EVIDENCE OF A GLYCEMIC THRESHOLD FOR THE FORMATION OF PENTOSIDINE IN DIABETIC DOG LENS BUT NOT IN COLLAGEN

The relationship between long-term glycemic control and the advanced M aillard reaction was investigated in dura mater collagen and lens prot eins from dogs that were diabetic for 5 years. Diabetic dogs were assi gned prospectively to good, moderate, and poor glycemic control and ma intained by insulin. Biochemical changes were determined at study exit . Mean levels of collagen digestibility by pepsin decreased (NS) where as collagen glycation (P < 0.001), pentosidine cross-links (P < 0.001) , and collagen fluorescence (P = 0.02) increased with increasing mean WA, values. Similarly, mean levels of lens crystallin glycation (P < 0 .001), fluorescence (P < 0.001), and the specific advanced lens Mailla rd product 1 (LM-1) (P < 0.001) and pentosidine (P < 0.005) increased significantly with poorer glycemic control. Statistical analysis revea led very high Spearman correlation coefficients between collagen and l ens changes. Whereas pentosidine cross-links were significantly elevat ed in collagen from diabetic dogs with moderate levels of HbA(1) (i.e. , 8.0 +/- 0.4%), lens pentosidine levels were normal in this group and were elevated (P < 0.001) only in the animals with poor glycemic cont rol (HbA(1) = 9.7 +/- 0.6%). Thus, whereas protein glycation and advan ced glycation in the extracellular matrix and in the lens are generall y related to the level of glycemic control, there is evidence for a ti ssue specific glycemic threshold for pentosidine formation, i.e., glyc oxidation, in the lens. This threshold may be in part linked to a dram atic acceleration in crystallin glycation with HbA, values of >8.0% an d/or a loss of lens membrane permeability. This study provides support at the molecular level for the growing concept that glycemic threshol ds may be involved in the development of some of the complications in diabetes.