3. Not so thrifty diabetes genes
jackie and ella Up to a third of the world’s population may be diabetic by the next century, and it can afflict just about anyone.
the pathology of diabetes There are two major types of diabetes, both due to lost regulation of blood glucose by insulin.
type 1 diabetes The rare form of diabetes arises because a child’s own body destroys the pancreatic cells that make insulin.
an epidemic genetic disease Fast foods and sedentary lifestyles add up to a whole lot of extra pounds and burgeoning diabetes risk.
genetics of obesity Hundreds of genes contribute to whether a person is likely to put on weight more than average.
type 2 diabetes Several alleles have recently been identified that promote diabetes in Caucasians, but they are slowly being displaced by protective variants in the human gene pool.
debunking the thrifty genes hypothesis Arguments that diabetes is caused by alleles that favored rapid assimilation of carbohydrates in times of famine fall short.
disequilibrium and metabolic syndrome We’ve pushed our genetic legacy to the limits of its ability to cope with modern diets and stress.
Jackie and Ella
Diabetes is the global warming of public health. A crisis that will affect the lives of literally billions of people is looming with an inevitability that borders on irrepressible. We pretty much know the causes and even have a fair idea about how to prevent it. Yet inertia is such that somewhere between one-quarter and one-third of the world’s population will become diabetic in the next few generations. These are the proportions about to beset North America and Europe, but the developing world is rapidly following in step. So pervasive is the switch to fast foods and sedentary lifestyles that obesity and its consequences will soon replace malnutrition as the predominant food-related malady of even the poorest nations.
Diabetes is also an equal opportunity killer. Young or old, man or woman, rich or poor, black or white, thin or fat: Everyone is at some risk. The list of prominent diabetics cuts across professions and includes some surprises that buck the popular impression that it is solely a disease of the morbidly over weight. Spencer Tracy, Mary Tyler Moore, and Halle Berry head a long list of actors; Menachem Begin, Anwar Sadat, and Mikhail Gorbachev suffered; Howard Hughes was afflicted as was, ironically enough, Ray Kroc, the founder of McDonald’s.
Like tens of millions of ordinary folks, these individuals were able to overcome daily discomfort and pain to lead highly productive lives. In most cases, though, the disease exerts its authority in the end. The brief life stories of two of the most influential African Americans of the twentieth century tell how.
Jackie Robinson was the man who broke the color barrier in professional sports. Born in rural Georgia and raised by a single mother in Pasadena, California, he encountered plenty of prejudice as a kid, yet managed to turn sorrowful lessons into his positive expression that “there’s not an American in this country free until every one of us is free.” Despite lettering in four sports, financial difficulties forced him to leave UCLA early and join the Army. That career was cut short by a court-martial and subsequent honorable discharge following his objections to racial slights such as being ordered to the back of the bus—11 years before Rosa Parks famously refused to do so. After one season in the Negro Baseball League, Jackie was noticed by the president of the Brooklyn Dodgers and invited to the big leagues. He went 0 for 4 in his first game on Opening Day, April 15, 1947, and took 21 at bats over a week to get his first hit, but then went on to win Rookie of the Year honors, a Most Valuable Player Award a couple of years later, and eventually induction to the Hall of Fame. A lifetime .311 hitter, extraordinary base runner, and natural second baseman over a ten-year career, Jackie Robinson would have been one of the greats of his era even had he not also changed the face of the game.
Tragically, Jackie’s life was cut short by heart disease at the age of 53, just 15 years after the end of his playing days. His relatively short life had been dedicated to opening doors for others, as a campaigner for the NAACP, and as a businessman, notably founding a construction company that built housing for low-income families. In the dozen years after retiring from baseball, he had gone almost blind, while chronic heart problems had taken away his athleticism. We could be forgiven for assuming that it was the burden of bearing daily insults while carrying the torch for a new generation of athletes that had eaten away his strength.
In actuality, it was the burden of too much glucose in the blood, slowly but surely eating away at the cells of his retina and his heart muscle. No doubt, stress did not help. The combination of high blood pressure with depositions of fatty materials inside the artery walls increases the demands on the heart. Diabetics who have already had one heart attack, as Jackie Robinson had a few years before his death, are at extreme risk. He didn’t have the benefit of our knowledge about the effects of saturated fats and of smoking, nor did he have access to all the modern drugs that make diabetes manageable.
Ella Fitzgerald’s story is equally inspiring, her battle with diabetes equally devastating. Someone once said of Ella that, “Music comes out of her. When she walks down the street, she leaves notes.” In a career that spanned five decades, she became synonymous with scat, legendary for the clarity and range of a distinctive voice that often borrowed from the horns in the big bands she accompanied. Orphaned at the age of 15, she managed to survive the endemic abuse of a reform school for girls, only to be turned out onto the streets of Harlem. In 1932 she was discovered at an amateur night and quickly found herself the leading lady of jazz, performing to packed houses at the fabled Savoy Ballroom, collaborating with all the greats: Count Basie, Duke Ellington, Nat King Cole, and Charlie Parker. A shy girl, born to poverty and disadvantage, she turned an untrained voice into one of the most improvisational instruments of a golden era, and one of the surest cures for the blues ever devised by humankind.
Inexorably, though, diabetes took over. Her eyesight fading, circulatory problems started to eat away at her body, and at the age of 66 she underwent quintuple coronary bypass surgery as well as heart valve replacement. Eight years later, ongoing heart disease drained the vessels of her legs of the lifeblood they needed, causing her to lose both to amputation. Then in 1996, the 81-year-old Ella Fitzgerald’s heart finally gave way due to complications of diabetes. Today, her Charitable Foundation, like Jackie Robinson’s, carries on her legacy. It provides educational opportunities for children; fosters a love of music; provides health care, food, and shelter for the needy; and supports medical research relating to the eye and heart disease caused by diabetes.
