Researchers show how insulin
helps fat cells take in glucose
Using high-resolution microscopy,
researchers have shown how insulin
prompts fat cells to take in glucose in a rat
model. The findings were reported in the 8
September 2010 in Cell Metabolism.
By studying the surface of healthy, live
fat cells in rats, researchers were able to
understand the process by which cells take
in glucose. Next, they plan to observe the
fat cells of people with varying degrees of
insulin sensitivity, including insulin resistance-
considered a precursor to type 2
diabetes. These observations may help
identify the interval when someone
becomes at risk for developing diabetes.
“What we’re doing here is actually
trying to understand how glucose transporter
proteins called GLUT4 work in
normal, insulin-sensitive cells,” said Karin
G. Stenkula, PhD, a researcher at the US
National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK)
and a lead author of the paper. “With an
understanding of how these transporters in
fat cells respond to insulin, we could detect
the differences between an insulin-sensitive
cell and an insulin-resistant cell, to
learn how the response becomes impaired.
We hope to identify when a person
becomes pre-diabetic, before they go on to
Like a key fits into a lock, insulin binds
to receptors on the cell’s surface, causing
GLUT4 molecules to come to the cell’s
surface. As their name implies, glucose
transporter proteins act as vehicles to ferry
glucose inside the cell.
To get detailed images of how GLUT4 is
transported and moves through the cell
membrane, the researchers used high-resolution
imaging to observe GLUT4 that
had been tagged with a fluorescent dye.
The researchers then observed fat cells
suspended in a neutral liquid and later
soaked the cells in an insulin solution, to
determine the activity of GLUT4 in the
absence of insulin and in its presence.
In the neutral liquid, the researchers
found that individual molecules of
GLUT4 as well as GLUT4 clusters were
distributed across the cell membrane in
equal numbers. Inside the cell, GLUT4
was contained in balloon-like vesicles,
which transported GLUT4 to the cell
membrane and merged with the
membrane, a process known as fusion.
After fusion, the individual molecules of
GLUT4 are the first to enter the cell
membrane, moving at a continuous but
relatively infrequent rate. The researchers
termed this process fusion with release.
When exposed to insulin, however, the
rate of total GLUT4 entry into the cell
membrane peaked, quadrupling within
three minutes. The researchers saw a
dramatic rise in fusion with release – 60
times more often on cells exposed to insulin
than on cells not exposed to insulin.
After exposure to insulin, a complex
sequence occurred, with GLUT4 shifting
from clusters to individual GLUT4 molecules.
Based on the total amount of glucose
the cells took in, the researchers deduced
that glucose was taken into the cell by
individual GLUT4 molecules as well as by
clustered GLUT4. The researchers also
noted that after four minutes, entry of
GLUT4 into the cell membrane started to
decrease, dropping to levels observed in
the neutral liquid in 10 to 15 minutes.
“The magnitude of this change shows
just how important the regulation of this
process is for the survival of the cell and for
the normal function of the whole body,”
said Joshua Zimmerberg, PhD, MD, the
paper’s senior author and director of the
Eunice Kennedy Shriver National
Institute of Child Health and Human
Development (NICHD) Program in
The research team next plans to
examine the activity of glucose transporters
in human fat cells, Zimmerberg
said. “Understanding how insulin prepares
the cell for glucose uptake may lead to
ideas for stimulating this activity when the
cells become resistant to insulin.”
New drug may make some
eye surgeries unnecessary
In the course of participating in a Phase 2
trial for the new drug microplasmin,
opthamologist Dr Matthew Benz and his
colleagues made an exciting discovery: a
pharmaceutical that had been developed
to make surgery easier actually had the
ability to make it unnecessary in some
Patients selected for the trial had been
diagnosed with one of two conditions. The
first was vitreomacular traction, in which
the vitreous (the central fluid part of the
eye) develops an abnormally strong adhesion
to the macula (a light-sensitive layer
of tissue at the back of the eye). The
second was the appearance of small holes
in the macula, which is usually age-related.
Both conditions can cause blurred and
distorted vision, and both are traditionally
treated with a vitrectomy, surgical removal
of some or all of the vitreous.
