The Doctor Weighs In

By Pat Salber, MD

We have known about the association between snoring and obesity for a long time. But we now know that sleep-disordered breathing (SBD) -- a sleep disturbance characterized by snoring and episodes of apnea or not breathing for periods of time -- is linked, independent of obesity, to insulin resistance, abnormal glucose metabolism, and Type 2 diabetes.

Sinziana Seicean, MD, MPH and colleagues published results of the Sleep Heart Health Study in the May 2008 issue of Diabetes Care. They studied 209 normal weight and 1,036 overweight/obese individuals who had a diagnosis of SDB, but did not have a diagnosis of diabetes. They found that SDB was associated with all of the manifestations of impaired glucose metabolism, including impaired fasting glucose, impaired glucose tolerance, and occult diabetes. The magnitude of the association between SDB and abnormal glucose metabolism was the same regardless of whether the individual was normal or overweight/obese.

This suggests that obesity is not the common cause of both insulin resistance and sleep-disordered breathing. Rather there appears to be an independent association between SDB and impaired glucose metabolism that is not explained by adiposity.

The authors suggest that the association of SDB with glucometabolic disturbances may relate to the “often-profound physiological stresses that occur overnight with sleep apnea.” They suggest that these stresses may transiently increase autonomic sympathetic activity, increase outpouring of the stress hormone, cortisol, and a decrease insulin sensitivity. Indeed, they point out that a human study of people with sleep apnea demonstrated improved insulin sensitivity after treatment of the SDB with continuous positive airway pressure (CPAP)

Why is this study important? Because it means that individuals with SDB who are normal weight may be at risk of impaired glucose metabolism. It also suggests that therapy aimed specifically at SDB and not just at obesity may be indicated to reverse that risk.

To learn if you are at risk of having SDB, answer the following questions based on the Berlin Questionnaire:

By Dov Michaeli MD, Ph.D

Have you ever looked at the list of ingredients on the foods you buy? I can guarantee that you’ll be hard put to find even one item that does not contain fructose in one form or another: it could be straight fructose, or masquerading as corn syrup, or sucrose (table sugar) whose content is 50% fructose. I recently checked 10 items in my foray to the local Safeway store; of the packaged foods, all ten contained fructose in one form or another. It's found in ketchup, fruits, jellies, pastries, and many processed foods. Even sugar substitutes can have high fructose corn syrup in them.

So what of it? Plenty.

Fructose and metabolic syndrome

One of the hallmarks of metabolic syndrome diagnosis is insulin resistance. What it basically means is the following: When glucose level in the blood gets to a certain level, glucose sensors in the beta cells of the pancreas initiate a commensurate release of insulin. The insulin binds to its receptors in the various tissues, and that results in uptake of the glucose by the cells and its utilization for energy and storage.

But something funny happens on the way to the insulin receptor when fructose undergoes metabolism: one of the end products is uric acid. Yes, the same compound that ends up in the urine, and that can cause such unpleasant things like kidney stones and gout. But uric acid turns out to do even more harm—it causes the cell to become insensitive to the message that insulin is trying to convey: take up more glucose from the blood. End result: increasing blood glucose levels, or hyperglycemia. And this, in turn leads to obesity and diabetes type 2.

The new food indexes

Beginning next year (and that’s in about 2 weeks) you will start seeing on the packaging of the foods you buy a new “index”: the nutritional value scale. One of these scales will use a numerical value, on a scale of one to one hundred, with 100 being the most nutritious. Others will use a star system, with 3 stars being the “best for you”. This is a laudable effort, initiate by academics specializing in nutrition science. But the subject of nutrition is so complex that I am sure each one of these scales will be subject to withering criticism. One of the reasons is that if real foods, no substance acts in isolation; grapes contain glucose, but dark-skin grapes also contain a high concentration of antioxidants. How do you balance the two? Or more relevant to the point of this article: apples, for instance, are high in fructose but also contain many other substances that far outweigh the latter’s deleterious effects. Will the new scales be able to account for that?

Caveat emptor

Be vigilant: check the label and look for fructose in all its disguises: corn syrup, corn fructose, or just fructose hiding in plain view. Sounds a bit paranoid? Next time when you in are the supermarket, do the experiment; check out the labels and you’d be amazed.

Interestingly, most food companies blamed the rising costs of corn (which nowadays is diverted to another political boondoggle—corn-based ethanol) for their poor financial results and the need to raise prices in the last two quarters. Corn, you might ask, in oat or wheat cereals? Yes, check the label: it is laced with corn syrup, which is nothing but a high-concentration solution of fructose.

Another interesting thought: could it be that our obesity/ diabetes epidemic is not entirely due to excess calories per se, but partly due to the ubiquitous fructose in our foods? This is quite conceivable; fructose is a food of extremely high glycemic value (namely, causes a rise in blood sugar) because of its high caloric content and because of its glucose resistance action.

So in this Christmas shopping season, here is one two-for-the-price-of-one bargain you should definitely pass up.

By Dov Michaeli MD, Ph.D

It is a well-known phenomenon: people under stress hit the fridge, and gorge on candy and fatty food. A gallon of ice scream in one sitting is not unheard of. But people who think deeply about such things asked themselves: why don’t they (people under stress) gorge on veggies? And what is the nature of the connection between stress and obesity? Is it simply overeating equalsobesity, or is there a deeper connection, involving the brain? After all, stress is a mind thing.

The physiology of acute stress

Almost every physiological action in our body is controlled by two systems: the autonomic nervous system, and the endocrine system.

The autonomic nervous system has this name because it is, well, autonomic: it marches to its own drum, if you will, independently of our whims, wishes or commands. This system is made up of two sub-systems: the sympathetic and the parasympathetic. Basically, they are the Yin and Yang of the autonomic nervous system: the sympathetic nerves secrete noradrenaline, a close relative of adrenaline, and it does everything you’d expect it to do: it accelerates the heart rate, increases blood pressure, in short: it readies the body to react to acute stress situations. My favorite example: you spot a lion coming at you. You want to supply ample blood to your muscles so you can run for your life, or if you are foolish enough, fight the lion; hence the increase in heart rate and blood pressure. The parasympathetic system secretes the neurotransmitter acetyl choline , and it has exactly the opposite action: it slows down the heart and reduces blood pressure.

