Thrifty Genes, Thrifty Bodies and the Barker Hypothesis
“They have sown the wind, and they shall reap the whirlwind.”
–The Bible (Hosea, 8:7)
In 1962, a geneticist named James Neel first proposed a “thrifty gene” theory to explain why 60% of adult Pima Indians living in the United States have diabetes, and 95% are overweight. Neel’s theory was that populations like the Pimas, that have for millennia relied on farming, hunting and fishing for food, would experience alternating periods of feast and famine. Neel hypothesized that in order to adapt to these extreme changes in caloric needs, people developed a “thrifty gene” that allowed them to store fat during times of plenty so that they would not starve during times of famine.
A similar theory was advanced to explain the high rates of diabetes in people from the Indian subcontinent, once they are exposed to plentiful supplies of food. These was traced by the great Diaspora from central Asia at the end of the last age, when the ancestors of modern Indians and Pakistanis made the great trek through modern Afghanistan into the Indus valley. A journey that had been impossible at the height of the Ice Age and which was still difficult. The idea was that people who could quickly lay down a lot of intra-abdominal fat would have a huge survival advantage.
This is an attractive hypothesis, but here have always been some problems with it:
- The gene or genes would have to be able to work with the environment: the Pimas of Mexico and people living in rural India do not have the high rates of diabetes and obesity
- Despite looking for over 40 years, no such gene has yet been found
- If the thrifty gene is so advantageous, why doesn’t everyone have it?
- Until recently, famines were rare and usually occurred every 100-150 years. As John Speakman has pointed out that would mean that most human populations have experienced at most 100 famine events in the course of their evolutionary history
- Famines do increase mortality but only in about 10% of the population
- In famines most people die of disease rather than starvation, and the worst affected are the young. Having a “thrifty gene” would not help them survive starvation OR disease
- Simple genetic models would suggest that famines would not provide enough selective advantage and there has not been enough time for a “thrifty gene” to have penetrated the population
There could yet be some complex genetic model involving “reserve” genes that appear when needed, or some epigenetic inheritance, but we have no evidence for that either.
A second concept is gaining a lot of traction. It is what is known as the “Thrifty phenotype,” and is part of a larger theory called the “Barker Hypothesis.” I’m going to stick my neck out, and predict that David Barker may receive the Nobel Prize in medicine for his discoveries. They are that important.
Essentially the Barker Hypothesis suggests that in addition to genetic, epigenetic and environmental factors in disease, there is another, and that is the intrauterine environment. The idea is that if a mother is malnourished, she can modify the development of her unborn child. From an evolutionary perspective, her body is preparing the unborn child to survive in an environment where food is in chronic short supply, resulting in the “Thrifty phenotype:” smaller body size, lower metabolic rate and a propensity to be less active.
The problem is this. If you are born with the thrifty phenotype and actually grow up in an affluent environment, you are more likely to develop obesity, diabetes and vascular disease later in life. If true – and virtually all the evidence suggest that it is – then it has serious implications for countries that are transitioning from sparse to better nutrition, and may have contributed to some of our current health problems. Many of us were born to mothers who had poor nutrition, either because of the Great Depression, the Second World War, poverty, or just plain poor information about good nutrition during pregnancy. And now we are reaping the whirlwind.
The hypothesis has become sophisticated. If you are born small or premature, then your liver and kidneys may not have completed their final growth spurt, which might predispose you to metabolic problems and hypertension.
The story of how this all came to light would be worthy of Sherlock Holmes himself.
English counties used to have people who were responsible for providing midwifery services. In the county of Buckinghamshire a single midwife collected data for almost thirty years. Information about the mother, the length and weight of the baby and the weight of the placenta. Information that would be impossible to collect these days. Some civil libertarian somewhere would probably dream up some way of hiding this enormously important information.
David Barker discovered these extraordinarily good records, and then set about finding the adults that these babies had become. And what he found has changed medicine: babies who had small placentas – a good measure of being small or premature – were more likely to develop obesity, diabetes or hypertension as adults. Then he and others turned their attention to other early physical characteristics and found correlations with health later in life. The highest risk of coronary heart disease was seen amongst people who were born small and became heavier during childhood.
The practical implications?
Find out your own birth weight and anything else that you can about your early development.
If you were a very large baby (bigger than nine and a half pounds), it implies that your mother may perhaps have had a metabolic problem. If you were small (less than five and a half pounds), then you should get the regular health checks that we recommend for anyone in a “high risk” group.
