Glucokinase:
Teaching An Old Dog New Tricks
Evan David Rosen, M.D., Ph.D.
Assistant Professor of Medicine,
Harvard Medical School
Glucose
from the blood gets into different cell types by a variety of
means, ranging from tightly regulated transport by special proteins
(as in muscle and fat), or by passive diffusion (as in the cells
that line blood vessels). Either way, once glucose gets into
the cell, it has to be trapped there so that it doesn’t
leave.
Cells accomplish this trapping
function through the actions of a family of enzymes called hexokinases.
Hexokinases come in several different forms, but they all share
the ability to stick a chemical known as a phosphate group onto
glucose, thus changing both the size and electrical charge of
the sugar molecule and preventing its escape from the cell.
Perhaps the best known of the hexokinase proteins is one found
in the liver and in the insulin-producing pancreatic beta cells,
known as glucokinase.
Glucokinase in liver and beta
cells traps sugar and allows it to be metabolized—broken
down into energy. Glucokinase serves as a signal to both the
beta cells and the liver that sugar levels in the blood are
high, leading to insulin secretion and reduced glucose production
by the liver. There are rare patients who carry a mutation in
the glucokinase gene that renders them deficient in the activity
of the enzyme. The result is a form of diabetes called MODY
(Maturity Onset Diabetes of the Young). On the flip side, there
are also patients with mutations that cause too much glucokinase
activity, and these folks have dangerously low blood sugar levels
associated with uncontrolled insulin secretion.
All this information about glucokinase
has been known for years, and there has long been speculation
that a drug that could juice up glucokinase activity a little
bit might be beneficial in treating type 2 diabetes. The problem
has been that while one can fairly readily find drugs that inhibit
enzymes, it is very difficult to find drugs that make enzymes
work better. One of my old professors used to give the example
of a finely tuned Swiss watch—if you hit it with a rock,
you can make it run less well quite easily. It would be pretty
unlikely, on the other hand, to deliver a blow that would make
the watch run better than it already does.
Amazingly, researchers at Hoffmann-LaRoche
have done just that to glucokinase. By screening 120,000 drugs
of different types, they were able to identify a single one
that actually made glucokinase work better than it already does.
This drug, which so far has been given the unsexy name of RO-28-1675,
seems to have no effect on other forms of hexokinase, an important
test of its specificity.
When the drug was given to obese,
insulin-resistant rats and mice, blood sugar levels dropped
in a predictable manner. By carefully controlling blood sugar
and insulin levels in the mice using special techniques, the
researchers were able to show that RO-28-1675 has effects in
both the liver and in beta cells. The beta cells, however, seem
to be the dominant site of action, as mice that lack insulin
no longer respond to the drug. (If the effect in liver were
dominant, one would expect to see the drug reduce blood sugar
at least a bit in the absence of insulin.) This is important
because it makes it unlikely that this drug will be useful for
patients with type 1 diabetes, or with type 2 diabetes of an
advanced stage where the beta cells have pooped out.
Given the close similarities
in the structure of rodent and human glucokinase, this drug
will probably have similar effects in people. Care will have
to be taken, however, because we already know that too much
glucokinase activity is a bad thing. I don’t see this
as a major obstacle: we already have several drugs on the shelf
that increase insulin secretion (e.g., sulfonylureas and metiglinide
drugs such as Prandin™ and Starlix™). We have learned
how to dose these properly without causing significant hypoglycemia.
I think we’ll figure this one out as well. On the contrary,
I wonder if the drug represents a big enough therapeutic leap
over what we already have to make it compelling enough to bring
to market.
Regardless of the answer to that
question, there is likely to be one very positive effect of
this new finding: it may spur the search for other "activator"
drugs for other targets. An activator of the Glut4 glucose transporter,
for example, would be useful, and activators of the pathways
that regulate appetite might also come in handy.
There are a lot of old dogs like
glucokinase out there; perhaps we can look forward to seeing
some of them perform some new tricks.
Reference:
Joseph Grimsby, Ramakanth Sarabu, Wendy L. Corbett, Nancy-Ellen
Haynes, Fred T. Bizzarro, John W. Coffey, Kevin R. Guertin,
Darryl W. Hilliard, Robert F. Kester, Paige E. Mahaney, Linda
Marcus, Lida Qi, Cheryl L. Spence, John Tengi, Mark A. Magnuson,
Chang An Chu, Mark T. Dvorozniak, Franz M. Matschinsky, and
Joseph F. Grippo. Allosteric Activators of Glucokinase: Potential
Role in Diabetes Therapy. Science 2003 July 18; 301: 370-373.
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