Skin autofluorescence in diabetes mellitus

AGEs ofwel advanced glycation endproducts zijn onomkeerbaar versuikerde stoffen, die voornamelijk aan eiwitten zijn gekoppeld, en die bij ieder mens stapelen. Bij iemand met diabetes mellitus gaat dit proces echter versneld. AGEs hebben een belangrijke rol bij het ontstaan van chronische complicaties van diabetes en atherosclerose. Tot recent werden weefsel-AGEs via huidbiopten gemeten. Dat is een belastende methode, ongeschikt voor toepassing op grote schaal, of voor herhaalde metingen. Het is vanuit de literatuur bekend dat sommige AGEs fluoresceren. Enkele jaren geleden is de Autofluorescence reader ontwikkeld, dat gebruikmakend van fluorescentieprincipes, niet-invasief autofluorescentie van de huid meet en een maat is voor weefsel-AGEs. Bij type 1, type 2 diabetes patiënten, met en zonder complicaties, werden autofluorescentie metingen gedaan met een monochromator, resulterend in excitatie-emissie maps. Hierbij wordt de huid met licht van een specifieke golflengte beschenen, om verschillende fluorophoren te identificeren. Hieruit bleek dat er geen verschil was in fluorescentiekarakteristieken tussen de onderzochte patiëntgroepen. In 2001 werd in een type 2 diabetes cohort (+/-1000) uit de regio Zwolle, huid autofluorescentie gemeten. Autofluorescentie bleek gerelateerd aan leeftijd, roken, HbA1c en aan microvasculaire en macrovasculaire complicaties. Na een follow-up van 3.5 jaar werden eindpunten verzameld als cardiovasculaire events en mortaliteit. Autofluorescentie blijkt een betere voorspeller t.a.v. mortaliteit en cardiovasculaire events dan HbA1c. Verder is meting van autofluorescentie van aanvullende waarde aan de UKPDS Risk score. Tot slot bleek na een follow-up van 5 jaar de levensverwachting van deze goed gereguleerde type 2 diabetes populatie niet anders dan die van de gemiddelde Nederlander.

Pitfalls in blood pressure measurement in daily practice

Background. Accurate blood pressure (BP) readings and correctly interpreting the obtained values are of great importance. However, there is considerable variation in the different BP measuring methods suggested in guidelines and used in hypertension trials. Objective. To compare the different methods used to measure BP; measuring once, the method used for a large study such as the UKPDS, and the methods recommended by various BP guidelines. Methods. In 223 patients with type 2 diabetes from five family practices BP was measured according to a protocol to obtain the following data: A = first reading, B = mean of two initial readings, C = at least four readings and the mean of the last three readings with less than 15% coefficient of variation difference, D = mean of the first two consecutive readings with a maximum of 5 mm Hg difference. Mean outcomes measure is the mean difference between different BP measuring methods in mm Hg. Results. Significant differences in systolic/diastolic BP were found between A and B [mean difference (MD) systolic BP 1.6 mm Hg, P < 0.001], B and C (MD 5.7/2.8 mm Hg, P < 0.001), B and D (MD 6.2/2.8 mm Hg, P < 0.001), A and C (MD 7.3/3.3 mm Hg), and A and D (MD 7.9/3.0 mm Hg, P < 0.001). Conclusion. Different methods to assess BP during one visit in the same patient lead to significantly different BP readings and can lead to overestimation of the mean BP. These differences are clinically relevant and show a gap between different methods in trials, guidelines and daily practice

Pregnancy Outcomes and Maternal Insulin Sensitivity:Design and Rationale of a Multi-Center Longitudinal Study in Mother and Offspring (PROMIS)

