June 27, 2009

Questions about The Lantus/Cancer Association

UPDATE: August 17, 2009: A safety review of an ongoing study of Lantus,sponsored by Sanofi-Adventus, the drug company who produces Lantus, but where the drug company supposedly has no access to the findings, found no evidence that people taking Lantus in that study were seeing a higher rate of cancer.

Science Daily: Research Team Responds To Concerns About International Insulin Drug Trial

By now you've probably heard the disturbing news about the epidemiological studies that connected Lantus to a higher incidence of cancer.

It says something about our health system that this news was reported by the business press long before the health press noticed it. And the business press coverage was concerned entirely with the impact this news would have on share prices of Sanofi-Adventis-not on the health of the people taking the drug. That's how capitalism works, folks, and it is the reason for a lot of unnecessary drug-related morbidity. Companies will hide and suppress bad news about a drug as long as possible in the hopes of supporting their share price.

You can find the news and the actual full texts of the studies connecting Lantus and Cancer here:

Diabetologia - Cancer & Lantus

I don't have the time right now to do a detailed analysis of these four studies. But here are my initial thoughts. We know that high glucose levels promote the growth of cancers. We also know the demographic of who is prescribed Lantus: Type 2s who have been out of control for more than a decade. This is because most doctors are reluctant to prescribe insulin until patients have taken every oral drug available for years, even if their A1cs continue to climb. The typical A1c of a patient who starts Lantus is 10% and their fasting blood sugar is usually near 200 mg/dl.

NOTE (added 7/2): The editor of the "PRESENT DIABETES Newsletter" mailed 7/2/09, "If you look at the actual study data, you see that it's not real world: 2/3 of the patients were excluded, because they were on a combination regimen, e.g. basal-bolus insulin. Moreover, the glargine patients were on quite different regimens and used more oral medications. [Emphasis mine]"

When doctors put out-of-control Type 2s on "insulin" it tends to only be basal insulin. This is because most Type 2s get their diabetes care from family practitioners, instead of endocrinologists, and family doctors don't have the resources to provide the detailed education patients need to use fast acting insulin with meals effectively and without causing themselves hypos.

Dr. Tamler's note confirms my suspicions, the patients found to have higher rates of cancer were Type 2s on inferior basal-only regimens and high carb diets which ensure
the high blood sugars that promote cancer.

Basal insulins like Lantus cannot counter the blood sugar spikes caused by the high carbohydrate meals most doctors still recommend, meals filled with so-called "healthy whole grains" and bananas. So even when people with Type 2 inject huge doses of Lantus--100 units is a typical Type 2 dose--most long-term Type 2s "on insulin" still experience post-meal blood sugars that spike into the 200s. That is why the A1c of all too many Type 2s "on insulin" (i.e. Lantus) are almost always considerably higher than the ADA's anemic 7% target.

This means that these people, despite injecting Lantus regularly experience blood sugars are high enough to a) turn off their immune system allowing cancerous cells to begin to grow and b) feed those cancerous cells.

Besides that, patients "on Lantus" have been on cocktails of powerful oral drugs for years before starting Lantus. So one would want to know if some these patients who contracted cancer were taking Januvia, the single most promoted new diabetes drug for Type 2s. There is significant evidence that Januvia turns off a tumor suppressor gene. We also do not know the impact on cancer of the TZD drugs, Actos and Avandia.

So the valid study comparison that would tell us whether Lantus is in fact promotion cancer would be a comparison between two groups of people with Type 2 diabetes who have been matched for the length of time since their diabetes diagnosis, who have the identical A1cs and oral drug consumption histories, where the ONLY difference between the groups is whether or not they are taking Lantus.

If that comparison shows a higher incidence of cancer in the Lantus group, then Lantus is, in fact, a very dangerous drug.

But comparing Type 2s taking Lantus, Avandia, Actos, Metformin and Januvia with Type 1s using R insulin or for that matter, Type 2s taking only Sulfonylureas and NPH (a common European protocol), may mean that you are comparing two different populations with different blood sugar histories and drug exposures. If that is the case, the cancer incidence in the two groups may not stem from the Lantus, but from the other factors applying to the group prescribed Lantus.

This latest alarm, as scary as it is to people who have been taking Lantus, is probably GOOD news, because it will trigger some serious research into the cancer profile of all the analog insulins and perhaps, even, of the oral diabetic drugs.

If you have been using Lantus and are still running damagingly high blood sugars capable of suppressing your immune system--sugars higher than 140 mg/dl after meals--the first thing to do is drop those blood sugar levels. Give your body the help it needs to nip cancer in the bud. Each of us develops a few cancerous cells every year, but a healthy immune systems kills them off before they can proliferate. Remember that cancer cells require a lot of glucose to grow (and don't need to be insulin sensitive to use that glucose). If you are taking Januvia, stop. It has definitely been connected with a mechanism that promotes cancer in a way that is well-understood.

If Lantus does promote cancer independent of its inability to tightly control the blood sugars of people with Type 2 diabetes who eat high carb diets, it would be helpful to know what exactly it is about Lantus that promotes cancers so we could know if the other analog basal insulin, Levemir, and the fast acting analog insulins, Novolog, Humalog, and Apidra, also cause cancer.

NOTE (Added 7/2): Dr. Tamler also states this: "However, use of the insulin-sensitizing agent metformin has been associated with decreased cancer risk."

I think the doctors commenting on the Lantus news did have it right this time: we don't think we have the evidence yet to understand this disturbing finding. Whether we will get that evidence or be handed a bunch of spin and persiflage from the drug manufacturers designed to prop up their share price at the cost of human lives, is another question.


June 26, 2009

Clear Indicators of Diabetes Three Years Before Formal Diagnoses

This week the Lancet published an epidemiological study which asked the question, "Can we see clear cut signs that a person is on the way to developing diabetes in the years before diagnosis?"

The answer was of course, "Yes."

The abstract of this article is here:

Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study.
Dr Adam G Tabák et al. The Lancet The Lancet, Volume 373, Issue 9682, Pages 2215 - 2221, 27 June 2009 doi:10.1016/S0140-6736(09)60619-X

This was a prospective study--i.e. one that takes measurements and then follows the subjects for a set period of time--in this case, almost 10 years, to see what happens. The subjects were 6,538 British civil servants, 71% of them males.

Diabetes was diagnosed using the most conservative measure: subjects had to have a 2 hour glucose tolerance test result over 200 mg/dl. This standard might have missed people who were going over 200 but who were below 200 mg/dl at 2 hours post challenge. Though according to the ADA official diagnostic criteria for Diabetes Mellitus anyone who scores over 200 mg/dl more than once should be considered diabetic. But the use of the 2 hour glucose tolerance test criteria tells us the people in this study who were diagnosed as diabetic were seriously diabetic.

What the researchers found was this: In the subjects who did not become diabetic, "metabolic measures followed linear trends in the group of non-diabetics ... except for insulin secretion that did not change during follow-up.

This finding is important, so let's repeat it: The normal people in this study saw their blood sugar creep up as they got older, but the researchers found that normal people's ability to secrete insulin did not change over time.

In the people who became diabetic,
... a linear increase in fasting glucose was followed by a steep quadratic increase (from 5·79 mmol/L [104 mg/dl] to 7·40 mmol/L [133 mg/dl]) starting 3 years before diagnosis of diabetes.
"Steep quadratic increase" means that their fasting glucose did not go up gradually, but shot up in a pattern that, when graphed, made a steep upwardly curving parabola.

In addition their 2 hour glucose tolerance test result showed a rapid increase starting 3 years before diagnosis from 7·60 mmol/L [137 mg/dl) to 11·90 mmol/L [214 mg/dl]).

Since we know that lots of people have pre-diabetic blood sugars that don't deteriorate, including the overwhelming majority of insulin resistant obese people who never develop diabetes, it's important to note that it is failing insulin secretion, not insulin resistance, that appears to sort out the people who go on to become diabetic.

Though insulin resistance rose starting five years before diagnosis, in the people who became diabetic,
HOMA β-cell function increased between years 4 and 3 before diagnosis (from 85·0% to 92·6%) and then decreased until diagnosis (to 62·4%).
These findings make one thing crystal clear. If you wait for an official diabetes diagnosis--one based on either a fasting glucose test or a two hour glucose tolerance test, you will be giving high blood sugars three years in which to ravage your body.

Consider all the people in this study who were classed as "nondiabetic" because their 2 hour glucose tolerance test result was "only" 180 mg/dl. How high do you think their blood sugars were at 1 hour?

