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Abstract
Serine protease dipeptidyl peptidase 4 (DPP-4) is involved in self/non-self-recognition and insulin sensitivity. DPP-4 inhibitors are conventional choices for diabetic treatment; however, side effects such as headache, bronchus infection, and nasopharyngitis might affect the daily lives of diabetic patients. Notably, natural compounds are believed to have a similar efficacy with lower adverse effects. This study aimed to validate the DPP-4 inhibitory activity of clerodane diterpene 16-hydroxycleroda-3,13-dien-15,16-olide (HCD) from Polyalthia longifolia, rutin, quercetin, and berberine, previously selected through molecular docking. The inhibitory potency of natural DPP-4 candidates was further determined by enzymatic, in vitro Caco-2, and ERK/PKA activation in myocyte and pancreatic cells. The hypoglycemic efficacy of the natural compounds was consecutively analyzed by single-dose and multiple-dose administration in diet-induced obese diabetic mice. All the natural-compounds could directly inhibit DPP-4 activity in enzymatic assay and Caco-2 inhibition assay, and HCD showed the highest inhibition of the compounds. HCD down-regulated LPS-induced ERK phosphorylation in myocyte but blocked GLP-1 induced PKA expression. For in vivo tests, HCD showed hypoglycemic efficacy only in single-dose administration. After 28-days administration, HCD exhibited hypolipidemic and hepatoprotective efficacy. These results revealed that HCD performed potential antidiabetic activity via inhibition of single-dose and long-term administrations, and could be a new prospective anti-diabetic drug candidate.
Highlights
Type 2 diabetes mellitus (TII DM) is a chronic disease that occurs in 366 million people worldwide and the effects of TII DM result in cardiovascular disease, obesity, eye problems, kidney problems, problems with the feet, nerves or microvascular complications, damage to large blood vessels, as well as brain, legs and macrovascular complications [1]
Two types of dipeptidyl peptidase 4 (DPP-4) are found in the body: soluble and membrane-bound forms that are only different in the presence or absence of cytoplasmic region at the N-terminal [5]. sDPP-4 is secreted from bone marrow, which can activate T-cell proliferation and may be involved in self/non-self-recognition [6,7]
This study examined the inhibitory potency of selected DPP-4 inhibitor candidates through in vitro methods and further tested their hypoglycemic efficacy via short-term and long-term administration in vivo
Summary
Type 2 diabetes mellitus (TII DM) is a chronic disease that occurs in 366 million people worldwide and the effects of TII DM result in cardiovascular disease, obesity, eye problems, kidney problems, problems with the feet, nerves or microvascular complications, damage to large blood vessels, as well as brain, legs and macrovascular complications [1]. Inhibitors of dipeptidyl peptidase 4 (DPP-4) have an alternative impact on diabetic strategy. Two types of DPP-4 are found in the body: soluble (sDPP-4) and membrane-bound (mDPP-4) forms that are only different in the presence or absence of cytoplasmic region at the N-terminal [5]. The biological role of m DPP-4 is associated with insulin sensitivity regulation by degrading incretin like glucagon-like peptide 1 (GLP-1), which stimulates insulin biosynthesis, inhibits glucagon secretion, slows gastric emptying, reduces appetite, and stimulates regeneration of pancreatic β-cells [9]. DPP-4 inhibition becomes a novel approach to overcome insulin insensitivity associated with TII DM. Synthetic DPP-4 inhibitors like sitagliptin and vildagliptin have clinically been used to treat TII DM. Scientists and physicians have paid more attention to the impact of searching for novel DPP-4 inhibitors from natural sources to provide new insights for TII DM patients
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