Oral DhHP-6 for the Treatment of Type 2 Diabetes Mellitus

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.

Anti-inflammatory effects of DhHP-6 in LPS-induced RAW264.7 macrophages and carrageenan-induced air pouch model in rat

“…Excessive accumulation of ROS can damage normal tissues further aggravating in ammatory reactions [10,20,14]. DhHP-6, a novel peroxidase mimetic peptide, can effectively scavenge ROS [32]. Previously, we showed the therapeutic effects of DhHP-6 in in ammation-related diseases;however, the mechanism remained unknown.…”

“…Notably, the peroxidase activity of DhHP-6 is ~93% (3.9 × 10 3 U•µmol -1 ) of that of natural peroxidase MP-11. Moreover, it is relatively more aqueous solubleand stable, and therefore, it can be easily synthesized and puri ed [32,31].…”

“…Previously, we showed that DhHP-6 could effectively eliminate ROS exhibiting protective effects in many oxidative stress-related diseases such as Type 2 diabetes [32,31], Alzheimer's disease [35,36], and cerebral ischemia-reperfusion [11]. Importantly, the pathological changes in these diseases have been linked to oxidative stress-induced in ammation.We showed that DhHP-6 administration reduced the levels of ROS, amyloid-β plaques in the cerebral cortex and hippocampus, and pro-in ammatory cytokines in APPswe/PSEN1dE9, a transgenic mouse model of Alzheimer's disease [36].…”