New Findings About What Metformin Really Does

As many of my readers know, there is no requirement that the companies that sell pharmaceutical drugs provide an accurate explanation of what it is that their drugs do or of how they do it. All that they have to prove is that the drug has an impact on some measurable phenomenon. The company may claim that a drug functions using a mechanism that is later proven to be untrue. This has been the case with the SSRI drugs which it turned out actually work by remodelling the nerves in the hippocampus, NOT by changing levels of serotonin.

Metformin, which has been used for decades, is another drug whose effect is well understood--it lowers blood sugar and reduces the amount of insulin needed to lower blood sugar. This has been interpreted to mean that it lowers insulin resistance.

But new findings are calling this into question, as we discover that metformin may actually be stimulating insulin release or blocking the liver's release of glucose rather than impacting insulin resistant cell receptors.

The first finding is one I stumbled over recently, one which seems to have gone unnoticed by the medical press. It is that metformin appears to boost GLP-1 levels. GLP-1 is an incretin hormone secreted in the gut which stimulates the beta cell to secrete insulin in the presence of high blood sugars. GLP-1 may also lower glucagon production at the same time. While Byetta and Januvia are higly promoted as being incretin drugs, some little known research suggests that metformin may also raise the level of GLP-1 in the body.

Enhanced secretion of glucagon-like peptide 1 by biguanide compounds. Yasuda N et al. Biochem Biophys Res Commun. 2002 Nov 15;298(5):779-84.

This was old news, but it may partially explain some of the stomach symptoms people experience with metformin. GLP-1 stops or slows stomach emptying and that often causes nausea--a side effect many people experience with metformin.

Meanwhile, some brand new findings are making metformin's function even more intriguing.

A mouse study published on May 15, 2009 suggests that Metformin lowers blood sugar by directly stimulating a gene in the liver which is not responding to insulin the way it should. When this gene is stimulated, the liver stops producing glucose. So rather than improving insulin sensitivity, what metformin may actually be doing is bypassing a broken insulin signaling system and doing the job itself that insulin should have done--making the liver stop secreting glucose. In this case metformin is not increasing insulin sensitivity, it is replacing insulin.

Metformin and Insulin Suppress Hepatic Gluconeogenesis through Phosphorylation of CREB Binding Protein Ling He et al,, Cell Volume 137, Issue 4, 635-646, 15 May 2009. doi:10.1016/j.cell.2009.03.016

You'll find this study explained in layman's language in today's edition of Diabetes in Control:

New Information on how Metformin works.

Metformin may also prevent beta cell death. Another new study published in the May 2009 issue of Diabetologia examined pancreases of autopsied organ donors with and without Type 2 diabetes and found increased evidence of beta cell apoptosis (cell suicide) in the beta cells of people with Type 2. This reconfirms the finding of an earlier pancreas autopsy study.

What is interesting, though, is that this study also found that

Metformin ameliorated autophagy alterations in diabetic beta cells and beta cells exposed to NEFA [nonesterified fatty acides], a process associated with normalisation of LAMP2 expression.

This suggests that metformin might work to prevent beta cell death due to apoptosis.

Autophagy in human type 2 diabetes pancreatic beta cells M. Massini et al. Diabetologia Volume 52, Number 6 / June, 2009, DOI 10.1007/s00125-009-1347-2.Pages 1083-1086

I was sent the full text of this article by a subscriber and it turns out that they are not talking about the effect of metformin on the pancreas when taken before death. Instead what they did here was rescue still living cells from dead organ donors, most of them dead of heart attack, separate the beta cells and culture them. Then they infused the cultures with the fats and a solution of metformin. The metformin prevented some genetic expression in the presence of the fat, but it is difficult to know whether this has much relevance to what goes on in your living pancreas. Or to what extent, being bathed in fats reflects what damages islets in diabetes.

Still it is interesting to see people attempt to find out the impact of metformin on gene expression, which is what is going on in both these studies.

Anecdotal Musings about Metformin

I am particularly interested in metformin of late, because I stopped taking it for a year and noticed that while my blood sugars stayed pretty much constant, I started gaining weight eating the diet on which I had, until then, successfully maintained a significant weight loss since 2003.

I went back on metformin in early April and, sure enough, seven weeks later my weight has dropped some 6 lbs while I have been eating the identical diet--and insulin doses--on which I had gained 6 lbs the previous month.

I am not insulin resistant. I usually use a tiny dose of insulin--2-3 units to cover up to about 60 g of carbs. (I don't eat 60 grams of carbs very often, but if I do I can cover it with 3 units.) When I am taking metformin my insulin dose might drop from 3 units to 2 units, so while that represents a large percentage drop, it but a very tiny drop in the actual amount of insulin used and the kind of dose an insulin sensitive person might use.

But metformin does appear to do something that makes it extremely hard for my body to gain weight. When I first started injecting insulin a few years ago, when I was still taking 1500 mg a day of metformin, I actually LOST weight using insulin. As soon as I stopped metformin I started packing on weight whenever I used insulin, even if my blood sugars were completely flat.

One thing I noticed was that metformin also changes the way my body gains and loses the weight associated with glycogen when I cut my carbs to a ketogenic level, (a topic discussed in detail HERE). If I am not using metformin and start eating a very low carb, ketogenic diet, I will drop 3 or 4 lbs of water weight within days. If I am taking metformin, I won't. On the other end, if I go over the ketogenic boundary when I am taking metformin I won't pack on that sudden 3 lbs water weight gain.