The Pathology of Diabetes
Diabetes mellitus is actually now recognized as a spectrum of diseases that converge on a common symptom, chronically high blood glucose. The name translates roughly from the Greek and Latin into “passing through honey,” meaning that a diabetic’s urine has a sweet taste. I’m not sure how the English physician Thomas Willis worked this out. Maybe urine tasting was more common back in the seventeenth century.
For some time, physicians have recognized three forms of the disease, which we know as juvenile, adult-onset, and gestational diabetes. Since so many obese children are now contracting the adult form in their teens, these terms are out the door and have been replaced by insulin-dependent and non-insulin-dependent diabetes mellitus (IDDM and NIDDM, respectively). Since these are confusing, we will stick to type 1 and type 2, or more simply T1D and T2D. The gestational form afflicts pregnant women and can be thought of as a special class of T2D that thankfully usually disappears after childbirth.
By far the more common of the two types of diabetes is T2D. This is the epidemic form that is now seen in more than 20 million Americans and 170 million people worldwide. Another 40 million Americans are considered prediabetic and at risk for full-blown disease. T1D by contrast has a relatively constant prevalence of a fraction of a percent of the population. Very few environmental factors are even suspected to increase the likelihood that a child will have T1D. By contrast, T2D is very much a product of modern diets and modern lifestyles.
The major difference between the two forms is the way that hyperglycemia (high blood glucose) comes about. When we eat, the food is rapidly broken down into sugars, and in particular into a sugar building block called glucose. This is the major source of energy for the body. As anyone who has ever taken college level biochemistry knows all too painfully, most carbohydrates are broken down into glucose through convoluted pathways of metabolism. Sheep and cows just let their food ruminate in the stomach for days, slowly releasing sugars, but other mammals have a highly evolved way to regulate glucose so that the levels stay fairly constant throughout the day. This way we can handle more complex and diverse diets, dining at Spago’s should we wish, instead of on the front lawn.
The main way that glucose levels are regulated is through the hormone insulin. Insulin tells your fat and muscle cells that you’ve just eaten and that they should be prepared to take up the sugars that find their way into the bloodstream. If insulin isn’t working, then glucose metabolism is out of whack and bad things follow. In T1D, insulin doesn’t work because the cells that make the hormone have been destroyed. T1D is an autoimmune disease, just like arthritis, lupus, and multiple sclerosis. The difference between these diseases lies in the nature of the cells that a person’s own immune system destroys. In T1D it specifically attacks just the islet beta cells in the pancreas. Without those cells, no insulin can be made, and glucose remains in the blood. In T2D by contrast, insulin levels are fine, but the body does not respond to the hormone. It is said to be insulin-resistant. You get the message, but just don’t respond to it.
It follows that treatments for these two classes of diabetes need to be different. People with type 1 diabetes must take insulin on a daily basis, mostly by injections that after a time become extremely painful. Drug companies are working on forms of the hormone that can be taken orally, but it tends to be digested before it can get to the liver where it is most needed. Long term, it will be better if physicians can work out ways to transplant healthy islet beta cells back into the pancreas, possibly using stem cell technology. Type 2 diabetics manage the disease with a variety of drugs that act principally to lower blood glucose levels. Even better, changes in lifestyle such as increased exercise, healthier eating habits, cessation of smoking, and generally reducing stress can all turn the tide of disease.
What is so bad about high blood glucose? If the whole point of eating is to provide energy for cells, what can be the problem with allowing them to bathe in sugar? Basically it is a matter of all things being better in moderation, that sometimes too much of a good thing can be bad for you. Harm manifests itself at several levels.
One of the most important is actually an indirect side effect of cells not absorbing glucose. Even though the glucose levels may be high in the blood, if the cells do not take up enough of the sugar, because they are not responding to insulin, they are forced to use a different source of fuel. This is the reserve of fats and proteins that they have. But burning fats produces things called ketones, which are acidic. If there are too many ketones, then the pH of the blood drops. If it gets below 7.35, the result is acid rain in the body: Our cells don’t like acid any more than trees do.
Turning to the direct effects, often the first problem is that the kidneys are upset. Their role is to clean up toxins in the blood, which they do by filtering them from the blood into what will become urine. The whole system depends on appropriate osmotic pressure, on the balance of electrolytes and sugars. If too much sugar is in the blood, it must be pumped into the urine, and excessive urination—often the first sign of diabetes—ensues. The lost fluids have to be replenished somehow, generally by excessive drinking (preferably of water), lest the body coaxes its own cells into giving up their water. Should this dehydration happen to cells in the brain, dizziness and fainting spells will result, and in extreme cases even unconsciousness.
Eventually the imbalance puts so much strain on the kidneys that they start to fail. Diabetic nephropathy is the most common cause of the need for dialysis in the United States. Once pathology starts to develop, it can progress quickly, particularly if blood pressure is poorly controlled.
A second common sign of diabetes is blurred vision. For one thing, constant absorption of glucose changes the shape of the cells in the lens of a person’s eye, which affects eyesight. But the bigger problem is that the blood cells of the retina are very sensitive and easily damaged by buildup of obstructions that cut off oxygen supply and kill the cells. When this happens new blood vessels start to grow in, and blood can seep into the back of the retina, so clouding the image that blindness ensues. Diabetic retinopathy will affect 80 percent of patients who have the disease for 15 years or more, unless they take careful steps to control the symptoms.
