Diabetes Mellitus: Novel Insights, Analysis and Interpretation of Pathophysiology and Complications Management with Imidazole-Containing Peptidomimetic Antioxidants

Abstract

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.

Protective Actions of Anserine Under Diabetic Conditions

“…Carnosine inhibits glycation [ 12 ], acts as an ACE inhibitor [ 13 , 14 ], reduces oxidative damage and improves enzymatic and non-enzymatic antioxidant activity [ 15 , 16 , 17 , 18 ], while its carbonyl scavenging function is debated [ 19 , 20 , 21 , 22 , 23 ]. In rodents, carnosine supplementation consistently improved diabetic complications, e.g., diabetic nephropathy, retinopathy, neuropathy and wound healing [ 1 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Oxidative Stress Genes, Antioxidants and Coronary Artery Disease in Type 2 Diabetes Mellitus

“…Long-term hyperglycemia-induced tissue damage ranges from micro- to macrovascular, resulting in diabetic retinopathy, nephropathy, neuropathy, cardiac and vascular disease [9, 12]. The main mechanism for consequential tissue damage is the overproduction of reactive oxygen species (ROS) which, in turn, activates the polyol pathway, increases the production of advanced glycation end product (AGEs) precursors, increases the expression of the nuclear factor κβ (NFκβ) through the activation of protein kinase C (PKC) and increases hexosamine pathway activity [9].…”

Intrinsic carnosine metabolism in the human kidney

“…These dipeptides have several important protective functions. The best-characterized histidine-containing dipeptide is carnosine (Boldyrev et al 2013 ; Budzen and Rymaszewska 2013 ), which plays many roles in maintaining health, including antioxidant activity (Babizhayev et al 2013 ; Boldyrev 1993 ; Mozdzan et al 2005 ) and the ability to scavenge carbonyls (Barski et al 2013 ; Negre-Salvayre et al 2008 ; Vistoli et al 2009 ), inhibit glycation (Alhamdani et al 2007 ), and inhibit angiotensin-converting enzymes (Hou et al 2003 ; Nakagawa et al 2006 ). Carnosine also has several neuroprotective roles (Baek et al 2014 ; Boldyrev et al 2013 ; Zhang et al 2011 ).…”