DPP-4 inhibition resembles exercise in preventing type 2 diabetes development by inhibiting hepatic protein kinase C_ε expression in a mouse model of hyperinsulinemia

Abstract

Objective Interventions for hyperinsulinemia (HINS), an early indicator of type 2 diabetes mellitus (T2DM), can significantly reduce the T2DM risk. This study aims to determine how dipeptidyl peptidase-4 (DPP-4) inhibition prevents HINS progression to T2DM through ameliorating hepatic steatosis. Methods KKay mice were used as a HINS model and they underwent exercise or received a DPP-4 inhibitor, MK0626. Hepatic steatosis was examined and liver diacylglycerol levels were determined. Human hepatic cells (LO2) were treated with MK0626 or transfected with DPP-4 siRNA. Protein kinase C ε isoform (PKCε) and DPP-4 expression and insulin receptor substrate 1 (IRS-1) phosphorylation were assessed using immunohistochemistry and western blot. Results KKay mice developed HINS spontaneously at 7 weeks of age. Similar to exercise, MK0626 ameliorated hepatic steatosis and reduced the liver triglyceride and diacylglycerol content. Both exercise and MK0626 suppressed diacylglycerol-induced PKCε expression and restored insulin signaling, which was shown by tyrosine phosphorylation of IRS-1, in the livers of KKay mice. Additionally, silencing DPP-4 or MK0626 treatment decreased PKCε expression in LO2 cells. Conclusions Our data demonstrate that DPP-4 inhibition resembles exercise and effectively delays T2DM onset by suppressing hepatic PKCε expression in the HINS mouse model.

Effects Of Exercise Training And Chlorogenic Acid Supplementation On Hepatic Lipid Metabolism In Prediabetes Mice

“…Hepatic dysfunction is known to contribute to the development of metabolic disorders, emphasizing the pivotal role of the liver in energy metabolism [ 19 ]. HFD increases lipid accumulation in the liver which can contribute to hyperinsulinemia and NAFLD [ 2 , 3 ]. ACSL3, a member of the ACSL family in lipid droplets, is known to play a role in DNL in the liver [ 20 ].…”

“…Additionally, exercise can transiently decrease hepatic lipid levels by increasing fatty acid (FA) uptake and β-oxidation in muscles, and thus hepatic lipid storage can be reversed after prolonged exercise training (EX). Combined, previous studies suggest the beneficial effect of exercise on diacylglycerol (DAG) accumulation in the liver [ 3 ].…”

“…Non-alcoholic fatty liver disease (NAFLD) is a pathological syndrome distinguished by excessive lipid droplets in liver cells, which are closely related to insulin resistance (IR), especially hepatic IR [ 2 ]. A high-fat diet (HFD) is known to increase lipid accumulation and impair β-oxidation in the liver and HFD-induced lipid accumulation can inhibit insulin degradation in the liver, therefore contributing to hyperinsulinemia [ 3 ]. Hyperinsulinemia increases the chance to precede prediabetes which is characterized by impaired glucose tolerance (140≤ glucose level ≤199 mg/dL in response to 70 g oral glucose) or impaired fasting glucose (IFG) (100≤ fasting plasma glucose ≤125 mg/dL) level in human [ 4 ].…”

Systematic analysis of the pharmacological function of Schisandra as a potential exercise supplement

“…For example, dipeptidyl peptidase-4 (DPP-4), which is highly expressed in the liver, is a type of transmembrane peptidase that inhibits type 2 DM [ 33 ]. DPP-4 inhibition potentially improves hepatic steatosis and insulin resistance, similar to exercise [ 34 , 35 ]. Our data confirmed that the active compound network in SC helps regulate DDP-4 expression.…”