Local damage to the small blood vessels throughout the body has other consequences. As glucose builds up, the vessels thicken and can constrict, resulting in mini strokes in the periphery of the body rather than the brain. These disrupt the general flow of blood. Starved of oxygen, nerves eventually stop working as diabetic neuropathy sets in. Impotence may be one concern, but numbness and diarrhea, loss of bladder control, and muscle weakness are all common signs of advanced disease.
From there, things can only get worse. Completely deprived of blood flow, the arms and legs start to waste away, and deprived of feeling it is easy for cuts, bruises, and calluses to turn into ulcers and open sores if not gangrene. Diabetes is the primary cause of nontraumatic amputation. The heart itself also needs a constant supply of blood, so cardiac failure is common. As blood pressure rises, so too does the risk of atherosclerosis, particularly in obese or hypertensive patients. Ultimately, heart disease and stroke are the most deadly consequences of all forms of diabetes.
Type 1 Diabetes
Somewhere in the vicinity of 1 in every 300 children will contract the fat-free form of diabetes, T1D. We currently have no way of identifying those at risk in advance and are powerless to stop the progression. On the other hand, we can be fairly confident about who will not be type 1 diabetics. The reason is that almost everyone who has the disease has one of a handful of genetic markers at one particular place in the genome. The Human Genome Project is telling us that they are likely to have a few other risk factors as well.
Even a cursory look at the distribution of T1D in families makes it clear that there is a sizeable genetic component to the disease. If one identical twin has it, then just over half the time the other one will as well. By contrast, regular brothers and sisters of a type 1 diabetic have only a 1 in 20 chance of contracting T1D, reflecting the fact that they only share half of their genes. But this incidence is itself 20 times greater than the prevalence of the disease in the whole population.
Starting in the 1980s, several groups of researchers across the world set out to see whether they could find those parts of the genome shared by people with T1D. This was to be the perfect situation for finding the genes that contribute to complex disease since there is a willing group of patients and neither the environment nor behavior seems to be much involved. Their strategy was to concentrate the search in families. By now, more than a dozen regions have been linked to T1D in multiple studies, and in the past few years half of them have been associated with a particular gene.
The surprise is that after all this effort, just one complex of genes stands out and explains almost half the incidence of T1D. This complex is the central player in immunity. Not so surprising, the next biggest factor is the insulin gene itself. The way it seems to promote disease was unexpected but certainly makes sense in hindsight. The other players are a supporting cast, interchangeable and barely noticeable by themselves.
The genes in the major risk complex are called Human Leukocyte Antigens (HLA). They live in a community of hundreds of genes known as the Major Histocompatibility Complex (MHC). These are perfectly reasonable names for an immunologist, but we’ll stick to HLA and MHC. The MHC is incredibly diverse, both in the range of things it does, and the variability you find in it. We’ll meet it again in the next couple of chapters.
The HLA genes are thought to be the most variable part of the human genome. Aside from immunity, one of the other things the MHC does is help us determine whether other people are genetically different. Believe it or not, we are constantly sniffing one another out. Happily, most of us are a little more subtle about it than dogs are, but studies of young adults indicate that they prefer mates who look different with respect to the makeup of their MHC.
Think of your HLA proteins as the many different picture hanging devices you can get for mounting things on the walls of your house. You’ve got your basic nail, then there are hooks of various sizes and shapes that slide over a nail, or there are ones with wires, and others that are sticky or made of Velcro. Inevitably, you don’t have the one you need lying around the house, but can usually make do, and if not, then a trip to the hardware store will solve the problem.
The HLA proteins basically hang little broken up pieces of molecules on the outside of your cells, where the policemen of your immune system, the T-cells, can look them over and decide whether they indicate trouble and whether to do something about it. Some viruses and microbes are able to avoid the immune system because their proteins have shapes that make them difficult for HLA to bind to. Since the range of pathogens is so great, the HLA must be diverse enough to show as many of them as possible. But evidently they cannot hang everything, so there is a constant turnover of variation based on the tug-of-war between pathogens and our collective immune systems. You’ll find different flavors of the HLA in different populations, reflecting the different recent history of infectious agents.
Soon after birth, your immune system has to make a whole bunch of decisions about which of the molecular pictures hanging on the walls of your cells are unlikely to indicate harm. In other words, it has to be able to identify your own proteins and make a memory of the difference between these and foreign ones. This is called distinguishing between “self” from “non-self.” When something goes awry at this step, it is likely that at some point your body will start attacking itself, with the immune system destroying your own cells as if they were bacteria or other foreign cells.
In T1D, the immune system fails to recognize insulin as self, and so as babies grow into children, it starts destroying the cells that make insulin, the islet beta cells in the pancreas. It looks very much as though two major genetic factors can contribute to this happening.
The first is if your HLA has the wrong set of picture hangers. It is as if when your mother-in-law shows up with the family portrait that must be hung over the mantelpiece where everyone in the world can see it, you just can’t bring yourself to hang the picture, and suffer the consequences forever. In Caucasians, the combination known as DR3/DR4 is the worst, while in Asians it is DR4/DR9. A change of one amino acid in DR4 probably disrupts the ability of HLA to bind to insulin, so insulin is not appropriately shown to the immune system. Three percent of white folks have the DR3/DR4 combination, having inherited either of the two from each parent. They have a fifteenfold greater risk of contracting T1D than everyone else, and account for 30 percent of all type 1 diabetics. If you don’t have either of these flavors, it is unlikely that you will have T1D. But if you do have the risky combination, you aren’t necessarily going to be diabetic.