And given that we know that blood sugars that go over 180 mg/dl increase insulin resistance, you have to wonder whether the insulin resistance that was observed to increase five years before diagnosis was due to some independent disease process or whether it was a direct result of the "nondiabetic" blood sugars these people were experiencing after each meal that exposed them to hours of damaging glucose toxicity as their blood sugars remained above 140 mg/dl.

Because, of course, prolonged exposure to blood sugars over 140 mg/dl kills beta cells. Which makes you wonder if the decrease in insulin secretion observed three years before diagnosis, that decrease which happened two years after the high IR was first observed, might have been caused by the subject's blood sugars going over 180 mg/dl meal after meal. Was the decrease in insulin secretion the final result of exposure to "nondiabetic" but much higher than normal blood sugars?

The study I'd like to see would be one that asked: what happens when you find people whose 2 hour glucose tolerance test result is over 140 mg/dl--high enough to damage their organs, and treat them with a protocol that lowers their post-prandial blood sugars by having them cut down on their carbohydrate intake?

Do you see insulin resistance drop when they stop experiencing those 1 hour 180 mg/dl and higher blood sugars after each meal?

Can they preserve their ability to secrete insulin because they aren't exposing their beta cells to those blood sugars over the 140 mg/dl level that we know produces organ damage?

Doctor's aren't likely to do this study, because there are so many medical-political forces fighting against letting the public know that the cheap carbohydrates that enrich the food industry are what raise blood sugars and ruin health. So we aren't likely to get a definitive answer to the question of whether normalizing blood sugars with dietary change can stop the progress to diabetes or not.

But if you have been diagnosed as prediabetic you have nothing to lose by making your own personal experiment to see if keeping your blood sugars in the normal range will prevent your own diabetes from progressing.

You can find out exactly how to do this on this page: How To Get Your Blood Sugar Under Control

Even if it turns out that this technique cannot prevent further progression of diabetes0though it is quite possible it CAN--you have nothing to lose by trying it.

Many of us who have already been diagnosed as diabetic have found that keeping our blood sugars in the normal range prevents us from developing diabetic complications. Since the reason we don't want to have diabetes is because we don't want diabetic complications, prediabetes who adopt a rigorous approach to normalizing their blood sugar with carb restriction will come out way ahead in the future, whatever their glucose tolerance test result might be.

Remember: A diagnosis of Diabetes doesn't cause complications. Prolonged exposure to high blood sugars cause complications. Whatever your diagnosis, if you keep your blood sugars in the normal range 70 mg/dl to 120 mg/dl after meals and under 100 mg/dl fasting you can have normal health.

June 24, 2009

More Evidence That Overweight is The Healthiest Weight

I have posted in the past about how analyzing the findings of NHANES III (The large, ongoing US national heath study) demonstrated, conclusively, that Overweight is the Healthiest Weight.

Now a second large-scale study confirms this finding. This one analyzed "11,326 adults in Canada over a 12-year period using data from the National Population Health Survey."

You can read a report about the study here:

Reuters: A few extra pounds can add years to your life: study

The actual study is here:

BMI and Mortality: Results From a National Longitudinal Study of Canadian Adults" Heather M. Orpana, et al. Obesity advance online publication, June 18, 2009; doi:10.1038/oby.2009.191

This study is particularly interesting to me because of one significant difference between it and the earlier NHANES III study. The NHANES study only found a health benefit to being overweight in older people. This study found the advantage extending to a much larger age range. The population studied here was age 25 and older.

The most salient finding of this study was that the most unhealthy weight was one that produced a BMI under 18.5. People with that weight were 73% more likely to die than people with a normal BMI.

But get this: People with a BMI of 25-30 were 17% less likely to die than people with a normal weight. Even those classified officially as "obese," people with a BMI of 30-35, had a 5% lower risk of death than normal people.

Only those who were seriously obese, with a BMI was greater than 35, had a greater risk of death than normal, but that risk was only one half the risk the skinnies ran--36% as opposed to 73%.

The researchers who discovered this are falling all over themselves arguing the public should ignore their results and continue to fear fat. Obviously they are influenced by their religious belief that Fat Is Bad.

For example, one of the researchers, David Kaplan, is quoted saying, "Our study only looked at mortality, not at quality of life, and there are many negative health consequences associated with obesity, including high blood pressure, high cholesterol, and diabetes."

Since over 12 years, the overweight and modestly obese people in this large sample were outliving the others, you have to wonder why the researchers didn't do some sub-analyses to see how many of these longer living folk had diabetes, high cholesterol and high blood pressure. Or, more importantly, whether they had been diagnosed with these conditions but had them under control. One almost wonders if these sub-analyses were done but turned up facts so incongruent with their religious belief the researchers dismissed them as impossible.

In any case, this study suggests to me that the current hysteria about obesity needs to be reexamined. The most frequently promoted cure for obesity is weight loss surgery (WLS) a procedure that studies find has a kill rate around 1%--though a kill rate as high as 3% has been reported in some studies. These new statistics suggest very strongly that the argument that these murdered obese people would have died soon anyway, so the high risk of death is justified, simply does not hold water.

A drug that killed that many people could not be sold legally in this country. That
a surgery that risky is being embraced by almost the entire medical community without question shows you just how insane the Fear of Fat has become.

This study also raises some interesting questions about what is killing those skinnies. One reason may be that they may be skinny because they are heavy smokers and drinkers--both addictions can keep weight down and both lead to early deaths.

My own experience over the years has also been that the thin and often vegan people my region are the people most likely to get fatal cancers at young ages. I don't know if that is because the defects in their genes that make them susceptible to cancer also keep them from putting on weight and incline them towards the diets they prefer or what. But you have to wonder now that two major epidemiological studies have shown that thin kills.

As a final note: many of those who contact me are very worried because, while they can take off some weight eating a low carb diet and watching their blood sugars, their weight stalls above the normal range and their doctors continue to assure them that they'd be healthier if they could only lose that last, resistant 20 or 30 lbs.

This study suggests very strongly that their bodies know something their doctors do not and that the weight at which you stall after a serious diet effort that includes blood sugar control may very well be the healthiest weight for you.

June 19, 2009

LADA: The Epidemic Your Doctor Doesn't Know About

The past few weeks my inbox has been filled with letters from desperate people with diabetes whose doctors have completely failed them.

They have blood sugars that continue to climb no matter what they eat. They ask me why when they eat no carbs at all their blood sugars are still over 140 mg/dl hours after a meal.

They are on all the oral drugs and sometimes even Byetta, but their blood sugars still go into the 300s.

Some have histories of Gestational Diabetes that came on when they were thin. Some gained a lot of weight very recently but were normal weight before that.

All have relatives with diabetes. Some have relatives with Type 1 diabetes. Most have relatives with other autoimmune disease.

And all of them, it turns out, though diagnosed with Type 2 diabetes and given the miserably ineffectual medical treatment doctors give people with Type 2, turn out to have LADA.

This isn't a guess on my part. Quite a few are writing to me after finally convincing their doctors to give them C-peptide tests or antibody tests. Others are responding to tiny doses of basal insulin which would not do anything for a person with Type 2.

I know that the reason I hear from so many people with LADA is because I discuss LADA on my web site, HERE. There is almost no other information on the web about slow adult onset autoimmune diabetes, so it makes sense that when people are finally diagnosed with it, they let me know.

But my impression that there is a hidden epidemic going on is not just because of all the mail I get. There are plenty of people with LADA posting on TuDiabetes.com and the other diabetes boards.

Most of the people who have a relatively easy time getting diagnosed with LADAs are young and thin. That is because their weight sometimes (but not always) raises the suspicion in the minds of their doctors that they don't have Type 2.

But the people I hear from who are having a really tough time getting a proper diagnosis are those who are struck with autoimmune diabetes in middle age, after they have experienced the usual middle aged weight gain that 95% of the normal population experiences. Because they are overweight, doctors refuse to consider the possibility that they don't have the kind of diabetes they mistakenly believe is "caused by obesity." (To read why they are mistaken, read THIS.)

If you are 20 lbs overweight when you develop autoimmune diabetes, the chances are very good you will not get your diagnosis of LADA until you end up in the ER with Diabetic Ketoacidosis (DKA), a condition so serious that if you do not get to the ER when you have it, you are likely to die.

I'm hearing from people misdiagnosed with Type 2 who have ended up in the ER with DKA. People with real Type 2 do not get DKA though if their blood sugar rises high enough they can develop another dangerous condition called hyperosmolar hyperglycemia which also requires hospitalization.

There has been a huge increase in the incidence of all autoimmune conditions over the past decade. The number of children with Type 1 diabetes is predicted to double over the next decade. (Details HERE.) It has already much more than doubled compared to its incidence even 30 years ago.