The endocrine system reacts to stress by releasing two ‘stress hormones’: cortisol from the brain and adrenaline from the adrenal gland. Their action is similar to that of the sympathetic nervous system: increase blood pressure and heart rate.

The other type of stress

So far so good; but how does increased heart rate cause obesity? The answer is: it doesn’t. What I just described is the response to acute stress, and our bodies are well-adapted to handle it. But modern life added another type of stress: chronic stress. And here, a peptide, called neuropeptide Y, or NPY, comes into play. Its existence has been known for several years, but its function was largely unknown. It is expressed throughout the brain, but is especially abundant in circuits that regulate feeding and response to stress. Not surprisingly, like many other brain hormones, it is also secreted in tissues outside the brain that are involved in metabolism; it is secreted by sympathetic nerve endings in adipose tissue. Its function there has only recently been defined by Kuo and his coworkers. It increases adipogenesis (formation of fat tissue) by triggering both the formation of new adipocytes (fat cells) from immature preadipocytes, and by increasing the blood supply to the adipose tissue by formation of new blood vessels (a process called angiogenesis). Even more intriguing: the new fat tissue was not formed just anywhere in the body; it was formed in the abdomen, and specifically around the internal organs of the abdomen. This is exactly the fat distribution that is implicated in the genesis of metabolic syndrome. And to clinch the case: it does it only under severe chronic stress conditions. When mice were subjected to 2 threatening and severe chronic stress protocols, they secreted NPY; when they were subjected to non-threatening mild stress—no NPY. In biological experiments demonstration of a relationship between the “dose” (e.g. severity of the chronic stress) and “response” (e.g. secretion of the peptide), lends credibility to the observation, simply because in biology almost everything is dose-dependent.

Why do we prefer sweets and fats?

The mice in the experiment secreted NPY only if allowed to eat fatty or sugary food. Regular mouse chow did not support secretion of the hormone even under severe chronic stress conditions. We know that high calorie food triggers the reward circuits in the brain. In fact, chronic feeding of high calorie foods activates all the circuits and brain centers that are involved in addiction. That, in turn, induces more eating, which increases the degree of addiction, which… you get the drift. Bottom line: obesity.

The details of the connection between secretion of NPY and high calorie food still need to be worked out. Why didn’t regular, low calorie food have the same effect? What are the specific neural circuits involved in this calorie/reward/peptide axis of evil? What is the mechanism for the specific accumulation of fat around internal organs? Will withdrawal of high-calorie food result in reversal of the accumulation of fat back to normal?

Obviously, many unanswered questioned are triggered by this research. But this is the hallmark of good science: every answer raises many more questions.

In summary

NPY is the link between stress and obesity. Its action:

• Secreted from the sympathetic nervous system only under conditions of chronic severe stress
• Increases adipogenesis by triggering adipocytes formation from preadipocytes, and by increasing blood supply to the adipose tissue
• Secreted only when high calorie diet is available
• Involves the activation of reward circuits in the brain
• And last but not least, it induced a state of metabolic syndrome (obesity, insulin resistance) in the experimental mice.

What is the relevance of this research to human obesity/metabolic syndrome?

Obviously, this phenomenon needs to be demonstrated in humans. Demonstration that NPY levels are markedly higher in chronically-stressed individuals will be a big step forward. Inhibition of secretion of NPY through drugs or stress reduction techniques will add weight to the hypothesis.

The big prize: demonstration of weight reduction through reduction of NPY secretion will be a boon to us and to our strained health care budget.

Here is a thought that may have occurred to you: can our increasingly stressful lifestyle be partly responsible for the obesity/metabolic syndrome epidemic?

Another thought: rather than wait for the results of these experiments to yield the ultimate proof, why not toss out all the sweets and high calorie foods, and stock the fridge with “good for you” veggies? No activation of the reward system in your brain=no NPY secretion. Not very appetizing solution, I know. I’d rather wait for the results of the human experiments, and then decide.

Epilogue

My estimate is that to carry out the required experiments in humans would cost about $10-20M. To develop and clinically test an NPY inhibitory drug could cost anywhere from $50-100M. Can the health care mavens quickly calculate what would be the ROI (return on investment) on this sum?

by Pat Salber

Today is the first ever UN-observed World Diabetes Day led by the International Diabetes Federation. It was established as a result of a resolution passed last December by the General Assembly of the UN. The idea behind the Day is to increase visibility of diabetes world-wide.  Hopefully this will lead to better funding, more research, public education, and other resources being applied to the condition.

The focus of this year’s World Diabetes Day campaign is diabetes in children and adolescents. Diabetes is one of the most common chronic disease of childhood. Children and teens can develop Type 1 diabetes – an autoimmune disorder in which the insulin producing cells in the pancreas are destroyed – or they can develop Type 2 diabetes – a condition caused by the development of resistance to the hormone, insulin.

Type 2 diabetes used to be rare in kids, but with the advent of the childhood obesity epidemic, Type 2 diabetes is now seen in even very young children. Both Type 1 and Type 2 diabetes are associated with serious complications, such as kidney, nerve and eye damage, as well as atherosclerotic vascular diseases, such as coronary artery disease.

Type 1 diabetes is rapidly fatal if not treated with insulin. Type 2 diabetes has a longer course, but if untreated or inadequately treated, lifespan is usually shortened significantly. In developing countries, access to early diagnosis and appropriate treatment of diabetes may be limited resulting in many children dying from a treatable disease. In countries with good access to health care, failure of family members, teachers, and others who care for children to recognize symptoms of diabetes can lead to delays in diagnosis that can occasionally be fatal.