It stands to reason that this deficit could be overcome by producing more insulin, forcing the HLA to show insulin to the developing immune system, whether it has the right hangers or not. This is the reason why the insulin gene itself is the next major risk factor. There is a very odd little repetitive stretch of DNA right in front of the insulin gene in humans. Anyone with hundreds of copies of the stretch makes more of the insulin protein where it matters, which is not the pancreas but rather the thymus. The thymus is the police station where the immune system does its surveillance. If more insulin is made there, it is more likely that insulin will be recognized as part of “self” and tolerated in the body. Later in life, the immune system will not attack the beta cells in the pancreas.
Unfortunately, only about 1 in 5 of us has the highly repetitive form of the insulin gene. Instead, the vast majority of people are at risk for T1D on account of having two copies of the other allele, the one without the repeats that causes less insulin to be made in the thymus. A consequence of this is that even though the repetitive allele makes quite a difference for any given individual, it is not protecting enough individuals to account for a whole lot of the variation in susceptibility in the population at large.
Inadvertently, it seems that northern Europeans might have been playing with their infants’ insulin levels over the last couple of generations. The baby formula derived from cow’s milk that contains bovine insulin might somehow be interfering with the establishment of self-recognition of human insulin. Studies in Scandinavia and Germany have repeatedly shown that mothers who stop breast-feeding after three months elevate the risk of their child having T1D, perhaps as much as twofold. This effect has not been established in North America, possibly because formula here is processed differently.
Two other genes that have been implicated in T1D have modest effects of much less than a twofold increase in risk, and like HLA they appear to be different in different racial groups. Their names, PTPN22 and CTLA4, conjure up images of everyone’s favorite Star Wars robots, R2D2 and C3PO, and indeed both are part of an elaborate T-cell machinery. These are the cells that recognize and respond to foreign invaders and usually leave familiar molecules such as insulin alone. The details are still being worked out, but particular alleles make it less likely that T-cells that do recognize insulin are eliminated from the blood.
I cannot resist finishing this section by making reference to the fifth T1D risk gene, SUMO4. Believe it or not, it has only been clearly established as a risk factor in Japan. The name is pure coincidence, but you can imagine that there are plenty of references to wrestling with diabetes genes in Asia. SUMO stands for Small Ubiquitin-related Modifier, and the SUMO proteins are involved in—you guessed it—sumoylation of other proteins. Just how this relates to T1D is not yet clear.
An Epidemic Genetic Disease
The story for type 2 diabetes is really quite different. T2D is essentially an epidemic disease. Prevalence has increased from a few percent to well more than ten percent over the past 30 years and continues to trend upward at an alarming rate. Genes alone cannot cause an epidemic; there must be some environmental agent. And we all know what that agent is: the transition to a fast food, slow couch-potato lifestyle. The genes are just accomplices—from their viewpoint unwitting ones. In the blame game, they are innocent victims of changes that humans have wrought upon themselves, caught up in a disease they have no business being associated with.
We can talk about hyperglycemia and insulin resistance as much as we want, but the root problem in T2D is that regulation of metabolism is out of control. Constantly exposed to high sugar levels in the diet, we produce insulin at higher levels than the body evolved to tolerate. Eventually it cries wolf, shutting down its response to the hormone. The modern lifestyle has pushed an exquisitely evolved system of checks and balances to the limits of its buffering capacity. Those who are unlucky enough to be genetically less buffered find themselves more susceptible to developing diabetes.
So genes are involved, but more as a facilitators than causal agents. If we want to understand what they are doing, we need to address three questions. First, why are some of us more prone to overeating than others? Second, why does overeating lead to obesity more readily in some than in others? Third, what is the relationship between weight gain and T2D, and are there genes that contribute to T2D independent of obesity?
It is not difficult to see how weight gain gets out of control. Just a small change in the ratio of caloric consumption to expenditure adds up over time. A 40-year-old man who is 20 pounds overweight, which is almost the norm these days, has been putting on an average of a pound a year since he left school. That equates to just 10 grams a week. How many grams of sugar are there in a can of Coke? 39. In theory, cut the extra beer for the road or the donuts at the weekly group meeting, and problem solved.
We all think, dipping our hand into a co-worker’s candy jar, that we will work it off on the walk back to our own office. At least the Europeans get to walk to the tram instead of the garage every morning. If simply adding up the calories translates into inches around the waist, it really doesn’t seem right that three half-hour workouts a week don’t add up to a lot more weight loss.
Other factors must be in play here. A major one is the transition to sedentary lifestyles that occurs when most people are in their twenties, especially in the modern economy where work is more likely to involve sitting in front of a computer than being active outside. Even if most of us get the eating part of the equation more or less right, too many of us don’t find time for the physical.
Another factor is socioeconomic: It is clear that obesity is proportionately a much greater problem for the less well off. In the space of a century this represents something of an inversion, since malnutrition in the developed world is now much less common than undue weight gain. The culprits are self-esteem issues and fast food. It is sadly most difficult to lose weight when you feel badly about yourself, when you notice that success goes to attractive and energetic people, and a negative cycle of worthlessness sets in. Diets never take effect straight away, and exercise programs usually make you feel really tired for the first few weeks, without producing results. It is easy to give up.
At the same time, chains of McDonald’s, Taco Bell, and Bojangles beckon with promises of cheap and tasty meals, supersized for just a few cents extra. Dollar for calorie, energy dense burgers, nuggets, and sodas—all in some way or another just processed corn—are three times better value than the South Beach foods we should be eating. A few dollars for a morning sausage biscuit and coffee seems like a good deal. The cost of feeding a family of four from one of these chains is rarely more than $30, but put together a nutritionally well-balanced and freshly spiced meal from Martha Stewart’s Living, and it will run you $50 plus. Equally important is budgeting time into lives filled with second jobs, kids’ needs, and a simple desire to collapse in front of the TV.