Researchers have also documented sharp rises in the incidence of many other autoimmune diseases including autoimmune thyroid disease, rheumatoid arthritis and multiple sclerosis.

Why? No one knows, and very little effort is being invested in finding out, because there isn't money in it for investors. Not only that, but the chances are very good that the toxic contamination of our air, water, and food supply by industrial chemicals, pesticides, pharmaceuticals,and plastics may have something to do with it. Which is not something industry is going to pay money to learn.

Whatever the explanation for the huge rise in the incidence of authoimmune conditions, it is time someone educated physicians about slow onset autoimmune diabetes a.k.a. LADA. Misdiagnosing people with LADA exposes them to years of debilitating poor health. In fact the one thing that everyone with LADA who writes me says is how exhausted, wretched and sick they felt through the years when they were misdiagnosed.

Patients with LADA are not producing insulin and their cells, including brain cells, are starving. They need basal/bolus insulin regimens, and they need them as soon as possible. They also need high quality diabetes education that will teach them how to use insulin properly to maintain good control and avoid hypos.

Studies have shown that on average it takes 4 years for a person with LADA to get to where they are completely insulin dependent--and likely to develop DKA without insulin. For too many of these people, those 4 years are being spent receiving the mediocre treatment (or lack of treatment) doled out to Type 2s. They are told to lose weight. They are told to exercise and eat low fat diets. They are given oral drugs and told to keep taking them even when they are having no effect on blood sugars.

If you have a family history of autoimmune disease or a form of diabetes that is not responding well to carb restriction and oral drugs, read THIS PAGE. Write down the names of the three kinds of antibody tests. Demand that your doctor order the antibody tests and a C-peptide or fasting insulin test.

Don't believe it when a doctor tells you that you are a Type 2 unless you show near normal amounts of C-peptide and despite having diabetes for a year do not have any diabetic antibodies. (The antibody tests may be negative until you have had autoimmune diabetes for a while.) If you are given Lantus and your fasting blood sugars responds to a dose that is less than 30 units, consider asking for C-peptide tests too. Typical doses of Lantus that will have an impact on someone with classic Type 2 diabetes range from about 30 to 100 units a day with the very low dose only found in people who are small and eating low carb diets.

If your doctor won't order these tests, find a new doctor.

My guess is that there is a hefty chunk of overweight people diagnosed with "garden variety" Type 2 who actually have autoimmune forms and who would benefit from insulin supplementation. The most recent statistic I saw was that something like 8% of people diagnosed with Type 2 turn out to have diabetes-related antibodies. It is not impossible to be insulin resistant and to have an autoimmune form of diabetes. But all people with autoimmune diabetes will, after four or five years show lower than normal levels of fasting C-peptide.


June 17, 2009

Metabolic Advantage of Ketogenic Diets Debunked? An Intriguing Study You Will Want to Read

I have been working my way through diet research lately, looking for those very few studies that are truly "scientific" in both design and execution. Because I'm interested in the impact of weight loss on metabolic rate, I did some searching for studies that measured REE--Resting Energy Expenditure, using techniques like the ones described in my post below about Dr. Liebel.

This led me to an intriguing study which compared a ketogenic low carb diet--which closely matched the Atkins diet as described in his 1998 book--to a nonketogenic lower carb diet very similar to Zone or South Beach.

You'll find it here:

Ketogenic low-carbohydrate diets have no metabolic advantage over nonketogenic low-carbohydrate diets Carol S Johnston, Sherrie L Tjonn, Pamela D Swan, Andrea White, Heather Hutchins and Barry Sears [emphasis mine]

Having recently reviewed some very poorly designed, high profile diet match up studies--including the NEJM Diet Bake-off study where the "Atkins" diet group turned out to be eating over 180 grams of carbohydrate a day, I did not expect much from this study. Especially not after noticing who was on the list of authors.

But after reading a few paragraphs, I realized I could not dismiss this study without giving it attention. The authors began by pointing out that other published studies of ketogenic diets had rarely found ketones in the urine of the study subjects who were supposedly eating these diets, a sure sign that they were not actually eating them. The design in this study ensured that the subjects were eating the diets they were studying because for the first six weeks the researchers provided their subjects with all their food.

Not only that, they tested them periodically for a ketone--ß-hydroxybutyrate, to ensure that the ketogenic dieters were in fact eating a ketogenic diet.

The two diets studied both were about 30% protein. The ketogenic diet was about 5% carbohydrate and 60% fat. This is exactly the ratio most of us who have used ketogenic diets successfully to lose weight have found most effective. The other diet (which probably is Zone given the authorship, but which also looks a lot like South Beach) was low fat 30% fat with 9% saturated fat and 40% carbohydrate. Since both diets were calorie controlled at 1500 calories a day, the non-ketogenic diet provided 150 grams of carbs.

Study participants ate nothing but prepared foods provided by the researchers for six weeks, which I felt was long enough for dieters to adapt to the ketogenic diet. After those six weeks were over, dieters were left to their own devices, but the ketogenic dieters were advised by dietitians to keep their carbohydrate intake below 40 grams a day and given counseling to help them achieve this.

Ten people pretty well matched were assigned to each group. (One dropped out of the ketogenic group after developing a heart arrhythmia). This is a small study, but given the expense of providing food and the costs of the detailed lab work that was done, this is understandable.

At the end of the six weeks the ketogenic dieters were in fact generating ketones. They were given a series of tests to track changes in lipids, CRP, liver function, kidney function, HOMA (insulin sensitivity), calcium levels, uric acid, and REE. Only weight and fat-free body mass were measured at ten weeks, so this should be treated as a six week study not a ten week study.

So what did they find that should interest us? A lot!

Where The Diets Matched

Dieters eating both diets lost statistically similar amounts of weight, fat mass, and BMI. Both diets caused a similar rise in HDL and a similar drop in the HOMA measure of insulin resistance. Both diets dropped triglycerides in a statistically similar manner.

Resting energy expenditure rose to a similar extent in both groups--a measure of increased metabolism- and dieters on both diets reported similar levels of hunger. Because the changes in REE did not correlate to the measured amount of ketones or changes in Fat-free mass, a major determinant of REE, the researchers attribute this finding to the very similar high protein content of both diets rather than to changes in carbohydrate intake.

Serum {gamma}-glutamyltransferase concentrations fell in both diet groups during the trial, a measure of liver health. C-reactive protein and 24-h urinary calcium concentrations were not significantly affected by either diet treatment. And though uric acid and creatinine clearance fluctuated, at the end of the six weeks they were lower than baseline in both groups, indicating both diets were not producing gout or damaging kidney function.

Where the Diets Differed

There were significant differences between the two diets in their impact on LDL. LDL rose significantly in some members the ketogenic diet group and it rose in direct proportion to the amount of ketones they were spilling.

The other difference was in self-reported vigor. To quote the study:
weekly fatigue-inertia scores, representing a mood of weariness, inertia, and low energy level, did not differ significantly by diet treatment or time; however, vigor-activity scores, representing a mood of vigorousness, ebullience, and high energy, were significantly higher in NLC dieters than in KLC dieters. These data suggest that, in the context of high-protein diets, small differences (as little as 50–60 g/d) in dietary carbohydrate may affect emotion, mood state, and, potentially, the desire to be physically active.
Though overall weight loss was statistically similar, the graphs presented show an interesting difference between the two diets. Through three weeks free fat mass and weigh loss are identical on the two diets. However, at week 4 the dieters on the low fat/moderate carb diet continue to lose while the ketogenic dieters look like they are beginning to experience the notorious Three Week Stall that is very often reported by people on ketogenic diets who post on diet forums.

At the end of ten weeks, the ketogenic diet group on average remains stalled, the higher carb dieters have continued to lose small amounts of body weight and free fat mass.

Implications for People With Diabetes

This is a small study, and given the financial interest of Dr. Sears, who is listed as an author, in the higher carb diet, one has to maintain some skepticism about the result.

It is also worth noting that this is a calorie controlled study, and that the claim made for the Atkins diet by those most enthusiastic about it is that it allows for weight loss at a much higher caloric intake than other diets. I experienced exactly that phenomenon early on in my first ketogenic diet, though after the "beginners luck" period I did find I had to lower calories to lose weight, as do many people who post on low carb diet boards.

Most obviously, the overweight participants in this study did not have diabetes or prediabetes, though their HOMA results at the beginning of the study were high enough to define them as having significant insulin resistance. Many people with diabetes cannot eat 150 grams of carbohydrate a day without experiencing dangerously high blood sugars.