The World Diabetes Day 2007 and 2008 campaigns are focused on changing the status quo with the stated goal that “no child should die of diabetes.”

Here are some statistics that highlight the magnitude of the problem:

• Type 1 diabetes is increasing by 3% per year in children and adolescents and by 5% in pre-school children - that translates into almost 200 children per day developing the disease.
• Of the approximately 440,000 cases of Type 1 diabetes in children worldwide, more than a quarter live in South East Asia and more than a fifth in Europe.
• Type 2 diabetes, previously rare in children, now constitutes between 8 to 45% of new childhood cases depending on geographic location.
• Over the past 20 years, type 2 diabetes has doubled in Japanese children. It is now more common than Type 1 diabetes.
• In native and aboriginal children in North America and Australia, type 2 diabetes range from 1.3% to 5.3%

Diabetes can be very difficult for adults to manage. It involves checking blood glucose levels, taking multiple medications, and in the case of Type 1 diabetes, multiple daily doses of insulin by injection. Imagine how hard it is for children who are also trying to do well at school, make and keep friends, and deal with the emotional issues related to growing up – particularly during adolescence. Families with diabetic children often find themselves overwhelmed by all there is to know and do. Add to that the socioeconomic challenges that people with limited resources face on a daily basis, for example, those living in poverty and the ability to manage diabetes must seem insurmountable. These families and other caregivers need help – to access needed health care and health education and support.

World Diabetes Day highlights these formidible challenges, but we must all respond by supporting this campaign with our time…and yes, with our money. To learn more, go to the World Diabetes Day website, http://www.worlddiabetesday.org.

By William H. Bestermann Jr. MD

Type 2 diabetes is a condition that costs Americans terribly in terms of death, disability, and health care expenditures. This chronic condition is a vicious cycle type of illness. Glucose control tends to deteriorate over time. Most of these patients also have problems with blood pressure and cholesterol. Only about a third of type 2 diabetics have their pressure, sugar, or cholesterol under control as individual risk factors. Only 7% have all three risk factors controlled simultaneously to conservative goals. This sad fact has dramatic consequences. The lifetime risk of a diabetic having a heart attack or a stroke is 80%. For each risk factor that is controlled to goal using the right medication, the risk is reduced by roughly half—so when we control pressure, sugar, and cholesterol the risk is reduced from 80% to 40% to 20% to 10%. Now maybe the risk is not really 10%, but it is very dramatically reduced and in 10 years of experience with 450 diabetics, I believe that I have seen a very important reduction in vascular events that has been achieved by aggressively controlling these risk factors..

Everything bad that happens to a diabetic is fundamentally arterial or vascular. Obviously the heart attacks, strokes and amputations are vascular, but even the kidney, nerve and eye damage relate to arterial damage as well. So the target here is not just the sugar or the cholesterol. The fundamental question is “how do we lower the sugar, cholesterol and pressure with the maximum benefit on the artery?” Furthermore, how do we accomplish this in such a way that the patient’s life is minimally altered and this is sustainable.

In this post, I will focus on sugar control. Everyone agrees that type 2 diabetes is at its core a life-style illness. As one of my colleagues in South Carolina said: “There is nothing that we can do for diabetes that you cannot outrun with a spoon.” In other words, if the patient does not make some effort with diet and exercise, it is difficult and perhaps impossible to get risk factors to goal. I have controlled the sugar in disabled patients, but it is more difficult. Type 2 diabetes is a disease of elevated blood sugar. It is self-evident that sugar consumption must be limited. Less widely appreciated is the impact of starch or carbohydrate consumption. Processed starch becomes sugar in 2 minutes once it is consumed. When a person eats 100 calories of white rice, in 2 minutes it is just as if he took a spoon and ate 100 calories of sugar out of the sugar bowl. The less processed a carbohydrate, the more slowly it is consumed.

Some understanding of nutrition is vital. Formal dietary instruction by a certified diabetic instructor is helpful but I see substantial variation in what patients are told. As a practical matter I have found the South Beach diet to be very useful and just bought the book for a friend at Walmart for $12.00. I have recommended that diet for patients and found it very effective with sustainable effects on weight and sugar control. Dr Agatson, the author, is a cardiologist famous for developing the cat scan calcium score we use to determine cardiac risk. He teaches two very important concepts. First, we have to learn to limit starch and to eat our starch in the form of whole foods. Second, we need to limit fats, especially animal fats and trans fat. This program is attractive because it is effective, widely available, and supported by recipe books and pre-packaged items.

Next we come to drug therapy. Doctors are trained in the treatment of diabetes with medication by learning about all of the medications that are available, and then they are left to decide which of these many medications they will use and in what order. There are several different classes of oral drugs with multiple drugs in each class. There are multiple types of insulin with differing durations of action. There is no real protocol that is universally agreed upon as best practice.

Type 2 diabetes is the later stage of the metabolic syndrome. Most type 2 diabetics have been metabolically abnormal for decades. They have been resistant to the effects of insulin for years and just before they become diabetic they have been maintaining their normal sugar by producing levels of insulin in the blood that are three times normal. As time goes on they are unable to sustain that level of insulin production and when insulin levels fall the sugar begins to rise. At the time of diagnosis, insulin production has fallen by 50% and the loss of the ability to produce insulin is aggravated by poor sugar control—a built-in vicious cycle. When it comes to diabetes, we just do too little too late.

In recognition of this fact, there was a recent consensus algorithm published in Diabetes Care. This is a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. They emphasized the importance of diet and exercise as first therapy. Most notably in my view the authors went on to say, “The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain metabolic goals, either because of failure to lose weight, weight regain, progressive disease, or a combination of factors. Therefore, our consensus is that metformin therapy should be initiated concurrent with lifestyle intervention at diagnosis.” Most medications for diabetes cause weight gain. Metformin has modest effects in assisting with weight reduction and it is the only medical treatment for diabetes that is proven to lower the incidence of heart attack and stroke by 40%. That effect is on a par with the best cholesterol and pressure treatments.

