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academies
Nov 22-23, 2018 | Paris, France
Joint Event
Nutrition and Health
16
th
International Conference on
26
th
International Conference on
Diabetes and Endocrinology
&
Journal of Insights in Nutrition and Metabolism | Volume 2
Novel Pharmacotherapies for the Treatment of Obesity and Diabetes
Timo Müller
Institute for Diabetes and Obesity (IDO), Germany
S
ince almost a decade our group has now, together with
lead international scientists, revolutionized the concept
of polypharmacology by generating peptides which combine,
through intermixed sequence hybridization, the beneficial
effects of several key metabolic hormones into a single
hormone entity. In line with this notion, we have shown that a
molecule with balanced dual-‐agonismat the receptors for GLP-‐1 and glucagon synergistically corrects diet-‐induced obesity
and glucose intolerance in a variety of rodent models (Day et al.,
Nat Chem Biol. 2009). A molecule with balanced dual-‐agonism
at the receptors for GLP-‐1 and GIP was further developed and
demonstrated to substantially correct glucose metabolism
in a variety of species, including obese and diabetic rodents,
non-‐human primates and humans (Finan et al., Sci Transl
Med 2013). Notably, the GLP-‐1/GIP dual-‐agonist improved
glucose handling with greater metabolic efficacy and with an
unmet level of safety relative to best-‐in-‐ class available FDA/
EMA approved drugs for T2D (Finan et al., Sci Transl Med 2013).
A single highly potent PK-‐optimized molecule with balanced
triple agonism at the receptors for GLP-‐1, GIP and glucagon
were further shown to correct obesity and glucose intolerance,
to reverse insulin resistance and to improve lipid and cholesterol
metabolism. The beneficial metabolic effects of this triple
agonist were demonstrated in various mouse models
of diet and genetically induced obesity (Finan et al., Nat Med
2015) and was shown to translate from obese rodents to non-‐
human primates (Tschöp et al., Cell Metab 2016). Expanding
the concept of polypharmacology, we recently reported GLP-‐1
mediated delivery of the nuclear hormone estrogen to selected
tissues relevant in systemic energy metabolism control (Finan
et al., Nat Med 2012). The tissue-‐specific delivery of estrogen
thereby maximized its beneficial effects on metabolism
and minimized its oncogenic potential in GLP-‐1R negative
tissues, such as the uterus and the breast tissue. Building up
on these findings, we recently report targeted delivery of
dexamethasone via GLP 1 as the peptide carrier to
improve hypothalamic inflammation (Quarta et al., Cell Metab
2017). In summary, our data emphasize the therapeutic utility
of several novel unimolecular polypharmacotherapies for the
treatmentofobesity, type2diabetesandcardiovasculardisease.
e:
timo.mueller@helmholtz-muenchen.de