午夜福利1000集合

NOTHING moves and nothing is to be heard in the brain-baking heat. There are
no obvious food sources鈥攁nything that鈥檚 green and succulent has prickles
on it, and the soil beneath your feet is dusty and dry like ashes. Water is the
biggest problem for anything living here. The desert tortoise obtains it
primarily by eating plants, and conserves it by urinating maybe once a month.
But for those (including humans) who choose to squander their precious fluids by
relieving themselves more often, the only other water is provided by a few small
rivers.

Welcome to the central Arizona desert, home of the Pima Indians and the
birthplace of one of the strangest stories in medical research.

No one knows when exactly the Pima arrived鈥攖heir stories say they came
after a great flood survived only by Earth Medicine Man, Elder Brother
Se-eh-ha, and Coyote. But in centuries past the Pima
built themselves an unlikely paradise here along the banks of the Gila River
(pronounced Hee-la), harvesting saguaro cactus fruit, hunting rabbits and
lizards and irrigating crops of cotton, beans and squash through a system of
canals. They called themselves the Akimel O鈥檕dom鈥擱iver
People.

In the late 1800s, that all started to change when Europeans settled
upstream, diverting the water for their own use. Nowadays, the Pima live just
outside of Phoenix, a city of 2.5 million people, frequently working in
sedentary jobs. Many are obese, and the traditional diet is gone, replaced by a
modern one rich in Twinkies, cheeseburgers and Coca-Cola.

The Pima also suffer the highest prevalence of diabetes in the world. Fifty
per cent of the over-thirties are affected, and whereas adult-onset diabetes
usually strikes in late middle age, many Pima teenagers already have the
disease.

If that wasn鈥檛 shocking enough, when the Pima epidemic was first discovered
in 1963 by Peter Bennett, who now heads the Phoenix branch of the National
Institute of Diabetes and Digestive and Kidney Diseases, local doctors insisted
that in their experience it wasn鈥檛 too much to worry about. These hardy folk
seemed not to suffer the blindness, limb-threatening ulcers and kidney disease
that afflicted Europeans with the disease. In reality, the disease had struck so
swiftly鈥攋ust 25 years earlier diabetes had been notably rare among the
Pima鈥攖hat those caught in the first wave had not had time to develop the
complications.

So what had happened in just 25 years? Answering that question has served as
a battleground for debates over how humans have adapted to different
environments over the millennia, and what that means for modern diseases.

On the one side is a hypothesis that has enchanted diabetes specialists and
anthropologists for decades: the so-called 鈥渢hrifty genotype鈥� hypothesis, the
idea that genes that once helped certain indigenous populations survive times of
scarcity now nudge them towards diabetes when they live a sedentary lifestyle
and are exposed to a constant oversupply of calories.

But not everyone agrees. The thrifty genotype theory has been called
ethnocentric, and just one more obstacle to decent healthcare for indigenous
people. A rival theory has duly emerged. This new hypothesis states that the
diabetes epidemics that have swept through native populations around the world
stem from poor maternal nutrition which forces the fetus to choose between
perishing early and allocating fewer resources to organs such as the
insulin-producing pancreas. Naturally, the fetus chooses the latter, with the
result that the organ is shoddily built and malfunctions later in life. As a
gesture of opposition to the thrifty genotype theory, the new theory has been
nicknamed the thrifty phenotype.

The term diabetes used to refer to a vague constellation of symptoms,
including rapid weight loss, fatigue and thirst. Nowadays, we know that there
are two main types of diabetes鈥攋uvenile-onset, in which an immune reaction
or perhaps an infection destroys the beta cells in the pancreas that make
insulin, and the far more common adult-onset, which is the type that strikes the
Pima.

Adult-onset diabetes involves the interplay between two processes, the body鈥檚
insensitivity to insulin or 鈥渋nsulin resistance鈥�, and the pancreas鈥檚 inability
to make enough insulin or 鈥渋nsulin deficiency鈥�. Following a meal, the pancreatic
beta cells release insulin, signalling the body to absorb glucose from the
blood. In some people鈥攅specially the obese and the sedentary鈥攖he
tissues ignore the insulin, absorbing glucose too slowly. The beta cells
compensate by secreting more insulin, and usually that鈥檚 enough, since many
people with insulin resistance never develop diabetes. Sometimes, however, the
beta cells can鈥檛 produce enough insulin to keep up with insulin resistance, and
diabetes sets in. The beta cells may even burn out, causing insulin production
to plummet, and the condition to worsen dramatically.