If treatment with metformin fails, it is generally because insulin production is at least relatively inadequate. The most effective and rational next step is to instruct the patient in a self-adjusted insulin shot using Lantus or Levemir. In the protocol I use, the patient is able to rapidly bring the sugar safely down and most patients are at goal with this reasonably simple approach. It seems to me that the proven vascular benefits of metformin would be preserved in these patients since all we are doing is replacing insulin that they cannot make themselves. Most patients are really surprised at how easy this is to work with and how much better they feel when their sugar is controlled.

The American Diabetes Association recently published Proceedings of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. The proceedings are published in a July 2007 supplement to Diabetes Care.

The experts participating in this conference have recommended the following screening strategy for Gestational Diabetes Mellitus (GDM):

Risk for gestational diabetes should be ascertained at the first prenatal visit.

Low risk:

• Member of an ethnic group with a low prevalence of GDM
• No known diabetes in first degree relatives
• Age < 25 years old
• Weight normal before pregnancy
• Weight normal at birth
• No history of abnormal glucose metabolism
• No history of poor obstetrical outcomes

If all of the following characteristics are present, low risk women are not required to have blood glucose tested routinely.

High risk:

• Severe obesity
• Strong family history of type 2 diabetes
• Previous history of GDM, impaired glucose metabolism (e.g., insulin resistance, metabolic syndrome, or type 2 diabetes), or glucosuria (glucose in the urine)

Perform blood glucose testing as soon as feasible if one or more of the high risk factors are present. If GDM is not diagnosed, blood glucose testing should be repeated at 24-28 weeks or at any time a patient has symptoms or signs that are suggestive of hyperglycemia.

Average risk (everyone who is not low or high risk):

Perform blood glucose testing at 24-28 week on all average risk women

New to the screening guidelines this year is the inclusion of “normal weight at birth” to the list of requirements to be considered low risk. This was added because of evidence that women who were at the extremes of birth weight have altered insulin action and/or insulin secretory capacity that may predispose them to the development of GDM as adults.

There is an increasing prevalence of GDM in the US that appears tied to the increase in obesity and type 2 diabetes incidence. Because impact of GDM on both the mother and the fetus can be ameliorated with aggressive treatment, it is imperative that all pregnant women seek early prenatal care, have their risk for GDM assessed, and have glucose tolerance testing as outlined above.

by Bill Besterman

The underpinning for much of the death and disability from arterial vascular disease in this country is the metabolic syndrome. One of the real authorities on the metabolic syndrome is a Dr. Ralph DeFronzo.  I particularly like his description of this collection of disorders as a “complex metabolic web.” 

The patients who have this diagnosis are burdened with multiple chronic conditions: hypertension, high LDL or bad cholesterol, high triglycerides, low HDL or good cholesterol, and high blood sugar ultimately resulting in type 2 diabetes. These patients routinely have vascular systems where the vessels are inflamed and the blood more likely to clot.

Early in the condition the arteries are thicker and less distensible than in people without the syndrome; progression of the arterial disease is the norm. Many of affected individuals also have gout. More recently, the metabolic syndrome has been called the cardiometabolic syndrome because this name underscores the impact of these conditions on the heart and the rest of the vascular system. Metabolic syndrome patients have an increased risk of coronary artery disease, cardiac enlargement and congestive heart failure.  Type 2 diabetes is the late stage of the syndrome

Dr. DeFronzo highlights a very important clinical reality in describing the cardiometabolic syndrome as a complex metabolic web. "Job one" of the clinicians who treat these patients is to unravel that complex web using every medical and lifestyle tool in the medical toolbox.

Only 7% of these patients have all of their risk factors (hypertension, blood sugar, and cholesterol) simultaneously controlled to the most conservative goals. For each risk factor that is controlled, using the proper interventions, the risk of all adverse outcomes is reduced by roughly 50%. So, the task of the clinician is not just to control hypertension or diabetes, but rather to control all risk factors to goal at the same time.

That is where the focus, skill and training of your provider come into play. The particular medical choices that are made are critical for success. For three decades now I have heard physicians blame patients for not being “compliant:”

 “Mrs. Brown is diabetic and she does not listen to a thing I tell her. She just stuffs herself with anything she wants and she continues to gain weight.”

Here is the reality. Every medication commonly used for the treatment of type 2 diabetes causes weight gain with the exception of metformin (Glucophage) and the Byetta-type medications. The new drug Januvia is weight neutral. Most patients do not have their sugar controlled to goal using a single medication. Most patients require multiple drugs and even then progressive loss of glucose control is the norm. Weight gain not only makes control of the sugar more difficult—the metabolic syndrome is itself worsened by increased abdominal weight—weight gain also makes controlling pressure, cholesterol, triglycerides and gout more difficult.

The patient that receives a prescription for two shots of NPH insulin a day will gain 10 pounds in a year. The patient that uses glyburide plus a single shot of NPH gains 9 pounds. The regimen combining  glyburide, metformin and a single shot of NPH, produces a similar weight gain. Metformin added to a single injection of NPH at bedtime produces no weight gain, the best control of the blood sugar and the least number of hypoglycemic attacks. The doctor with the prescription pad is producing this result—not the patient. These are impressive weight changes and they make a big difference over time. I have treated 450 type 2 diabetics for nearly 10 years with a regimen based on metformin and a long-acting insulin injection with durable control in most patients.

