingelheim, Delta Medical Communications, Fresenius, GE Healthcare, Kidney and Liver Foundation in Finland, Novo Nordisk. Support to attend medical meetings: CVRx., Sanofi Aventis. J.M. Lecture Honoria Santen. T.T. has/has had research contracts with Bayer, Boehringer Ingelheim, and Portola Pharm. He has been advisory board member for Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Portola Pharm. P.-H.G. has received lecture honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Medscape, Merck Sharp & Dohme (MSD), Mundipharma, Novartis, Novo Nordisk, PeerVoice, Sanofi, SCIARC, and is an advisory board member of AbbVie, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Medscape, MSD, Novartis, Novo Nordisk, and Sanofi. No other potential conflicts of interest relevant to this article were reported.
Ethical approval
The study was carried out in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Helsinki and Uusimaa Hospital District.
Consent to participate
Each participant signed a written informed consent before participation.
Additional information
Managed by Massimo Porta.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Inkeri, J., Adeshara, K., Harjutsalo, V. et al. Glycemic control is not related to cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes. Acta Diabetol 59, 481–490 (2022). https://doi.org/10.1007/s00592-021-01821-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00592-021-01821-8