Polyagonists for the Treatment of Obesity and DiabetesFriday, May 31, 2019
This morning, I spoke at the German Diabetes Congress in Berlin on the issue of whether or not metabolic surgery offers a cure (or just remission) in patients with type 2 diabetes.
I also had the pleasure of attending the Hans Langerhans Award Lecture, the highest distinction awarded by the German Diabetes Society, given by my colleague Matthias Tschöp, who is also the Director of the Helmholtz Centre for Diabetes Research in Munich.
Tschöp focussed his acceptance speech on his ground-breaking work on polyagonists, i.e. molecules that can co-stimulate two or more peptide receptors (e.g. for GLP-1, GIP, and glucagon).
Tschöp began his presentation by declaring that we could almost completely reverse the global epidemic of type 2 diabetes, if only we had more effective treatments for obesity.
As we now know, appetite and energy regulation is tightly controlled by a host of neuroendocrine signals, which act on the central nervous system as part of a complex homeostatic system that acts to sustain and defend body weight.
Based on these findings, Tschöp’s work has pursued the notion that effective obesity treatments require targeting of the homeostatic centres in the brain. As we have learnt from the extensive research on bariatric surgery, there are a number of signal molecules released by the gut (incretins) that directly affect central mechanism of appetite and satiety.
However, given the complexity and redundancy of the system, just targeting one of these molecules may not be effective enough to counteract the powerful mechanisms that defend against long-term weight loss. This insight, led Tschöp to pursue the idea that developing single synthetic molecules, that could simultaneously stimulate several distinct but synergistic pathways, may prove to be more effective than targeting a single molecular target.
This idea, ultimately led to the development of molecules that simultaneously act as dual co-agonists (e.g. for GLP-1 and glucagon or for GLP-1 and GIP ) or even tri-co-agonists (e.g. for GLP-1, GIP, and glucagon). These co-agonists appear to have potent metabolic and anti-obesity effects both in animal models and in early human studies. Indeed, this approach is now being actively pursued by a number of pharmaceutical companies hoping for more effective anti-obesity medications.
While these studies are currently underway, they certainly hold great promise for the future of medical treatments for obesity and diabetes.
Congratulations to Matthias Tschöp and his team for this most well-deserved award.
p.s. As an aside, I will have the pleasure of playing guitar with the “Sugar Daddies”, featuring Matthias Tschöp on drums (along with other prominent German diabetes researchers) at the Diabetes Gala Evening this evening.
Monday, July 8, 2019
The list of evaluated drugs includes, among many others, sheep-derived thyroid extracts, mitochondrial uncouplers, amphetamines, serotonergics, lipase inhibitors, and a variety of hormones produced and secreted by the gastrointestinal tract or adipose tissue. Unfortunately, when used as a single hormone therapy, most of these drugs are underwhelming in their efficacy or safety, and placebo-subtracted weight loss attributed to such therapy is typically not more than 10%. In 2009, the generation of a single molecule with agonism at the receptors for glucagon and the glucagon-like peptide 1 broke new ground in obesity pharmacology. This molecule combined the beneficial anorectic and glycemic effects of glucagon-like peptide 1 with the thermogenic effect of glucagon into a single molecule with enhanced potency and sustained action. Several other unimolecular dual agonists have subsequently been developed, and, based on their preclinical success, these molecules illuminate the path to a new and more fruitful era in obesity pharmacology. In this review, we focus on the historical pharmacological approaches to treat obesity and glucose intolerance and describe how the knowledge obtained by these studies led to the discovery of unimolecular polypharmacology…(mygenericpharmacy)