“As one of the top five retinal research
sites in the United States, Methodist
Hospital was chosen as one of the sites for the Phase 2 trial of microplasmin,”
explains Dr Benz. “It was going to be used
as a pre-surgery treatment with the idea of
making the vitrectomy easier.”
Administering the drug was a fairly
simple procedure that could be carried out
in a doctor’s office. First the white of the
eye was numbed with a local anesthesia,
then a tiny amount of microplasmin
(between 1/10 and 1/20 cc) was injected
directly into the vitreous with a small
needle. “Intravitreal injections are actually
quite common,” says Dr Benz. “We do
them fairly often in treating patients with
macular degeneration or eye infections.”
Much to the surprise of Dr Benz and his
colleagues, about 44% of the trial patients
ended up not needing surgery at all. “We
found out that microplasmin actually has
the potential to be a nonsurgical intervention
for what have up to now been surgical
problems,” he says. “In some of the patients,
we saw even better outcomes than we
would have expected from the surgery.”
Microplasmin is not yet approved by the
US FDA or in Europe. Trials are on-going.
Malaria mosquito becoming new
species, say scientists
Two strains of the type of mosquito responsible
for most of malaria transmission in
Africa have evolved such substantial
genetic differences that they are becoming
different species, according to researchers
behind two new studies published recently
in the journal Science.
Over 200 million people globally are
infected with malaria, according to the
World Health Organisation, and the
majority of these people are in Africa.
Malaria kills one child every 30 seconds.
The international research effort, co-led
by scientists from Imperial College London,
carried out a detailed look at the genomes of
two strains of the Anopheles gambiae
mosquito, the type of mosquito primarily
responsible for transmitting malaria in sub-
Saharan Africa. These strains, known as M
and S, are physically identical. However,
the new research shows that their genetic
differences are such that they appear to be
becoming different species, so efforts to
control mosquito populations may be effective
against one strain of mosquito but not
The scientists argue that when
researchers are developing new ways of
controlling malarial mosquitoes, for
example by creating new insecticides or
trying to interfere with their ability to
reproduce, they need to make sure that
they are effective in both strains.
The authors also suggest that mosquitoes
are evolving more quickly than previously
thought, meaning that researchers need to
continue to monitor the genetic makeup
of different strains of mosquitoes very
closely, in order to watch for changes that
might enable the mosquitoes to evade
control measures in the future.
Nanoscale transducers could
Scientists and engineers at the University
of Nottingham have built the world’s
smallest ultrasonic transducers capable of
generating and detecting ultrasound.
These revolutionary transducers which
are orders of magnitude smaller than
current systems — are so tiny that up to
500 of the smallest ones could be placed
across the width of one human hair.
While at an early stage these devices offer
a myriad of possibilities for imaging and
measuring at scales a thousand times
smaller than conventional ultrasonics.
They can be made so small they could be
placed inside cells to perform intracellular
ultrasonics. They can produce ultrasound of
such a high frequency that its wavelength is
smaller than that of visible light.
Theoretically they make it possible for
ultrasonic images to take finer pictures than
the most powerful optical microscopes.
The work, by the Applied Optics Group
in the Division of Electrical Systems and
Optics has been deemed so potentially
innovative that last year it was awarded a
£850,000 (about $1.36 million) five year
Platform Grant by the Engineering and
Physical Sciences Research Council
(EPSRC) to develop advanced ultrasonic
The team has also been
supported by additional funding of
£350,000 from an EPSRC grant to
underpin aerospace research.
Matt Clark, of the Applied Optics
Group, said: “With the rise of nanotechnology
you need more powerful diagnostic
tools, especially ones that can operate
non-destructively and ones which can be
used to access the mechanical and chemical
properties of the samples at this scale.
These new transducers are hugely exciting
and bring the power of ultrasonics to the
The ultrasonic transducers consist of
sandwich or shell like structures carefully
engineered to possess both optical and
ultrasonic resonances. When they are hit
by a pulse of laser light they are set ringing
at high frequency which launches ultrasonic
waves into the sample.
are excited by ultrasound the transducers
are very slightly deformed and this changes
their optical resonances which are
detected by a laser.