But I have heard from so many readers of this blog and my Blood Sugar 101 web site who have used the "test, test, test" method to craft a diet that lowers their blood sugars who have ended up eatng a restricted carb diet that is closer to the non-ketogenic diet described here than an Atkins diet. They report achieving A1cs in the 5% range and significant weight loss.

So my thoughts after considering this study are these.

1. The study, like many others, finds no evidence for claims that a high protein diet of about 125 grams of protein a day damages kidneys or that it changes the calcium balance in a way that that damages bone.

2. The study suggests that a high protein intake of around 125 g per day revs up the resting metabolism at least in the first weeks of a high protein diet.

3. The study suggests that people who are concerned about their LDL rising on a low carb diet can continue to lose weight on a higher carb/lower fat diet as long as they monitor their blood sugars closely. From other studies we know that high blood sugar will adversely affect lipids, independent of fat intake, so there will be no benefit in lowering fat intake if we replace fat with carbohydrate to the extent that we lose blood sugar control.

4. People without diabetes who find themselves stalled on a Atkins-style diet might consider experimenting with a lower fat, slightly higher carb, calorie controlled diet and see if that helps break their stall.

5. This study does not address the question of whether ketogenic dieters can lose as much weight as non-ketogenic dieters do while eating a higher calorie intake. Other studies have suggested this may be true.

6. This diet does not address the big problem with all diets studied by researchers, which is what happens after six months when many dieters stall on all diets and compliance becomes a huge problem. Nor does it look at the changes in metabolism--measured carefully--that occur after 10% of starting weight has been lost. Given the expense of a large scale study that would look into these questions, it isn't likely we'll have solid answers any time soon. All large scale diet studies rely on cheap, superficial lab tests and diet and exercise questionnaires rather than careful measurements and controlled feeding because because of the huge expense of the latter approach.

UPDATE: As luck would have it, I found another study of people with Type 2 diabetes given 1500 calorie high protein/Low Fat/40% carb diets and tracked for 12 weeks.

This study tracked changes through 12 weeks and found the high protein made NO difference in the Resting Energy Expenditure when compared to the classic low fat/low protein diet.

Effects of Energy-Restricted Diets Containing Increased Protein on Weight Loss, Resting Energy Expenditure, and the Thermic Effect of Feeding in Type 2 Diabetes. N.D. Luscomb et al. Diabetes Care. April 2002 vol. 25 no. 4 652-657

The researchers supplied some, but not all the foods, which were the usual low fat frankfood.
These included preweighed portions of beef and chicken suitable for six meals per week, shortbread biscuits [i.e. cookies], Canola Lite margarine, and Sunola oil-plus (MeadowLea Foods, Mascot, Australia), Kraft Free cheese (3% fat; Kraft Foods, Melbourne, Australia), skim milk powder, and diet yogurt for the HP diet and sultanas [raisins] and rice for the LP diet
As the subjects were eating more freely in this study, one has no way of knowing what they were eally eating. I know what I would have been eating after a month of diet marge and rubber low fat cheese. . .

June 15, 2009

A Hint of Intelligent Thought about Tight Control and CVD

Remember the much touted Veterans study where people with Type 2 diabetes who attempted what doctors call "tight control" (defined as an A1c of 6.5%) supposedly ended up with more heart attacks than those who didn't?

Well someone has finally put on what passes for a Thinking Cap in the medical community and looked more carefully at the findings. Their conclusions were presented at the 2009 ADA Scientific Sessions.

What they found was this: If you start shooting for tight control in the first fifteen years after a diabetes diagnosis you DO cut way down on heart attacks. By a whopping 40%.

But, if you start tight control only after the patient has had 15 years of poor control--fifteen years in which high blood sugars clog arteries, overgrow heart tissue, and destroy nerves and beta cells, tight control may make things worse, mostly, though mostly things worsen in people who suffer dramatic hypos.

You can read about this analysis here: ENDOCRINE TODAY: VADT: Early intensive control reduced risk for CV events.

This is a tiny step forward. If you'll remember, since the earlier study was published, along with the ACCORD (Avandia Can Corrupt Our Rotten Data) study, many family doctors have been warning patients with diabetes that it is dangerous to attempt to lower A1c to 6.5%. Some have even been urging patients to maintain the 155 mg/dl average blood sugar that will give them the 7.0% A1c these doctors consider "safe." Since we know that extended exposure to blood sugars over 140 mg/dl cause neuropathy, this is tragically flawed advice.

So if your doctor tells you that shooting for tight control is dangerous, remind him that this is only true if you have had A1cs well above 7% for 15 years. Otherwise, tight control will drop your risk of heart attack by 40%, which many times more than can be achieved by any other medical intervention or drug.

If your doctor continues to urge caution in lowering blood sugar and push statins on you as a proven way of preventing heart attack, find a new doctor, immediately. Because a doctor who doesn't understand the power of normalizing blood sugar in preserving health is as dangerous to you as a diet full of Krispy Kremes.

This finding reminds me a lot of what happened when the WHI results hit the headlines "proving" that estrogen supplementation worsened heart disease in older women. Later analysis of the data discovered that this was only true if you started the estrogen supplementation decades after the end of menopause, after the woman had already developed significant cardiovascular changes. Women who supplemented estrogen at the start of menopause did experience benefits and did not have more CVD.

Unfortunately, the public got the message that estrogen worsened heart disease, and the follow up, that it provided benefits if started near the onset of menopause, never made it out of the specialty conferences. I learned of it only after reading Hot Flashes, Hormones & Your Healtha book written by the doctor who was the lead investigator on the WHI. I am afraid the same thing may happen here with this new analysis of the Veteran's data. Doctors, and the public, got the message "Tight Control Causes Heart Attacks" they won't hear the rest: "Only in people who ignored their blood sugar for fifteen years or more."

Insight into Why Tight Control is Problematic after 15 Years of Uncontrolled Blood Sugar

A secondary finding that came out of the data analysis was this: "...patients who had severe hypoglycemia had an 88% increase in primary CV events and a threefold increase in CV death."

This is a smoking gun, people, but the researchers, who like most people researching diabetes seem to be woefully clueless about the impact of high blood sugars on the body, seem to have missed what this finding really means.

In a healthy person, there is an intact counterregulatory system which involves the autonomic nervous system. When you start to go hypo, it kicks in to force blood sugar back into the normal range. This system is so powerful that I have heard a person with Type 1 who as a teen attempted to kill himself with a huge insulin overdose report that it did not work--because that counterregulatory kicked in.

You can weaken your counterregulatory response over time if you experience mild hypos frequently enough that your blood sugar set point drops. This is a problem mostly for people with Type 1 diabetes who if they go low a lot may develop "hypo unawareness".

But the real reason that people who have had uncontrolled diabetes for many years develop a tendency towards hypos is actually something else: exposure to very high blood sugars causes neuropathy--nerve damage. And this damage doesn't just impact the sensory and motor nerves. It also impacts the autonomic nervous system. The system our body uses to regulate blood sugar which should kick in to prevent hypos.

So the extreme hypos that leave people with long histories of uncontrolled high blood sugars from Type 2 diabetes unconscious are a result of those years of high blood sugar, not an independent issue.

This is made crystal clear by this statement in the Endocrine Today report:
“It is important to note that this association between severe hypoglycemia and MI and mortality occurred in both the intensive and the standard groups, in contrast to prior perceptions that such hypoglycemia was just a problem with people on intensive control,” Stephen N. Davis, MD.
The hypos don't result from the use of insulin or other drugs in the effort to get tight control. The hypos stem from the destruction of the autonomic nervous system caused by years of glucotoxicity [poisoning by high blood sugar]. It is also very possible that the same autonomic nerve death that promotes hypos leads to dysregulation of the heart beat that increases the likelihood of heart attack.

So it is reasonable to conclude that people who maintain really tight control as soon as they are diagnosed--who maintain blood sugars low enough to avoid neuropathy--are going to preserve their autonomic systems intact, which will make it much less likely that they will suffer extreme hypos.

But Doctors Are Still Not Thinking Clearly

The one disturbing thing I see in the response to this latest study is this imbecilic comment:
“Unless other factors are present that would contraindicate intensive treatment, such as hypoglycemia, intensive control is appropriate in the first 15 years after diagnosis,” he added. However, it is unknown whether patients who have already been assigned to intensive treatment for many years can safely continue beyond the 20-year mark.
Using this kind of logic it's almost certain doctors will tell patients who have maintained perfectly normal blood sugars for 20 years that it is now "dangerous" for them to continue with tight control. Based solely on the experience of people who suffered 20 years of damagingly high blood sugars.

