The Association of Skin Intrinsic Fluorescence With Type 1 Diabetes Complications in the DCCT/EDIC Study

Abstract

OBJECTIVETo determine whether skin intrinsic fluorescence (SIF) is associated with long-term complications of type 1 diabetes (T1D) and, if so, whether it is independent of chronic glycemic exposure and previous intensive therapy.RESEARCH DESIGN AND METHODSWe studied 1,185 (92%) of 1,289 active Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants from 2010 to 2011. SIF was determined using a fluorescence spectrometer and related cross-sectionally to recently determined measures of retinopathy (stereo fundus photography), cardiac autonomic neuropathy (CAN; R-R interval), confirmed clinical neuropathy, nephropathy (albumin excretion rate [AER]), and coronary artery calcification (CAC).RESULTSOverall, moderately strong associations were seen with all complications, before adjustment for mean HbA1c over time, which rendered these associations nonsignificant with the exception of sustained AER >30 mg/24 h and CAC, which were largely unaffected by adjustment. However, when examined within the former DCCT treatment group, associations were generally weaker in the intensive group and nonsignificant after adjustment, while in the conventional group, associations remained significant for CAN, sustained AER >30 mg/24 h, and CAC even after mean HbA1c adjustment.CONCLUSIONSSIF is associated with T1D complications in DCCT\EDIC. Much of this association appears to be related to historical glycemic exposure, particularly in the previously intensively treated participants, in whom adjustment for HbA1c eliminates statistical significance.

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

“…The non-significant association with these outcomes is due to the low power to detect small effects, since we have good power for detecting an OR >1.50 for a sustained AER >30 mg/24 h with α = 0.05 [15]. In line with this, the rs1495741 G-allele has previously been associated (OR 1.06, p  = 2 × 10 −5 ) with an increased risk of coronary artery disease (CAD) [36].…”

“…SIF excited with a light-emitting diode (LED) centred at 375 nm, and emission detected over 435–655 nm (with the reflectance adjusted by the dimensionless exCitation and emission exponents, k x  = 0.6, k m  = 0.2, respectively), referred to as SIF1, was the primary outcome [15, 18]. In secondary analyses, we examined SIFs measured using excitation LEDs centred at 405 nm, 416 nm, 435 nm and 456 nm (SIF2–SIF15; ESM Table 6).…”

Role of Glycated Proteins in the Diagnosis and Management of Diabetes: Research Gaps and Future Directions

“…A meta-analysis of seven studies showed that skin autofluorescence was positively associated with mortality, neuropathy, nephropathy, and cardiovascular events (79). Certain studies found that skin autofluorescence predicted microvascular and macrovascular complications of diabetes independent of HbA 1c (80,81), whereas others found that adjustment for HbA 1c rendered these associations nonsignificant (82). These discrepant findings are possibly accounted for by differences in the patient population and statistical methods.…”

Biomarkers in Diabetic Retinopathy

“…Noninvasively assessed skin AGEs were also associated with retinopathy in the DCCT/EDIC cohort [173]. Skin collagen AGEs measured biochemically on skin biopsies were independent predictors of diabetic retinopathy (and other microvascular complications) in the DCCT/EDIC cohort [174][175].…”

“…Many studies in diverse ethnic groups have demonstrated correlations between skin AGEs measured non-invasively or biochemically and concurrent retinopathy status, including its presence and/or severity [66,70,169,[171][172][173]. Noninvasively assessed skin AGEs were also associated with retinopathy in the DCCT/EDIC cohort [173].…”