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Multicenter Study
. 2015 Jan;64(1):266-78.
doi: 10.2337/db14-0215. Epub 2014 Sep 3.

Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes

Saul Genuth  1 , Wanjie Sun  2 , Patricia Cleary  2 , Xiaoyu Gao  2 , David R Sell  3 , John Lachin  2 ; DCCT/EDIC Research Group; Vincent M Monnier  4
Affiliations
Multicenter Study

Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes

Saul Genuth et al. Diabetes. 2015 Jan.

Abstract

Six skin collagen advanced glycation end products (AGEs) originally measured near to the time of the Diabetes Control and Complications Trial (DCCT) closeout in 1993 may contribute to the "metabolic memory" phenomenon reported in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. We have now investigated whether the addition of four originally unavailable AGEs (i.e., glucosepane [GSPNE], hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, and carboxyethyl-lysine) improves associations with incident retinopathy, nephropathy, and neuropathy events during 13-17 years after DCCT. The complete 10-AGE panel is associated with three-step Early Treatment of Diabetic Retinopathy Study scale worsening of retinopathy (P ≤ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose-lysine (furosine [FUR]) correlate with retinopathy progression, independently of A1C level. The complete panel also correlates with microalbuminuria (P = 0.008) and FUR with nephropathy independently of A1C level (P ≤ 0.02). Neuropathy correlates with the complete panel despite adjustment for A1C level (P ≤ 0.005). MG-H1 and FUR are dominant, independent of A1C level (P < 0.0001), whereas A1C loses significance after adjustment for the AGEs. Overall, the added set of four AGEs enhances the association of the original panel with progression risk of retinopathy and neuropathy (P < 0.04) but not nephropathy, while GSPNE and MG-H1 emerge as the principal new risk factors. Skin AGEs are robust long-term markers of microvascular disease progression, emphasizing the importance of early and sustained implementation of intensive therapy.

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Figures

Figure 1
Figure 1
AGE levels in those with (yes) or without (no) three-step progression of retinopathy on the ETDRS scale from DCCT closeout up to EDIC study year 16.
Figure 2
Figure 2
AGE levels in those with (yes) or without (no) development of AER >40 mg/24 h from DCCT closeout to EDIC study years 15–16.
Figure 3
Figure 3
AGE levels in those with (yes) or without (no) development of confirmed clinical neuropathy or abnormal autonomic nervous system function from DCCT closeout to EDIC study years 13–14.
See this image and copyright information in PMC

References

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