My guess is that metformin somehow interferes with the creation and/or burning of glycogen which may make the body more likely to burn fats instead of stored glycogen. I have been told that some body builders use metformin to hasten the process of getting into a ketogenic state.

Another observation which repeats what I found in the past is that while I am taking metformin, I do not need to take my blood pressure medication to keep my blood pressure in the normal range. When I stop metformin, I do.

The worst side effect I experience with metformin is exhaustion. While taking it I tend to drop off to sleep around 9:30 whereas when I stopped metformin I was much more energetic and always stayed up to 11. My muscles tire more easily too. These side effects were a major reason I stopped taking it. It also gives me a heart-burn like pain (without reflux) which is annoying though my doctor did tests which suggest I don't have an ulcer, though that is what it feels like.

However, gaining 6 lbs in one month eating about 1600 calories a day is also annoying, and I have been battling weight gain all year since I stopped the metformin. I spent more than 6 months of the last 12 eating a very low carb diet and controlling calories and still found myself at the highest weight I'd been in 6 years. So for now, I'm back to taking the metformin.

Once I get my weight stabilized I'm going to experiment to see if I can find the very lowest dose that is still effective for weight purposes. In the past, I found that I had to take 1500 mg to see any impact on my blood sugars, and then it only lowered them about 10-20 mg/dl per meal (or reduced the insulin dose by that 1 unit.)

I am hoping that less might still help prevent weight gain, but this new study that suggests that metformin is working by stimulating a gene that stops the production of glucose makes me wonder if I won't see weight prevention effects until I see that slight lowering of post-meal blood sugars that suggests that my liver's glucose production has been stopped.

What's your experience with metformin and weight gain, loss, or maintenance? Does your experience cast any light on any of these new findings?

 

Even MORE Bad Science: Triglycerides Predict Neuropathy

Today's issue of Science Daily alerted me to a new study published in the journal Diabetes which is being interpreted in a way that leaves me, not for the first time, wondering whether these researchers got their Ph.D. degrees from the "prestigeous unaccredited universities" that send out degrees over the internet.

The study is here:

Elevated Triglycerides Correlate with Progression of Diabetic NeuropathyTimothy D. Wiggin et al. Diabetes. May 1, 2009, doi: 10.2337/db08-1771

What the researchers found here was nothing all that remarkable. it was:

In this cohort of participants with mild/moderate DN [diabetic neuropathy], elevated triglycerides correlated with MFD [nerve myelinated fiber density]loss independent of disease duration, age, diabetes control or other variables. These data support the evolving concept that hyperlipidemia is instrumental in the progression of DN.

Where the science gets bad is in how the researchers interpret their finding.

From Science News we read that a lead researcher on the study had this to say:

"Aggressive treatment can be very beneficial to patients in terms of their neuropathy," says Feldman, who is also director of the A. Alfred Taubman Medical Research Institute and director of the Juvenile Diabetes Research Foundation Center at U-M for the study of complications in diabetes.

People can reduce blood triglyceride levels with the same measures that reduce cholesterol levels: by avoiding harmful fats in the diet and exercising regularly. [emphasis mine]

But wait! High triglycerides are NOT produced by eating "harmful fats." They are produced by eating excess carbohydrate. Lower your carbohydrate intake for even a month and you'll see your triglyceride levels plummet no matter how much fat you eat.

So what this study actually found is not more proof of the dangers of eating a high fat diet. What we have is instead more proof that diabetic complications are a associated with the excess consumption of carbohydrates. Which makes total sense since when people with diabetes eat excess carbohydrates they not only get high triglycerides, they get high blood sugars.

DUH.

You can lower your fat intake all you want and exercise daily, but if you are a person with diabetes whose blood sugars are running higher than normal because you are eating more carbs than your body can burn you are going to have blood sugars at least reaching the pre-diabetic level after meals, the level where solid research has proven diabetic neuropathy begins to occur, if not at frankly diabetic levels.

Is the neuropathy caused by the high triglycerides? Probably not. It's probably caused by the high glucose levels in your blood stream that clog your tiny capillaries and starve nerve fibers.

So what this study probably "proved" is only that high triglycerides are a marker for the elevated carbohydrate intake that produces the high blood sugars that cause neuropathy.

If you want to lower your triglycerides, lower your carbs. Eat all the fat you want. Your triglycerides will plummet. Metformin also helps lower triglycerides, possibly because it blocks the processes in the liver that convert carbohydrate to triglycerides.

The fact that the people who peer reviewed this article--and the researchers who conducted it--do not seem to understand that carbohydrate intake correlates directly to triglyceride level is very troubling. Once again we see a religious belief--that eating fat is bad--translate into poor science--the belief that lowering fat intake will lower blood fats.

It is understandable that scientists might have believed this back in the days when poor quality research, spun by important research divas shaped medical belief, as has been so brilliantly documented in Gary Taubes's book, Good Calories, Bad Calories.

But this is 2009, not 1989 and if these people had been paying any attention at all to dietary research they should have known of the connection between carbohydrate intake and triglyceride levels.

