AIMS/HYPOTHESIS: The aim of this study was to determine the protective effects of human insulin and its analogues, B28Asp human insulin (insulin aspart) and B29Lys(ε-tetradecanoyl),desB30 human insulin (insulin detemir), against glucose-induced lifespan reduction and neuronal damage in the model organism Caenorhabditis elegans and to elucidate the underlying mechanisms. METHODS: Nematodes were cultivated under high glucose (HG) conditions comparable with the situation in diabetic patients and treated with human insulin and its analogues. Lifespan was assessed and neuronal damage was evaluated with regard to structural and functional impairment. Additionally, the activity of glyoxalase-1 and superoxide dismutase (SOD) and the formation of reactive oxygen species (ROS) and AGEs were determined. RESULTS: Insulin and its analogues reversed the life-shortening effect of HG conditions and prevented the glucose-induced neuronal impairment. Insulin treatment under HG conditions was associated with reduced concentration of glucose, as well as a reduced formation of ROS and AGEs, and increased SOD activity. These effects were dependent on the Forkhead box O (FOXO) homologue abnormal dauer formation (DAF)-16. Furthermore, glyoxalase-1 activity, which was impaired under HG conditions, was restored by human insulin. This was essential for the insulin-induced lifespan extension under HG conditions, as no change in lifespan was observed following either suppression or overexpression of glyoxalase-1. CONCLUSIONS/ INTERPRETATION: Human insulin and its analogues prevent the reduction in lifespan and neuronal damage caused by HG conditions. The effect of human insulin is mediated by a daf-2/insulin receptor and daf-16/FOXO-dependent pathway and is mediated by upregulation of detoxifying mechanisms.
AIMS/HYPOTHESIS: The aim of this study was to determine the protective effects of humaninsulin and its analogues, B28Asp humaninsulin (insulin aspart) and B29Lys(ε-tetradecanoyl),desB30 humaninsulin (insulin detemir), against glucose-induced lifespan reduction and neuronal damage in the model organism Caenorhabditis elegans and to elucidate the underlying mechanisms. METHODS: Nematodes were cultivated under high glucose (HG) conditions comparable with the situation in diabeticpatients and treated with humaninsulin and its analogues. Lifespan was assessed and neuronal damage was evaluated with regard to structural and functional impairment. Additionally, the activity of glyoxalase-1 and superoxide dismutase (SOD) and the formation of reactive oxygen species (ROS) and AGEs were determined. RESULTS:Insulin and its analogues reversed the life-shortening effect of HG conditions and prevented the glucose-induced neuronal impairment. Insulin treatment under HG conditions was associated with reduced concentration of glucose, as well as a reduced formation of ROS and AGEs, and increased SOD activity. These effects were dependent on the Forkhead box O (FOXO) homologue abnormal dauer formation (DAF)-16. Furthermore, glyoxalase-1 activity, which was impaired under HG conditions, was restored by humaninsulin. This was essential for the insulin-induced lifespan extension under HG conditions, as no change in lifespan was observed following either suppression or overexpression of glyoxalase-1. CONCLUSIONS/ INTERPRETATION:Humaninsulin and its analogues prevent the reduction in lifespan and neuronal damage caused by HG conditions. The effect of humaninsulin is mediated by a daf-2/insulin receptor and daf-16/FOXO-dependent pathway and is mediated by upregulation of detoxifying mechanisms.
Authors: D Schmoll; K S Walker; D R Alessi; R Grempler; A Burchell; S Guo; R Walther; T G Unterman Journal: J Biol Chem Date: 2000-11-17 Impact factor: 5.157
Authors: Michael Morcos; Xueliang Du; Friederike Pfisterer; Harald Hutter; Ahmed A R Sayed; Paul Thornalley; Naila Ahmed; John Baynes; Suzanne Thorpe; Georgi Kukudov; Andreas Schlotterer; Farastuk Bozorgmehr; Randa Abd El Baki; David Stern; Frank Moehrlen; Youssef Ibrahim; Dimitrios Oikonomou; Andreas Hamann; Christian Becker; Martin Zeier; Vedat Schwenger; Nexhat Miftari; Per Humpert; Hans-Peter Hammes; Markus Buechler; Angelika Bierhaus; Michael Brownlee; Peter P Nawroth Journal: Aging Cell Date: 2008-01-21 Impact factor: 9.304
Authors: Yonghak Seo; Samuel Kingsley; Griffin Walker; Michelle A Mondoux; Heidi A Tissenbaum Journal: Proc Natl Acad Sci U S A Date: 2018-03-06 Impact factor: 11.205
Authors: Andrea Schlotterer; Friederike Pfisterer; Georgi Kukudov; Britta Heckmann; Daniel Henriquez; Christian Morath; Bernhard K Krämer; Hans-Peter Hammes; Vedat Schwenger; Michael Morcos Journal: Biomed Rep Date: 2018-04-03
Authors: Christin Riedinger; Michael Mendler; Andrea Schlotterer; Thomas Fleming; Jürgen Okun; Hans-Peter Hammes; Stephan Herzig; Peter P Nawroth Journal: J Biol Chem Date: 2018-02-02 Impact factor: 5.157
Authors: Ana L Martínez-López; Carlos J González-Navarro; Paula Aranaz; José L Vizmanos; Juan M Irache Journal: Acta Pharm Sin B Date: 2021-03-01 Impact factor: 11.413
Authors: Jonathan Alcántar-Fernández; Rosa E Navarro; Ana María Salazar-Martínez; Martha Elva Pérez-Andrade; Juan Miranda-Ríos Journal: PLoS One Date: 2018-07-10 Impact factor: 3.240