BMI R.I.P.
For experts in metabolism, we have long worried about the over-emphasis on the use of body mass index (BMI) as the arbiter of a "healthy" weight. It is one of those measurements that is in some senses too easy, and the results are deceiving. I regularly see people claim that a certain BMI will "predict" the risk that someone will develop cardiovascular disease or diabetes. The truth is very diferent.
There are two ways to calculate your BMI:
1. Metric system – Kilograms and Metres
[Your weight] divided by [Your height squared]
2. Imperial System – Pounds and Inches
[You weight] divided by [Your height squared] times 703.5
A person is said to be healthy if his or her BMI is between 18.5 and 24.9.
The trouble with this is that the calculation lumps together fat and muscle: a muscular six foot tall football player weighing 300 pounds and with 3% body fat, would have an "unhealthy" BMI of 26.3. That is clearly absurd, and one of the reasons that most experts use BMI only as one part of an evaluation of health.
Our scepticism has been confirmed by an important study from the Mayo Clinic in Rochester, Minnesota, and published in this week’s issue of the medical journal The Lancet.
The researchers looked at 40 studies involving 250,152 patients. Their analysis revealed that people with a BMI of 30-35 were at lower risk of cardiovascular disease than those whose BMI was below 20.
BMI does not correlate well with fat. A better way to distinguish between fat and muscle is to take a cross-sectional view of the abdomen, and to focus on the waist-hip ratio.
A separate study by researchers at the London School of Hygiene and Tropical Medicine of 14,833 people over the age of 75 was published in the American Journal of Clinical Nutrition. They also came to the conclusion that BMI is a poor indicator of health in both men and women in this age group. These researchers also agreed that waste-hip ratio was a better indicator of mortality risk.
This is all music to my ears. For almost three decades we have been teaching about the importance of different stores of fat and the limitations of the BMI calculation. It has been known since the 1940s that gaining weight on the hips, or developing "lover’s handles" are only very weak predictors of diabetes and vascular disease: it is the intra-abdominal fat that is the problem.
There are particular problems with using BMI in the elderly and in some ethnic groups, especially people from the Indian sub-continent and Japan.
The bottom line?
BMI is misleading, and in some age groups and races, grossly misleading.
Much better to use weight and waist-hip ratio.
And BMI only if there is a space on the medical forms where they still need to have it filled in.
Insulin Resistance, Polycystic Ovarian Syndrome and Sleep Apnea
Polycystic ovarian syndrome (PCOS) is a common endocrine disorder that affects between 5-10% of women in the Western World. It is a leading cause of infertility, and although the underlying cause is still speculative, it is very heavily associated with insulin resistance.
There was an International Consensus Workshop sponsored by the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine came up with this set of criteria. PCOS is present if a woman has at least two out of three of:
- Oligoovulation and/or anovulation (ovulating only occasionally or not at all)
- Excess androgen (male sex hormone) activity
- Polycystic ovaries (which needs a gynecological ultrasonography) and other causes of PCOS are excluded
There is still a great deal of debate about the precise way to define the syndrome. We are currently preparing a scholarly article on the subject and our literature review has included over three thousand papers.
The combination of an excess of the male (androgenic) hormones and insulin resistance can cause an array of symptoms apart form the menstrual disturbances and infertility, including:
Central obesity
Acne
Hirsutism, while at the same time experiencing alopecia
Skin flaps and dark patches of skin, usually on the neck or in the armpit
Sleep apnea
It is the last of these that I would like to highlight today.
A new study by Dr. Esra Tasali and her colleagues from the University of Chicago has found that in women with PCOS, sleep apnea is, as expected, associated with high fasting insulin levels. Sleep apnea might worsen the metabolic consequences of insulin resistance.
Regular readers may recall that I highlighted the association between insomnia, insulin resistance, weight and diabetes a couple of months ago. Here we have yet more confirmation of this link.
Not getting enough sleep – for any reason – can play havoc with your metabolism. It seems that in women with PCOS, it’s really easy for a vicious circle to become established:
Insulin resistance -> weight gain -> sleep apnea -> insomnia -> more insulin resistance -> more weight gain and so on.
It is important for everyone to know about this association, because chances are that you know someone with PCOS and/or sleep apnea.