But they don't, so you can be sure that doctors will now be urged to force their diabetic patients into low fat diets to prevent complications. And thousands of thousands of people will end up with precisely the complications they were trying to avoid as they eat their "healthy" diets of Cheerios, bananas, pasta, whole grain bread and fat free starchy sauces.

Don't be fooled. You do want to keep your triglycerides low. The lab sheets suggest under 150 mt/dl is normal, but you will do a lot better to get them under 100. And the way most of us do that is to eat diets that are modestly carb restricted--i.e. under 120 grams of carbs a day, or whatever amount of carbohydrates it takes to keep your blood sugars in the safe, normal range.

To learn how to lower your blood sugars visit this page: How To Lower Your Blood Sugar

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Bad Science: Study of Diabetic Women's Sexual Response Gets it Backwards

The latest contribution to the growing genre, "More Bad News for People with Diabetes" is a study which is being reported with headlines like this one from Diabetes in Control: Diabetes Affects Women's Sex Life.

But as is always the case we see a different picture emerge when we look more closely at what was actually reported.

The study cited is this one:

Sexual Dysfunction in Women with Type 1 Diabetes. Paul Enzlin, et al. doi: 10.2337/dc08-1164 Diabetes Care, May 2009 vol. 32 no. 5 780-785

The full text is (temporarily?) available HERE.

Here is the conclusion presented in the abstract:

Depression is the major predictor of sexual dysfunction in women with type 1 diabetes. These findings suggest that women with type 1 diabetes should be routinely queried about the presence of sexual dysfunction and possible co-association with depression.

Sounds pretty clear cut doesn't it, and the final sentence suggests strongly that doctors should be cross examining women with Type 1 to see if they have any of the long laundry list of "depressive symptoms" that suggests 99.3% of all human beings need expensive SSRI anti-depressive drugs.

These questionnaires, helpfully supplied by the drug manufacturers, consider things like "always hungry" and "not hungry", "sleep easily" and "can't sleep" all as indicators of depression. So are positives answers to "sometimes I feel sad" or "Sometimes I feel anxious". Unless you are manic, you probably get diagnosed as depressed, if you're manic you get diagnosed as bi-polar and put on the drugs anyway.

But that said, let's look at what the study actually did and what it really found.

For starters, the study took a subset of 550 female participants in DCCT and had them answer a seven question questionnaire about their sexual response. The researchers then discarded the responses from women who weren't sexually active during the past year and ended up with 434 women whose average age was 42.8 ± 7.1 years old. They'd had diabetes for an average of 22.8 ± 5.0 years.

Now given that the conclusion of this study was that depression was the only factor they found that predicted sexual dysfunction more strongly than expected in this group, it's worth asking "how did they determine if these women were depressed?"

And here's the answer:

the prevalence of depression was assessed by means of a composite depression variable, which was based on study coordinator ratings of clinical depression, based on DSM-IV criteria, in addition to patient self-reports of use of antidepressant medications and/or psychological counseling for depressive symptoms

Am I the only person who sees a huge methodological problem here?

I hope not. Because what they are saying is that the use of antidepressant medication was the main way they determined if someone was depressed.

But hold on folks, did everyone forget that loss of libido is one major very common side effect of the use of antidepressant medication is in women?

So what we have here is the finding that people who are taking drugs that destroy libido have higher than normal loss of libido. NOT that women with diabetes who are depressed need antidepressants.

And if we read the extended conclusion section of this study, what we discover is NOT that women with diabetes have lousy sex lives. Instead, we find the exact opposite!

Here's some of the detailed finding:

the overall prevalence of FSD among sexually active women in this study was found to be 35.4%. Univariate analyses revealed that women meeting criteria for FSD were on average older than women without FSD (P = 0.0041), were more likely to be married (P = 0.0016), be (post)menopausal (P = 0.0019), have evidence of microvasculopathy (composite diabetes complications variable, P = 0.0092), and be depressed (P = 0.0022) than women without FSD (Table 2).

Among those women who met the criteria for FSD, 57% reported a problem with decreased desire, 51% had problems with orgasm, 47% had inadequate lubrication, 38% had problems with sexual arousal, and 21% reported pain during intercourse. Additionally, 25% of sexually active women reported low overall sexual satisfaction. For all sexual domains, study participants without FSD scored higher (i.e., had better function) than women with FSD (P < 0.001).

What this says is that slightly over 1/3 of the women had some form of sexual dysfunction. This it turns out is BETTER than what is found in normal patients seen in gynecological practice who responded to a similar questionnaire:

Prevalence of female sexual dysfunction in gynecologic and urogynecologic patients according to the international consensus classification..

In that study the prevalence of female sexual dysfunction was 50%!

Their analysis of statistics yielded this finding:

When controlling for the effects of other variables, depression status (depressed vs. nondepressed) and marital status (married vs. not married) were the only variables in the multivariate model that were significant predictors of FSD.

Other statistics cited reveal that the diabetic women most likely to report dysfunction were older post-menopausal ladies who were having sex with husbands. If this strikes you as an amazing finding, you aren't an older menopausal lady having sex with a long-term husband.

In the extended conclusion section we read this:

Although rates of sexual dysfunction in women are not dissimilar to those in men, the pattern of specific effects of diabetes on men and women is markedly different.... while ED is strongly correlated with A1C and the cardiovascular and neuropathic complications of diabetes (3,4,10).... The lack of association between any measurement of A1C and FSD in this study suggests that compared with men, the sexual response in women with diabetes is more likely to be affected by the psychosocial aspects (e.g., depression) than by the metabolic control or complications of the disease.

