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.