Oral Administration of Bis(aspirinato)zinc(II) Complex Ameliorates Hyperglycemia and Metabolic Syndrome-Like Disorders in Spontaneously Diabetic KK-Ay Mice: Structure-Activity Relationship on Zinc-Salicylate Complexes

Abstract

The number of patients suffering from diabetes mellitus in the 21st century is increasing worldwide.1) Several types of injectable insulin preparations are available for patients with type 1 diabetes, characterized by progressive b-cell destruction and deficiency of intrinsic insulin secretion. On the other hand, various types of synthetic pharmaceutics are clinically used for the treatment of type 2 diabetes, characterized by insulin resistance. In recent years, new types of anti-diabetic pharmaceutics such as glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitors are developed and clinically available for treatment. 2)For many years, the relationship between diabetes and biometals such as vanadium, copper, and zinc ions has been recognized and discussed.3) We have developed anti-diabetic metal complexes as new candidates for hypoglycemic agents. Since 2000, we have proposed several types of zinc(II) (Zn) complexes with various coordination modes, [4][5][6][7][8] in which Zn complexes with Zn(O 4 ) and Zn(N 2 O 2 ) coordination environments showed anti-diabetic effect on oral administration. 9)Coincidently, a high dose of salicylates was found to reverse hyperglycemia and hyperinsulinemia in type 2 diabetic patients.10) These findings strongly suggest that the combined use of Zn and salicylates achieves the synergism in treating diabetes. We then tried to use aspirin (acetylsalicylic acid) and its related compounds with two oxygen atoms as ligand to Zn.Salicylic acid, a colorless crystalline organic acid, functions as a plant hormone.11) It is probably the best known compound that is chemically similar but not identical to the active component of aspirin. The medicinal property of salicylic acid has been known mainly for pain and fever relieves since ancient times. A side effect of salicylic acid such as stomachache, however, was replaced by aspirin with low side effect. Aspirin, which is a medicine in the family of salicylates, has been used as an analgesic, anti-pyretic, and antiinflammatory. 12,13) It has also an anti-platelet effect with low doses to prevent both heart attacks and thrombus formation in hyper-coagulate states.14,15) On the other hand, over 100 years ago, a high-dose salicylic acid treatment was reported to reduce the glycosuria in type 2 diabetic patients.16) Later in 1957, treatment of diabetes with aspirin for 10-14 d was found to improve the impaired oral glucose tolerance test in the diabetic patients.17) The mechanism how salicylic acid may affect the whole-body glucose homeostasis remains unknown until a recent finding that salicylic acid inhibits the activity of inhibitory kB kinase-b (IKKb), a known serine kinase. 10,18,19) In light of these findings, we hypothesized that Zn-salicylate complexes might be effective for not only treating type 2 diabetes and its complications but also improving metabolic syndrome. To verify this hypothesis, we have examined whether Zn-salicylate complexes containing Zn-aspirin complex show the anti-diabetic activi...

Zinc and diabetes mellitus: understanding molecular mechanisms and clinical implications

“…Zinc ions and its’ complexes, have shown insulin-like action both in-vitro and in-vivo experiments (Table 1 ) [ 96 – 117 ]. In-vitro , Zinc complexes inhibit the release of FFA from cultured rat adipocytes [ 96 – 104 , 106 , 108 , 110 – 112 , 114 , 116 ]. In cultured 3 T3-L1 adipocytes these Zinc complexes activates the insulin signaling cascade through Akt/PKB (protein-kinase B) phosphorylation resulting in GLUT4 translocation to the plasma membrane and enhanced cellular glucose uptake [ 105 , 107 , 113 ].…”

Biological efficacy of zinc oxide nanoparticles against diabetes: a preliminary study conducted in mice

“…The purpose of zinc in diabetes has been established by supplementation studies in diabetic rats [32]. Several zinc complexes were synthesized, and they are proven to be very useful in the biological system [33,34]. Many types of research demonstrate that zinc is secreted along with insulin served as an autocrine molecule which enhances the glucose-stimulated insulin secretion from the rat-isolated pancreatic islets [29].…”

The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus

“…The role of Zn 2+ in oxidative stress and hypoxia Besides its specific role in insulin storage and secretion in the pancreatic beta cell, zinc is known for its antioxidative properties (22,27,147) and has been studied extensively as a possible treatment option in the context of diabetes in animal models (3,208,211) as well as human patients (50,63). However, the results have been inconclusive possibly because changes in zinc intake are often too small to alter intracellular levels of Zn 2+ to an extent that allows a measurable effect on oxidative stress.…”