Endocrine Abstracts

Emerging insights from recent advances in metabolic diseases research suggest that one or several patterns of multiple neuro-endocrine factors are necessary for sustained modulation of body fat or metabolism set points. Gut hormones appear to reside at the core of these master–key-like signaling patterns, as indicated for example by bariatric surgery research. Over the last 7 years, we have therefore tested a large series of combination therapies based on multiple gastrointestinal and adipocyte derived signals. Balanced single molecule peptide hormone based GLP1-glucagon and GIP-GLP1 co-agonists exhibited superior body weight loss and glucose metabolism benefits in mouse models of obesity and diabetes, as compared to any established mono-agonists. Preliminary translational data indicate efficacy of GIP-GLP1 co-agonists in non-human primates. Since co-infusion of a soluble and stable glucagon mono-agonist in parallel with GIP-GLP1 co-agonist treatment provided additional benefits, a series of single molecule GIP-GLP1-glucagon tri-agonists were generated and validated. These novel tri-agonists again showed unprecedented metabolic and body weight benefits in mouse and rat models of obesity and diabetes. In a parallel approach single molecule conjugates combining a peptide (e.g. GLP1) with a steroid (e.g. estrogen) were generated to maximize metabolic benefits and minimize potential toxicity by specifically targeting a subset of estrogen receptors in GLP1-receptor carrying cells. Such peptide carrier based targeting of a specific subset of nuclear hormone receptors was successful: Administration reversed hallmarks of the metabolic syndrome in diet induced obese and insulin resistant mice without causing any detectably side effects or toxicity. The above described novel single molecule approaches to polypharmaceutical therapeutics carry the potential to open new perspectives for the treatment of metabolic diseases such as diabetes and obesity.