The devices can be constructed either
by micro/nano lithography techniques
similar to those used for microchips or by
molecular self assembly where the transducers
are constructed chemically.
Perhaps the most familiar application of
ultrasonics is medical imaging but it is also
widely used in engineering applications
and for chemical sensing.
These tiny transducers
open up the possibility of using
these techniques on the smallest scales, for
instance inside cells and on nano-engineered
Dr Clark said: “Imagine imaging inside
cells in the same way that ultrasonic
imaging is performed inside bodies.
Theoretically we could get higher resolution
with the nano-ultrasonics than you
can with optical microscopes and the
contrast would be very interesting.”
New malaria drug shows promise
A chemical that rid mice of malariacausing
parasites after a single oral dose
may eventually become a new malaria drug
if further tests in animals and people
uphold the promise of early findings. The
compound, NITD609, was developed by an
international team of researchers including Elizabeth A. Winzeler, PhD, a
the US National Institute of Allergy and
Infectious Diseases (NIAID), part of the
US National Institutes of Health.
“Although significant progress has
been made in controlling malaria, the
disease still kills nearly 1 million people
every year, mostly infants and young children,”
says NIAID Director Anthony S.
Fauci, MD. “It has been more than a
decade since the last new class of antimalarials
– artemisinins – began to be
widely used throughout the world. The
rise of drug-resistant malaria parasites
further underscores the need for novel
Dr Fauci adds: “The compound developed
and tested by Dr Winzeler and her
colleagues appears to target a parasite
protein not attacked by any existing
malaria drug, and has several other desirable
features. This research is also a
notable example of successful collaboration
scientists and private sector researchers."
The study, in the 3 September issue of
Science, was led by Thierry T. Diagana,
PhD, of the Novartis Institute for Tropical
Diseases (NITD), and Dr Winzeler. Dr
Winzeler is affiliated with The Scripps
Research Institute and the Genomic
Institute of the Novartis Research
Foundation, La Jolla, California.
Work began o in Dr Winzeler’s lab in
2007 where scientists screened 12,000
compounds active against Plasmodium falciparum,
the most deadly malaria parasite.
“From the beginning, NITD609 stood
out because it looked different, in terms of
its structure and chemistry, from all other
currently used antimalarials,” says Dr
Winzeler. “The ideal new malaria drug
would not just be a modification of
existing drugs, but would have entirely
novel features and mechanism of action.
NITD609, which could be formulated as a
tablet and manufactured in large quantities,
is one of a new class of chemicals, the spiroindolones, which have been described
in recently published research by Dr
Winzeler and colleagues as having potent effects against two kinds of malaria
In the current study, the scientists detail
attributes of NITD609 that suggest it
could be a good malaria drug. For example
– In test-tube experiments, NITD609
killed two species of parasites in their
blood-stage form and also was effective
against drug-resistant strains. In humans,
malaria parasites spend part of their life
cycle in the blood and part in the liver.
– The compound worked faster than
some older malaria drugs, although not as
quickly as the best current malaria drug, artemisinin.
– Other laboratory tests showed that
NITD609 is not toxic to a variety of
When given orally to rodents, the
compound stayed in circulation long
enough to reach levels predicted to be effective
against malaria parasites. According to
Dr Winzeler, if NITD609 behaves similarly
in people, it might be possible to develop
the compound into a drug that could be
taken just once. Such a dosage regimen, she
says, would be substantially better than the
current standard treatment in much of the
world in which uncomplicated malaria
infections are treated for three to seven days
with drugs that are taken between one and
four times daily.
Typically, she says, rodents infected with
the mouse malaria parasite, Plasmodium berghei, die within a week. But a single
large dose of NITD609 cured all five
infected mice that received it, while half of
six mice receiving a single smaller dose
were cured of infection. Three doses of the
smaller amount of NITD609 upped the
cure rate to 90%.
Additional tests in animals are under
way and NITD609 could enter early-stage
safety testing in humans later this year,
says Dr Winzeler.
But, she adds, many drug
candidates fail in clinical trials and thus it
will be important for the community to
continue to work on developing other
potential antimalarial compounds.
