What the Gila
Monster Can Teach Us About Diabetes
Evan David Rosen, M.D., Ph.D.
Assistant Professor of Medicine,
Harvard Medical School
A
hot question in biology these days is "How many genes do
we have?" Perhaps a more important question is "How
many proteins are encoded by our genes?", because proteins
actually do the work inside cells. The reason for the distinction
is that some genes can give rise to many different proteins.
Some hormone genes, for example, yield a single large protein
that is then diced and sliced into several smaller proteins,
each with its own specialized function.
One such "super-gene"
encodes the hormone glucagon, which causes blood sugar levels
to rise when they are too low. As it turns out, the gene for
glucagon also contains the instructions for at least two other
hormones, called glucagon-like peptides 1 and 2 (GLP-1, GLP-2).
Not only do the GLPs come from the same gene as glucagon, but
they actually have a very similar amino acid sequence as well.
Despite these parallels, the GLPs have very different functions
than glucagon, and there is a lot of excitement about using
these hormones to treat problems ranging from diabetes and obesity
to chemotherapy-induced intestinal damage.
From a diabetes perspective,
the interesting GLP is GLP-1. GLP-1 is secreted from special
cells in the gut in response to a meal, and helps to integrate
many of the normal physiological responses that occur after
eating. For one, GLP-1 induces insulin secretion from the pancreas,
and simultaneously reduces glucagon release. This release of
insulin actually seems to occur only when the ambient glucose
concentration is high, thus reducing the chance that hypoglycemia
will develop (an especially attractive feature in a diabetes
therapy). Over a longer period, GLP-1 actually increases the
number of insulin-producing beta cells. GLP-1 also acts directly
on the GI tract, reducing the rate at which food spills out
of the stomach and into the intestine, making the absorption
and storage of energy more efficient. Finally, and perhaps most
intriguingly, GLP-1 acts on the central nervous system to signal
a sense of fullness so that we don't overeat. It doesn't take
a Ph.D in metabolism to figure out that these effects would
all be beneficial in type 2 diabetes.
So why aren't we prescribing
GLP-1 to everyone with type 2 diabetes already? Well, there
are a few problems, but one of the most daunting has been that
our bodies destroy GLP-1 within a few minutes. This means that
it needs to be continuously infused (Because it is a protein,
GLP-1 cannot be given orally), which is clearly not going to
work for most people. The enzyme that destroys GLP-1 is called
dipeptidyl-peptidase IV (DPP IV), and intense focus has been
placed on figuring out ways to disable the enzyme so that GLP-1
can do it's thing for longer periods of time.
One way to get around the problem
of DPP IV is to administer a form of GLP-1 that is resistant
to destruction. Such forms of GLP-1 have already been found,
and the source is delightfully unexpected--the poisonous saliva
of the Gila monster lizard. GLP-1 (called exendin-4) from these
reptiles has a few key differences from the form found in humans,
one consequence of which is immunity to DPP IV. There are pharmaceutical
companies working on synthetic forms of exendin-4 (one imagines
that it's easier to make the chemical from scratch than it is
to harvest toxic lizard spit). Phase 2 clinical trials of exendin-4
in patients with type 2 diabetes show improvements in hemoglobin
A1c levels comparable to those seen with currently available
antidiabetic drugs. Other studies show reductions of caloric
intake after exendin-4 administration.
Another strategy that is being
pursued is the use of drugs that will inhibit DPP IV directly.
A preliminary study showed that 24 hours after taking such a
drug, patients with mild type 2 diabetes have reduced fasting,
post-meal, and average blood sugar levels. The primary advantage
of this approach (vs. exendin-4) is that DPP IV inhibitors can
be given orally. On the other hand, DPP IV affects other hormones
besides GLP-1, and there is concern that blocking the enzyme
could cause other problems. One reassuring piece of data is
that mice that are genetically engineered to lack DPP IV are
viable and appear to do well, and this provides some reassurance
that the strategy is sound. Still, longer term studies with
both DPP IV inhibitors and exendin-4 need to be performed to
assess possible toxicity. It is also unclear if the beneficial
effects of GLP-1 will be sustained over time, and this too will
have to be tested. Nonetheless, a drug that that causes weight
loss as well as improved insulin secretion in type 2 diabetes
would be a potential blockbuster, so you can bet that those
studies are going to get done.
References:
Ahren B, Simonsson E, Larsson
H, Landin-Olsson M, Torgeirsson H, Jansson PA, Sandqvist M,
Bavenholm P, Efendic S, Eriksson JW, Dickinson S, Holmes D.
Inhibition of dipeptidyl peptidase IV improves metabolic control
over a 4-week study period in type 2 diabetes. Diabetes Care.
2002 May; 25(5):869-75.
Meier JJ, Gallwitz B, Schmidt WE, Nauck MA. Glucagon-like peptide
1 as a regulator of food intake and body weight: therapeutic
perspectives. European Journal of Pharmacology 2002 Apr 12;
440(2-3):269-79.
Drucker DJ. Biological actions and therapeutic potential of
the glucagon-like peptides. Gastroenterology. 2002 Feb; 122(2):531-44.
Review.
Edwards CM, Stanley SA, Davis R, Brynes AE, Frost GS, Seal LJ,
Ghatei MA, Bloom SR. Exendin-4 reduces fasting and postprandial
glucose and decreases energy intake in healthy volunteers. Am
J Physiol Endocrinol Metab. 2001 Jul; 281(1):E155-61.
Dr.
Rosens Archives
