John D. Maynard

Caffeine Consumption Contributes to Skin Intrinsic Fluorescence in Type 1 Diabetes

Abstract Background: A variant (rs1495741) in the gene for the N-acetyltransferase 2 (NAT2) protein is associated with skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation end products and other fluorophores in the skin. Because NAT2 is involved in caffeine metabolism, we aimed to determine whether caffeine consumption is associated with SIF and whether rs1495741 is associated with SIF independently of caffeine. Materials and Methods: SIF was measured in 1,181 participants with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications study. Two measures of SIF were used: SIF1, using a 375-nm excitation light-emitting diode (LED), and SIF14 (456-nm LED). Food frequency questionnaires were used to estimate mean caffeine intake. To establish replication, we examined a second type 1 diabetes cohort. Results: Higher caffeine intake was significantly associated with higher SIF1LED 375 nm[0.6, 0.2] (P=2×10−32) and SIF14LED 456 nm[0.4, 0.8] (P=7×10−31) and accounted for 4% of the variance in each after adjusting for covariates. When analyzed together, caffeine intake and rs1495741 both remained highly significantly associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8]. Mean caffeinated coffee intake was also positively associated with SIF1LED 375 nm[0.6, 0.2] (P=9×10−12) and SIF14LED 456 nm[0.4, 0.8] (P=4×10−12), but no association was observed for decaffeinated coffee intake. Finally, caffeine was also positively associated with SIF1LED 375 nm[0.6, 0.2] and SIF14LED 456 nm[0.4, 0.8] (P<0.0001) in the replication cohort. Conclusions: Caffeine contributes to SIF. The effect of rs1495741 on SIF appears to be partially independent of caffeine consumption. Because SIF and coffee intake are each associated with cardiovascular disease, our findings suggest that accounting for coffee and/or caffeine intake may improve risk prediction models for SIF and cardiovascular disease in individuals with diabetes.

New Locus for Skin Intrinsic Fluorescence in Type 1 Diabetes Also Associated With Blood and Skin Glycated Proteins

Skin fluorescence (SF) noninvasively measures advanced glycation end products (AGEs) in the skin and is a risk indicator for diabetes complications. N-acetyltransferase 2 (NAT2) is the only known locus influencing SF. We aimed to identify additional genetic loci influencing SF in type 1 diabetes (T1D) through a meta-analysis of genome-wide association studies (N = 1,359) including Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) and Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). A locus on chromosome 1, rs7533564 (P = 1.9 × 10−9), was associated with skin intrinsic fluorescence measured by SCOUT DS (excitation 375 nm, emission 435–655 nm), which remained significant after adjustment for time-weighted HbA1c (P = 1.7 × 10−8). rs7533564 was associated with mean HbA1c in meta-analysis (P = 0.0225), mean glycated albumin (P = 0.0029), and glyoxal hydroimidazolones (P = 0.049), an AGE measured in skin biopsy collagen, in DCCT. rs7533564 was not associated with diabetes complications in DCCT/EDIC or with SF in subjects without diabetes (nondiabetic [ND]) (N = 8,721). In conclusion, we identified a new locus associated with SF in T1D subjects that did not show similar effect in ND subjects, suggesting a diabetes-specific effect. This association needs to be investigated in type 2 diabetes.

Epidemiology of Dysglycemia in Pregnant Oklahoma American Indian Women

CONTEXT Minority communities are disproportionately affected by diabetes, and minority women are at an increased risk for glucose intolerance (dysglycemia) during pregnancy. OBJECTIVES In pregnant American Indian women, the objectives of the study were to use current criteria to estimate the prevalence of first-trimester (Tr1) dysglycemia and second-trimester (Tr2) incidence of gestational diabetes mellitus (GDM) and to explore new candidate measures and identify associated clinical factors. DESIGN This was a prospective cohort study. In Tr1 we performed a 75-g, 2-hour oral glucose tolerance test (OGTT) and glycated hemoglobin (HbA1c) to determine the following: fasting insulin; homeostasis model assessment of insulin resistance; serum 1,5-anhydroglucitol; noninvasive skin autofluorescence (SCOUT). We defined dysglycemia by American Diabetes Association and Endocrine Society criteria and as HbA1c of 5.7% or greater. In Tr2 in an available subset, we performed a repeat OGTT and SCOUT. PARTICIPANTS Pregnant American Indian women (n = 244 at Tr1; n = 114 at Tr2) participated in the study. OUTCOMES The prevalence of dysglycemia at Tr1 and incidence of GDM at Tr2 were measured. RESULTS At Tr1, one woman had overt diabetes; 36 (15%) had impaired glucose tolerance (American Diabetes Association criteria and/or abnormal HbA1c) and 59 (24%) had GDM-Tr1 (Endocrine Society criteria). Overall, 74 (30%) had some form of dysglycemia. Associated factors were body mass index, hypertension, waist/hip circumferences, SCOUT score, fasting insulin, and homeostasis model assessment of insulin resistance. At Tr2, 114 of the Tr1 cohort underwent a repeat OGTT and SCOUT, and 26 (23%) had GDM. GDM-Tr2 was associated with increased SCOUT scores (P = .029) and Tr1 body mass index, waist/hip circumferences, diastolic blood pressure, fasting insulin, and triglyceride levels. Overall, dysglycemia at Tr1 and/or Tr2 affected 38% of the women. CONCLUSIONS Dysglycemia at some point during pregnancy was common among American Indian women. It was associated with features of insulin resistance and may confer long-term health risks for mother and child.

