Adult-onset diabetes, obesity cured in lab mice, scientists report

In preclinical trials, the new peptide -- a molecular integration of three gastrointestinal hormones -- lowered blood sugar levels and reduced body fat beyond all existing drugs, according to the work co-led by IU Distinguished Professor of Chemistry Richard DiMarchi and Matthias Tschöp, director of the Institute for Diabetes and Obesity at the German Research Center for Environmental Health. The new findings were published today in Nature Medicine.

These preclinical results advance the clinical work the team announced last year that a peptide combining the properties of two endocrine hormones, GLP-1 and GIP, was an effective treatment for adult-onset diabetes. This new molecule includes a third hormone activity, glucagon.

"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 who earned his Ph.D. in biochemistry at IU in DiMarchi's lab. "A number of metabolic control centers are influenced simultaneously, namely in the pancreas, liver, fat depots and brain."

In constructing the new single-cell molecules with triple-hormone action, the researchers found they could reduce body weight in rodents by about 30 percent, almost twice as much as the GLP-1/GIP double hormone. The molecules are called triple agonists -- three hormones combined molecularly that can bind to and activate receptors to 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," DiMarchi said. "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."

In the paper, the team described the new results as "unparalleled" when compared to earlier tests using the three hormones alone and together as co-agonists. It is a clear demonstration that combining GLP-1, GIP and glucagon can produce improved therapeutic effects.

The triple hormone specifically and equally targets three receptors of GLP-1, GIP and glucagon. GLP-1 and GIP predominantly contribute to enhancing insulin action and reducing blood glucose. GLP-1 also curbs appetite, while glucagon primarily increases the long-term rate at which calories are burned and improves liver function.

Human clinical trials are being managed by Roche, which also co-authored the new paper. Inventions associated with this work have been licensed through the Indiana University Research and Technology Corp. to Marcadia Biotech Inc., which Roche acquired in 2010.

Additional scientists affiliated with IU and DiMarchi's lab were co-first author Bin Yang and Joseph Chabenne, Vasily Gelfanov, David Smiley and Ma Tao.