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Three Hormones in One Molecule May Offer Powerful New Treatment for Adult-Onset Diabetes

A new treatment for adult-onset diabetes and obesity developed by researchers at Indiana University (IU) and the German Research Center for Environmental Health has essentially cured lab animals of obesity, diabetes, and associated lipid abnormalities through improved glucose sensitivity, reduced appetite, and enhanced calorie burning. In preclinical trials, the new peptide (image)-- 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 Dr. Richard DiMarchi and Dr. Matthias Tschöp, Director of the Institute for Diabetes and Obesity at the German Research Center for Environmental Health. The new findings were published online on December 8, 2014 in 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 Dr. Brian Finan, a scientist at the Helmholtz Diabetes Center who earned his Ph.D. in biochemistry at IU in Dr. 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,” Dr. 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 Dr. DiMarchi’s lab were co-first author Bin Yang (Marcadia Biotech) and Joseph Chabenne AT Laboratories, Vasily Gelfanov (IU), David Smiley (IU) and Ma Tao (Beijing Hanmi Pharma).

[Press release] [Nature Medicine abstract]