The treatment of high blood pressure hides the same kind of traps. Until very recently beta blockers like propranolol (Inderal), metoprolol (Toprol) and atenolol (Tenormin) were recommended as first line therapies for the treatment of hypertension.  Many patients continue to be on these medications for the one purpose of treating high blood pressure. These medications have important metabolic effects:

• Propranolol increases triglycerides by 25%, decreases HDL by 10%, increases total cholesterol by 9% and increases insulin resistance by 33%
• Metoprolol increases triglycerides by 30%, decreases HDL by 7%, decreases total cholesterol by 1%, and increases insulin resistance by 21%

Tricor (fenofibrate) is prescribed to treat the lipid or cholesterol abnormalities that go with the metabolic syndrome decreases triglycerides by 29%, increases HDL by 11%, and decreases total cholesterol by 18%.  When we prescribe propranolol and fenofibrate simultaneously, we have simply cancelled the lipid effect of two drugs.

The prescription of propranolol makes it 28% more likely that the patient will develop diabetes. Choosing an ACE inhibitor makes it 33% less likely that a patient will develop diabetes. These are critical metabolic issues. There is a newer beta blocker carvedilol, with dramatically improved metabolic effects relative to the older drugs.

The point of all this is that treatment of these patients is very complex if it is done properly. 95% of type 2 diabetes care is provided by primary care doctors who are under tremendous pressure to see patients at the rate of 5-6 per hour. They are required to be experts in the whole massive knowledge base of medical practice We need focused clinics of the type described by the Institute of Medicine to treat metabolic syndrome patients. The providers in these clinics will need to be very expert in the coordinated, integrated management of metabolic syndrome patients and the resulting complications. Until that happens, we will continue to produce the same poor levels of risk factor control and pay a terrible price in lives, disability and treasure.

Yesterday’s New York Times ( May 8, 2007 ) carried a front page article by one of the paper’s premier science reporters, Gina Kolata. The article, titled “genes take charge, and diets fall by the wayside”, is an excerpt of her newly published book “Rethinking thin: the new science of weight loss- and the myths and realities of weight loss”. In the article she reviews the succession of studies started in the late 1950’s by Dr Jules Hirsch at Rockefeller University , which culminated in recent studies demonstrating conclusively that the tendency to weight gain and obesity is genetically determined. Ms. Kolata describes the heartbreak of dieting, a constant struggle of losing weight, trying to maintain, gaining, dieting again, and so on and so on. Psychological testing showed the toll this struggle can take; people are perpetually unhappy, many are chronically depressed, some are suicidal.

One of the major conclusions Kolata cites is that each body has a metabolic “comfort zone”, and dieting to go below this zone is painful, metabolically unsound, and essentially futile.

I admit I haven’t read the book yet, but if the excerpt reflects the message of the book, I strongly disagree.

Why?

For several reasons:

· Yes, a metabolic range specific to each body makes a lot of intuitive sense. But to accept it we need to see the genetic/molecular/physiological mechanisms. The evidence is still not in. Having been around the block a few times, I never cease to marvel at nature outsmarting us, and upending our ‘no brainers’ and ‘slam dunks’.

· The fact that genes control our metabolism does not mean that they are the sole players. Genes interact with the environment, and the outcome of this interaction is all important. The old debate of nature vs. nurture set up a false choice; nature and nurture operate together in biology. The best example is diabetes type 2. An individual may have the genes that predispose to this disease. But it will be expressed clinically only if that individual overeats and exceeds a certain BMI.

· The most obvious evidence that genes are not the final word in weight regulation is the recent obesity epidemic. If  "obesity genes",which undoubtedly have been with us for eons, were such an all-controlling factor, why is it that only in the last few years did this epidemic break out? The answer is well-known: we take in a lot more calories, and we exercise a lot less. Yes, the genes were there all along, but they were not expressed.

I believe that research into the genetic basis of obesity and diabetes is absolutely essential. But it should not become an excuse for the fatalistic attitude of “it’s beyond my control”. Counteracting and ovecoming the genetic dictate may be unpleasant, tough, exasperating—but it beats the alternative.

Dov Michaeli MD, Ph.D

We all know the devastating statistics:

· 13.5 million people in the US suffer from coronary artery disease

· 8 million people have diabetes type 2.

· 95,000 people are diagnosed every year with colon cancer, and a sedentary lifestyle increases the likelihood of getting this disease by 40%.

· People who don’t exercise have about a 60% increase in osteoporosis; 250,000 suffer from hip fracture every year.

· 50 million suffer from hypertension.

· More than 60 million people in the US are overweight.

You might conclude from the last bullet that obesity is the culprit. You’d be only partly right. Lack of physical fitness is the other culprit, regardless of percentage of body fat. Even if we take people with a high % of body fat (more than 25%), the relative risk of death from all causes in the fit person is half that of the unfit.

Exercise and the body.

The effects of exercise on the body are well known:

· Exercise increases HDL, the good cholesterol, by an average of 4.6%. This, in turn, results in a decreased risk of coronary artery disease.

· Exercise increases insulin sensitivity, reducing the risk of metabolic syndrome and diabetes type 2.

· Exercise strengthens the heart muscle, improving its function.

· Exercise increases bone size and density, reducing bone loss due to aging and osteoporosis.

· Exercise increases muscle strength, coordination and reaction time. Result: improved balance and stability; reduction in falls and bone fractures.

What about mind?

This is a truly fascinating story, and you can read about it in more detail in an article in Newsweek, March 26, 2007 , by Michael Craig Miller, MD, from Harvard Medical School . Here are the salient points:

· Exercise has been known for many years to give, during and after exercise an “endorphin high”. This is the feeling of satisfaction, well being, and increased self-esteem that many people experience. This effect is short term, on the order 1-2 days in duration.

· Aerobic exercise increases blood supply to the brain, thus increasing oxygen and nutrient supply to the neurons, and removing metabolic waste materials from the brain.

· Aerobic exercise increases the production of neurotrophic factors in the hippocampus.

What are neurotrophic factors?

