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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.

Metabolism: Clinical and Experimental
|August 23, 2000
PubMed

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.

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