Effects of Liraglutide on Caenorhabditis elegans

Aims: C. elegans was used as a model organism to study effects of glucagon-like peptide-1 (GLP-1) analogue liraglutide, which is known to have neuroprotective effects, on glucose driven changes of lifespan and neuronal function. The short lifespan, good accessibility and strong homologies between human and C. elegans insulin signal transduction system offers excellent opportunities to study molecular mechanisms being responsible for these changes. In C. elegans, high glucose conditions impair neuronal function and reduce lifespan, likely driven by formation of advanced glycation end products (AGEs). In addition, GLP-1 homologue can be found in C. elegans. Aim of the study was to study effects of liraglutide on C. elegans with respect to lifespan and neuronal function under standard (ST) and high glucose (HG) conditions. Relative head motility, body angular velocity and body bending frequency were used as a parameter of neuronal function or damage, respectively.

Results: Under HG conditions liraglutide increased mean lifespan from 23.2±0.57 to 27.2±1.43days (P<0.01), maximum lifespan from 31.0±0.58 to 33.0±1.12days (P<0.05). In contrast, under ST conditions, liraglutide decreased mean lifespan from 26.0±0.33 to 19.4±0.23days (P<0.001), maximum lifespan from 35.0±0.00 to 26.7±1.16days (P<0.001). An increase of relative head motility was observed in C. elegans treated with liraglutide under HG conditions from 0.07±0.00 to 0.11±0.01mm/s (P<0.05) whereas under ST conditions liraglutide decreased this parameter from 0.12±0.00 to 0.07±0.01mm/s (P<0.05). A similar protective result was observed with body angular velocity and body bending frequency under HG conditions, which increased from 3.48±0.19 to 4.98±0.46^°Deg/s (P<0.05) and from 0.22±0.00 to 0.25±0.01Hz (P<0.05), respectively. Not surprisingly, under ST conditions changes in these two parameters were similar to relative head motility, which decreased from 8.37±0.00 to 5.05±0.28^°Deg/s (P<0.001) and from 0.26±0.00 to 0.25±0.00Hz (P<0.05), respectively. Liraglutide prolonged the glucose driven reduced lifespan, correlated with changes in reduction of Methylglyoxal (MG)-derived AGE formation. Under HG conditions, liraglutide decreased MG-derived AGE formation from 8.60±1.22 to 4.63±0.79 meanAU/pixel (P<0.05) whereas under ST conditions, liraglutide did not significantly decrease the MG-derived AGE formation from 3.61±0.00 to 3.48±1.35 meanAU/pixel (P=0.06).

Conclusions: Liraglutide enhanced the reduced lifespan under HG conditions and showed neuroprotective effects. These effects correlated with a reduction of MG-derived AGE formation. Further studies will show if a reduction of MG-derived AGEs plays a causative role in prolonging lifespan and reducing neuronal damage. Even though C. elegans is not a mammal organism, it is a very useful tool to study molecular mechanisms of glucose induced shortening of lifespan and the development of late diabetic complications like neuropathy.