In fact, our entire food culture is set up around rapid consumption. Michael Pollan’s fascinating and frightening book The Omnivore’s Dilemma explores the reshaping of the American food economy starting with the industrialization of corn. He gives a hefty wag of the finger to Richard Nixon’s Secretary of Agriculture, Earl “Rusty” Butz, whose policies led directly to the massive surpluses of corn production that drive the feed mills of Kansas and the wet mills of the upper Midwest that process kernels into a thousand varieties of bottled glucose.
The end product of the tens of billions of dollars of government subsidies behind the oceans of maize that float across the great plains each summer is in a very real sense the thickened waistlines and the clogged arteries of the modern suburbanite. Only, those at the bottom of the socioeconomic food chain are the most heavily affected. Next time you pick up a fast food meal, just double the price mentally and put the difference toward the several hundred dollars of health care premiums you’re paying to cover the billion dollars of heart disease treatment we take for granted.
Despite temptation, our genes do have a say in establishing how each of us responds to excessive caloric intake. We all know fat people who seem to eat like a kitten, and jealously regard those who can eat whatever they like yet slip into a size two comfortably. Hollywood caricatures of big fat men exploding as they shovel down yet another turkey leg aside, the morbidly obese are just as much victims of a raw hand in the genetic lottery as from their eating habits.
Genetics of Obesity
Anyone in any doubt about the power of genes to influence weight gain need only consider the case of obese mutant mice. These are a strain of otherwise normal mice that appeared in a laboratory colony as a result of a spontaneous mutation in 1950. Animals that inherit two copies of the mutation are really big, up to four or five times bigger than littermates with just a single bad copy of the affected gene, big enough to swallow up their siblings in the flabby folds of their skin. They get this way because they are unable to control their appetite, and just keep eating.
In the mid-1990s it was discovered that the obese mutation knocks out a gene that encodes the peptide hormone leptin. Leptin is one of the primary signals that the brain uses to stop us eating when it senses that we’ve had enough. The crucial part of the brain is called the hypothalamus, which among other things is also known as the satiety center. In other words, we don’t just stop eating after a meal because there’s no more food on the plate, but rather because we have finely tuned sensors that actively tell us it is time to stop eating. Disrupt those sensors, and we keep eating, and obesity is sure to follow.
Imagine the glee with which would-be pharmaceutical giants met this discovery. Surely administration of leptin as a drug would provide the panacea for weight loss that would slip into the void left by the tragic demise of Fen-Phen. Alas, it turns out that obese people actually tend to have higher levels of circulating leptin than people of normal weight, indicating that they have become resistant to it. In a small number of cases of morbidly obese families the leptin gene is deleted, just as in the mice, but it appears that the gene plays only a minor role, if any, in general human obesity.
Three varieties of drugs do seem to work to control weight gain: appetite suppressants, carb-blockers, and fat-burners. Fen-Phen is an appetite suppressant that, like several other drugs, acts to reduce signaling between neurons by serotonin in the hypothalamus. Not surprisingly, these drugs have many side effects, including upsetting the heart, so you should take them at your peril.
Appetite regulation gets a lot more complex the more physiologists look into it. A complex network of signals keeps everything in the appropriate balance, preventing excessive eating habits that lead either to obesity or anorexia. The range of hormones that moderate energy and glucose homeostasis reads like Santa’s reindeer: go leptin and visfatin, on adiponectin and omentin, there’s ghrelin and resistin, and oxytomodulin and amylin, not to mention peptide YY, glucose-dependent insulinotropic polypeptide, and the glucagon-like peptides. All these need to be integrated with daily rhythms—appetite must be suppressed while we sleep—and with how we’re feeling.
The network of interactions likely remained almost unchanged over tens of millions of years of primate evolution but has suddenly had to cope with the double whammy of first a dramatic change in human body size and now a fundamental shift in diet. It is no wonder that the system is confused by the constant availability of sugary foods in the modern world, no wonder that the natural balance is upset; the genome is out of equilibrium with the modern world.
Just this short discussion has suggested 20 or so genes that may be involved in weight gain. Each one of these genes is a candidate for a place in the genome where variation could contribute to the obesity epidemic. We haven’t even begun to talk about digestion, fat deposition, energy burning, or basic metabolism, and if we did the list would rapidly expand to more than 100 genes.
Studies over the years have actually implicated more than 250 places in the human genome that might lead toward obesity, without actually finding the culprit genes. Individually these studies are barely worth the paper they are written on, and most lead to investigative dead-ends. Collectively though they tell a truism that weight gain really does take a genome.
In other words, we need to completely abandon the notion that there is a gene for obesity, or even that there are a few genes for obesity. Instead embrace the concept that hundreds of genetic variants are a part of the normal regulation of body weight, and it is an inevitable corollary that some individuals have combinations that predispose them to disease.
This is the notion introduced by an analogy in Chapter 1, “The Adolescent Genome,” that many times companies fail not so much because of an incompetent CEO, but rather because of the accumulation of myriad natural incompatibilities. Every company deals with employees going through a divorce, coping with rebellious teenagers, pushing their own agenda at the expense of the team, or struggling with the latest software. Change the pressures slightly, and a relatively functional group can become dysfunctional. Something like this is contributing to the obesity epidemic.
What has been discovered by randomly testing hundreds of thousands of variable places in the genome to see which ones are correlated with obesity? One striking result is that a gene called FTO has a lot to say about who is overweight, across most human populations. The 16 percent of adults who have two copies of a particular allele of the gene FTO are about one and a half times more likely to be obese than everyone else. Conversely, the 36 percent of adults who have both copies of the other allele have almost half the likelihood of being obese, and they are on average 5 pounds lighter. This conclusion is based on measuring 40,000 people in 13 different studies, so there is little doubt about it. Shockingly, the effect of the gene starts to appear as early as seven years of age, before the kids themselves can be expected to take responsibility for their eating and exercise habits. That is definitely not to say they cannot do anything about it as they get older, but the deck is stacked a little against them from birth.