When will doctors bet taught that all the complications of diabetes are caused by high blood sugars and that in the absence of high blood sugars people will not develop diabetic complications? It is such a simple concept, but one that is so alien to so many doctors who still behave as if "Diabetes" were a discrete disease which ravages the body no matter what blood sugar level the patient maintains.

Huge Impact of HDL

One last very interesting finding of this study was that HDL was highly predictive of heart attack. As reported in Endocrine Today
HDL level strongly affected the primary outcome of CV events and total mortality. The benefit was as high as a reduction of 90%...For every 10 mg increase in HDL above baseline, patients had an 88% decrease in risk for CV events and mortality, a 50% decrease in risk for first primary CV event and a 55% decrease in risk for all-cause mortality.
This is huge folks. Statins do not increase HDL. Cutting carbohydrates dramatically will raise HDL for many of us.

Let's Talk about Truly Tight Control

The A1c of 6.5% which is what mainstream medicine defines as "extremely tight control" translates into an average blood sugar of 140 mg/dl. Since blood sugars that are over 140 mg/dl for more than an hour or two are linked to nerve damage, retinal damage and kidney damage, the 6.5% A1c, while an improvement on a 7.0% A1c, is not low enough to prevent the classic diabetic complications.

And because EPIC-Norfolk and other huge epidemiological studies find heart attack incidence rises dramatically as A1c rises in the 6% range, an A1c in the 5% range or lower would be much safer, if you can achieve it.

Not all of us can--I've discussed this elsewhere. The reasons may have to do with individual variants in the red blood cells measured in the A1c test.

So rather than obsessing about your A1c, which measures blood sugar only indirectly, by assessing its impact on something irrelevant to complications--proteins bound to hemoglobin molecules, why not cut to the chase? Measure your actual post-meal blood sugar. Highs after meals are the blood sugars that damage our organs.

Keep your post-meal blood sugars under 140 mg/dl (7.7 mmol/L) at all times as much as possible. Studies have shown that neuropathy does NOT correlate to either A1c or fasting blood sugar in people who are not diagnosed with diabetes, but it does correlate to their 2 hour glucose tolerance test results. When those are over 140 mg/dl the incidence of neuropathy starts to climb.

Prediabetics This is Your Wake Up Call

Obviously, the earlier you strive for extremely tight control, the happier your heart--and other organs will be. I run into so many people with pre-diabetes whose doctors seem to think that there is no point in doing anything until pre-diabetes turns into diabetes. This is like telling people it's a waste of time putting out small fires. Wait until the whole house is engulfed in flames before calling the fire department.

Diabetes is not a disease that suddenly appears when you get a diagnosis. The diagnostic criteria are arbitrary and recent research has proven that organ damage begins as soon as post-meal blood sugars rise above 140 mg/dl and stay there for any period of time. This may happen long before a person is diagnosed as prediabetic with a oral glucose tolerance test or fasting plasma glucose test.

So if you have prediabetes, or think you might be on your way towards it, based on having a family history of diabetes or a stubborn weight problem, start measuring your blood sugar after meals and take aggressive steps to lower your blood sugar to the safe level. You'll find the instructions for how to do that using a blood sugar meter (the Wal-Mart Relion works fine) here:

How To Get Your Blood Sugar Under Control.

I have heard from hundreds of people over the years who have followed these instructions and achieved A1cs in the 5% range, even though some started with A1cs well over 10%.

You can too. And now there is no reason at all for anyone diagnosed within the last 15 years to fear tight control.


June 11, 2009

Research Updates: Avandia, Actos and Byetta

UPDATE (April 2, 2013): Before you take Byetta, Victoza, Onglyza, or Januvia please read about the new research that shows that they, and probably all incretin drugs, cause severely abnormal cell growth in the pancreas and precancerous tumors. You'll find that information HERE.

Original Post:

One nice thing about writing this blog lately, is that people have started sending me press releases and full text versions of new research studies that relate to topics I have blogged about. They also send me a lot of commercial spam and offers of free samples in exchange for my promise to blog about their diabetic-exploiting product which I ignore. But keep sending the studies!

Right now there are four studies that you need to know about. Three were presented at last week's ADA session.

Byetta Does Not Increase The Incidence of Pancreatitis

The first is a study that should put to rest fears that Byetta causes pancreatitis. The people at Medco a huge prescription management company ran a database analysis to answer the question of whether the incretin drugs might be causing pancreatitis and their findings are encouraging.

The methodology was to analyze "pharmacy and medical claims from the National Medco Integrated Database."
A total of 123,621 patients were divided into three groups: 9,260 patients were taking exenatide, 2,143 patients were on sitagliptin and 112,218 were in the control group. Patients were followed for 540 days to measure the incidence of acute pancreatitis....A total of 123,621 patients were divided into three groups: 9,260 patients were taking exenatide, 2,143 patients were on sitagliptin and 112,218 were in the control group. Patients were followed for 540 days to measure the incidence of acute pancreatitis.
The finding was that "Only 41 patients (.44%) on exenatide, 6 patients (.28%) on sitagliptin and 438 (.39%) in the control group had pancreatitis during the study period."

While this is a very short term study--less than two years--it looks like the incidence of pancreatitis is not statistically significant compared to controls. Pancreatitis does occur in the general population for reasons not entirely understood. Another recent study discussed HERE finds smoking to be strongly dose-related to pancreatitis incidence, heavy drinking somewhat related, and mentioned that there is probably a genetic component involved too.

So that's good.

What is NOT good is the news about the TZDs, the evil twins Actos and Avandia.

Confirmed: Avandia Doubles Heart Failure Risk and Causes Osteoporosis

Two studies have confirmed earlier findings that these drugs cause an elevated risk of fractures and heart failure. But so strong is the power of the drug companies, that you might not know this if you read the studies--and headlines describing the studies--that proved this.

The study, presented at last week's ADA conference is being reported like this:

Overall Cardiovascular Safety of Rosiglitazone [Avandia] Confirmed in 5 and 1/2 Year Study

UPDATE 6/19: You can read the published study here:

Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Philip D Home, et al. The Lancet, The Lancet, Volume 373, Issue 9681, Pages 2125 - 2135, 20 June 2009. doi:10.1016/S0140-6736(09)60953-3

Sounds like great news, doesn't it. Until you read this:
...the only adverse finding was a doubled risk of heart failure [emphasis mine], but positive findings in other areas – especially CV death and stroke – almost exactly balanced out the total numbers for the primary outcome, thus meeting the criterion of non-inferiority for rosiglitazone (hazard ratio 0.99: CI 0.85, 1.16).
Reading further, we find:
The key secondary outcome, mentioned above, is a composite of CV death, stroke, and heart attack, in which the result was slightly but not statistically significantly in favor of rosiglitazone versus its metformin and sulfonylurea comparators, with a hazard ratio of 0.93 (CI 0.74, 1.15).
The "slightly but not statistically significant" phrase tells you just how low these people will go to confuse their readers. Not statistically significant means that there is no way this result means Avandia was better than the other drugs. "Statistical significance" often means that there is only a very tiny difference, but when there is none it means the items being compared, statistically are absolutely equivalent. To phrase the finding in this way is to attempt to get around this by influencing statistically ignorant readers--which are 99% of all readers including most physicians whose one statistics course was decades in the past

So what this study really found is that the very expensive drug, Avandia, doesn't work any better than cheap $4 a prescription metformin or the sulfonylureas, but doubles the risk of heart failure. Which is a condition that shortens life dramatically and does very bad things to quality of life while the person is alive.

But the findings of this study get even worse. Here's a quote from the chief researcher.
“We have also confirmed that it is not wise to prescribe rosiglitazone for older women who are fragile and at risk of falling because the risk of arm and lower leg fractures is doubled in women,” said Home. This finding confirmed results in the ADOPT study and was statistically significant.
The only statistically significant finding here is that this drug which doesn't do anything metformin doesn't do also causes severe osteoporosis. And when you realize that fractures are a leading cause of death in older women you have to realize just how important this finding is.

UPDATE 6/19/2009 : Note that this study was funded entirely by GlaxoSmithKline plc, UK, makers of Avandia.

Note also that not only was the risk of "Heart failure causing admission to hospital or death" much higher, but that the incidence of "Heart failure causing admission to hospital or death" was extremely high. Sixty-one out of 321, or one out of every five people in this study who were taking Avandia ended up in the hospital or dead thanks to heart failure. In the control group the incidence was 9 out of 100.

One in Five dead or hospitalized gives you worse odds than does Russian Roulette.

