Linagliptin Improves Insulin Sensitivity and Hepatic Steatosis in Diet-Induced Obesity

Abstract

Linagliptin (tradjenta™) is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 inhibition attenuates insulin resistance and improves peripheral glucose utilization in humans. However, the effects of chronic DPP-4 inhibition on insulin sensitivity are not known. The effects of long-term treatment (3–4 weeks) with 3 mg/kg/day or 30 mg/kg/day linagliptin on insulin sensitivity and liver fat content were determined in diet-induced obese C57BL/6 mice. Chow-fed animals served as controls. DPP-4 activity was significantly inhibited (67–89%) by linagliptin (P<0.001). Following an oral glucose tolerance test, blood glucose concentrations (measured as area under the curve) were significantly suppressed after treatment with 3 mg/kg/day (–16.5% to –20.3%; P<0.01) or 30 mg/kg/day (–14.5% to –26.4%; P<0.05) linagliptin (both P<0.01). Liver fat content was significantly reduced by linagliptin in a dose-dependent manner (both doses P<0.001). Diet-induced obese mice treated for 4 weeks with 3 mg/kg/day or 30 mg/kg/day linagliptin had significantly improved glycated hemoglobin compared with vehicle (both P<0.001). Significant dose-dependent improvements in glucose disposal rates were observed during the steady state of the euglycemic–hyperinsulinemic clamp: 27.3 mg/kg/minute and 32.2 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 20.9 mg/kg/minute with vehicle (P<0.001). Hepatic glucose production was significantly suppressed during the clamp: 4.7 mg/kg/minute and 2.1 mg/kg/minute in the 3 mg/kg/day and 30 mg/kg/day linagliptin groups, respectively; compared with 12.5 mg/kg/minute with vehicle (P<0.001). In addition, 30 mg/kg/day linagliptin treatment resulted in a significantly reduced number of macrophages infiltrating adipose tissue (P<0.05). Linagliptin treatment also decreased liver expression of PTP1B, SOCS3, SREBP1c, SCD-1 and FAS (P<0.05). Other tissues like muscle, heart and kidney were not significantly affected by the insulin sensitizing effect of linagliptin. Long-term linagliptin treatment reduced liver fat content in animals with diet-induced hepatic steatosis and insulin resistance, and may account for improved insulin sensitivity.

Effects of sitagliptin on circulating zinc-α2-glycoprotein levels in newly diagnosed type 2 diabetes patients: a randomized trial

“…Further studies will be required to address this issue. In addition, these results are also consistent with prior work investigating the insulin sensitivity of DDP-IV inhibitor in db/db mice by means of eugycemic hyperinsulinemic clamp techniques (24). However, one study in patients with T2DM showed that the DPP-IV inhibitor had no effect on HOMA-IR or ADI levels (25).…”

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

“…By 20 weeks after the induction of diabetes, the diabetic mice were divided into two groups (linagliptin [5 mg/kg body weight (BW)/day in drinking water] and untreated). Dose of linagliptin was decided based on the dose-dependent effects of this drug between 3 and 30 mg/kg BW/day (19). Linagliptin was diluted directly in drinking water.…”

Preservation of Glucagon-Like Peptide-1 Level Attenuates Angiotensin II-Induced Tissue Fibrosis by Altering AT1/AT2 Receptor Expression and Angiotensin-Converting Enzyme 2 Activity in Rat Heart

“…Animals were randomized into one of four groups (n=6/each observational period): 1) Sham control: rats were infused with a saline pump; 2) Control: rats were received Ang II infusion at a rate of 500 ng/kg/min; 3) Ang II + liraglutide (Novo Nordisk Pharma Ltd., Gladsaxe, Denmark): rats were received a subcutaneous injection of liraglutide at a dose of 0.3 mg/kg twice daily during Ang II infusion; 4) Ang II + linagliptin (Boehringer Ingelheim Pharmaceuticals Inc. CT, USA): linagliptin at a dose of 8 mg/kg was administered via oral gavage daily during Ang II infusion. The doses selected for liraglutide and linagliptin were based on previous reports showing a significant improvement in glycemic control and insulin sensitivity as well as a reduction in inflammation-mediated steatohepatitis in diet-induced obesity animals [14,15,18].…”