Unfortunately, as yet we have almost no idea what FTO does, where it does it, or why the different flavors do it differently. Surely it will not take long for scientists to figure this out, but it is one of the frustrating things about contemporary genetics. Like rising gasoline prices, often we can see what the problem is but can’t do anything about it.
Another example of this is the gene called INSIG2. My first thought on reading the paper describing the discovery of this particular obesity gene was that the researchers must have a wry sense of humor and a fearless attitude toward funding agencies. So many findings of highly significant associations between genes and diseases have turned out to be false leads that it is almost asking for trouble to give your gene a name that conjures up “insignificance.” But it turns out that INSIG2 actually stands for Insulin-induced gene 2. The protein encoded by the gene seems to be involved in the synthesis of fatty acids and cholesterol, which obviously makes sense if you are looking for something to do with obesity.
The actual DNA changes that alter the function of the gene have yet to be identified, but three different studies of several thousand Caucasians on both sides of the Atlantic, and of African Americans, suggest that the ten percent of individuals who have two versions of the less common allele are more likely to be obese. The risky variant is at a relatively constant frequency of around one-third of the alleles in all populations examined, but oddly it does not seem to promote weight gain in all populations. The obesity-associated allele seems to be the ancient one that was present in humans before they began moving around the globe and practicing agriculture. The protective type is the more modern one, implying that we are evolving a genetic constitution that is less predisposed to putting on weight.
Another gene, ENPP1, also known as PC1, popped out of a search for genes that might be involved in diabetes. It encodes a protein that binds to and turns down the function of the insulin receptor. If you think of the insulin receptor as the main control on your dashboard that allows you to work the air conditioning in your car, then ENPP1 is like the knob on the air vent that provides a little more control. Cell biology is full of such devices that you can do without, but that make life easier.
A common form of ENPP1 in humans has one different amino acid, affecting how the protein binds to the insulin receptor. Many other alleles also affect how much of the protein is made in particular tissues such as the pancreas, the liver, and fat cells. It is easy to imagine that such different forms affect the development of resistance to insulin, and hence susceptibility to diabetes, and it seems that they do. But it turns out that they also predispose carriers toward obesity. Not a lot, but enough to make a difference, at least in Caucasians: One study of Japanese found no effect at all. This is emerging as a common occurrence in the genetics of disease: Whether a variant flavor of a gene matters is peculiar to each population.
Just like cancer, a few percent of morbid obesity is actually explained by heritable cases that can be attributed to single severe mutations. One of the main culprits is a gene that mediates the feeling of satiety, called the fourth melanocortin receptor, MCR4. Melanocortin is one of those fascinating genes that seem to be involved in everything. Variation in one receptor gene, MCR1, is responsible for the white patches on many of our furry friends, while another one is implicated in erectile dysfunction, and seasonal affect disorder ties in there somehow as well. Numerous studies now encompassing tens of thousands of cases establish a weak link between common variation in MCR4 and obesity. I can’t wait for the advertising campaigns that, after drugs are developed that overcome the genetic legacy here, solemnly warn that if you experience an erection lasting for more than four hours while trying to lose weight, consult your doctor.
Type 2 Diabetes
Diabetes is to obesity as crime is to unemployment. You can have one without the other, but the latter certainly leads to the former. Consequently, the obesity gene map heavily overlaps with the diabetes gene map, though we now know that it is not sufficient. Many common polymorphisms contribute to diabetes without playing much of a role in normal weight control.
The body has evolved exquisite mechanisms based around insulin to keep glucose concentrations in balance. Normally it copes with excess by storing it as fat. But if the system is overloaded for too long, it becomes stressed, and eventually throws in the towel. Diabetes then arises from a double dose of disequilibrium. First is the disequilibrium between genes and the environment; second is the loss of equilibrium in the balance of hormones that function to ensure that energy reserves are kept within a healthy range.
Why would the body build up resistance to the very hormone that makes life possible? Why would evolution tolerate the accumulation of genetic variants that cause insulin signaling to go so terribly wrong? This is really not a case of bad genes, but rather of good genes forced to do bad things under abnormal circumstances.
Insulin levels go up after a meal because the hormone tells the body systemically how to deal with all the new glucose, but the levels cannot stay up indefinitely. While there is a tap on insulin production at the source in the production, it is more efficient to control usage of the hormone at each tissue. This provides a type of buffering.
It might help to think of insulin resistance as caller ID. Telephones are great things when they help us remember to pick up some tomatoes on the way home or let us talk to loved-ones thousands of miles away. But when telemarketers worked out that they are also an effective device for hawking unwanted banking services just as we sit down to dinner, telephones became a threat. So we evolved caller ID so that we can locally screen the incoming messages, thereby making a relatively simple communication device somewhat complicated, but much better regulated and controlled.
One of the wondrous features of the insulin buffering mechanism is that it is flexible enough to adjust its sensitivity as life unfolds. During puberty or pregnancy, for example, we have different physiological responses to eating and adjust glucose metabolism accordingly, in part by elevating insulin release. Similarly, what is ordinarily a good level of insulin to get the job done, may not be so good as we go through phases of weight gain and healthy exercise, or illness, or just getting older. So the body is constantly adjusting levels of insulin resistance in proportion to the production of insulin in the first place. As insulin production goes up, so too does resistance. This sort of feedback loop serves to keep the whole system in equilibrium.
