Abstract
Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction which can be induced by oxidative stress. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6) is a microperoxidase mimetic that can scavenge reactive oxygen species (ROS) in vivo. In our previous studies, we demonstrated an increased stability of linear peptides upon their covalent attachment to porphyrins. In this study, we assessed the utility of DhHP-6 as an oral anti-diabetic drug in vitro and in vivo. DhHP-6 showed high resistance to proteolytic degradation in vitro and in vivo. The degraded DhHP-6 product in gastrointestinal (GI) fluid retained the enzymatic activity of DhHP-6, but displayed a higher permeability coefficient. DhHP-6 protected against the cell damage induced by H2O2 and promoted insulin secretion in INS-1 cells. In the T2DM model, DhHP-6 reduced blood glucose levels and facilitated the recovery of blood lipid disorders. DhHP-6 also mitigated both insulin resistance and glucose tolerance. Most importantly, DhHP-6 promoted the recovery of damaged pancreas islets. These findings suggest that DhHP-6 in physiological environments has high stability against enzymatic degradation and maintains enzymatic activity. As DhHP-6 lowered the fasting blood glucose levels of T2DM mice, it thus represents a promising candidate for oral administration and clinical therapy.
Highlights
Type 2 diabetes mellitus (T2DM) has increased in prevalence and emerged as one of the largest public health problems globally [1]
In order to verify the possibility of DhHP-6 as an oral drug for the treatment of T2DM, we examined the stability of DhHP-6 in simulated gastrointestinal (GI) fluid and plasma, and found that DhHP-6 had high stability
We examined the effect of oral DhHP-6 in a T2DM mouse model, and found that DhHP-6 could effectively reduce the symptoms of blood glucose and insulin resistance
Summary
Type 2 diabetes mellitus (T2DM) has increased in prevalence and emerged as one of the largest public health problems globally [1]. According to the World Health Organization (WHO) report on diabetes, the number of people suffering from diabetes rose from 108 million to 422 million from 1980 to 2014, respectively [2]. T2DM is characterized by obesity and insulin resistance due to an inadequacy of pancreatic β-cell mass and function [3,4]. Excessive oxidative stress contributes to the pathogenesis of T2DM by promoting β-cell dysfunction and reducing the sensitivity of peripheral tissues to insulin [5]. Oxidative stress modifies many signaling pathways within a cell that can lead to insulin resistance [8]. Oxidative stress can reduce insulin sensitivity and damage insulin-producing cells in the pancreas [5]. The production of ROS in diabetes impairs the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The supplementation of exogenous microperoxidases represents a new direction for T2DM studies
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