So what they really found was that diabetes and complications made no difference in women's reporting of sexual functioning.

What did correlate was depression--which was in many of these women's cases (stats not given) a synonym for "taking antidepressants known to depress libido." The other significant factor associated with sexual dysfunction was being married to the same old boring husband.

So one wonders why the abstract does not conclude this way:

Measures of blood sugar and indications of complications did not correlate to self-reported sexual dysfunction in women. Use of antidepressants and marriage to boring spouses did. Doctors should wean diabetic patients complaining of sexual dysfunction off these deleterious drugs and suggest they find new and more stimulating sex partners.

Instead, doctors will be told by the ever helpful drug companies that DCCT results prove that diabetic women need more antidepressants.

Who the heck peer reviewed this pathetic excuse for a study?

 

Metastudy Confirms Metformin Appropriate Treatment for Prediabetes

A study that reviewed several previous studies about the impact of using metformin on the progression of prediabetes to diabetes confirms that yes, people with prediabtes who take metformin end up with better blood sugars after 3 years than those who don't and are therefore less likely to be diagnosed with full-blown diabetes.

This isn't original research, it's just a look at the major studies that have examined the impact of metformin on prediabetes. But because I hear from so many people with prediabetes whose doctors won't give them any help at all, I though it worth a look.

Treating prediabetes with metformin: Systematic review and meta-analysis Muriel Lilly, Can Fam Physician Vol. 55, No. 4, April 2009, pp.363 - 369

The key issue to remember here is that the concept that "prediabetes" progresses to "diabetes" which treats the two conditions as if they were separate diseases is flawed.

In fact, the medical definition of "diabetes" is completely arbitrary. A committee years ago chose some blood sugar test results and defined them as "diabetes." They could have--and many argue should have--chosen different test result numbers. But they chose the ones they did mainly, their own documentation showed, to diagnose people with diabetes as late as possible, because of the severe penalties the American medical system imposes on people who have pre-existing conditions.

You can read about how the diagnostic standards for diabetes were set HERE.

"Prediabetes" was also defined arbitrarily at the same time as "diabetes" was defined and as has been the case with diabetes, the definition has changed over the years.

But what you, the person with abnormal blood sugar, need to understand is that there's no sudden change in your health that happens when you get an official diabetes diagnosis. Any blood sugar that is elevated above normal for hours each day can and will damage your organs. So if your concern is to keep your nerves, heart, kidneys and retinas healthy your focus should be on keeping your blood sugars normal, not in avoiding a technical "diabetes" diagnosis.

With this in mind you can see why the argument the medical establishment uses to argue that "more research is needed" re the use of metformin in prediabetes is a red herring. The argument is this: "We don't know whether metformin is preventing diabetes or just masking the symptoms by lowering blood sugar."

Those who argue this point out that if people stop taking metformin, their blood sugar may go right up to where it would have been without it. So if that is the case, the metformin didn't "prevent" diabetes and there is no point in prescribing it.

But hold on a minute. The damage from "diabetes" is done by the elevated blood sugars, which clog capillaries, block kidney filtration units, and destroy the nerves of the autonomic nervous system that regulate the heart. If we lower blood sugar we avoid this damage. There has never been a single study that shows that people with "diabetes" by diagnosis who maintain completely normal blood sugars develop any of the complications of diabetes. These are caused by the exposure to high blood sugars, not the underlying dysfunction that caused the high blood sugars.

So if giving people metformin lowers people's blood sugar to where it isn't going up to diabetic levels, this is good no matter how you look at it. Even if it doesn't change a thing except their blood sugar levels.

The real problem with using metformin to "prevent diabetes" lies in how "diabetes" is diagnosed in these studies. Most doctors and studies diagnose diabetes as meaning that the patient's fasting blood sugars have risen over 125 mg/dl. Because metformin often lowers fasting blood sugar 5, 10 or 20 mg/dl, someone who might have a blood sugar of 128 mg/dl and be diagnosed as "diabetic" will take metformin, get a fasting blood sugar of 123 mg/dl and be diagnosed "Non-diabetic" in the studies.

This makes a pretty graph or two for the researcher but it doesn't make much functional difference in the health of this patient. Because functionally there isn't much difference in how much damage you are doing to your body with a fasting blood sugar of 123 mg/dl vs 128 mg/dl.

What is much more significant if you are trying to keep people from going blind or losing their kidneys is what happens to the blood sugar after meals--which is a statistic these large "diabetes prevention" studies rarely track since it requires much more expensive testing.

A person with the fasting blood sugar of 108 mg/dl may be be going up to 180 mg/dl after meals and coming back down to 100 mg/dl in two hours. Or they may be going up to 270 mg/dl and drifting back down to 108 in 4 hours. Both people are prediabetic, but the first person is much less likely to develop diabetic complications than the second. And, in fact, the second is technically diabetic given the ADA diagnostic criteria since they have random blood sugars over 200 mg/dl--except that their true diabetic state never gets discovered since the doctors and researchers only look at their fasting blood sugar.