Measuring Insulin Resistance
After doing so much research, lecturing and writing about insulin resistance, I have constant requests for more information on how to measure it in clinical practice. This is not an academic exercise: it is estimated that a person on the road to developing type 2 diabetes may have been insulin resistant for as long as twelve years before the disease is diagnosed.
In high-risk populations, there is a lot of value in regularly checking plasma glucose, but the problem is that once glucose begins to rise, it implies that the pancreas can no longer keep up with the demand for insulin and that we may be passing the point of no return.
These are the most common questions that I get::
- Should you be having your insulin level measured?
- Should you have your insulin resistance measured?
- What’s normal?
First, measuring insulin levels themselves is not of much value: they bounce around a good deal in the course of a day, and many things can alter your circulating insulin levels.
Second, accurate measurement of insulin resistance is an expensive and cumbersome procedure involving intravenous sampling of blood and in some cases also giving intravenous insulin.
Third, there is no such thing as “normal.” Results derived from any kind of test are a “reference range.” This means that they show how a result related to a large group of apparently healthy people. This is an important concept. I often have students say, “What’s normal?” There is no such thing. Blood tests help and guide us but can only be understood in the context of the whole person.
We never treat a laboratory value: we treat people. You may be interested to have a look at an earlier article about this important issue.
But all is not lost: we do have a blood test that can be used to guide us. We don’t have evidence to suggest that we should be using it to screen the whole population for insulin resistance. Instead it is a test to help guide us in high-risk populations. The test is called the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR).
The original paper was published by a group of experts form the university of Oxford in 1985. The drawback of the HOMA-IR is that it is a mathematical model, and it’s only as good as the accuracy of an individual laboratory’s insulin assay.
Since then, the HOMA-IR has been used in epidemiological studies such as the famous Framingham study and there has been a lot of work on trying to correlate the HOMA-IR with other measures of insulin resistance. There are now over one thousand papers that reference it, and we have had a great deal of experience in using it in our studies of insulin resistance in people with mental illness.
Apart from research, we only use the HOMA-IR as a guide in high-risk individuals. A simultaneous fasting glucose and insulin are taken.
Insulin resistance (HOMA IR) =
Fasting insulin (µU/ml) X Fasting glucose (mmol/l) divided by 22.5.
Most studies now suggest that the cut-off for insulin resistance should be 1.7; although some have been slightly more forgiving, and suggested that up to 2.5 may be acceptable. But remember that the HOMA-IR is only giving us an estimate to help with the overall evaluation of a high-risk individual, and we do not treat a laboratory value.
If the value is above 2.5 many experts would suggest intervention if there are also features of the insulin resistance syndrome. The key interventions are diet and exercise, both of which have been proven to reduce insulin resistance. A very interesting approach adopted in two European studies has been to treat high risk people with a medication called metformin, and were able to show that within a year several cardiovascular risk factors improved.
Gall Bladder Disease and Insulin Resistance
When I was a young student, everyone learned that gallstones were more common in people who were “Fat, female, fair and forty.” As you can see we lived in different times and nobody would say anything quite like that today. Not least because it’s now only partially correct. Gallstones are occurring at ever-earlier ages, because they are a recognized complication of obesity. And we all know that we are in the midst of a pandemic of overweight and obesity.
We have also been remarking on the number of people with bipolar disorder who have a history of gallstones.
For many years now, the explanation for the link has been to do with an increasing levels of cholesterol, which are a major precipitant of gallstones. There’s also evidence that high carbohydrate diets increase the risk of gallstones. Weight loss reduced the risk of developing them, though suddenly losing a lot of weight with an unbalanced diet may increase the risk of gallstones.
Now a paper from colleagues at three medical schools has just been published this month, and it helps clarify the connection. The conclusion of the scientists is important: insulin resistance itself seems to cause problems with the normal emptying of the gallbladder, and that would predispose people to the development of gallstones.
Insulin resistance is a feature of increasing weight. Several studies that have found increased rates of insulin resistance in people with bipolar disorder implying an increased risk of gallstones. Though gallbladder disease didn’t show up in a recent study from some friends in Toronto, I could not find any systematic studies of gallstones and bipolar disorder. And it is a study that needs to be done.
So there’s a tip for a researcher who can’t think of a project!
There's More to Weight Than Meets the Eye
There’s an interesting article about the associations between obesity and mental illness.
We’ve all become so used to people telling us about the physical consequences of carrying extra weight, so it is interesting to learn that obesity may also be associated with higher rates of mental illness.