UPDATE: In reviwing these statistics about Avandia, it is very important to keep in mind that both heart failure and fractures are what are known as "Class Effects" of the TZD drugs, which means that they occur in both Avandia and Actos because they occur in direct response to the way they affect PPAR-gamma.

But there was more news about fractures and TZD drugs presented at the ADA sessions, which did not make press coverage.

Avandia and Actos Cause Significantly Higher Rate of Fractures in Women and Men

Another MEDCO database study presented confirmed that both TZD drugs, Avandia AND Actos cause fractures, and in everyone, not just in older women.

The methodology here was similar to the Byetta study.
The sample, consisting of 144,399 people, was divided into two cohorts; one group was made up of 69,047 patients who were taking a TZD, and the other included 75,352 patients who were not prescribed a TZD. The average age for both groups was 56. Fracture rates were also compared between a subset of subjects who were prescribed a TZD for the first time during the study period (n=11,738) and 13,563 patients who were newly prescribed one of the other diabetes treatments but not a TZD. The analysis also compared fracture rates according to gender; women made up 49% of the sample and men 51%. A logistic regression model was adjusted for age and conditions including COPD, asthma, osteoporosis, stroke and prior fracture, and was used to compare fracture risks between diabetes patients prescribed TZD and those not taking TZD.
The finding was chilling:
Among patients taking a TZD, there were a total of 3,346 fractures, a 43% higher rate than those not taking a TZD. The risk was the same no matter if the patient was on rosiglitazone or pioglitazone. When analyzed by gender, both men and women had an increased risk associated with a TZD. Women on a TZD were 55% more likely to have a fracture than females not using the drug, and men on a TZD had a 26% higher likelihood of a fracture than the male control group. [emphasis mine]

While women who were new to TZD treatment were at a 40% higher risk for a fracture within 18 months of initiating therapy than females new to treatment but not on a TZD, men newly started on TZD treatment showed no difference than those not taking a TZD.

WHY Avandia and Actos Cause Heart Failure Discovered: It's the PPAR-Gamma

And finally, another study was published last week that was not presented (as far as I know) at the ADA sessions. It was published in German, unfortunately, it explains why TZD drugs cause heart failure. You can read about it in Science Daily:

Stopping Fatty Change in Heart Cells

This study found that that. "A healthy heart burns fat. But the abnormally enlarged heart cells burn sugar in the form of glucose because this form of energy is quickly available. The protein HIF1-alpha is responsible for this conversion to sugar combustion." Furthermore "One of the genes regulated by HIF1-alpha is known as PPARgamma. It causes the cardiac cells to produce and store fat. This results in the cells becoming fatty and dying off. Myocardial contraction is disrupted and this can lead to fatal heart failure." When you put this together with the fact that the mechanism by which the TZD drugs work is by stimulating PPAR-gamma it all falls into place.

The Science Daily report explains
"...some diabetics are given PPARgamma-promoting medicine to help muscles and other organs better respond to insulin. Clinical studies have shown that these patients have a higher risk of dying from heart failure. This research by Krishnan and Krek has shown why these drugs may be risky.
There you have it folks. TZD drugs double your chances of developing heart failure and raise the risk that you will break bones--because they divert osteoclasts (baby bone cells) and turn them into baby fat cells. You can read the research that explains this HERE.

These drugs do not prevent the most serious complication of diabetes any better than metformin or sulfonylureas. So why would you put them in your body?

Byetta, on the other hand, is looking a lot better. It is starting to generate safety studies that are compelling and though it only works for one out of three people who take it, for those for whom it works, it works very well.

June 9, 2009

Good Science: Dr. Leibel Explains Metabolic Slowdown with Weight Loss

I first learned about Dr. Rudolf Leibel's groundbreaking work in obesity studies when I read the book, Fat : Fighting the Obesity Epidemic back in the 1990s.

Dr. Leibel and Dr. Jules Hirsch research obesity at Rockefeller University. In a field where 99% of the published research would not earn a grade of "A" in a 9th grade science class, these researchers stand out. They use rigor and carefully applied scientific techniques and it is very hard to find flaws in their research.

Where other nutritional researchers based their studies of food intake on infamously inaccurate nutritional questionnaires filled with questions of appalling vagueness, like "How many times in the last month did you eat cheese", these researchers study subjects who live at their lab for months at a time where every bite that goes into their mouth is measured and tracked.

And not just what goes in. Because their focus is on the metabolic changes that occur with various food intakes, they also measure a lot more.

Rather than summarizing, I'll give you a quote from Dr. Leibel, which appeared in a wonderful interview published in Scientific American. The whole interview is well worth reading. You'll find it HERE.

In that interview, Dr. Leibel explains how he determines calorie expenditure when tracking metabolic changes in his subjects. What follows is a lengthy excerpt, but it is impossible to communcate the rigor of his research without quoting the whole thing:
... We use heavy isotopes of water. Here we give the patient two isotopes of water to drink... We give them deuterated water [also known as heavy water] and O18 water. So one is tagged on the hydrogen and one is tagged on the oxygen.

The interesting thing is that when you give somebody water like this, the deuterium comes out of the body which is determined by water turnover in the individual. The O18 is in equilibrium with carbon dioxide, so the O18 comes out by two mechanisms: first with normal water by transpiration, perspiration and urine, but also in the breath. The difference between those two decay curves (the O18 comes out faster), which we obtain by getting urine from these patients every day for 10 days-that gap is proportional to carbon dioxide production in that individual. By doing this, we can figure out how much carbon dioxide this person made over a period of 10 days. Knowing that, and knowing what the so-called diet quotient is-in other words, what the ratio of carbohydrates to fat in their diet is-you can back-calculate the amount of oxygen used to produce that amount of carbon dioxide. So by some simple algebra using the rate of carbon dioxide excretion, you can actually calculate how much oxygen their body used in the process of oxidative metabolism. That is a very critical number because it tells you how much energy they burned. Oxygen consumption can be immediately converted into calories.

Then we take the individual and we measure their body composition-how much fat is in the body-by different techniques. We weigh them in air, then weigh them in water, using Archimedes' principle. We do a scan of the body with low-energy x-rays. And we also do it by isotope distribution, since when we administer the doped water, it gets distributed in the body's water space, not in the fat. So by looking at the partitioning of that water we can get another measure of body composition. So we very carefully document the amount of body fat in these people at the end of these periods of weight stability.

Then we put them through a series of metabolic studies: looking at how they metabolize glucose, how much insulin the pancreas produces, what thyroid hormone is doing, what the catecholamines are doing-in other words, how much epinephrine and norepinephrine they're producing-and how much dopamine they're producing.

... We use a technique called spectral analysis, in which you deconvolute the heart rate and also by drug blockade techniques, where we give doses of atropine and esminol sufficient to totally lyse the activity of one limb of the autonomic nervous system. By then studying heart rate in these people we can actually tell whether either their sympathetic or parasympathetic nervous system has been cranked up or cranked down as a result of changing their body weight.

Finally, these people are put through a series of measures of exercise physiology. We look at how skeletal muscle converts energy into work.... This is done by bicycle odometers and treadmills and also by putting one the of the large muscles into a nuclear magnetic resonance (NMR) device.

...we also measure the energy expenditure of the patient at rest. We put a hood over their head and measure the rate of oxygen consumption while they are resting. We measure the energy expenditure that occurs when they ingest a fixed number of calories-this is called the thermic effect of feeding.
Quite a step from giving a questionnaire with the question, "How many hours did you exercise in the past month" which is the usual way nutritional research papers attempt to answer the question of how many calories were burned.

One of the most intriguing findings of Dr. Leibel's exceedingly technical research has been that normal people appear to have a very powerful weight "set point." When they eat more than needed to maintain their weight at that set point, their body becomes 15% more efficient in burning off the excess calories. When they eat less than they need for maintenance, which is what happens with intentional weight loss dieting, their bodies become 15% LESS efficient.

Here's Dr. Leibel again, explaining this:
When you do these studies you find that when you force an individual's weight up 10 percent, they require more energy to maintain that higher body than you would predict based on their requirements at usual body weight.

There is some degree of heterogeneity. It is not that great, although you do occasionally see people who have very little increase in energy expenditure when they gain weight [emphasis mine] . Why somebody who has this change in body weight doesn't increase is a very interesting question.

...When a person goes down 10 percent in body weight, lean or obese their reduction in energy expenditure is in the 15 percent range. If you take them down by 20 percent, it doesn't get any more. So it appears that whatever this defense mechanism is, if you want to look at it teleologically like that, it kicks in quite early: 10 percent is enough to bring it out. We don't know whether five percent is, because we've never tested that small an increase in weight.