When the nerve cells are getting organized to form the organ that we call ‘brain’ (a process that doesn’t end at birth, it actually continues until about age 20), they do it under the direction and control of peptides and proteins that are secreted by the nerve cells themselves. But the job of these factors doesn’t end there: they continue to shape, modify, and re-shape several areas of the brain. They are essential for the formation of new neurons from stem cells—a process called neurogenesis. They also are important in the formation of new connections between existing neurons—a process called neuroplasticity. These two processes are important because they are the basis for learning and memory; everything we know and remember is stored in neuronal circuits. Furthermore, the thicker the connections between the neurons the faster the flow of information in the circuits—very much like the broadband required for fast transmission of electronic signals. The brain factors cause this thickening as well.

There are several known neurotrophic factors that have been shown to increase in concentration due to a sustained, long term exercise regimen:

· BDNF (Brain-Derived Neurotrophic Factor).

· NPY (Neurpeptide Y).

· VEGF (Vascular Endothelial Growth Factor).

The fact that we can identify specific brain peptides that increase neurogenesis and neuroplasticity is interesting enough. But what makes it even more fascinating is where in the brain this increase happens.

Enter the Sea Horse.

In the temporal lobe of the brain there is an area, called the hippocampus, because it is shaped like a sea horse. This area regulates emotions and stores memories. In fact, it has been known that in aging brains and in depression, two situations in which neurogenesis and neuroplasticity are reduced, the hippocampus gets smaller. Furthermore, electroshock therapy and antidepressants caused an increase in the size of the hippocampus, apparently due to increase in neurogenesis and neuroplasticity.

It was especially gratifying to read in the latest Proceedings of the National Academy of Sciences (PNAS, vol. 104, p. 4647, 2007) the report by Warner-Schmidt and Duman. The unequivocally demonstrated that the antidepressant drug fluoxetine (Prozac) and the pain-control drug desipramine (Norpramine, Pertofran), cause a large increase in VEGF in a specific area of the hippocampus (The subgranular zone). Interestingly, desipramine’s action is inhibition of pain signals ascending through the spinal cord to the brain; in other words, it inhibits the perception of pain.

Not surprisingly, aerobic exercise does the same thing. We even know how this happens on the molecular level—through the action of the very same brain factors: BDNF, NPY, and VEGF.

The take home lessons

· We now know beyond the shadow of a doubt that aerobic exercise increases the feeling of well being, increases learning capacity and improves memory.

· Aerobic exercise ameliorates depression and is becoming an additional tool in the treatment of this disease.

· Aerobic exercise reverses the effects of aging on the brain.

· Aerobic exercise may reduce the perception of pain—an important implication for people suffering from chronic pain, such as arthritis.

One final note: to all you Yoga practitioners, iron pumpers, and assorted other exercise enthusiasts—these effects on the brain were demonstrated only with aerobic exercise. Sorry.

Dov Michaeli, MD, Ph.D

It isn’t often that you get a good chuckle while reading a medical journal. But today I did. I am on a plane again (not United Airlines, thank heavens) .  I am flipping through some recent issues of the Journal of the American Medical Association (JAMA). One article catches my eye. It describes the case of a woman with polycystic ovary syndrome (PCOS).   I decided to read it in detail to see if there was anything new in the cause, diagnosis, or treatment of women PCOS since I last wrote about it – there wasn’t.

PCOS is one of the most common causes of anovulatory infertility. Women with the condition have irregular periods, and cycles where they don’t ovulate. They also have physical findings related to hyperandrogenism (excess hair growth, acne), and they are frequently overweight or obese. Many are insulin resistant and some will go on to develop Type 2 diabetes. PCOS is risk factor for that condition.

As I read through this case study, I found that I didn’t really agree with the physician expert’s take on the case. The patient, “Ms R,” was worried because she had gained weight despite a pretty rigorous exercise regimen (she bikes 20 miles a day and swims regularly). She was described as 59 inches and 122 pounds with a BMI of 25. Did I do the math right? That means she is quite short to be packing around 122 pounds. She says she eats the same as she always has, but at the ripe old age of 27, she finds that she has gained weight.

The doctor discussing this case kept saying it was good that Ms R was “normal” weight, but we never learn whether she is slender or. in fact, is “abdominally” obese. And, he doesn’t mention whether he actually assessed how much she eats in a typical day or if he just believed her uncritical self-assessment. Before I started logging my food intake, I probably would have told you that I ate the same amount of calories as I did when I was thirty and thin. But once I started weighing and measuring and counting and recording my intake, surprise, surprise, I was actually quite an oink-oink. The weight started dropping when I decreased my intake to a caloric amount more appropriate for my height.

This article also does not mention Ms R’s ethnic background. Asians and South Asians can have abdominal obesity (and associated insulin resistance) at BMIs that are considered “normal.” It isn’t the BMI that is the problem, it is the abdominal, and in particular, intraabdominal or visceral fat – that is the problem. (I am willing to bet Ms R has plenty of fat around her middle.

Although her most recent fasting glucose level is normal, this woman is at risk for Type 2 diabetes because her father had it. And, as the doctor discussant pointed out he didn’t test her to see if she was glucose intolerant. You have to do a glucose tolerance test (drink a sugary substance and have blood drawn at regular intervals after that) to detect this type of insulin-resistance-related abnormality in glucose metabolism.

So I am already a little annoyed by the way this case is being discussed, but then, on the last page, this doctor says that he would counsel the patient that she appears to have a mild case of PCOS (not sure if this is the equivalent of doctors who tell their patients that they have a “touch of sugar.”) He recommends she keep on taking birth control pills that help her have regular periods and counteract the hair growth and acne cause by the increased androgen levels characteristic of PCOS (I agree). He enthuses that Ms R has “done an admirable job at weight control.” Yeah? But he did say he would refer her to a dietitian for further counseling on diet.

And then, comes the comic bombshell: He says, “I would counsel her against excessive “Googling” of PCOS on the web. I kid you not…I can hear it now, “No excessive googling, dear, you might learn something I don’t agree with?”

I have already written about Google’s ability to diagnose. This doctor has taken “Googling” to a new level by including this admonition in his case discussion in a respected medical journal. What a hoot.