We have here a typical chicken and egg problem.
Do people become depressed because they are overweight, or does depression and its treatments cause obesity?
The answer is probably "Yes." It is both.
Depression may cause insulin resistance and hypercortisolemia, which may result in weight gain. But insulin resistance alters the kinetics of some of the amino acids that are the building blocks of key neurotransmitters in the brain.
And this study re-emphasizes the importance of treating the physical, psychological, social, subtle and spiritual aspects of a problem simultaneously.
If we address only one of these dimensions, people will continue to suffer needlessly.
When our clinicians see overweight people with depression or bipolar disorder, they start by treating the mood disorder, but then immediately get to work on the weight problem. And all of it is part of the five vector, or five dimensional approach to treatment: physical, psychological, social, subtle and spiritual.
If we fail to respect and work with every aspect of a person, each problem will return to make us respond appropriately.
After all, illnesses are like any other problem: sent to educate us. Not just you, but also the person to whom you went for help.
Insulin Resistance, Diabetes and the Timing of Meals
At a meeting of the American Diabetes Association in June 2006, Professor Markus Stoffel from the Eidgenossische Technishe Hochschule in Zurich and Rockefeller University in New York, received the Outstanding Scientific Achievement Award for his extremely interesting and important research on the molecular mechanisms involved in the developmental insulin resistance.
This may sound as interesting as watching paint dry, but in actual fact the research is supremely practical, and may lead to a complete re-working of some commonly used dietary strategies.
Many physicians have not yet been taught that the liver is the key organ involved in the genesis of insulin resistance and of type 2 diabetes mellitus. Up to 90% of the glucose circulating in your blood has come from your liver. As the liver becomes less sensitive to the actions of insulin, it starts producing more glucose, particularly after meals. This in turn causes blood glucose to rise and with it insulin levels. One of the other consequences of insulin resistance is that the liver stops storing triglycerides, which then start circulating, while at the same time storing other types of fat, leading to what we call, not surprisingly, fatty liver. Or in the dog Latin that doctors use to confuse the general public, hepatic steatosis.
When we are fasting, the liver switches on banks of genes that produce the enzymes responsible for oxidizing fatty acids to produce fuel.
The main objective of a balanced diet is to maintain balance: we want to avoid sudden swings in glucose, fatty acids or insulin: it is these sudden changes that can cause inflammatory changes in blood vessels and in the liver and may lead to some of the circulatory problems that are such distressing complications of diabetes. We want to try and keep our insulin levels smooth and low. The best way not to do that is to have frequent high calorie snacks and to eat late at night. The best way is to follow the plans that I’ve talked about before. Eat little and often, keep the balance of nutrients just right, and be aware of the exact times at which you eat. Nothing except a little protein in the 2-3 hours before you retire for the night, and go very easy on alcohol, which can wreck your metabolism.
“The secret of life is balance, and the absence of balance is life’s destruction.”
–Hazrat Inayat Khan (Founder of the Sufi Order of the West, 1882-1927)
Technorati tags: Insulin resistance Diabetes mellitus Fasting Weight management
Migraine and Bipolar Disorder
Back when the world was new, I cut my teeth in migraine research, and migraine and other headaches were the topic of my first book. So I’ve always kept an eye out for new developments.
There’s an interesting case report from India, about a nineteen year old who developed mild mania as part of the aura or warning of his attacks. This sort of case is interesting for what it might be able to teach us about each illness. It is also good for us to know that bipolar disorder is highly co-morbid: it is associated with many other illnesses apart from migraine:
1. Anxiety disorders
2. Substance abuse disorders
3. Attention deficit disorders
4. Personality disorders
5. Impulse control disorders
6. Eating disorders
7. Insulin resistance
8. Obesity
9. Diabetes mellitus
10. Cardiovascular diseases
11. Pain disorders
This is why diligent clinicians are always on the lookout for bipolar disorder: if it is missed and remains untreated, it can cause havoc: suicide attempts, damaged relationships, substance abuse and general misery.
Migraine is one of the vascular headaches that is occasionally associated with an array of other vascular problems, like Raynaud’s phenomenon, ischemic heart disease and stroke. But the aura is something else altogether. For many years it was thought that the migrainous aura was a result of a reduction in blood flow to regions of the cerebral cortex. Almost 25 years ago that was shown to be inaccurate. It is due to a release of witches’ brew of excitatory and inhibitory amino acids in the cortex. It is highly likely that the release of excitatory amino acids is the explanation for the manic symptoms.