But at some level diabetes depends on genes. Identical twins get adult-onset
diabetes more often than nonidentical twins, and the Pima exhibit greater
insulin resistance than the general population in the US, with the trait running
in families. The idea that those genes may have something to do with surviving
starvation was proposed way back in 1962 by James Neel, a population geneticist
at University of Michigan in Ann Arbor. Even then, diabetes struck up to 3 per
cent of Americans鈥攏owadays it strikes up to 9 per cent. 鈥淚 wondered,鈥�
recalls Neel, 鈥渉ow genes with potentially such deleterious effects could ever
reach a frequency that high.鈥� He concluded that it couldn鈥檛 happen unless those
genes also provided some benefit, much like the genes that cause sickle-cell
anaemia are known to guard against malaria.

Neel intended his hypothesis to apply to all diabetics, but as one indigenous
population after another fell victim to levels of diabetes never seen in
European populations, other researchers began to modify it. According to their
new version, peoples that were deemed more likely to have experienced hundreds
of years of intermittent feast and famine were more likely to carry the thrifty
genes and to be susceptible to diabetes.

For example, the island-hopping colonisation of the Pacific some 1500 to 3000
years ago could have selected for a thrifty genotype. Reaching the islands of
Polynesia and Micronesia (where diabetes is prevalent today) often required
canoe voyages of 1000 to 3000 kilometres, whereas reaching the islands of
Melanesia (where diabetes is less prevalent) rarely took voyages over 300
kilometres. Since virgin islands offered little natural food, settlers were
forced to bring their own domestic plants.

鈥淲e鈥檙e not talking about a month of deprivation while they鈥檙e at sea,鈥� says
James Bindon, an anthropologist at University of Alabama in Tuscaloosa. 鈥淲e鈥檙e
talking about a couple of years of deprivation while they get their gardens
producing.鈥� Studies of ancient kill sites suggest that the Palaeo-Indian
ancestors of some Native American tribes depended heavily on mammoth and other
big game long after these animals got so scarce that food shortages were
inevitable.

No change

But while the thrifty genotype hypothesis has never lacked supporters,
despite decades of sleuthing it鈥檚 proved unexpectedly hard to find genes and
physiological traits associated with diabetes that could also conceivably help a
person survive famine. Bennett鈥檚 group has looked in the Pima for changes in the
insulin and insulin receptor genes, but found none. For changes in the gene for
leptin, a hormone that regulates food intake, but found none. For changes in the
leptin receptor genes, but found none. For differences in basal metabolic rate,
but found none. For differences in the proteins that transport glucose into
cells, but found none.

And then there鈥檚 the rival theory. Nick Hales, a biochemist at the University
of Cambridge, and David Barker of the University of Southampton say that the
epidemics stem not from genes, but from maternal malnutrition鈥攕omething
that is common and preventable in rapidly Westernising populations.
Malnutrition, they say, forces the fetus to short-change development of
noncritical organs like the pancreas in favour of mandatory ones like the brain
(seeNew Scientist, 17 July, p 26).
Flimsy beta cells then burn out later in life, causing diabetes.

In 1991, Hales and Barker published a study showing that men born in
Hertfordshire, England, during the 1920s were more likely to develop diabetes by
age 64 if they were born light鈥攁 sign of poor fetal nutrition. They鈥檝e
since demonstrated similar relationships between low birth weight and
adult-onset diabetes in English women, and in men and women born during the
Dutch Hunger Winter of 1944-45. What鈥檚 more, under the microscope, the
insulin-producing beta cells are visibly altered in rats born to mothers fed on
low-protein diets.

Touting the importance of intrauterine environment, Hales says genes play
only a minor role in the development of adult-onset diabetes. 鈥淭here鈥檚 no real
evidence for [the thrifty genotype],鈥� he says, arguing that much of the
鈥渆vidence鈥� supporting a genetic cause for diabetes supports his theory just as
well. For example, identical twins with diabetes share not only genes, but also
fetal nutrition. And statistically speaking, 鈥渋f you have identical twins, one
of whom has diabetes, the one with diabetes has the lighter birth weight鈥�, he
says.

