Terry Monks, Ph.D.
- Apr 12, 2017
- Topic: “Metformin, Methylglyoxal, and Diabetes"
- Date: Wednesday, October 25th, 2017
- Time: 12pm
- Place: B448 Life Science Bldg
For a drug that is recommended in one of every two prescriptions for non-insulin
anti-hyperglycemic therapy, metformin remains an enigma. Thus, although metformin’s
primary role in lowering hyperglycemia is considered to occur via inhibition
of hepatic gluconeogenesis and suppression of hepatic glucose production,
the precise mechanism(s) by which these effects are achieved remain uncertain.
Metformin is unique in that it is linked to lower levels of advanced glycation end
products (AGE), proteins (and lipids) that undergo glycation under conditions of
high sugar and oxidative stress, conditions which produce reactive dicarbonyls.
Methylglyoxal (MG) is a highly reactive dicarbonyl found at elevated levels in the
plasma of patients with T2DM. We explored the chemistry of the metformin-MG
reaction in detail and performed thorough structural characterization of the product(
s). We unequivocally identified the primary product as a five-membered
imidazolinone (IMZ) and identified the IMZ metabolite in urine samples from
metformin-treated T2DM patients. Because (i) the precise mechanism(s) of metformin
action remain unclear, (ii) the structure of IMZ is drug-like in nature, (iii)
and the activation of imidazoline receptors may have beneficial effects in T2D, we
have begun to explore the potential role of IMZ in the therapeutic response to
metformin. Data from these studies will be presented.