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Effects of advanced glycation end-product inhibition and cross-link breakage in diabetic rats
P S Oturai1, M Christensen, B Rolin
1Novo Nordisk, Health Care Discovery, Bagsvaerd, Denmark.
Abstract:
The accelerated formation of advanced glycation end-products (AGEs) due to elevated glycemia has repeatedly been reported as a central pathogenic factor in the development of diabetic microvascular complications. The effects of a novel inhibitor of AGE formation, NNC39-0028 (2,3-diaminophenazine), and a breaker of already formed AGE cross-links, N-phenacylthiazolium bromide (PTB), were investigated in streptozotocin-diabetic female Wistar rats. Diabetes for 24 weeks resulted in decreased tail collagen pepsin solubility, reflecting the formation of AGE cross-linking. Collagen solubility was significantly ameliorated by treatment with NNC39-0028, whereas PTB had no effect. Increased urinary albumin excretion (UAE) in diabetic rats was observed in serial measurements throughout the study period, and was not reduced by any treatment. Vascular dysfunction in the eye, measured as increased clearance of 125I-albumin, was induced by diabetes. NNC39-0028 did not affect this abnormality. This study demonstrated a pharmacological inhibition of collagen solubility alterations in diabetic rats without affecting diabetes-induced pathophysiology such as the increase in UAE or albumin clearance. Treatment with PTB, a specific breaker of AGE cross-links, had no effects in this study.
Insights
A novel inhibitor of advanced glycation end-product (AGE) formation, NNC39-0028, improved collagen solubility in diabetic rats. However, it did not impact other diabetic complications like albuminuria or vascular dysfunction.
Area of Science:
- Biochemistry
- Endocrinology
- Pharmacology
Background:
- Elevated blood glucose accelerates advanced glycation end-product (AGE) formation, a key factor in diabetic microvascular complications.
- AGE cross-linking reduces tissue elasticity and function, contributing to disease progression.
- Inhibiting AGE formation or breaking existing cross-links are potential therapeutic strategies for diabetes.
Purpose of the Study:
- To investigate the effects of a novel AGE formation inhibitor (NNC39-0028) and an AGE cross-link breaker (PTB) on diabetic complications in rats.
- To assess the impact of these compounds on collagen solubility, urinary albumin excretion, and vascular permeability.
Main Methods:
- Streptozotocin-induced diabetes in female Wistar rats for 24 weeks.
- Administration of NNC39-0028 (AGE inhibitor) and PTB (AGE cross-link breaker).
- Measurement of tail collagen pepsin solubility, urinary albumin excretion (UAE), and 125I-albumin clearance in the eye.
Main Results:
- Diabetes significantly decreased collagen solubility, indicating AGE cross-linking.
- NNC39-0028 treatment significantly ameliorated the decrease in collagen solubility.
- PTB treatment had no effect on collagen solubility.
- Neither NNC39-0028 nor PTB reduced increased urinary albumin excretion or increased albumin clearance in the eye.
Conclusions:
- NNC39-0028 effectively inhibited AGE-induced alterations in collagen solubility in diabetic rats.
- This study demonstrates pharmacological inhibition of collagen cross-linking without affecting other diabetic pathologies.
- PTB, a breaker of AGE cross-links, showed no therapeutic effect in this diabetic rat model.