The Relationship between Anagliptin Concentration Showing Over 80% Inhibition of Plasma Dipeptidyl Peptidase-4 Activity and its Protective Effect against Glucagon-like Peptide-1 Degradation

Abstract

In dipeptidyl peptidase-4 (DPP-4) inhibitors, the inhibition of plasma DPP-4 activity by 80% is considered sufficient to have an effect on glycemic control improvement through the elevation of intact glucagon-like peptide-1 (GLP-1). To clarify whether or not the 80% inhibition is sufficient to protect against GLP-1 degradation, we investigated rats with a continuous infusion of exogenous GLP-1. When GLP-1 was infused into the femoral or portal vein, the steady state active GLP-1 levels in plasma significantly increased (P<0.05) at the 80% inhibitory concentration (IC80) of anagliptin (a highly selective DPP-4 inhibitor) against plasma DPP-4 activity, compared with control. In addition, the peptide levels increased in a concentration-dependent manner at drug concentrations from IC80 to 10-fold IC80, and the levels at the 10-fold IC80 were significantly higher (P<0.05) than those at IC80. The concentration dependency on GLP-1 increment was also confirmed based on the experiment in which the endogenous active GLP-1 levels were measured after an oral carbohydrate load. These findings suggest that an almost complete inhibition (80%) of plasma DPP-4 activity was insufficient to protect GLP-1 degradation, and much higher drug concentrations such as 10-fold IC80 are necessary to potently protect GLP-1 from degradation by DPP-4 commonly present in blood and tissues.

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

“…The antihyperglycemic action of DPP‐4 inhibitors, including anagliptin, depends on GLP‐1 and GLP‐1 receptor 13. Consequently, we investigated whether a GLP‐1–dependent pathway is involved in the anti‐inflammatory action of anagliptin.…”

“…The antihyperglycemic action of DPP-4 inhibitors, including anagliptin, depends on GLP-1 and GLP-1 receptor. 13 Consequently, we investigated whether a GLP-1-dependent pathway is involved in the anti-inflammatory action of anagliptin. Exendin fragment 9-39 is an inverse agonist of the GLP-1 receptor and inhibits insulin secretion by GLP-1 in pancreatic b cells.…”

The Effect of Transplacental Administration of Glucagon-Like Peptide-1 on Fetal Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia

“…The result for the GLP-1-injected fetuses was normalized to the values of the placebo-injected fetuses to remove background [35]. GLP-1 fetuses showed a 3.59-fold increase in the GLP-1 level in comparison to controls at 24 h.…”