Scientific Achievement Award 2011: Defeating Diabesity
In spite of some enlightened arguments and encouraging preclinical data, it certainly would be naïve not to acknowledge the difficult path forward in treating human obesity and diabetes. While natural peptides have frequently proven themselves to be miraculous medicines with minimal off-target toxicity, the potential for dose-limiting, on-target toxic side effects remains a possibility. Insulin serves as an excellent example of the unprecedented efficacy but life-threatening risk with excessive agonism. Another potential danger is the inherent crossreactivity of single molecule polyagonists increasing the potential for unintended effects through individual receptors or some synergy in undesired signaling. A final obvious reservation is the acceptance that studies in mice and rats do not always predict efficacy or toxicity in humans. Will chronic glucagon agonism function equally in humans as it has in rodents, and furthermore is the preferred ratio for minimizing adverse effects common across species? One point to note in that regard is the unusually progressive wasting syndrome observed in patients suffering with glucagonomas.
Yet even an advanced approach such as single molecule co- and triagonists will benefit from—and quite possibly depend upon—advances in deep phenotyping of patients with diabesity. We will need to define and identify subgroups that would benefit most from distinct personalized drugs, as well as the prospect that different agents might serve the same patient differently at different points in the treatment of their disease. For example, reliable predictive characterization on GLP-1 responders and nonresponders within patient populations with diabetes and obesity could help to predict suitable therapy and minimize the risk of an inappropriate therapeutic prescription. Undoubtedly, efficient parallel progress toward multiple choices of clinically tested single molecule polyagonists along with a deeper patient phenotyping will enable a more personalized metabolic prescription and represent our best chance for a nonsurgical management of diabesity.
We are in our infancy in formulating the best medicinal approach to treat the global epidemic of disease. The integration of drug therapy to facilitate less invasive surgical procedures (such as gastric banding) may offer synergistic potential. Furthermore, single molecule drug combinations are likely not to be limited to macromolecule combinations. Peptide and protein-based targeted delivery of more traditional small molecule medicines holds great potential for enhanced efficacy. In particular, we favor single molecule combinations of peptides with nuclear hormones as the effect of the latter can be highly targeted to select tissues that possess the peptide receptor as a prerequisite to accessing the nuclear-location hormone receptor. We have most recently explored such single molecule combinations as GLP-1 and steroids to achieve sizable expansion in efficacy without the hallmark toxicities frequently mediated by nuclear receptors (data not provided).
Healthy skepticism is an important element in drug discovery, especially when one is aiming to cure a disease for which decades of research have failed to achieve the needed breakthrough. Frequently, the argument is made that redundancy among the considerable number of circulating signals regulating metabolism render it impossible to design a drug that can continuously lower body fat and improve glucose tolerance. The argument is grounded in the so-called thrifty gene hypothesis, which professes that our genetic constitution was shaped to survive long periods under variable and uncertain caloric supply. Therefore, multisignal-based efficiency might have developed in order to optimally store calories and defend body fat, although the role of the thrifty gene hypothesis for diabetes has recently been challenged. If securing calorie intake and maintaining caloric storage are so important for the survival of our species than it seems plausible that pharmacological intervention may be wishful thinking. This could be the case, but we should recognize that endocrinologists have been down this path before. Contraceptives were developed by pharmacologically modifying one or several afferent signals in "tricking the brain to perceive pregnancy" when none existed, thereby shutting down parts of the reproductive system. Since reproduction is seminal to survival of the species, there is hope in analogy that we might just be equally fortunate in replicating one more time a similar strategy to defeat diabesity.
Risks and Limitations
In spite of some enlightened arguments and encouraging preclinical data, it certainly would be naïve not to acknowledge the difficult path forward in treating human obesity and diabetes. While natural peptides have frequently proven themselves to be miraculous medicines with minimal off-target toxicity, the potential for dose-limiting, on-target toxic side effects remains a possibility. Insulin serves as an excellent example of the unprecedented efficacy but life-threatening risk with excessive agonism. Another potential danger is the inherent crossreactivity of single molecule polyagonists increasing the potential for unintended effects through individual receptors or some synergy in undesired signaling. A final obvious reservation is the acceptance that studies in mice and rats do not always predict efficacy or toxicity in humans. Will chronic glucagon agonism function equally in humans as it has in rodents, and furthermore is the preferred ratio for minimizing adverse effects common across species? One point to note in that regard is the unusually progressive wasting syndrome observed in patients suffering with glucagonomas.
Yet even an advanced approach such as single molecule co- and triagonists will benefit from—and quite possibly depend upon—advances in deep phenotyping of patients with diabesity. We will need to define and identify subgroups that would benefit most from distinct personalized drugs, as well as the prospect that different agents might serve the same patient differently at different points in the treatment of their disease. For example, reliable predictive characterization on GLP-1 responders and nonresponders within patient populations with diabetes and obesity could help to predict suitable therapy and minimize the risk of an inappropriate therapeutic prescription. Undoubtedly, efficient parallel progress toward multiple choices of clinically tested single molecule polyagonists along with a deeper patient phenotyping will enable a more personalized metabolic prescription and represent our best chance for a nonsurgical management of diabesity.
We are in our infancy in formulating the best medicinal approach to treat the global epidemic of disease. The integration of drug therapy to facilitate less invasive surgical procedures (such as gastric banding) may offer synergistic potential. Furthermore, single molecule drug combinations are likely not to be limited to macromolecule combinations. Peptide and protein-based targeted delivery of more traditional small molecule medicines holds great potential for enhanced efficacy. In particular, we favor single molecule combinations of peptides with nuclear hormones as the effect of the latter can be highly targeted to select tissues that possess the peptide receptor as a prerequisite to accessing the nuclear-location hormone receptor. We have most recently explored such single molecule combinations as GLP-1 and steroids to achieve sizable expansion in efficacy without the hallmark toxicities frequently mediated by nuclear receptors (data not provided).
Healthy skepticism is an important element in drug discovery, especially when one is aiming to cure a disease for which decades of research have failed to achieve the needed breakthrough. Frequently, the argument is made that redundancy among the considerable number of circulating signals regulating metabolism render it impossible to design a drug that can continuously lower body fat and improve glucose tolerance. The argument is grounded in the so-called thrifty gene hypothesis, which professes that our genetic constitution was shaped to survive long periods under variable and uncertain caloric supply. Therefore, multisignal-based efficiency might have developed in order to optimally store calories and defend body fat, although the role of the thrifty gene hypothesis for diabetes has recently been challenged. If securing calorie intake and maintaining caloric storage are so important for the survival of our species than it seems plausible that pharmacological intervention may be wishful thinking. This could be the case, but we should recognize that endocrinologists have been down this path before. Contraceptives were developed by pharmacologically modifying one or several afferent signals in "tricking the brain to perceive pregnancy" when none existed, thereby shutting down parts of the reproductive system. Since reproduction is seminal to survival of the species, there is hope in analogy that we might just be equally fortunate in replicating one more time a similar strategy to defeat diabesity.
SHARE