Pat Salber, MD, MBA

An article in the NY Times declares that one in eight adults in NY City has diabetes. That is 12.5% of the population or 700,000 people. Lest you feel relieved that you don’t live there, let me remind you that the rest of the country is not all that far behind. Overall, about 10.3% of Americans have diabetes and about a quarter of them don’t know it (yet). 

An additional 24% of adults in NY (and in the rest of the country) have abnormally high blood sugars that have not yet reached diabetic levels.  This condition is known as pre-diabetes.

Not too many years ago, the diabetes rate was 6%--half of the current NY rate. But our self-indulgent ways have caught up with us. Too little exercise, too many calories plus too much stress adds up to an epidemic of obesity, particularly abdominal obesity.  Abdominal obesity, especially visceral obesity, is linked to the development of Type 2 diabetes in genetically predisposed individuals.

It’s just a “touch of sugar.” Why all the concern? Because diabetes and it precursor, pre-diabetes, are the most familiar manifestations of a constellation of metabolic changes, known as cardiometabolic syndrome. Other manifestations of this syndrome are high blood pressure, dyslipidemia ((high triglycerides and low HDL (“good”) cholesterol)), clotting abnormalities, and problems with inflammation. People with cardiometabolic syndrome, even if they haven’t yet developed full-blown diabetes, have an increased risk of heart attacks and strokes.

Cardiovascular disease, strokes, and peripheral vascular disease are all very expensive conditions to treat in our technologically sophisticated health care system. These conditions already occupy some of the top slots when it comes to where our health care dollar are spent. So imagine what is going to happen now that the rates of diabetes have doubled (with no end in sight).

So, this epidemic of diabetes and pre-diabetes is not just a health care issue that burdens individuals and their families living with the disease. It is a looming societal problem that threatens to bankrupt our already fragile health care system. It could cause health care insurance premiums to escalate even further, impacting not only employers who provide coverage, but also public payors, like Medicaid and Medicare.

It is time to get deadly serious about doing something about prevention. We need to rapidly move to institutionalize regular exercise programs in school and at work. And we need affordable, easily accessible healthy eating options. That means we must be willing to regulate, legislate, and maybe even implement taxes (oh, oh, the tax word!) that can get us to where we need to be. Failure to do something now will almost certainly result in huge adverse financial consequences that will ripple through society in the not too distant future.

We have known for a long time that the distribution of fat in the body is important in determining important health risks, such as type 2 diabetes and cardiovascular disease. “Apples” (or the abdominally obese) are at much greater risk than pear-shaped people who tend to deposit their fat in the hips, thighs and butts.

More recently, researchers have determined that one type of belly fat, called visceral fat, is worse than belly fat just below skin.  Visceral fat is deposited the omentum, the tissue that drapes around the intestines and other abdominal cavity organs (or viscera). You don’t have to be obese to have visceral fat. One the other hand, not all people who are obese develop significant amounts of this “bad fat.”

An article in the San Francisco Chronicle reports that recent research suggests that abdominal fat is related to the release of the stress hormone, cortisol. According to UCSF’s assistant professor of psychiatry, Elissa Epel, an expert on the physiological effects of stress, cortisol which is released when people are under stress, seems to interact with the pancreatic hormone, insulin, to create visceral fat. At the same time, cortisol stimulates a craving for “comfort foods” – the sweet stuff and the stuff high in fat. This is a double whammy – you desire and, as a result, often consume high calorie foods and you deposit those excess calories as bad fat in your belly.

To test the hypothesis that stress is related the deposition of visceral fat, researchers at the University of California San Francisco are recruiting 50 overweight women to participate in a study on the impact of stress relief techniques on body fat, particularly visceral fat. The study is not designed to help the participants lose weight per se, rather it is designed to reduce stress and stress-related eating.

The 50 women will be divided into two groups. One group will start stress reduction classes right away, the other won’t start these classes until after 6 months have passed. The classes will teach women stress reduction techniques and will also teach them how to recognize triggers that prompt stress-related eating. They will also be taught “mindful eating.”

I described mindful eating in my recent post “Getting in touch with your feelings…about raisins.” In that post, I describe a “raisin exercise” developed by the author of Soul-Full Eating, Maureen Whitehouse. This approach to eating involves really engaging with the foods you eat. As opposed to gulping them down as many of us do in the course of our hectic lives, you are taught to visually examine the food and then explore it with your fingers and hands. When you put it in your mouth, you explore it with your tongue and chew it, ever so slowly, letting the flavors linger in your mouth and in your mind.

According to a co-researcher on the UCSF study, Jennifer Daubenmier, a postdoctoral fellow with the UCSF Center for Obesity Assesment, Study and Treatment, mindful eating helps participants to think about how and why they eat. The goal of the UCSF program is to ultimately help the participants make better, smarter food choices. Although weight loss is not the goal, it is hoped that the program will result in a reduction of bad belly fat.

To qualify for the study, women must weigh less than 300 pounds and have apple-shaped figures. They must be between 21 and 50 years old. They must not be recently pregnant, diabetic or have heart disease. If you fit these criteria and are interesting in participating in the study, send an email to ucsfcalmmstudy@yahoo.com. If you want to learn more about what it means to participate in a clinical trial, click here.

In the old days….

When I trained in endocrinology many moons ago, we used to categorize diabetes as either “juvenile-onset” or “adult-onset.” We knew it wasn’t a perfect classification scheme  since a small number of older individuals contracted juvenile diabetes  -- a disorder characterized by immune destruction of the pancreatic islet cells (in particular, the Beta cells that produce insulin). People with this type of diabetes cannot make insulin and, therefore, require exogenous insulin, such as insulin injections, for long term survival.

Then, we really didn’t think the adult-type diabetes occurred in kids…but now it is found in children of all ages, even toddlers. What we called adult-onset diabetes, at that time, is actually a form of diabetes commonly found in overweight or obese individuals. At least initially, people with this type of diabetes have higher than normal levels of insulin.  It just doesn't work as well because these individuals are insulin resistant.

