In 2012, we covered work led by Professor Richard DiMarchi that showed linking two hormones into a single molecule held promise as a treatment for obesity. DiMarchi followed this up last year by combining the properties of two endocrine hormones to provide an effective treatment for both obesity and adult-onset diabetes. Continuing in this vein, DiMarchi has now co-led a study whereby obesity and diabetes were effectively cured in lab animals by adding a third hormone to the molecular mix.

Clinical work carried out last year, which included human clinical trials, showed a peptide combining the properties of two endocrine hormones, GLP-1 (glucagon-like peptide 1) and GIP (gastric inhibitory polypeptide), provided an effective treatment for adult-onset diabetes. Now the team, co-led by DiMarchi, the Indiana University (IU) Distinguished Professor of Chemistry, and Matthias Tschöp, director of the Institute for Diabetes and Obesity at the German Research Center for Environmental Health, has developed a new molecule that includes a third hormone, glucagon.

GLP-1 and GIP are involved in enhancing insulin action and reducing blood glucose in the body, with GLP-1 also acting to reduce appetite. Meanwhile, glucagon is involved in improving liver function and increasing the long-term rate at which calories are burned. Molecularly combining these three hormones forms what is known as a triple agonist, which can bind to and activate receptors in the body and produce certain biological responses.

"This peptide represents the first rationally designed, fully potent and balanced triple agonist ever achieved in the treatment of any disease," says DiMarch. "The benefits of the previously reported individual co-agonists have been integrated to a single molecule of triple action that provides unprecedented efficacy to lower body weight and control metabolism."

The researchers say that in preclinical trials, this new peptide lowered blood sugar levels and reduced body fat better than all existing drugs. By triggering improved glucose sensitivity, reducing appetite and enhancing calorie burning, it was able to reduce body weight in rodents by around 30 percent, (nearly twice as much as the preceding GLP-1/GIP double hormone), and essentially cured the animals of obesity, diabetes and associated lipid abnormalities.

"This triple hormone effect in a single molecule shows results never achieved before," said co-first author Brian Finan, a scientist at the Helmholtz Diabetes Center. "A number of metabolic control centers are influenced simultaneously, namely in the pancreas, liver, fat depots and brain."

IU Distinguished Professor Richard Di Marchi (Photo: Indiana University)

The researchers say the triple action molecule is more than the sum of its parts, producing "unparalleled" results when compared to earlier tests where the three hormones were used alone and together as co-agonists. They claim this is clear evidence that combining GLP-1, GIP and glucagon in one molecule can produce improved therapeutic effects by targeting the three receptors of the three hormones.

The team's findings appear in the journal Nature Medicine, with planned human clinical trials on the molecule to be managed by pharmaceutical giant Roche.

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