A fraction is due to changes in resting energy expenditure. But the majority of the change occurs in the energy cost of physical activity.... We're trying to figure out the mechanism by which a change in body weight not only would cause an alteration in resting energy expenditure but also in the energy cost of physical activity. Is something happening in muscle or in the autonomic nervous supply to skeletal muscle, which influences blood flow?
What I like about Dr. Leibel is his truly scientific objectivity. He doesn't speculate. He looks at the evidence and when the evidence does not explain his findings, he does more research. If everyone researching diet would do this, rather than doing idiotically designed studies intended only to prove their preesisting beliefs, we might actually understand what happens in a broken metabolism that causes people to adjust their setpoint ever upward, in contrast to what is observed to happen in a normal person.

Having reviewed the 1990s research, I did some Googling to see what Dr. Leibert was up to now, and I was rewarded with a wonderfully insightful study published last year.

Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight. Rosenbaum M, Hirsch J, Gallagher DA, Leibel RL. Am J Clin Nutr. 2008 Oct;88(4):906-12.

In this study, the researchers took 21 people all of the same weight into their lab for the kind of "every molecule measured" study of their energy metabolism you read about above. Seven subjects had not lost weight. Seven had dieted down to that weight--a 10% loss from their starting weight in the past two months. Seven had dieted down to that weight--also a 10% loss from their starting weight at least a year before.

All subjects were fed precisely titrated nutritional formulas which matched their observed nutritional and caloric needs.
Twenty-four-hour total energy expenditure (TEE) was assessed by precise titration of fed calories of a liquid formula diet necessary to maintain body weight. Resting energy expenditure (REE) and the thermic effect of feeding (TEF) were measured by indirect calorimetry. Nonresting energy expenditure (NREE) was calculated as NREE = TEE - (REE +TEF).
When the last drop of urine and sweat had been accounted for here's what they found:

"Declines in energy expenditure favoring the regain of lost weight persist well beyond the period of dynamic weight loss."

Even a whole year after losing weight, people's metabolisms remained depressed.
TEE [total energy expenditure}, NREE [nonresting energy expenditure], and (to a lesser extent) REE [resting energy expenditure] were significantly lower in the Wt(loss-sustained) and Wt(loss-recent) groups than in the Wt(initial) group. Differences from the Wt(initial) group in energy expenditure were qualitatively and quantitatively similar after recent and sustained weight loss.
Now it's important to keep in mind that these are metabolically normal people--they don't have to contend with autoimmune attacked thyroids, flaky adrenals, or failing beta cells. Those of us who have diabetes who have embarked on intense stints of dieting and emerged with little to show for it may find in the experience of these normal people, some hint of what we are up against.

This research suggests very strongly, and Dr. Leibel stresses that everyone can lose weight by cutting back on calories. But after the set point is attained, the body will fight back against further weight loss by decreasing how much it burns even when we are sleeping.

In considering this research, it's worth noting that the study subjects were eating so called "balanced" diets, high in carbohydrates. One can only dream of seeing studies that look at what happens, metabolically to people on long term low carb diets subjected to this kind of study.

Because of what we see with leptin studies, my guess is that there is still a significant, persistent metabolic slowdown no matter what nutrient mix a person eats. But my own observations and the data I have collected--through feeble questionnaires of course, since no one is entrusting me with their precious bodily fluids--suggest that low carb dieting may give us another 5-10% worth of leeway before the inevitable metabolic slowdown kicks in.

That might explain why so many people who responded to my low carb diet questionnaire report stalling at 20% of initial weight lost and regaining when they get below that figure. My own maintainable set point appears to be at 15% of initial weight lost. Below that and regain is inevitable.

OTOH, most people eating carb controlled diets or using strategies that keep their blood sugars normal do report that they are able to maintain their 15-20% weight loss long term. Many more than the statistics on weight loss maintenance drawn from studies of people on standard diets would predict. I weighed in at 142 lbs this morning which represents complete maintenance of my 2002-2003 weight loss coming from a high of 170 lbs.

I do have to restrict calories to maintain and it takes effort. But it can be done. Metformin REALLY helps. I am starting to think that whatever it does to liver and muscles may fight the metabolic slowdown that Dr. Leibel has so brilliantly discovered and described.

June 4, 2009

Leptin, Weight Loss, and Health Improvement

You've probably heard you could reverse your diabetes if you lost weight. And if you have lost a lot of weight and kept it off, you've probably learned this claim is bunk.

Despite the intensity which which this claim is made by doctors, my experience and that of dozens of people who responded to my weight loss poll has been that weight loss, even large amounts of weight loss do little or nothing to change our ability to metabolize glucose.

You might wonder then why there is so much data suggesting that weight loss prevents diabetes. I've given this some thought, and my conclusion is that in the large population studies used to support the "weight loss prevents diabetes" meme what we are really seeing is something else entirely: Fat people who can lose weight easily are most likely those who do not have the fatally disturbed glucose metabolisms characteristic of Type 2 diabetes.

I have never seen a prospective study in which people positive for the genes associated with diabetes were able to prevent diabetes by losing weight. I have seen studies where thin people with diabetic genes already demonstrated defects in energy metabolism and mitochondrial function that made it much easier for them to gain weight.

But even though losing weight will not heal diabetes, weight loss does have some benefits beyond the obvious vanity ones. Everyone knows that weight loss decreases blood pressure--the other major cause of heart disease besides elevated blood sugar.

What they may not know is that weight loss may also decrease systemic inflammation--the inflammation, measured with the CRP (C-Reactive Protein) test that has been strongly associated with heart disease.

One reason that weight loss has these benefits is because of its impact on leptin, a hormone that has a major impact on whether our body stores or releases fat. I'm not going to go into the details of how leptin functions on the body here. It's a fascinating topic I've just started researching. A lot of hooey has been written about it by people selling miracle weight loss cures, so it will take me some time to sort the hype from the truth.

But some fascinating findings about leptin are these: When leptin is high, CRP rises, platelets tend to clot aggressively, and blood pressure rises--all factors contributing to heart disease. Some of the studies documenting this are:

Serum Leptin Level in Hypertensive Middle-Aged Obese Women de Moraes, Camila. The Endocrinologist. July/August 2005 - Volume 15 - Issue 4 - pp 219-221


Effects of Physiological Leptin Administration on Markers of Inflammation, Platelet Activation, and Platelet Aggregation during Caloric Deprivation Bridget Canavan et al. The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 10 5779-5785

There are a couple reliable ways of lowering leptin. One is by losing a lot of weight. All studies show that by the time an overweight person loses 10% of their starting weight their leptin levels have dropped dramatically. Interestingly, further weight loss appears to have no further effect on leptin level.

But significant weight loss is only one way of lowering leptin. As the Canavan study demonstrates, in normal people, at least, you can also lower leptin with a one day complete fast, even if no significant weight loss occurs. The graph on page 5 of the pdf version of the Canavan study shows leptin dropping from about 11 ng/ml to slightly above 3 ng/ml. Over three more days of fasting leptin does not drop much further.

By now my alert, physiologically aware readers are probably seeing where this is going. Because one thing we know about ketogenic diets is that physiologically they mimic starvation, i.e. fasting. Which suggests very strongly that it may be possible to get the leptin lowering effects of a fast from a ketogenic diet--i.e. a diet whose level of carbohydrates is low enough to switch muscles from burning glucose to burning ketones and, eventually, free fatty acids.

The actual carbohydrate intake that corresponds to a ketogenic diet varies with body size and probably with other physiological idiosyncrasies. One size does not fit all despite what you may have read. But you can tell when you've crossed the ketogenic boundary with your own diet when you lose or gain 2-4 lbs of water in a single day. This water fluctuation represents the draining or refilling of your body's glycogen stores. You can learn more about carbohydrate intake, water, and glycogen storage HERE.

For me, the boundary where I start to refill glycogen is at an intake of about 70 grams of carbs a day. I weigh around 142 lbs. A larger person may not hit that boundary until they take in 100 g of carbs.

There's some suggestion in the research that people on a ketogenic low carb diet do experience the same impact on leptin as do people who fast. To find the data exploring the relationship of leptin to a low carbohydrate diet is not easy, because the majority of studies in high impact journals which discuss "low carbohydate diets" do not describe true, ketogenic, low carb diets. For example, a famous study published in The New England Journal of Medicine which purported to show that the so-called Mediterranean diet was more effective than the Low Carb diet used a "Low Carb" diet where people were eating 120 g of carbs a day after the first few weeks. You can read the details of that diet HERE.

