Evidence of a glycemic threshold for the development of cataracts in diabetic rats.
OBJECTIVE
This study was aimed to establish a possible correlation between the levels of plasma glucose and degree of lens opacification. Levels of glycation- and glycoxidation-products in different lens protein fractions were also estimated with an aim to determine the involvement of these products in lens opacification.


METHODS
A wide range of hyperglycemia was induced by injecting different doses of streptozotocin to 1 month old rats and lenses were examined on the 75th, 90th and 150th day post-injection. Lens opacification was measured by Scheimpflug imaging and densitometry. Levels of plasma glucose and glycated hemoglobin were measured after overnight fasting. On 90th day, levels of Amadori products in lens water soluble (WS) fraction were measured by affinity chromatography. Similarly, advanced glycation end products (AGEs) in lens WS, urea soluble (US) and alkali soluble (AS) fractions were measured immunochemically using a monoclonal antibody against the major glycoxidation product, carboxymethyl lysine (CML).


RESULTS
Different dosages of streptozotocin injection resulted in a broad range of plasma glucose levels in the rats which were grouped into three groups on the basis of their plasma glucose levels: mildly diabetic (< 170 mg/dl plasma glucose), moderately diabetic (190-350 mg/dl) and severely diabetic (> 400 mg/dl). On the 75th, 90th and 150th day post-injection, only the moderately and severely diabetic rats developed cataracts whereas lenses of the mildly diabetic rats remained clear. As seen on 90th day, levels of glycated hemoglobin and Amadori products in lens WS fraction increased significantly in the moderately and severely diabetic groups whereas in the mildly diabetic rats these levels remained more or less same as in the control group. Levels of CML in WS fractions remained unchanged between control rats and different diabetic groups, while US fractions showed a decrease in CML in both the moderately and severely diabetic groups compared to the controls and the mildly diabetic group. Interestingly, AS fractions contained the highest level of CML; the moderately and severely diabetic groups showed about 2-fold higher levels than the controls and the mildly diabetic group.


CONCLUSIONS
This study strongly supports the existence of plasma glycemic threshold above which incidence of diabetic cataract formation increases exponentially. This threshold level seems to be at approximately 180 mg/dl or 10 mM plasma glucose. Significant increase in the levels of glycation and glycoxidation products mainly in cataract lenses suggests that glycation and glycation-mediated oxidation play an important role in the development of diabetic cataracts.
Swamy-Mruthinti
S
S
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta 30912-2100, USA.
Shaw
S M
SM
Zhao
H R
HR
Green
K
K
Abraham
E C
EC
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism*; D002386:Cataract / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology; D003720:Densitometry; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D004056:Differential Threshold / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005654:Fundus Oculi; D006442:Glycated Hemoglobin / Q000032:analysis; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D017127:Glycation End Products, Advanced; D008239:Lysine; D013311:Streptozocin; C048496:N(6)-carboxymethyllysine