But when it comes to interpreting findings to fit your favourite hypothesis,
the knife cuts both ways. After Hales and Barker published their results
demonstrating increased diabetes in low birthweight people, Bennett published a
similar analysis among Pimas, showing similar results. Yet Bennett concluded the
results could just as easily reflect a thrifty genotype that helps small babies
survive fetal malnutrition, but also predisposes them to diabetes later on. Most
mortality occurs during the first few weeks of life, he says, 鈥渟o even a small
selective advantage at that stage could translate into very big effects鈥�.
Bennett also says it鈥檚 hardly surprising that it鈥檚 taking time to track down the
genes for diabetes. A genetic phenomenon this complex鈥攊t could easily
involve 10 genes or more鈥攈as never been deciphered before.

Big gripe

Yet Hale鈥檚 biggest gripe is as much philosophical as scientific. The thrifty
genotype hardly qualifies as a theory, he says, because it鈥檚 too ill-defined to
test. Neel originally proposed that 鈥渢hrifty鈥� individuals possessed a
hyperactive insulin response that allowed them to absorb glucose from the blood
more easily鈥攁 mechanism that was proved wrong as the physiology of
diabetes became better understood.

Hales reckons that in their subsequent search for a mechanism, proponents of
the thrifty genotype have been far too happy to fit candidate genes into the
鈥渢hrifty鈥� mould, by coming up with post hoc rationales for how they might
promote survival. If you are going to search for a gene, says Hales, then the
thing to do is to use far-flung genome scans that ignore the question of
mechanism and that simply look for the segments of DNA that are characteristic
of diabetics. 鈥淚f they do that,鈥� he says, 鈥渁nd they can鈥檛 find a gene, then
hopefully they鈥檒l come out and say so. They won鈥檛 of course. They鈥檒l say, `well
no, it鈥檚 gotta be this combination or that combination鈥�. They鈥檒l keep the
argument going forever.鈥�

As it happens, many groups are now conducting genome scans, including
Bennett鈥檚 group and a group led by Graeme Bell and Nancy Cox of the University
of Chicago. Their findings are still secret, but many specialists say that they
expect to hear the announcement of a new diabetes gene in an area on chromosome
2, dubbed NIDDM1, any day now.

While Hales has been content to needle Bennett politely through his academic
publications, in other quarters the criticisms have waxed vitriolic. Teresa
Wall, Executive Director of the Department of Public 午夜福利1000集合 for the Gila River
Indian Community, gets edgy when you start mentioning genes, and counters that
genes would be a moot point if lifestyles could be improved. Robyn McDermott, an
epidemiologist at the Tropical 午夜福利1000集合 Unit in Cairns, Australia, who works with
severely diabetic Aborigine and Pacific Island populations, goes a step further.
She says that the thrifty genotype theory actually does harm. 鈥淚t completely
ignores important environmental and social influences,鈥� she says. 鈥淎nd my
ethical problem with that is it leads to inaction by clinicians鈥攖his
therapeutic nihilism鈥攁nd inaction at a public health level in terms of
addressing parts of the incredibly diabetagenic environment these people are
living in.鈥�

Dilute the genes?

McDermott drives her point home by recalling an alarming conversation she had
several years back with some officials at a major international health
organisation. 鈥淥ne senior official,鈥� she says, 鈥渉ad the opinion that the only
hope for these people was to intermarry and dilute these genes with different
genes better adapted to a Western lifestyle.鈥� Not a winning proposition,
especially when you consider that, although Native American and Pacific Island
communities have the highest incidences of diabetes, the list of populations
with unusually elevated levels of the disease has continued to grow. It now
includes Ethiopians living in Israel, Indians living in Britain, and almost
every other non-European group adopting a Western lifestyle.

