Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity.
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 trea...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3382200?pdf=render |
| _version_ | 1811213270746398720 |
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| author | Matthias Kern Nora Klöting Heiko G Niessen Leo Thomas Detlef Stiller Michael Mark Thomas Klein Matthias Blüher |
| author_facet | Matthias Kern Nora Klöting Heiko G Niessen Leo Thomas Detlef Stiller Michael Mark Thomas Klein Matthias Blüher |
| author_sort | Matthias Kern |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T05:44:06Z |
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| id | doaj.art-6417ea3d3b144574a357c1f70fd871b9 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T05:44:06Z |
| publishDate | 2012-01-01 |
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| series | PLoS ONE |
| spelling | doaj.art-6417ea3d3b144574a357c1f70fd871b92022-12-22T03:45:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0176e3874410.1371/journal.pone.0038744Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity.Matthias KernNora KlötingHeiko G NiessenLeo ThomasDetlef StillerMichael MarkThomas KleinMatthias BlüherLinagliptin (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.http://europepmc.org/articles/PMC3382200?pdf=render |
| spellingShingle | Matthias Kern Nora Klöting Heiko G Niessen Leo Thomas Detlef Stiller Michael Mark Thomas Klein Matthias Blüher Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. PLoS ONE |
| title | Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. |
| title_full | Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. |
| title_fullStr | Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. |
| title_full_unstemmed | Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. |
| title_short | Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity. |
| title_sort | linagliptin improves insulin sensitivity and hepatic steatosis in diet induced obesity |
| url | http://europepmc.org/articles/PMC3382200?pdf=render |
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