What people with prediabetes need to understand is this. Organ damage starts when blood sugars spend a few hours a day over 140 mg/dl. It doesn't matter what the fasting blood sugar is. It matters how long blood sugar stays over 140 mg/dl. Neurologists studying neuropathy (nevre damage) have found no relationship at all between fasting blood sugar or A1c and the likelihood of developing neuropathy. They've found a very tight correlation between the rise in incidence of neuropathy and 2 hour blood sugar values that are 140 mg/dl and higher on glucose tolerance testing. (You can read more about studies linking organ damage to blood sugar levels HERE.)

So if you have prediabetes defined either by fasting blood sugar greater than 100 mg/dl or post-meal blood sugars that go over 140 mg/dl for significant periods of time the thing you really want to avoid is neuropathy, because it is among the earliest diabetic complications and one that affects all of your body. (The very earliest appears to be carpal tunnel syndrome.)

Almost half of all "newly diagnosed" Type 2s have neuropathy--a complication that can take up to a decade to develop in people diagnosed with sudden onset Type 1 diabetes. That tells us how damaging all those years of untreated "prediabetes" really are.

Metformin can help lower blood sugar, but if you are a person with prediabetes who tests your blood sugar after meals while taking metformin, you'll often see that your blood sugar will still go high enough to cause damage unless you also cut back on your carbohydrate intake.

But metformin definitely can help, and it can allow you to eat more carbs and still get decent blood sugar numbers, which in turn makes it easier to eat in a way that maintains health since it's a matter of cutting down rather than cutting out the carbs.

So as soon as you find your blood sugar is higher than normal, the better off you'll be if you take steps to get your blood sugar back down to the normal range. Whether or not you reverse the underlying condition that made your blood sugar abnormal is irrelevant. Most of us can't, contrary to what many doctors tell people. But as long as we can keep our blood sugar in the normal range, we'll feel much better, since fluctuating blood sugars make for rabid hunger and depressive mood swings, and we will also maintain the normal blood sugars that will keep our organs functioning in a normal way.

If you are not getting normal blood sugars with reasonable dietary changes and your doctor won't let you try a course of metformin, ask why, and if the reasons don't sound credible, find a doctor who will be a better partner with you in the struggle to maintain your health.

PS: Legitimate reasons not to use metformin are known liver and kidney problems.

If metformin does not lower your blood sugars and they continue to deteriorate, it is possible you have an autoimmune form of diabetes. Metformin does not help diabetes caused by damaged beta cells and immune disease and people whose blood sugar does not respond to metformin often turn out not to have Type 2 diabetes.

 

Bad Science: The Low Fat vs Low Carb Debate

The diabetes establishment just can't get their head around the idea that cutting carbs helps people with diabetes. You can see this in the way the most recent study comparing low carb and low fat diets reports its results.

This was a metastudy just published in Diabetes Care.

Influence of Fat and Carbohydrate Proportions on the Metabolic Profile in Patients With Type 2 Diabetes: A Meta-Analysis Satoru Kodama, et al. Diabetes Care 32:959-965, 2009

Let's cut to the chase. This study which is a metastudy, glommed together the findings of 19 previous studies and concluded:

the L[ow]F[fat]H[high]C[carb] diet significantly increased fasting insulin and triglycerides by 8% (P = 0.02) and 13% (P < 0.001), respectively, and lowered HDL cholesterol by 6% (P < 0.001) compared with the HFLC diet.

Translated into English this says that when you feed low fat diets to people with diabetes, their insulin levels (if they make insulin) rise, because the high carb intake has pushed up their blood sugar, their triglycerides--the blood lipid most closely associated with heart attack--rises and their HDL, good cholesterol, drops.

Pretty straightforward. But wait. That's not all they report, because the first sentence in their results section is this: Changes in values for A1C, fasting plasma glucose (FPG), and total and LDL cholesterol did not differ significantly between the LFHC and HFLC groups.

So what they're saying is that it makes no difference in the blood sugars of people with Type 2 diabetes whether they eat a low carb or high carb diet.

And here's the punchline: the final conclusion of this study is;

However, stratified analysis indicated that the increase in triglycerides was insignificant when accompanied by energy intake restriction" and "the adverse effect on triglycerides from the LFHC diet could be avoided by restricting energy intake to a degree sufficient for the attainment of weight reduction.

This translates to, "People with diabetes should continue to eat a low fat/high carb diet. They should just eat even less calories so they lose weight."

We could debate whether people with type 2 diabetes will lose weight on any diet that increases their insulin resistance, but that's not what I'm going to do here.

Instead, I'm going to show you the glaring error in this study that makes it irrelevant to its subject. And what is that? It's the definition of "low carbohydrate." Because it turns out that the "low carbohydrate" diet being compared to the high carb diet is one made up of 40% carb 40% fat and 20% protein.

Working this out against the daily input for a typical women, 2000 calories, we find that 800 calories would be contributed by carbohydrate. Since each gram of carbohydrate contains 4 calories, this means that the "low carbohydrate diet" being discussed here--the "low carb" diet explored in 19 studies--contains 200 grams a day of carbohydrate.

Can anyone not obsessed with the need to prove the worth of the low fat diet honestly argue that a woman with Type 2 diabetes who is eating 200 grams of carbohydrate a day is eating a low carb diet?

