Scientists develop a new drug candidate to treat diabetes.
A novel hormone combination has been created by a research team from Helmholtz Munich, the German Center for Diabetes Research (DZD), and Novo Nordisk for the potential treatment of type 2 diabetes in the future. The researchers combined the blood sugar-lowering actions of the medications tesaglitazar and GLP-1 (Glucagon-like peptide-1) to create a new and extremely effective drug.
The benefit of combining Tesaglitazar with GLP-1 is that the Tesaglitazar only penetrates the tissue with GLP-1 receptors. This increases the effects on sugar metabolism while lessening the side effects of tesaglitazar. Scientists have already successfully tested the new drug in animal studies. The study was recently published in the journal Nature Metabolism.
Tesaglitazar enhances glucose and fat metabolism in type 2 diabetic patients. It increases insulin sensitivity by acting on two receptors inside the cell nucleus. This was demonstrated in phase 3 clinical trials. However, tesaglitazar has side effects such as kidney damage.
However, in order to utilize the drug therapeutically, the researchers employed a trick: they biochemically combined tesaglitazar with the gastrointestinal hormone GLP-1. As a result, the combined drug can only work on cells and tissues that have GLP-1 receptors.
“This trick enabled us to combine the blood sugar-reducing effects of GLP-1 and tesaglitazar into a single highly effective molecule while keeping tesaglitazar away from tissues that it could damage,” explains PD Dr. Timo Müller, corresponding author, director of the Institute of Diabetes and Obesity, and scientist at DZD.
The new drug improves glucose tolerance and sugar metabolism
The new drug has already been successfully tested in animal studies: “The sugar metabolism of obese and diabetic male mice improved to a far greater extent compared with treatment using only the GLP-1 hormone or tesaglitazar alone – and with no damaging adverse effects to the liver or kidney,” says Professor Kerstin Stemmer, one of the lead authors of the study.
The substance was particularly effective in increasing glucose tolerance levels. Only minimal doses of the new drug were required to achieve sustainable improvement of glucose metabolism.
“This drug has great potential for the acute treatment of elevated blood sugar levels associated with type 2 diabetes,” says Aaron Novikoff, another lead author of the study.
The researchers now want to investigate whether this drug also has the potential to treat humans with type 2 diabetes and whether the efficacy of this new combination therapy can be optimized further using biochemical modifications.
The team comprised of Professor Dr. Matthias Tschöp (scientific director of Helmholtz Munich), PD Dr. Timo Müller, Richard DiMarchi, Ph.D. (Indiana University), and Dr. Brian Finan (Novo Nordisk) has been working for many years on new drug candidates for the treatment of type 2 diabetes and obesity. Poly-agonists simultaneously mimic the effects of various hormones. Clinical trials have shown that some poly-agonists are exceptionally promising in the treatment of obesity and type 2 diabetes and are already in phase 2 and phase 3 trials.
This year in the USA the first dual agonist drug for the treatment of type 2 diabetes was approved. The drug combines GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptor agonists that mimic the effects of the intestinal hormones GLP-1 and GIP.
Reference: “GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice” by Carmelo Quarta, Kerstin Stemmer, Aaron Novikoff, Bin Yang, Felix Klingelhuber, Alex Harger, Mostafa Bakhti, Aimee Bastidas-Ponce, Eric Baugé, Jonathan E. Campbell, Megan Capozzi, Christoffer Clemmensen, Gustav Collden, Perla Cota, Jon Douros, Daniel J. Drucker, Barent DuBois, Annette Feuchtinger, Cristina Garcia-Caceres, Gerald Grandl, Nathalie Hennuyer, Stephan Herzig, Susanna M. Hofmann, Patrick J. Knerr, Konxhe Kulaj, Fanny Lalloyer, Heiko Lickert, Arek Liskiewicz, Daniela Liskiewicz, Gandhari Maity, Diego Perez-Tilve, Sneha Prakash, Miguel A. Sanchez-Garrido, Qian Zhang, Bart Staels, Natalie Krahmer, Richard D. DiMarchi, Matthias H. Tschöp, Brian Finan, and Timo D. Müller, 22 August 2022, Nature Metabolism.