In obese people with constantly high levels of something called non-esterified fatty acids and with large rolls of abdominal fat deposits, long-term increase in resistance occurs, and the body enters something of a cry-wolf situation. Used to receiving the insulin signal all the time, eventually the person’s cells become insensitive to it. At that point, resistance eventually leads to impaired insulin release in the pancreas as the beta cells shut down. What normally functions as a negative feedback loop to keep glucose in the normal range becomes the source of disease after a lifetime of stress. The genes aren’t bad; they’re just trying to do the right thing, but are getting it wrong because they are out of equilibrium with their environment.
Among the 50 or so genes thought to contribute to diabetes in this way, three are well enough characterized that even the most hardened skeptics would have difficulty refuting their involvement.
Calpain 10 is the textbook example both for how to find a gene for a complex disease and for differences among populations in the effect it has. Initially identified in Finland and quickly confirmed in Mexican Americans, for whom it is responsible for as much as one-tenth of disease susceptibility, it is nevertheless not involved in diabetes in Japanese, Samoans, or Africans.
PPARG has such a long formal name that it even puts biochemists to sleep: peroxisome proliferator-activated receptor-gamma. It encodes a growth factor receptor involved in regulation of adipocyte (that is, fat cell) development, whereas Calpain10 encodes a protein that digests other proteins and affects pancreatic function. PPARG’s oddity is that the susceptibility allele, thought to be a change of the twelfth amino acid from one type to another, is the common type in humans. More than three-quarters of us have what simplistically might be called the bad gene, but it has such a small effect that it does not lead to diabetes for most of us. On the other hand, most diabetics have it, so in the end it explains quite a bit of the disease susceptibility.
A third gene only just emerged from a series of whole genome scans late in 2006. It is evidently such a bad gene that it gets a criminal name: TCF7L2. Call it the Lex Luthor of genes, because it is also a mastermind, encoding a transcription factor whose role it is to control other genes. Like the other two genes, variation in TCF7L2 accounts for as much as 20 percent of the incidence of diabetes in Africans and Europeans. Even more telling, the old, risky, allele has almost disappeared from east Asia, where correspondingly diabetes is relatively rare.
Debunking the Thrifty Genes Hypothesis
We now need to address the issue of why risk alleles are found at a common frequency in the human genome. There are logically three possibilities. First, they are just drifting around, too inconsequential for natural selection to pay much attention to. Second, a balance between the advantages and the disadvantages they confer may actively keep them around. Third, some of the alleles may be truly beneficial, but they are too young and there has not yet been enough time for them to displace the old ones. Evidence is accumulating that all these mechanisms are involved.
Let’s start our discussion, though, with an explanation that you might have read about in the Sunday papers, the so-called “thrifty genes hypothesis.” To be thrifty is to be wise with your resources, to be economical and not wasteful, to plan for the future. It follows that thrifty genes would be ones that allow you to conserve your food reserves for a rainy day, or another cache of berries or kill of wild meat as the case may have been for an early human.
It is precisely this concept that the University of Michigan geneticist Jim Neel had in mind back in 1962 when he coined “thrifty genes” as an explanation for the recent upsurge in obesity. Individuals who are better able to convert a surplus of calories into fat reserves would be more likely to see through times of famine that were presumably common as the species was first evolving. Yet confronted with the supermarket diet rich in sugars and fats and all things in plenty, those genetically same individuals are now predisposed to develop unwanted fat reserves.
Professor Neel was one of the world’s leading human geneticists in the latter half of the twentieth century, but he had a case of foot-in-mouth disease at the end of his seminal paper. In a section titled “Some Eugenic Considerations” he made the precious remark that:
If...the mounting pressures of population numbers means an eventual decline in the standard of living with, in many parts of the world, a persistence or return to seasonal fluctuations in the availability of food, then efforts to preserve the diabetic genotype through this transient period of plenty are in the interests of mankind.
He concluded: “Here is a striking illustration of the need for caution in approaching what at first glance seem to be ‘obvious’ eugenic considerations!” We might conclude that here is a striking illustration of the need for prominent geneticists to shut the heck up when they start speculating about and proposing genetic remedies for the future of mankind.
He should have known better. Food scarcity is going to cause a lot more pressing problems for humankind than preserving genetic variants, as the situations in places such as the Sudan and Rwanda indicate. Just how he envisaged the West implementing this engineering of thrifty gene prevalence in developing countries is disturbing to contemplate. We should give him the benefit of the doubt, though: Perhaps he was writing in late May as gray winter in Ann Arbor was finishing its eighth straight month, a stress mere mortals cannot be reasonably expected to handle with grace.
Lamentable eugenics does not however invalidate the thrifty genes argument, which seems to be thriving. Humans have a magnetic attraction to simple ideas that seem to have great explanatory power without a whole lot of tangible evidence in their favor. All the bits and pieces to the argument seem to make sense. All three premises of the theory of natural selection are met: There is variation among individuals, this is somewhat heritable, and there is differential survival related to the trait. Put them together, and you arrive at the conclusion that genetic variants predisposing to obesity must have been positively selected in modern human history.
Alas, close reading uncovers three features that a lot of evolutionary medicine arguments have in common: hyperadaptationism, the hereditarian fallacy, and sloppy quantitative reasoning. Hyperadaptationism is the notion that if an organism exhibits a trait, the trait must have evolved for that purpose. We now know that often traits evolve as a side effect of something else. Rather than assuming adaptation, evolutionary geneticists now accept a high burden of proof in establishing it.