The worldwide prevalence of overweight and obesity in women of reproductive age is rapidly increasing and a risk factor for the development of gestational diabetes (GDM). Excess adipose tissue reduces insulin sensitivity and may underlie adverse outcomes in both mother and child. The present paper describes the rationale and design of the PRegnancy Outcomes and Maternal Insulin Sensitivity (PROMIS) study, an exploratory cohort study to obtain detailed insights in insulin sensitivity and glucose metabolism during pregnancy and its relation to pregnancy outcomes including early infancy growth. We aim to recruit healthy pregnant women with a body mass index (BMI) ≥ 25 kg/m2 before 12 weeks of gestation in Northern Netherlands. A total of 130 woman will be checked on fasted (≤7.0 mmol/L) or random (≤11.0 mmol/L) blood glucose to exclude pregestational diabetes at inclusion. Subjects will be followed up to six months after giving birth, with a total of nine contact moments for data collection. Maternal data include postprandial measures following an oral meal tolerance test (MTT), conducted before 16 weeks and repeated around 24 weeks of gestation, followed by a standard oral glucose tolerance test before 28 weeks of gestation. The MTT is again performed around three months postpartum. Blood analysis is done for baseline and postprandial glucose and insulin, baseline lipid profile and several biomarkers of placental function. In addition, specific body circumferences, skinfold measures, and questionnaires about food intake, eating behavior, physical activity, meal test preference, mental health, and pregnancy complications will be obtained. Fetal data include assessment of growth, examined by sonography at week 28 and 32 of gestation. Neonatal and infant data consist of specific body circumferences, skinfolds, and body composition measurements, as well as questionnaires about eating behavior and complications up to 6 months after birth. The design of the PROMIS study will allow for detailed insights in the metabolic changes in the mother and their possible association with fetal and postnatal infant growth and body composition. We anticipate that the data from this cohort women with an elevated risk for the development of GDM may provide new insights to detect metabolic deviations already in early pregnancy. These data could inspire the development of new interventions that may improve the management of maternal, as well as offsrping complications from already early on in pregnancy with the aim to prevent adverse outcomes for mother and child

Is skin autofluorescence (SAF) representative of dermal advanced glycation endproducts (AGEs) in dark skin?:A pilot study

Aims: Non-invasively assessed skin autofluorescence (SAF) measures advanced glycation endproducts (AGEs) in the dermis. SAF correlates with dermal AGEs in Caucasians and Asians, but studies in dark-skinned subjects are lacking. In this pilot we aimed to assess whether SAF signal is representative of intrinsic fluorescence (IF) and AGE accumulation in dark skin. Methods: Skin biopsies were obtained in 12 dark-skinned subjects (6 healthy subjects, median age 22 years; 6 diabetes mellitus (DM) subjects, 65 years). SAF was measured with the AGE Reader, IF using confocal microscopy, and AGE distribution with specific antibodies. CML and MG-H1 were quantified with UPLC-MS/MS and pentosidine with HPLC and fluorescent detection. Results: SAF correlated with IF from the dermis (405nm, r = 0.58, p < 0.05), but not with CML (r = 0.54, p = 0.07). CML correlated with IF from the dermis (405nm, r = 0.90, p < 0.01). UV reflectance and the coefficient of variation of SAF were negatively correlated (r = -0.80, p < 0.01). CML and MG-H1 were predominantly present around blood vessels, in collagen and fibroblasts in the dermis. Conclusion: This proof of concept study is the first to compare non-invasive SAF with AGE levels measured in skin biopsies in dark-skinned subjects. SAF did not correlate with individual AGEs from biopsies, but was associated with IF. However, the intra-individual variance was high, limiting its application in dark-skinned subjects on an individual basis

GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence

Aims/hypothesis Skin fluorescence (SF) is a non-invasive marker of AGEs and is associated with the long-term complications of diabetes. SF increases with age and is also greater among individuals with diabetes. A familial correlation of SF suggests that genetics may play a role. We therefore performed parallel genome-wide association studies of SF in two cohorts. Methods Cohort 1 included 1,082 participants, 35–67 years of age with type 1 diabetes. Cohort 2 included 8,721 participants without diabetes, aged 18–90 years. Results rs1495741 was significantly associated with SF in Cohort 1 (p \u3c 6 × 10−10), which is known to tag theNAT2 acetylator phenotype. The fast acetylator genotype was associated with lower SF, explaining up to 15% of the variance. In Cohort 2, the top signal associated with SF (p = 8.3 × 10−42) was rs4921914, also in NAT2, 440 bases upstream of rs1495741 (linkage disequilibrium r 2 = 1.0 for rs4921914 with rs1495741). We replicated these results in two additional cohorts, one with and one without type 1 diabetes. Finally, to understand which compounds are contributing to the NAT2–SF signal, we examined 11 compounds assayed from skin biopsies (n = 198): the fast acetylator genotype was associated with lower levels of the AGEs hydroimidazolones of glyoxal (p = 0.017). Conclusions/interpretation We identified a robust association between NAT2 and SF in people with and without diabetes. Our findings provide proof of principle that genetic variation contributes to interindividual SF and thatNAT2 acetylation status plays a major role

