Patients suffering from the severe complications associated with both
insulin- (
IDDM) and
non-insulin-dependent diabetes mellitus (
NIDDM): nephropathy, retinopathy, neuropathy, and
atherosclerosis are still largely left without a prospect of an efficient treatment. Chronic hyperglycaemia, the primary clinical manifestation of diabetes, is associated with development of certain of the
diabetic complications. 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.
Glucose and α-dicarbonyl compounds chemically attach to
proteins and
nucleic acids without the aid of
enzymes. Initially, chemically reversible
Schiff base and Amadori product adducts form in proportion to
glucose concentration. The major biological effects of excessive nonenzymatic glycosylation are leading to increased
free radical production and compromised
free radical inhibitory and scavenger systems, inactivation of
enzymes; inhibition of regulatory molecule binding; crosslinking of
glycosylated proteins and trapping of soluble
proteins by glycosylated extracellular matrix (both may progress in the absence of
glucose); decreased susceptibility to proteolysis; abnormalities of
nucleic acid function; altered macromolecular recognition and endocytosis; and increased immunogenicity. The discovery of chemical agents that can inhibit deleterious glycation reactions is potentially of great therapeutic benefit to all diabetes-associated pathologies. This study demonstrates the progress in development of patented
carnosine mimetics resistant in formulations to enzymatic hydrolysis with human carnosinases that are acting as a universal form of
antioxidant, deglycating and transglycating agents that inhibit
sugar-mediated
protein cross-linking, chelate or inactivate a number of transition
metal ions (including ferrous and
copper ions), possess
lipid peroxidase type of activity and protection of
antioxidant enzymes from inactivation (such as in a case of
superoxide dismutase).
Carnosine biological mimetics react with
methylglyoxal and they are described in this study as a glyoxalase mimetics. The
imidazole-containing
carnosine biological mimetics can react with a number of deleterious aldehydic products of lipid peroxidation and thereby suppress their toxicity.
Carnosine and
carcinine can also react with
glycated proteins and inhibit
advanced glycation end product formation. These studies indicate a therapeutic role for
imidazole-containing
antioxidants (non-hydrolized
carnosine,
carcinine, D-
carnosine, ophthalmic
prodrug N-acetylcarnosine, leucyl-histidylhidrazide and patented formulations thereof) in therapeutic management strategies for
Type 2 Diabetes.