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The Joslin Gold Medalists comprise 351 U.S. residents who have survived with type 1 diabetes for >50 years. A high proportion of Medalists remain free from proliferative diabetic retinopathy (PDR) (42.6%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%). Current and longitudinal (the past 15 years) glycemic control were unrelated to complications. Advanced glycation end product (AGE) concentrations include carboxyethyl-lysine (CEL), an AGE derived from methylglyoxal; pentosidine, a glycoxidation ascorbate product; and carboxymethyl-lysine (CML), a glycoxidation and advanced lipoxidation product. Fructose-lysine CML and CEL were significantly elevated in the Medalists as compared with nondiabetic, age-matched control subjects ( N = 23, mean age 67.7 years). Subjects with both CEL >5.3 μmol/mol lysine and pentosidine (>1.0 pmol/mg protein) were the most likely to have any complication (7.2 times more likely) ( P = 0.001), or suffer from nephropathy (3.1 times more likely) ( P = 0.007), neuropathy (2.5 times more likely) ( P = 0.005), or cardiovascular disease (2.3 times more likely) ( P = 0.002). These data are the first to suggest that specific AGEs may decrease risk for diabetes complications because high current CML and fructose-lysine concentrations were negatively correlated with PDR development. Previous reports indicated that AGEs and their precursors may be important in the pathogenesis of diabetes complications; however, it is unexpected that lower current levels of CML and fructose-lysine are inversely related to PDR development in light of reports indicating an association between elevations of these AGEs measured in other tissues and retinopathy. The Medalist population is likely enriched for protective factors against complications. The question is, what are the protective factors?### Metabolic memory in diabetesThe notion of good metabolic memory has been applied to the beneficial effects of an initial period of good glycemic, lipid, and blood pressure control resulting in effects going beyond that of the period of near euglycemia and followed …

The Question Is, My Dear Watson, Why Did the Dog Not Bark?