Transfer learning for diabetic retinopathy

Diabetic Retinopathy (DR)1, 2 is a leading cause of blindness worldwide and is estimated to threaten the vision of nearly 200 million by 2030.3 To work with the ever-increasing population, the use of image processing algorithms to screen for those at risk has been on the rise. Research-oriented solutions have proven effective in classifying images with or without DR, but often fail to address the true need of the clinic - referring only those who need to be seen by a specialist, and reading every single case. In this work, we leverage an array of image pre-preprocessing techniques, as well as Transfer Learning to re-purpose an existing deep network for our tasks in DR. We train, test, and validate our system on 979 clinical cases, achieving a 95% Area Under the Curve (AUC) for referring Severe DR with an equal error Sensitivity and Specificity of 90%. Our system does not reject any images based on their quality, and is agnostic in terms of eye side and field. These results show that general purpose classifiers can, with the right type of input, have a major impact in clinical environments or for teams lacking access to large volumes of data or high-throughput supercomputers.

Association of Skin Intrinsic Fluorescence with Retinal Microvascular Complications of Long Term Type 1 Diabetes in the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

ABSTRACT Objective: To determine the association between skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation endproducts and oxidative stress in skin, and retinal microvascular complications of long duration type 1 diabetes, proliferative diabetic retinopathy (PDR) and macular edema. Methods: A cross-sectional cohort study of persons with type 1 diabetes in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) who participated in a 32-year follow-up examination in 2012–2014. Subjects underwent a physical examination, answered a health questionnaire, and had fundus photographs taken. SIF was measured on the underside of the left forearm near the elbow with the SCOUT DS® skin fluorescence spectrometer. Two representative SIF measures were used for these analyses: SIF01 excited by an LED centered at 375 nm with correction factors Kx = 0.6 and Km = 0.2 and SIF15 excited by an LED centered at 456 nm with correction factors Kx = 0.4 and Km = 0.9. Results: The 414 participants had mean diabetes duration of 42.2 years (standard deviation 6.8 years, range 32.9–67.9 years). PDR was statistically significantly associated (p < 0.05) with both SIF measures in multivariate models including other relevant factors (odds ratio [OR] = 1.17 for SIF01 and 1.20 for SIF15). Conclusion: Skin intrinsic fluorescence measures are independently associated with PDR in the WESDR. Incidence information is needed to evaluate whether there is a causal relationship.

Skin Intrinsic Fluorescence and Age-Related Macular Degeneration: The Beaver Dam Eye Study

Purpose To determine if skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation endproducts and oxidative stress in skin is associated with AMD. Methods SIF was measured with the SCOUT DS skin fluorescence spectrometer in a cross-sectional cohort study of 969 persons aged 68 to 102 years from the 1181 who participated in the 25-year follow-up examination in the Beaver Dam Eye Study (BDES) in 2014 to 2016. The SCOUT DS skin fluorescence spectrometer uses five light-emitting diodes, centered at 375 nm to 456 nm. AMD was assessed by grading of digital color 45° stereoscopic fundus photographs of the macula using the Wisconsin Age-Related Maculopathy grading scheme. Analyses included logistic regression with generalized estimating equations to account for correlation between the eyes of a person. Results There were data for 1827 eyes for analyses. Early AMD was present in 22% and late AMD in 4% of the eyes. While adjusting for age, sex, smoking status, and history of cardiovascular disease, there were no significant associations of any SIF measure with any AMD or exudative AMD. SIF01 (odds ratio per 1 SD difference on the log scale, 95% confidence interval) (1.66, 1.00–2.74, P = 0.05) and SIF03 (1.81, 1.16–2.81, P = 0.008) were associated with geographic atrophy. Conclusions There was a suggestive relationship of two SIF measures, SIF01 and SIF03, using different correction factors from the excitation centered at 375 nm, with the prevalence of geographic atrophy in the BDES. Longitudinal follow-up is indicated to assess a temporal relationship.