No wonder these people with diabetes saw no difference in their A1cs. They were eating twice as much carbohydrate as even the most flexible low carb dieter would consider low carb.

And the actual carb intake here probably was worse, because these weren't normal sized women. They were people with Type 2 diabetes, most of whom were overweight who were probably eating a lot more calories than 2,000. So their actual carbohydrate intake may have been as much as 300 grams a day.

How idiotic research papers like this get through peer review escapes me. Whatever your scientifico-religious beliefs, you'd think if someone is going to use the term "low carbohydrate" in your title and conclusions, they should be describing people eating low carbohydrate diets.

A diet that is 40% carbohydrates is not a low carb diet. A low carb diet is one that ranges from 7-20% of calories coming from carbohydrates and for that woman eating 2,000 calories it would top out at 100g a day of carb.

Try that diet, and you WILL see dramatic differences in A1c.

Just this week I received another email from a happy visitor to my web site reporting this:

My A1C at dx was 10.9%, (Dec. 4, 2008). As of May 4, it was 5.2%. Mainly low carb diet and exercise , plus metformin. Surprisingly, to me, quite mild exercise.

There is no drug on the market that will make that kind of improvement in the blood sugar of a person eating a high carb diet.

But the powers that be in the diabetes establishment continue to waste paper and electrons disseminating garbage studies like the one cited above. And because they do, and because doctors only pay attention to the conclusion, not the methodology, hundreds of thousands of people with diabetes are seeing their kidneys fail, their feet succumb to gangrene, and their hearts stop.

This isn't an abstract philosophical debate. It's a matter of life and death. The American Diabetes Association who fund the journal Diabetes Care are largely funded by junk food companies (Cheerios anyone?) and the drug manufacturers whose profits will fall if the diabetes community ever discovers the power of low carb diets to control their blood sugars.

Shame on them.

Study Finds Dietary Counselling Increases Weight

Scanning today's Science Daily I noticed a report of a study that found that giving pregnant women probiotics decreased their weight gain very significantly. This isn't a surprise. We've learned that there are some gut bacteria that are reliably associated with obesity.

You'll find the report here:

Probiotics May Ward Off Obesity

But here's the interesting part of this study:

Central obesity - defined as a body mass index (BMI) of 30 or more or a waist circumference over 80 centimetres - was found in 25% of the women who had been given the probiotics as well as diet advice. That compared with 43% of the women who got dietary counselling alone and 40% of the women who got neither diet advice nor probiotics. The average body fat percentage in the probiotics group was 28%, compared with 29% in the diet advice only group and 30% in the third group

So what they found is that the group that ended up with the fattest subjects was the group of women who'd been given dietary advice 3% more of whom became obese than those who were left completely alone.

Though far fewer of those who got probiotics and advice ended up obese, given how much better subjects did who didn't get dietary advice, you have to wish the study had included a group of subjects were given probiotics without dietary advice. They probably would have done even better.

In case you wondered what the "dietary counselling" consisted of (though most of my readers already can guess, given the results) here it is:

Two of the groups received dietary counselling consistent with what's recommended during pregnancy for healthy weight gain and optimal foetal development. They were also given food such as spreads and salad dressings with monounsaturated and polyunsaturated fatty acids, as well as fibre-enriched pasta and breakfast cereal to take home[emphasis mine].

The researchers provided the average body fat percentage of all three groups--which showed no statistically significant difference between all three groups, because it is the only statistic that gave them the kind of statistic they were looking for--one that make counseling look more effective than doing nothing. In fact, since all three groups had almost identical average body fat, and since averages are a meaningless statistic when the groups differed so significantly in terms of how many individuals were obese, this is a statistical red herring.

In conclusion, this study suggests it might be worth trying probiotics for a few months if you are having trouble losing weight. But just as important this study also tells us: If you want to become obese, go to a nutritionist who is still wedded to the discredited low fat diet religious belief and base your diet around the pasta and cereal she sends you home with. It will work.

 

Smoking Gun: Did Avandia Kill those ACCORD Patients Who Attained 6.5% A1cs?

Doctors in the US have been told the ACCORD study "proved" it was dangerous for people with diabetes to shoot for a 6.5% A1c. ACCORD study found that a higher rate of heart attack was seen in the group with lower blood sugars. This is leading many doctors to give the tragically flawed advice to patients that they should keep their A1cs up, closer to 7% to preserve health.

In contrast, another, larger and longer study, ADVANCE, found no harm and slightly fewer heart attacks in the intensive control group who attained those A1cs of 6.5% over a period of five years.

The full text publications describing both the ACCORD and ADVANCE studies are now available for free and it seems to me they make it crystal clear what killed people in the ACCORD study.

ACCORD is the study that found excess deaths in the group that attained A1cs below 6.5%. ADVANCE did not. You'll find both studies here:

Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes. The ADVANCE Collaborative Group. NEJM, Volume 358:2560-2572, June 12, 2008, Number 24

Effects of Intensive Glucose Lowering in Type 2 Diabetes The Action to Control Cardiovascular Risk in Diabetes Study Group.[ACCORD] NEJM Volume 358:2545-2559, June 12, 2008 Number 24

So let's look at what the differences were in how these studies lowered A1c.

You can find out exactly what drugs people took in the ADVANCE study in the supplementary material published with this study.