Skin color independent assessment of aging using skin autofluorescence

Skin autofluorescence (AF) for the non-invasive assessment of the amount of accumulated tissue Advanced Glycation Endproducts (AGEs) increases with aging. In subjects with darker skin colors, measurements typically result in lower AF values than in subjects with fair skin colors, e.g. due to selective absorption by skin compounds. Our aim was to provide a new method for calculating skin AF, yielding values that are independent of skin color. The deviation of skin AF of healthy subjects with various darker skin types (N = 99) compared to reference values from Caucasians showed to be a function of various parameters that were derived from reflectance and emission spectra in the UV and visible range (adjusted R(2) = 80%). Validation of the new algorithm, based on these findings, in a separate dataset (N = 141) showed that results of skin AF can now be obtained to assess skin AGEs independently of skin colo

Skin autofluorescence is increased in patients with carotid artery stenosis and peripheral artery disease

Advanced glycation end products (AGEs) have a pivotal role in atherosclerosis. We evaluated skin autofluorescence (SAF), a non-invasive measurement of tissue AGE accumulation, in patients with carotid artery stenosis with and without coexisting peripheral artery occlusive disease (PAOD). SAF was measured using the AGE Reader™ in 56 patients with carotid artery stenosis and in 56 age- and sex-matched healthy controls without diabetes, renal dysfunction or known atherosclerotic disease. SAF was higher in patients with carotid artery stenosis compared to the control group: mean 2.81 versus 2.46 (P = 0.002), but especially in the younger age group of 50–60 years old: mean 2.82 versus 1.94 (P = 0.000). Patients with carotid artery stenosis and PAOD proved to have an even higher SAF than patients with carotid artery stenosis only: mean 3.28 versus 2.66 (P = 0.003). Backward linear regression analysis showed that age, smoking, diabetes mellitus, renal function and the presence of PAOD were the determinants of SAF, but carotid artery stenosis was not. SAF is increased in patients with carotid artery stenosis and PAOD. The univariate and multivariate associations of SAF with age, smoking, diabetes, renal insufficiency and PAOD suggest that increased SAF can be seen as an indicator of widespread atherosclerosis

Skin advanced glycation end product accumulation is poorly refected by glycemic control in type 2 diabetic patients (ZODIAC-9)

Background: Glycemic memory can be reflected by tissue accumulation of advanced glycation end products (AGEs). In type 1 diabetes mellitus (T1DM) patients, hemoglobin A1c (HbA1c) levels over various time periods poorly predicted the accumulation of different AGEs in skin biopsies. Our aim was to investigate whether HbA1c assessments can predict the change in skin AGEs during time in type 2 diabetes mellitus (T2DM). Methods: We included 452 T2DM patients participating in a shared-care setting, who are screened annually for HbA1c and diabetic complications. Baseline and follow-up levels of skin AGEs were assessed with a validated noninvasive autofluorescence (AF) method, which is based on the fluorescence characteristics of certain AGEs. Results: Our study population had a mean age of 65 years and 54% were female. After a mean follow-up duration of 3.3 years, linear regression analyses showed weak relationships among different assessments of HbA1c (baseline, maximum, mean, and variance of HbA1c) and skin AF at follow-up. Baseline skin AF and age were predictors of skin AF at follow-up, but diabetes duration, smoking, and creatinine were of less or no predictive value for skin AF at follow-up. Conclusions: In our T2DM population, integrated HbA1c assessments over years poorly predict the change in skin AGE level measured by skin AF. These findings agree with results in patients with T1DM. This suggests either the need for longer exposure to glucose disturbances to change tissue AGEs or other mechanisms, such as oxidative stress, leading to AGE accumulation.</p