The growing list has even prompted some tacit supporters of the thrifty
genotype concept to label the theory 鈥淓urocentric鈥� and warn that it may send
researchers chasing after the wrong leads. 鈥淭he real question,鈥� suggests Boyd
Swinburn, a public health professor at the University of Auckland, 鈥渋s how come
Europeans have such a low rate of diabetes.鈥�

But regardless of the criticism, pursuit of the elusive thrifty genotype
continues. Gerald Reaven, an endocrinologist at Stanford University in Palo
Alto, suspects that preventing muscle breakdown during starvation may be the
ticket. 鈥淚f you and I are two cave men,鈥� says Reaven, 鈥渁nd you鈥檙e dumb enough to
break down your muscle, when the enemy attacks or the deer runs by, I win and
you lose, because I maintain muscle mass and you don鈥檛.鈥�

While most of the body鈥檚 organs can consume fatty acids, the brain can only
use glucose, and it may sometimes need to get it from muscle. After a few days鈥�
starvation, the body鈥檚 glucose and glycogen stores run dry, and the only way it
can manufacture its own glucose is by breaking down muscle proteins.

But if other organs burnt as much fatty acid and as little glucose as
possible, more glucose would remain for the brain, and protein breakdown would
be minimised. Insulin resistance accomplishes this goal by making muscles and
other organs ignore insulin, leaving glucose in the blood where the brain can
get it. The brain, alone, does not need insulin to absorb glucose.

In other words, the elusive thrifty genes could make people more insulin
resistant, and that could lead to diabetes. 鈥淚nsulin resistance is the
pre-diabetic phenotype,鈥� Reaven says, 鈥淸and] insulin resistance is clearly
genetic.鈥� Geneticists have just discovered a gene variant that is associated
with insulin resistance (Diabetes, p 1881, September 1999).

The idea that healthy muscles never hurt in a hostile environment has also
breathed new life into the idea that fat accumulation is the survival trait that
predisposes a person to diabetes. During starvation, the body maintains a memory
of its pre-starvation fat to protein ratio, and consumes fat and protein roughly
in proportion to this ratio. The idea is for both fat and protein to run out
simultaneously. When either runs out you die, so this scheme postpones the
grisly end as long as possible. The more fat you start with, then, the more
slowly your muscles waste away.

If you take a non-obese population, says Abdul Dulloo, a starvation
physiologist at University of Fribourg in Switzerland, 鈥渏ust shifting between 10
per cent and 20 per cent body fat makes a tremendous difference in capacity for
蝉耻谤惫颈惫补濒鈥�.

But the most thought-provoking development in the search for thrifty genes
may be a piece of DNA called Mt16189. Discovered by Jo Poulton, a geneticist at
University of Oxford, Mt16189 is associated with low birthweight, insulin
resistance and diabetes. Only 10 per cent of British people carry the gene, but
its frequency approaches 100 per cent in at least one group where you would
expect a thrifty gene to be most common鈥� Pacific islanders.

Poulton鈥檚 intriguing idea for how Mt16189 helps a population survive hard
times, if it stands up to experimental scrutiny, could even bridge the gap
between the two competing hypotheses. Her gene is mitochondrial, and therefore
transmitted only through the mother. Perhaps, she speculates, the gene performs
the dirty job a loving mother could never wilfully do鈥攊mposing growth
restraint on the developing fetus when food is scarce. 鈥淭he mother has other
offspring,鈥� Poulton explains, 鈥渁nd if the child in utero kills off the
mother by being fatter and depriving her of nutrients, the survival advantage is
blown.鈥� In other words, during times of malnutrition, could the gene trigger
both smaller infants and鈥攍ater鈥攄iabetes?

While Hales says that Poulton鈥檚 data is preliminary and needs to be verified
in other populations, he鈥檚 not entirely unhappy with that notion. 鈥淚 really
don鈥檛 think until we entered the debate, [proponents of the thrifty genotype
hypothesis] had ever thought that genes that control the growth of the fetus
could matter,鈥� he says. Meanwhile, thrifty genotypers like Bennett now
acknowledge that the thrifty genotype and thrifty phenotype may not be mutually
exclusive.

Of course, for the Pima Indians, a cosy resolution to the debate won鈥檛 change
a thing. 鈥淭hat should not make any difference, if there are [already] ways to
prevent diabetes,鈥� says Wall. Which, of course, there are. All sides agree that
whether you are predisposed to diabetes because of poor fetal nutrition, genes
or both, eating well and exercising will more than likely protect you from the
disease.

How to bring home that message to the Pima Indians, poor people who for now
lack the incentive and the opportunity to join the local gym and buy yuppie
food, is something that the Gila River Indian Community is currently working
on.