Study unravels clues to infertility
among obese women
Obese women have a well-known risk for infertility, but a new Johns Hopkins
Children’s Center study has unraveled
what investigators there believe is the
mechanism that accounts for the risk.
The research conducted in mice and
published online 8 September 2010 in Cell
Metabolism, shows that the pituitary gland
actively responds to chronically high
insulin levels, triggering a cascade of
hormonal changes that disrupt ovarian
function and impair fertility.
The findings challenge the widely held
belief that infertility is a result of insulin
resistance and suggest a new culprit:
heightened sensitivity to insulin’s effects
on the pituitary gland.
“What we propose is a fundamentally
new model showing that different tissues
respond to obesity differently, and that
while cells in the liver and muscle do
become insulin resistant, cells in the
pituitary remain sensitive to insulin,”
says principal investigator Andrew
Wolfe, PhD, of Hopkins Children’s.
Scientists traditionally have focused on
treating infertility by lowering insulin
levels as a way to treat insulin resistance.
However, the new model suggests that
decreasing the pituitary’s sensitivity to
insulin could be an important new target
for treatment instead.
Insulin resistance, marked by persistently
elevated insulin, abnormal regulation
of blood sugar and insensitivity to
insulin in the liver and muscle cells,
occurs in type 2 diabetes, metabolic
syndrome and polycystic ovary syndrome
(PCOS). PCOS is the most common
cause of infertility, affecting up to one in
Because ovarian function and fertility
are mostly regulated by the pituitary, the
body's master gland, the Hopkins team
set out to find out exactly how elevated
insulin levels affect the pituitaries of
obese women to render them infertile.
The investigators focused on a class of
pituitary cells called gonadotrophs,
which secrete luteinizing hormone
(LH), critical for ovulation and fertility.
The researchers suspected that when
awash with too much circulating insulin, the gonadotrophs of obese mice start
out large amounts of LH, thus disrupting ovulation.
To test their hypothesis, the scientists engineered mice
with missing insulin receptors in their pituitary glands and
compared them to mice with intact insulin receptors. After
three months on a high-fat diet, the obese mice with intact
insulin receptors developed all the classic symptoms of PCOS: elevated LH levels, high testosterone, irregular
reproductive cycles and fewer ovulations. The mice with
missing insulin receptors, however, maintained nearnormal
LH levels, regular cycles and normal ovulation
despite their obesity.
To further clarify the effect of insulin on the pituitary,
the researchers compared the gonadotrophs of
obese mice to those of lean mice by injecting the
animals with gonadotropin-releasing hormone
(GnRH), which stimulates LH and is critical for ovulation
and fertility. Lean mice, with and without pituitary
insulin receptors, had normal elevations of LH.
Obese mice with intact insulin receptors experienced
increases of LH twice as high. Yet, the obese mice with
missing insulin receptors in their pituitaries had nearnormal
These results, the researchers say, show that the high
levels of insulin seen in obesity make the pituitary more
sensitive to GnRH and help initiate a hormonal chainreaction
that disrupts fertility.
To demonstrate insulin’s direct effects on the pituitary,
the scientists injected mice with insulin. Mice with intact
insulin receptors, lean or obese, had mild LH elevations,
while mice with deleted insulin receptors, lean or obese,
To determine whether these hormonal differences would
carry over into actual differences in fertility, the
researchers allowed the mice to mate. The pregnancy
outcomes mirrored the hormonal findings. Lean mice, with
or without pituitary insulin receptors, had six times the
number of successful pregnancies as obese mice. However,
obese mice with missing pituitary insulin receptors had
near-normal pregnancy outcomes, with five times more
successful pregnancies than obese mice whose pituitary
insulin receptors were intact.
By deleting the insulin receptors in the pituitary cells of
mice, the researchers managed to restore normal LH
levels, maintain ovulation and near-intact fertility even
in obese mice with elevated insulin levels. Despite
normal hormonal levels and ovulation, the obese mice
with missing insulin receptors were not as fertile as lean
mice with normal insulin levels. The finding suggests that
since the ovaries share partial control of ovulation and
fertility with the pituitary, they too may be affected by
high insulin levels.