Research from the Johns Hopkins
Children's Center reveals that the drug most commonly
used in type 2 diabetics who don't need insulin works on a
much more basic level than once thought, treating
persistently elevated blood sugar — the hallmark of
type 2 diabetes — by regulating the genes that
control its production.
Reporting in the May 15 issue of Cell,
investigators say they have zeroed in on a specific
segment of a protein called CBP made by the genetic
switches involved in overproduction of glucose by
the liver that could present new targets for drug therapy
of the disease.
In healthy people, the liver produces glucose during
fasting to maintain normal levels of cell
energy production. After people eat, the pancreas releases
insulin, the hormone responsible for
glucose absorption. Once insulin is released, the liver
should turn down or turn off its glucose
production, but in people with type 2 diabetes, the liver
fails to sense insulin and continues to make
glucose. The condition, known as insulin resistance, is
caused by a glitch in the communication between
liver and pancreas.
Metformin, introduced as frontline therapy for
uncomplicated type 2 diabetes in the 1950s, up
until now was believed to work by making the liver more
sensitive to insulin. The Johns Hopkins study
shows, however, that metformin bypasses the stumbling block
in communication and works directly in
the liver cells.
"Rather than an interpreter of insulin-liver
communication, metformin takes over as the
messenger itself," said senior investigator Fred
Wondisford, who heads the
Metabolism Division at Johns Hopkins Children's.
"Metformin actually mimics the action of CBP, the critical
signaling protein
involved in the communication between the liver and the
pancreas that's necessary for maintaining
glucose production by the liver and its suppression by
insulin."
To test their hypothesis, researchers induced insulin
resistance in mice by feeding them a high-
fat diet over several months. Mice on high-fat diets
developed insulin resistance, and their high blood
glucose levels did not drop to normal after eating. Once
the mice were treated with metformin,
however, CBP was activated to the levels of nondiabetic
mice, and their blood glucose levels returned
to normal. However, when metformin was given to diabetic
mice with defective copies of CBP, it had no
effect on blood glucose levels, a proof that metformin
works through CBP.
Researchers further were able to determine that
metformin worked on one particular section
of CBP by studying the drug's effects in mice with normal
CBP and in mice missing this section of their
CBP. The mice with normal CBP responded to metformin with a
drop in their fasting blood glucose —
much like diabetes patients do — while the mice
missing that section in their CBP had no decrease in
their blood sugar.
Because CBP is involved in growth and development and
a variety of metabolic processes in other
organs, this newly discovered pathway may hold therapeutic
promise for conditions like growth
retardation, cancer and infertility, investigators say.
Another important finding in the study: Investigators
have discovered a biomarker that can
predict how well a person will respond to treatment with
metformin and help doctors determine the
optimal therapeutic dose, which can vary widely from person
to person. The Johns Hopkins team has
found that in mice, metformin changes CBP in white blood
cells — just as it does in liver cells —
creating
a molecular marker that is easily measured via a standard
blood test.
"This is the quintessence of individualized medicine:
We have found an easily obtainable
biomarker with great predictive power that can tell us
whether and how well an individual will respond
to treatment and help us determine the best dose right away
instead of trying to do it by trial and
error," Wondisford said.
Researchers caution that while promising, their
findings must be first replicated in humans.
Diabetes (type 1 and type 2) is a leading cause of
kidney failure, eye disease and amputations,
and one of the main causes of heart disease and stroke.
Nearly 24 million Americans have type 2
diabetes, according to the U.S. Centers for Disease Control
and Prevention.
Lead author of the paper is Ling He. Other
investigators in the study are Amin Sabet, Stephen
Djedjos, Ryan Miller, Mehboob Hussain and Sally Radovick,
all of Johns Hopkins; and Xiaojian Sun, of
the University of Chicago.
The research was funded by the National Institutes of
Health and by the Baltimore Diabetes
Research and Training Center, a joint endeavor between
Johns Hopkins and the University of Maryland
for basic science, clinical research and community outreach
on diabetes and obesity in both adults and
children.