Abstract
Insulin-degrading enzyme (IDE) is the major zinc-metalloprotease involved in the cleavage of insulin, β-amyloid protein and mainly contributes to the pathophysiology of type 2 diabetes and Alzheimer’s disease. Therefore, this enzyme is expressed as candidate target for drugs used in the management of diabetes and peptide hydroxamates have been reported recently as inhibitors for IDE. Novel synthesized peptide hydroxamic acid II containing tryptophan and a sulfonamide bond has been prepared in our laboratory. The aim of this study was to determine whether this drug could be of value in modulating diabetic states in rats. In this study, forty adult male Wistar albino rats received 20% fructose in drinking water (HFW) for six weeks to induce diabetes. Administration of the prepared compound at two dose level (5 and 10 mg/kg body weight, p.o) to diabetic rats significantly reduced IDE protein, glucagon levels, improved insulin receptor signaling (phosphorylation), insulin sensitivity and lipid profile. However, it induced certain up-regulation of IDE mRNA expression. These findings may confirm its role in the modulation of glucose homeostasis through IDE and insulin receptor signaling. Key words: Insulin degrading enzyme, insulin receptors phosphorylation, insulin resistance, glucagon, hyperlipidemia.
Highlights
Pancreatic beta cells failure is the major contributing factor to the development of type 2 diabetes since insulin resistance of target tissues is usually associated with abnormal insulin secretion
Insulin-degrading enzyme (IDE) is the major zinc-metalloprotease involved in the cleavage of insulin, βamyloid protein and mainly contributes to the pathophysiology of type 2 diabetes and Alzheimer’s disease
Administration of the prepared compound at two dose level (5 and 10 mg/kg body weight, p.o) to diabetic rats significantly reduced IDE protein, glucagon levels, improved insulin receptor signaling, insulin sensitivity and lipid profile. It induced certain up-regulation of IDE mRNA expression. These findings may confirm its role in the modulation of glucose homeostasis through IDE and insulin receptor signaling
Summary
Pancreatic beta cells failure is the major contributing factor to the development of type 2 diabetes since insulin resistance of target tissues is usually associated with abnormal insulin secretion. Insulin receptor is a hetero tetramer consisting of 2 alpha subunits and 2 beta subunits that are linked by disulphide bonds. Insulin binds to the 2 alpha subunits of insulin receptors and activates tyrosine kinase in the beta subunits. The synthesis and antidiabetic activity of a novel peptide hydroxamic acid II containing typtophane and a sulfonamide bond through examination of IDE gene expression and protein level as well as insulin receptor phosphorylation were reported (Figure 2)
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