title: 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.
authors: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors: Matthias
authors: M
authors: Kern
authors: Nora
authors: N
authors: Klöting
authors: Heiko G
authors: HG
authors: Niessen
authors: Leo
authors: L
authors: Thomas
authors: Detlef
authors: D
authors: Stiller
authors: Michael
authors: M
authors: Mark
authors: Thomas
authors: T
authors: Klein
authors: Matthias
authors: M
authors: Blüher
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004032:Diet / Q000009:adverse effects*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000069476:Linagliptin; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D011687:Purines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D018819:Dipeptidyl Peptidase 4; D005947:Glucose