The hereditarian fallacy is the idea that if there is genetic variation for a trait, and the frequency of the trait varies among populations, then genetics must account for the differences between the populations. It is that old racist curveball that keeps coming up in discussions of American IQ, raised here as evidence that selection accounts for the high prevalence of obesity among Pacific Islanders. None other than Jared Diamond, author of two brilliant books about the rise and fall of civilizations (Guns, Germs and Steel and Collapse), has even gone so far as to suggest that Polynesian founders were likely to have been especially enriched for thrifty genes; otherwise they would not have survived the voyages across the Pacific. But Captain Bligh and his Bounty men were lean exemplars of the British Navy and survived their 49-day postmutiny ordeal, and there are numerous modern examples of survivors of calamities twice this long, so such inference of strong selection must be taken with a grain of salt.
Quantitative reasoning needs to be carefully applied to any proposal for adaptation, and on close examination the thrifty genes hypothesis falls apart. We can calculate what sort of benefit a genetic difference must afford for it to arise in an individual and be found in one-fifth of people a few thousand years later. It is in the vicinity of five percent, meaning that people with the advantageous allele have a 1 in 20 better chance of having children than those without it.
However, a thrifty genes critic from Aberdeen, John Speakman, has demonstrated that famine survival is highly unlikely to be anywhere near this strong. Basically, famines only rarely kill more than a few percent of the population in any generation, when they do they preferentially affect the very young and very old and so have little effect on genetic transmission. In any case, usually people die of infectious disease, not starvation. So we should be skeptical about claims that diabetes is the result of genes for weight gain being advantageous to nomads and pastoralists but bad for modern urbanites.
One gene actually does fit the thrifty criteria, but it is responsible for lactose tolerance, not weight gain. Prior to the domestication of goats and cattle, humans would not have drunk milk after weaning, or eaten cheese, yogurt, or any of those other great dairy products, as adults. The reason why many of us can digest lactose as adults is because we’ve converted a baby gene into an adult one. The enzyme lactase-phlorizin hydrolase (LPH or lactase for short) is used in the small intestine to allow babies to turn lactose into glucose and other sugars. On at least two different occasions in the past 10,000 years, once in Europe and once in East Africa, novel mutations have arisen that allow the gene to keep on working in adults. Population geneticists can estimate that possessing the mutation would have conferred something like a five percent fitness advantage to individuals in early pastoral societies that came quickly to depend on milk as a staple.
By contrast, the most compelling argument that diabetes susceptibility didn’t get into the gene pool a few tens of thousand years ago actually comes from the genes themselves. In just about every case, it turns out that the ancestral allele, the one we share with chimpanzees and other primates, is the one that is more risky. In other words, the protective types are the ones that have been increasing in frequency for the last few millennia. Without these, obesity and diabetes would be even more prevalent than they are. Frankly, we have no idea yet what forces, if any, are favoring them, but we can thank our lucky stars that they are around.
Disequilibrium and Metabolic Syndrome
A possible explanation for the increase in resistance factors is that there has been selection against the disease of diabetes. This seems unlikely since until recently it was not prevalent enough to affect reproduction with the necessary selection intensity. Perhaps there is selection involving a more subtle aspect of diet, and the impact of diabetes incidence is a side effect of this. Alternatively, the regulation of metabolism may be so complicated, involving hundreds of genes each with a variety of alleles, that it is inevitable that the network malfunctions in some people after a few key components of the system change.
One of the central ideas of this book is that humans are now outside their normal buffering zone. Instead of thinking of some optimal body mass or blood glucose level, we ought to be thinking of well-buffered systems of interactions that keep weight and energy within a critical range in the face of a constantly shifting environment. On this view it is absolutely critical that there be genetic variation to absorb the environmental insults that any organism faces: seasonal food sources, droughts, famines, illness, pregnancy, and growing old. They all put pressure on our metabolism, and it pays to have a flexible response.
For millions of years primates had a relatively constant range of pressures and evolved a system of hormones based around insulin, leptin, and some others that worked pretty efficiently. Then we decided as a species to start migrating around the world, to have odd monthly menstrual cycles, and to live longer than we were ever meant to. At various times we’ve switched from being herbivores to carnivores to omnivores, from hunter-gatherers to pastoralists, and most recently to cornivores. Our metabolic systems are stressed and confused.
Disequilibrium. Imbalance. Desynchronization. Instability. Mismatch. Call it what you will, but the fundamental problem is that our modern lifestyle is out of step with the genetic legacy of millions of years. Our omnivorous diet exposes us to a much wider range of toxins and pathogens than most species see, putting pressure on the exquisite network of cytokines and other signaling molecules that regulate fat and sugar metabolism.
Our wanderings have exposed us to such a wide range of climates and food sources that the metabolic system is forced to adapt locally. All these pressures and others are nudging the metabolic genetic network away from a balance forged over the course of mammalian evolution. More than a third of all people living in developed countries are now at risk for a metabolic syndrome of ill health that includes diabetes and heart disease. It will take tens, if not hundreds, of thousands of generations to find a new equilibrium to cope with the impact of a few thousand generations of profound perturbation.
Disequilibrium also exists between the energy dense Western diet and our genetic constitution, however, it has been shaped by human evolution. When you push any well-buffered system to the limits, it breaks down. We push the biochemistry and physiology of glucose homeostasis to the limits every day, and it is inevitable that some genetic combinations are less able to cope than others.
What to do about it? Western practice is to treat the symptoms. More drugs, please! Eventually, perhaps too society will call for eugenic approaches that will rid the gene pool of this scourge. Surely we will recognize instead that it is much easier and more human to change attitudes and shift lifestyles. Change what we eat and how we eat, and change our parenting practices that permit or even encourage young children to adopt the very habits that threaten their future happiness.