Migrainous mania is evidently rare, but apart from visual disturbances, I’ve seen all sorts of strange auras: sudden food cravings; intense sweating; extreme irritability and many other things besides.
The treatment of migraine still revolves around avoidance or modulation of triggers, pain relief and prophylaxis. The big change in recent years has been the increasing amount of experience and small amount of evidence indicating the value of non-pharmacological approaches like spinal manipulation, temporomandibular joint adjustment, acupuncture, the tapping therapies and homeopathy.
To an integrated practitioner, the key is to understand the problem as more than just headache: we can guide a person to see the problem in its broader context, as a challenge designed to find a path toward inner wellness. We also see it as a process that has meaning and purpose and is a Divinely inspired invitation to grow spiritually and as an individual.
That may sound a lot for a headache, but it is the best possible way to triumph over the problem!
“The cure of the part should not be attempted without treatment of the whole.”
–Plato (Athenian Philosopher, 428-348 B.C.E.)
Technorati tags: Migraine Bipolar disorder Insulin resistance Attention deficit disorder AnxietyIntegrated medicine
How Many Angels Can Dance on the Head of a Needle? Moving Beyond the Metabolic Syndrome
I have written a great deal both on this blog and in scholarly articles, about insulin resistance and the insulin resistance and metabolic syndromes.
You will have noticed that I’ve always used the term insulin resistance syndrome.
This is not a matter of semantics. For years now I’ve been worried about the splitting that’s been going on in the field: we currently have six sets of definitions of the metabolic syndrome. And apart from the fun of going to all those conferences in exotic parts of the world, you have to ask what’s been achieved by these ever more divisive attempts to “define” the medical consequences of insulin resistance.
The American Diabetes Association has begun to promote the concept of “cardiometabolic risk.” The Association has established a national Cardiometabolic Risk Initiative (CMRI) to stress the association between diabetes, heart disease and stroke. The idea of introducing this umbrella term is to help people better understand and manage all diabetes and cardiovascular risk factors, and to side-step some of the controversy surrounding the definition of insulin resistance or metabolic syndrome and which cluster of variables are in and out.
A new Cardiometabolic Risk (CMR) Calculator to help us evaluate an individual’s risk of diabetes or vascular disease should be available by the end of the year.
The formula already includes factors such as:
1. Body mass index
2. Waist circumference ratio
3. Fasting plasma glucose
4. HDL-cholesterol
5. LDL-cholesterol
6. Triglycerides
7. Apolipoprotein B
8. Blood pressure
9. C-reactive protein
10. Age
11. Sex
12. Race/ethnic origin
13. Family history
14. Tobacco use
Part of the reason for this new initiative is the discovery that pre-diabetes, or impaired fasting glucose, where plasma glucose levels are 100-125 mg/dl, is associated with a high prevalence of cardiovascular disease risk factors such as obesity, hypertension and dyslipidemias.
The person who first proposed the insulin resistance syndrome, a.k.a. syndrome X, a.k.a. metabolic syndrome, is Gerald Reaven who first recognized the syndrome in a landmark paper in 1988. He recently gave a lecture entitled; “Insulin Resistance Versus Metabolic Syndrome: Different Names, Different Concepts, Different Goals.” I am in complete agreement with his basic proposition, which is that insulin resistance explains the clustering of all of the components that make up the metabolic syndrome. So Gerry’s position is that there’s no point in trying to make a diagnosis of metabolic syndrome: everything is due to insulin resistance.
So instead of wasting time and resources in trying to diagnose metabolic syndrome, it is much better to understand the pathophysiology: what is going on at the molecular level, how these processes produce risk factors, and whether we can predict others. We should identify and treat each of the underlying processes and the complications of insulin resistance. If we are going to have a syndrome, it should be called insulin resistance syndrome.
And let’s stop these academic debates and get on with the job at hand: there is a 600% variation in peoples’ ability to have insulin transport glucose into cells. More than half the US population is destined to develop at least some degree of insulin resistance, so we need to look for better ways to identify people who have it, and to apply the principles of integrated medicine to keeping them healthy.
Technorati tags: Insulin resistance Insulin resistance syndrome Metabolic syndrome Cardiovascular disease Hypertension Inflammation Hyperlipidemia Weight gain Integrated medicine