As you'll see, ADVANCE relied mostly on a sulfonylurea drug, Gliclazide, which isn't available in the US, though in the UK, Australia, and Canada it is considered the best of the sulfonylurea drugs.

Patients who did not get to goal with gliclazide were put on metformin and several other drugs including basal insulin, usually NPH (33% vs 18% on Lantus or Levemir). Only 19% of the participants in the tight control group used fast acting insulin, half of these used R and half analogs.

The actual breakdown of who took what in ADVANCE shows that the preponderance of study subjects (77%) were taking the gliclazide, metformin, or a combination of the two. Only 32 (.6%) of the 5,571 people in the intensive control arm of ADVANCE were taking Avandia or Actos.

Contrast this with ACCORD. You can see what drugs people were taking in ACCORD in this table.

It turns out 4,702 of the 5,128 people in the intensive treatment arm of ACCORD were taking at TZD drug. That's 91.7% of all of them. But here's the kicker: almost all of them--4,677 or 91.2%--were taking Avandia.

I read this and found myself baffled at how many reports on the differences between these two studies I'd read claimed there was no one drug associated with the excess deaths. The disparity between the two studies could not be clearer. One study used almost no Avandia and people who attained tight control had no negative outcomes compared to those with standard control. The other gave Avandia to 9 out of 10 participants in the tight control arm and saw excess deaths.

Yet ACCORD--the Avandia study--is the study doctors and insurers are using to argue that tight control is dangerous and causes heart attacks.

I'm flabbergasted and you should be too. We already knew that Avandia killed people before this study was published. So why wasn't the "Danger" of lowering A1c pinned to the drug people were taking in the study, a drug already known to kill people? And why did the ADA urge patients on Avandia to keep taking it, even after its danger became evident?

I'll let you draw your conclusions, but my guess it has something to do with what drug companies donate what to the American Diabetes Association.

Another bit of information that got lost in the reporting of ACCORD is that the increased risk of excess death in the tight control group was largely found in people who already had experienced heart attacks before the study started--those most prone to heart failure, the condition both Actos and Avandia promote. Among those who had not had heart attacks before the study, the risk of heart disease dropped with tight control.

Two more factors associated with increased risk of negative outcomes with tight control in ACCORD was age over 65 and an A1c at the start of the study that was greater than 8%.

In contrast ACCORD found improvements with tight control for every subgroup of participants.

So now you know why "tight control" CAN be dangerous: It's dangerous when it's achieved using drugs we know can kill people, especially people prone to heart failure, i.e. Avandia and Actos. If you aren't taking these drugs, relax. Lower your blood sugar as much as you want using diet, metformin, gliclazide, and insulin and be secure in the knowledge that you are not going to worsen your risk of having a heart attack.

If your doctor tells you "tight control is dangerous" ask him if he realizes that Avandia was given to over 91% of the subjects in the study that "proved" tight control dangerous.

The other hazard often cited when tight control is discussed is the possibility of serious hypos. So it's worth noting that ADVANCE put people who needed insulin largely on NPH, the notoriously hypo-causing insulin. Even so, during the five years of the study, the researchers found far fewer hypos than they were expecting based on UKPDS. Had they used the more easily controlled newer long acting insulins, they might have seen even fewer hyps than they did.

The breakdown of insulins used wasn't published in the ACCORD study.

We'll return to what ELSE these studies found in future blog posts.

 

New Study Links Januvia to Pancreatitis and Pancreatic Cancer

NOTE (April 2, 2013): Before you take 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:

It's a rat study but the rats are "Human transgenic rats" which might mean that the study is more applicable to humans than you'd think at first glance.

But the reason this new study is so important is that it is the FIRST study I have seen published that even looks at the question of whether Januvia might be promoting cancer. Since the study was funded by the maker of Januvia, Merck, it was spun in a way to make it sound like a solution has been found but close reading makes me question that this is true.

Given all the other forms of cancer that have been linked to the presence of DPP-4 inhibition--ovarian, lung, melanoma, and prostate, my guess is this study is only the beginning of the bad news we will be seeing about Januvia--unless the company is able to shut down such research with threats of lawsuits like those that were used to keep researchers from publishing data linking Avandia to heart attacks.

Here's the study:

Beneficial Endocrine but adverse Exocrine effects of Sitagliptin in the HIP rat model of Type 2 Diabetes, interactions with Metformin. Aleksey V. Matveyenko, , Sarah Dry, Heather I. Cox, Artemis Moshtaghian, Tatyana Gurlo1, Ryan Galasso, Alexandra E Butler and Peter C. Butler Diabetes DOI: 10.2337/db09-0058.

Note that the authors of this study include the Butlers, whose Mayo pancreas autopsy study I have discussed on my web pages. They are scientists who really know something about the pancreas.

You can read a more complete discussion of what this Januvia study found in Science News:

Popular Diabetes Treatment Could Trigger Pancreatitis, Pancreatic Cancer, Study Suggests

The rats used in this study are described thusly:

IP rats approximate both the islets and metabolism of people with Type 2 diabetes. The drugs were tested in 40 rats for 12 weeks.

Note also that the study lasted only 3 months.

What it found was that after exposing the human pancreas islets grown in these transgenic rats for only 3 months:

With the sitagliptin alone, however, the rats had abnormally high rates of cell production in their pancreatic ducts; a few developed an abnormality known as ductal metaplasia, and one developed pancreatitis.