Insulin dependent vs insulin taking

Because individuals with the juvenile form of diabetes can’t make insulin, and therefore have to take insulin shots to survive, we started calling this form “insulin-dependent diabetes mellitus” or IDDM. Since people with the adult form of diabetes did not die quickly without administered insulin, we started calling it “non-insulin dependent diabetes mellitus” or NIDDM. (The mellitus part of the name refers to the fact that both forms of diabetes are characterized by having glucose in the urine….mellitus means honey.)

We changed the names of these conditions again because many people with NIDDM were found to eventually require insulin for good glucose control. Some people got confused by this and incorrectly labeled insulin-taking NIDDM patients as insulin-dependent. Are you following all of this?

Changing names again: Type 1 and Type 2

As a result of the confusion about dependence vs. use, it was decided to change the names again. IDDM became Type 1 diabetes. And NIDDM became Type 2 diabetes.

The problem is, however, that some individuals whom appear clinically to have Type 1 diabetes, do not have the immune markers associated with pancreatic islet cell destruction – a feature that is considered characteristic of that disorder. The American Diabetes Association has proposed calling this type of diabetes, Type 1b with “true” autoimmune diabetes mellitus being called Type 1a.  

In addition, some people who initially look like Type 1 diabetics – because they have diabetic ketoacidosis (DKA) [*]  and serologic markers of islet cell autoimmunity at the time they are initially diagnosed -- eventually go on to resolve their insulin deficiency.  Unlike "true Type 1 diabetes, the insulin insufficiency in these individuals appears to be reversible.

Yet another classification:  The AB classification of ketosis-prone diabetics

Now, it is proposed that we adopt yet another classification scheme. And this one makes a lot of sense on  paper. In the December 2006 issue of Diabetes Care, Ashok Balasubramanyam, MD and colleagues make the case for placing certain types of diabetics -- those who have ketosis at the time of their initial diagnosis -- in new categories depending on their immunologic status and beta cell function.

They propose an “AB” classification scheme comprised of four categories. The categories are based on whether or not the individual has immune markers related to destruction of their beta cells (that's the “A” component”) and whether or not their beta cells are able to produce the hormone insulin (that's the “B” component).

Here are the categories:

KPD type 1A (for ketosis-prone diabetes). These individuals would be labeled A+B-. The A+ means they have immune markers, evidence of immunity to their own pancreatic islet cells (aka, “autoimmunity”). The B- means they have complete and permanent loss of beta cell function. KPD type 1A diabetics must take insulin treatments for life.

KPD type 1B individuals are A-B-. Like people with type 1A, these folks cannot make, and therefore must take, insulin for life. Unlike 1As, they do not have serologic evidence of autoimmunity to their islet cells.

KPD type 2A individuals are A+B+. They have preserved beta cell function at the time of diagnosis, but they also have evidence of autoimmunity. Their prognosis varies. Some appear to have a reversible form of beta cell dysfunction and are able to eventually discontinue insulin shots. Others progress to full beta cell failure, and like Type 1 individuals will then require insulin treatments for the rest of their life.

KPD type 2Bs are A-B+ patients. They have preserved beta cell function and also lack any markers of islet cell autoimmunity. Although they initially had ketosis when diagnosed, they ultimately do not behave like people with true Type 1 diabetes. Most will be able to discontinue exogenous insulin therapy. In this respect, they are similar to “pure” Type 2 diabetics who do not require insulin for long-term survival.

Although this new classification system is not perfect, at first glance it seems better than the current Type 1, Type 2 dichotomy even with the addition of the catch-all, Type 1B:

• It is easy to understand.
• It provides information related to prognosis (although you have to wait a while to confirm exactly which category someone finally falls into).

But is it practical?

An editorial accompanying the article, written by Guillermo Umpierrez, MD, points out that this new classification scheme may be hard to operationalize in clinical practice. It is not easy to measure insulin secretion outside of research settings and it can be costly. Dr. Umpierrez points out that more than half of blacks and Hispanics with Type 2 diabetes present with ketosis. He suggests instead of the AB classification, simply modifying the current ADA classification so that Type 1b patients are called “ketosis-prone Type 2 diabetes.”   Perhaps, he should also suggest that they be called Type 2 b instead?

Regardless of what the final outcome of this debate is, the paper by Balasubramanyam and the accompanying editorial helps to remind us that the clinical condition we call diabetes mellitus, in fact is much more complicated that it seemed 30 years ago.

[*] (DKA is a life-threatening condition characterized by having a build-up of “ketone bodies” in the blood stream. It occurs when there is not enough insulin to process glucose normally. The body begins to use fatty acids (FA) as an energy source instead. When FAs are metabolized, the end result is the production of ketone bodies. Thus, the term ketosis.)

The front page of the NY Times Business section has a lead article, written by Damon Darlin, titled “Extra Weight, Higher Costs.” It has the usual information about how obesity is linked to a number of costly diseases, including diabetes, heart disease, stroke and renal failure. But it also contains data that suggests that overweight individuals, particularly obese white women, earn less than their normal weight counterparts. Studies show obese people earn less One study that is described in the Times article was led by John H. Cawley, an associated professor of human ecology at Cornell University. He found that a weight increase of 64 pounds above the average for white women was associated with 9% lower wages. That’s huge! Indeed, in addition to being dangerous to you health, Jay L. Zagorsky, an economist at Ohio State University, is quoted as saying, “Being overweight can be dangerous to your wealth." He has studied the relationship between body mass index (a measure of overweight and obesity) and various economic factors, such as wages and overall accumulation of wealth. He used data from a multiyear sampling survey, the National Longitudinal Survey of Youth, done by the Bureau of Labor Statistics. He found for every one-point increase in BMI, net worth dropped by $1000. According to the the results of his study, the typical middle aged woman earned $313.70 less per year for every one-point increase in BMI; the typical male earned $161.30 less for every one-point increase.

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