But there is a small amount of research tracking what happens to leptin on a low carb diet and it is quite impressive. You can read about this research in this metastudy published in Nature's journal Obesity Research:

Cardiovascular and Hormonal Aspects of Very-Low-Carbohydrate Ketogenic Diets. Jeff S. Volek and Matthew J. Sharman. Obesity Research (2004) 12, 115S–123S; doi: 10.1038/oby.2004.276

That study found:
There were greater reductions in leptin after the VLCKD [Very Low Carb Diet] (-50%) than the low-fat diet (-17%). The ratio of leptin/total fat mass also decreased more after the VLCKD (-45%) than the low-fat diet (-21%).
This impact on leptin, which occurs very fast during a ketogenic diet because of its physiological similarity to the fasting state may explain the dramatic drop in blood pressure many people experience during the early stages of a low carb diet.

It also suggests that the low carb diet, independent of weight loss, might also have a positive effect on lower CRP and help decrease inflammation and the tendency of blood to clot.

There is one more take away message from this research. One that is lost on many doctors and the health media. Even on the worst weight loss diets--like the famed medically supervised controlled fasts where people are fed mostly on vitamin enriched fluids containing protein, sucrose and omega-6 vegetable oil, which make up an alarming about of mainstream 1990s obesity research--weight loss stops lowering leptin levels once 10% of weight has been lost.

So no matter how fat you are, you should be getting the leptin-related benefits of weight loss, whatever they are, from a weight loss of no more than 10% of your starting weight. And as most low carb weigh loss dieters have learned, while it is difficult and often impossible to get to goal on even a perfect low carb diet, it is easy to lose that 10% of starting weight. Most heavy low carb dieters can easily achieve 20% weight loss, though after that it gets tough-to-impossible, depending on how damaged your metabolism might be.

There's a down side to this, of course. Because when leptin levels drop our metabolisms slow and our brains start hunting for food. Boosting leptin, which many pop diet gurus advocate, may not be the answer, given the negative cardiovascular effects associated with boosting leptin especially the dramatic rise in CRP it causes.

So there's no miracle cure here, folks, but a lot to think about.


June 1, 2009

Good Science: How Organochlorines Are Making Us Fat

You've dieted. You've lost 20, 30, 100 lbs. It all came back as soon as you stopped starving yourself.

Perhaps you blamed yourself for weak will. Perhaps you thought being fat was "in your genes." But there's a new possibility revealed in research that was published without any fanfare 5 years ago.

Perhaps you are being poisoned by the plastics, pesticides and industrial solvents that have contaminated our air and water and which are now being found in the blood streams of 60% of Americans.

Here's the study:

Thermogenesis and weight loss in obese individuals: a primary association with organochlorine pollution. A Tremblay1 et al. International Journal of Obesity (2004) 28, 936–939. doi:10.1038/sj.ijo.0802527 Published online 18 May 2004.

In this study researchers measured the sleeping metabolic rate of fifteen obese subjects, male and female, before and after they pursued a 15 week weight loss regimen. The researchers predicted the degree of metabolic slowdown they would find in their subjects after weight loss using formulas derived from a control group of 86 non-obese individuals with a wide range of body weights whose sleeping metabolism had been studied with a whole body calorimeter. The formula they came out with was validated by being compared with the findings of another study by other researchers.

At the start of the study the obese subjects had much higher metabolic rates than the controls. After weight loss, though their final metabolic rate value was within the range for normal people who weighed on average considerably less than they did, the amount by which their metabolic rate had dropped was almost twice what had been predicted. You can view the graph showing the result HERE.

Analysis of the blood of the participants for
fasting plasma leptin, total T3,free T4, and total plasma OC concentrations after weight loss as well as their changes induced by weight loss were used as predicting variables. As the change in plasma OC concentration is associated with the loss of FM [fat mass], and since Dulloo and Jacquet have reported that fat depletion (loss in FM as a %
of initial FM) is a determinant of the adaptive fall in basal metabolic rate during weight loss, fat depletion was correlated with the change in plasma OC concentration. This correlation was significant (r2 >0.37, P0.05), and fat depletion was thus included as the predicting variable in the analysis. As shown in Table 2, the change in total plasma OC concentration was the main factor explaining deviations in SMR from predicted values in response to weight loss (r2¼0.47).
In their summary they restated this more simply:

Increased plasma OC concentration was the factor explaining the greatest proportion of the difference between predicted and measured SMR [sleeping metabolic rate] changes induced by body weight loss. OC [organochlorine] pollution seems to be a new factor affecting the control of thermogenesis in some obese individuals experiencing body weight loss.

So what, you may ask are "organochlorines?"

The answer is a host of organic pollutants that pervade our environment. At the top of the list is vyinyl chloride, an ingredient in PVC plastics. The NIH's Report on Carcinogens (11th ed) describes vinyl choride as a known cause of cancer known to cause genetic damage. It also explains
PVC is a plastic resin used in many consumer and industrial products, including automotive parts and accessories, furniture, medical supplies, containers, wrapping film, battery cell separators, electrical insulation, water distribution systems, flooring, windows, videodiscs, irrigation systems, and credit cards.
But that is only one source of organocholorines. They also found in pesticides, industrial solvents, and the PCBs still found in our environment thanks to decades of industrial use.

The researchers also calculated the impact of the dramatic drop in leptin (expected with weight loss) and concluded that
The main finding of this study was that the changes in plasma OC concentration were the main predictor of adaptive thermogenesis, and explained about 50% of its variance. As discussed above, this is not a surprise since these compounds produce significant alterations of mitochondrial activity and of the thyroid function.
In short, while we expect dieters to experience slowed metabolisms after dieting thanks to some natural changes, a major one of which is the drop in leptin levels, it appears that the presence of these chemical pollutants in our body is causing the metabolic slowdown to be much steeper than predicted.

And from a practical standpoint what this means is that a person whose body is filled with these chemicals who manages to lose weight will have an extremely hard time maintaining that weight loss--harder than would be the case were their bodies not filled with these chemicals that damage their mitchondria (the cell units that burn energy) and their thyroids.

This finding correlates with others we have discussed elsewhere that link incidence of diabetes in various populations with their exposure to PCBS, plastics, and pesticides. These other studies suggest that the organochlorines not only explain why it is so difficult to lose weight, but possibly why people gain weight in the first place, since these chemicals destroy the systems used to control blood sugar, and ravenous hunger is a side effect of poor blood sugar control.

Coincidentally, as I was getting ready to write this blog post I found a new article in Science Daily which linked the high level of liver damage found in Americans exposure to their blood-load of pollutants. That report can be read here:

Environmental Pollution Increases Risk Of Liver Disease, Study Finds

In that report we read:
""Our study found that greater than one in three U.S. adults had liver disease, even after excluding those with traditional risk factors such as alcoholism and viral hepatitis," said Matthew Cave, MD, assistant professor, department of medicine, division of gastroenterology and hepatology at the University of Louisville. "Our study shows that some of these cases may be attributable to environmental pollution, even after adjusting for obesity, which is another major risk factor for liver disease."

Using the 2003-2004 National Health and Nutrition Examination Survey (NHANES), researchers from the University of Louisville study examined chronic low-level exposure to 111 common pollutants including lead, mercury, PCBs and pesticides and their association with otherwise unexplained liver disease in adults. The specific pollutants included were detectable in 60 percent or more of the 4,500 study subjects. [emphasis mine]
You hear a lot about how fat people should be blamed for causing their obesity by indulging in gluttony and sloth. I don't question that people who get fat do so by eating a lot more than they should. But I go further than this. I ask WHY are the inbuilt physiological mechanisms which, in normal people, control appetite and maintain weight at a set point, all of a sudden completely nonfunctional in so many people?

Decades of research show that if you overfeed a normal person, they will quickly return to their normal weight thanks to the existence of a built-in weight set point regulation system. Decades of research also show that normal people have appetite control systems that control their food intake so exquisitely that a normal person will gain only 20-30 lbs over 40 years of life--which means that over a lifetime they are only overeating ten calories a day.

The obesity epidemic is a measure of how damaged our bodies have become and studies like this one--completely ignored by the media--point to why they are damaged.

It isn't moral failure, it's chemical poisoning. I personally believe chemical pollution and its effects on our bodies, worldwide, is a far greater crisis than the energy crisis and one a lot more likely to put human survival into doubt. More and more of our children are being born with conditions reflecting severe genetic damage. More and more people are battling infertility, too.

Personal responsibility is not going to solve this problem. Until we, as a society, demand that corporations stop poisoning our environment and selling us products that damage our bodies, it will only get worse.