When Januvia was combined with Metformin, the researchers did not see this effect. They speculate:

... metformin, trade name Glucophage, seems to counteract sitagliptin's adverse effect.

"The apparent protection against the unwanted actions of sitagliptin in the exocrine pancreas are intriguing and may offer a potential way of using the GLP-1 class of drugs safely," Butler said. "The protective effect may have been either by the actions of metformin to decrease blood glucose values or its recently appreciated properties as a tumor suppressive agent."

Left undiscussed are some major questions.

1. What happens when those pancreatic cells are exposed to Januvia for three years, rather than three months?

2. What happens to all the other cells in the body that also start overgrowing when DPP-4, a tumor suppressing gene, is turned off round the clock?

3. Why is this overgrowth only attributed to the impact of GLP-1 when researchers have linked DPP-4 inhibition to the spread of cancers in numerous published studies?

There's some very important information included in the abstract of this study that did not get discussed in the Science News report:

SIT+MET had synergistic effects to preserve beta cell mass in HIP rats. MET more than SIT inhibited beta cell apoptosis. MET enhanced hepatic insulin sensitivity, SIT enhanced extrahepatic insulin sensitivity with a synergistic effect in combination. Beta cell function was partially preserved by SIT + MET.

What this is saying is basically Metformin alone had the same healthful effects as Januvia. Metformin inhibited beta cell death MORE than Januvia alone. Metformin alone lowered Liver insulin sensitivity--which will lower post-meal blood sugars dramatically in insulin resistant type 2s. Finally, though Januvia increased insulin sensitivity outside of the liver, it did so mostly in the presence of Metformin. Which also lowers insulin resistance outside of the liver on its own.

So the question you have to ask yourself if this: do you want to pay $185 a month to take Janumet, a drug whose efficacy mostly comes from Metformin--and risk cancerous changes in your pancreas cells (metaplasia) or pancreatitis? Or will you stick to the $4 generic Metformin which does pretty much the same thing without the cancer risk.

New Study Proves Conclusively Byetta Does Not Regrow Beta Cells

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:

A study published in this month's Diabetes Care is titled in a way that makes it sound like Byetta "improves beta cell function."

But if you read even the abstract you will see that "improving beta cell function" is NOT the same as rejuvenating beta cells--the claim that the drug manufacturer has been making for Byetta ever since it was released. In fact, what this study proves is the exact opposite: . While Byetta causes more insulin to be secreted in people who are taking the drug, this effect ends as soon as the drug is discontinued.

Here's the study:

One-Year Treatment With Exenatide Improves β-Cell Function, Compared With Insulin Glargine, in Metformin-Treated Type 2 Diabetic Patients. A randomized, controlled trial Mathijs C. Bunck. Diabetes Care 32:762-768, 2009

What they did here was this:

Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period.

What they found was:

Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: –0.8 ± 0.1 and –0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference –4.6 kg, P < 0.0001).

This means A1c didn't change on average in people using Byetta compared to those using Lantus., though they were secreting more insulin. However, on average, weight decreased significantly in the Byetta group compared to the Lantus group.

But here's the kicker:

β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy.

After a year of use, once people stopped taking Byetta their beta cell function went right back to what it had been. Obviously, had their beta cells been rejuvenated, we would have expected to see improved insulin production even without the Byetta. And as most of us would have predicted, losing weight doesn't appear to have changed their ability to control their blood sugars either.

There's an important point to keep in mind here. If you'll remember, and earlier study showed that averages are very misleading when evaluating Byetta's performance. Byetta works very well for about 1/3 of those who take it and barely at all in the rest. You can read about that study HERE.

Dctors have been prescribing Byetta to people who do not experience significant weight loss or improved blood sugar control because they believe it is rejuvenating their beta cells. This claim was based on test tube and rodent studies and has never been confirmed by any human studies. All human studies, like this one, evaluate "beta cell function" simply by seeing how much insulin the beta cell is pumping out in response to a stimulus. Byetta, like the sulfonylurea drugs, does improve the beta cell's ability to secrete insulin, while Byetta is in the system.

But this new study should make it clear that if you aren't one of the lucky people who respond to Byetta with dramatic improvements in blood sugar and weight loss, there is no reason to keep taking it.

Still, over the past two years I have heard from friends who have tried Byetta and have experienced near "miracle weight loss" and dramatic decreases in their need for injected insulin even when eating meals with up to 40 or 50 grams of carb. Some of these are people who required insulin even while eating low carb diets.

So my feeling about Byetta is that it is well worth a trial. Give it two months. If you don't see weight loss and significant improvement in your blood sugars, there is no reason to continue with it.

What disturbs me is how many people I hear from whose doctors insist they continue Byetta when their blood sugar deteriorates while taking it and they don't see weight loss. If that's your situation, you will want to use insulin instead.

It's also worth noting that while Byetta is not officially approved for people using insulin, I have heard from quite a few people who are using that combination successfully. If you combine the two you will probably need to lower your insulin dose other wise hypos are likely.

It's also worth noting that the mechanism by which Byetta was supposed to be rejuvenating beta cells is the same mechanism used by the other incretin drug, Januvia, for which the identical claim is being made. This new study suggests that Januvia is not regenerating beta cells either.