gms | German Medical Science

The prevalence of obesity and diabetes has reached alarming proportions and obesity represents one of the greatest health threads of modern societies. Obesity gives rise to a series of co-morbid disorders, such as type 2 diabetes, hypertension, cardio-vascular-diseases, and certain types of cancer. In the United States alone, it is estimated that each year 280,000 adults die directly due to the consequences of obesity. In light of the growing socioeconomic burden that obesity and diabetes represent for our health care system, the development of safe yet effective treatment options to tackle this ‘diabesity’ epidemic is urgently required.

Since the beginning of the 20’th century, a series of weight lowering drugs appeared on the marked. Nearly all of them vanished after a short time due to insufficient efficacy or inacceptable adverse effects. Although the history of anti-obesity drugs is a history of disappointments, hope is resting on the development of novel polypharmacological approaches, i.e. those that combine the beneficial effects of several independent hormones in a single molecule of enhanced potency and improved pharmacokinetics. In this regard, a molecule with dual-agonism at the receptors for glucagon-like peptide 1 (GLP-1) and glucagon was shown to correct obesity, glucose intolerance and hepatic steatosis of diet-induced obese (DIO) mice by combining the anorectic effect of centrally acting GLP-1 with the thermogenic and lipolytic effect of glucagon in a single hormone entity.

Spurred by the success of the GLP-1/glucagon co-agonist, another dual-agonist was engineered, one that combined the glycemic effect of GLP-1 with those of the glucose-dependent-insulinotropic polypeptide (GIP). This dual-incretin GLP-1/GIP peptide corrected obesity and improved glycemic control in a variety of species, including rodents, non-human primates and humans. The success of the dual-agonists paved the way for the generation of an even more advanced molecule, one that simultaneously activates the receptors for GLP-1, glucagon and GIP. This triagonist peptide showed greater potency at each of the three constituent receptors as compared to the native hormones and once weekly administration of diet-induced mice with as little as 3nmol/kg corrected several acute hallmarks of the metabolic syndrome, such as diet-induced obesity, dyslipidemia, glucose intolerance and hepatic steatosis.

New ground in obesity research was then broken by the development of a chimeric peptide that covalently linked GLP-1 to the nuclear hormone estrogen. Whereas estrogen exerts a series of beneficial effects on metabolism, such as inhibition of food intake, stimulation of energy expenditure and improvement of insulin sensitivity, its oncogenic potential and gynecological action limits its pharmacological use in weight management. A certainly revolutionary approach was thus the generation of a GLP-1/estrogen hybrid that selectively and exclusively delivered the estrogen into cells that express the GLP-1 receptor but that at the same time prevents the estrogen from entering cells that do not express GLP-1R. In rodents, the GLP-1/estrogen hybrid potently corrected obesity, insulin resistance and abnormalities in cholesterol and lipid metabolism. Notably, the GLP-1/estrogen molecule did not show any off-target effects in GLP-1R negative tissue, as assessed in MCF-7 xenograft studies. Building up on the principle of targeted steroid hormone delivery, new chimeras were generated that specifically deliver their nuclear hormone cargo into either the CNS (using GLP-1 as the peptide carrier) or into the liver (using glucagon as the peptide carrier). These new molecules (which are in the process of being published) emphasize the principle that novel peptides can be engineered that simultaneously activate selected pathways to sustainably improve systems metabolism. Extension of this approach to include more endocrine factors and to target other diseases might lead to an enormous boom in the development of novel pharmacotherapies in the future.