Friday, May 29, 2015

Insulin Resistance Strongly Predicts Cardiovascular Disease Risk

I recently came across a very interesting paper by the research team of Gerald Reaven, an endocrinologist at Stanford.  He has long been one of the leading researchers studying insulin resistance, the metabolic syndrome, and their association with obesity.  Reaven's research, and that of many others, suggests that insulin resistance is a central part of the constellation of metabolic disturbances that are so common in affluent nations*.  We also have good reason to believe that it contributes to cardiovascular risk.

All the way back in 1998, Reaven's group published a paper that should raise the eyebrows of anyone interested in cardiovascular health (1).

The study

The study was relatively simple: first, they recruited 147 lean and overweight volunteers without diabetes or diagnosed cardiovascular disease.  Then, they measured the volunteers' insulin sensitivity.  While most studies of this nature indirectly estimate insulin sensitivity simply by using a formula based on fasting insulin and glucose measurements (HOMA-IR), which can be inaccurate, Reaven's group directly measured insulin sensitivity using a gold standard method**.

Next, they waited nearly 5 years and watched who developed cardiovascular disease over that period.

The results

To analyze the results, they divided the volunteers into three equal-sized groups based on their degree of insulin resistance (inverse of sensitivity). Group I had the lowest level of insulin resistance, group II had an intermediate level, and group III had the highest level.  The following graph illustrates the number of people who were diagnosed with cardiovascular disease, or suffered a cardiovascular event, in each group over the course of the study:

None of the people in the most insulin-sensitive group developed cardiovascular disease over the five-year period, while a full 14 percent of the most insulin-resistant group developed disease over the same period.  That's a huge difference.

Clearly, if you care about your cardiovascular health, you should care about your insulin sensitivity.

People who were the least insulin resistant (group I) were also the leanest, exercised the most, had the lowest blood pressure, the lowest levels of LDL ("bad") cholesterol, and the highest levels of HDL ("good") cholesterol.  Was insulin resistance really an important predictor of cardiovascular disease risk, or was it simply associated with other unhealthy characteristics?  To answer this question, the research team analyzed the relationship between insulin resistance and cardiovascular disease risk while mathematically holding the other variables constant.

What this analysis showed is that insulin resistance was the strongest "independent predictor" of cardiovascular risk-- moreso than other established risk factors like LDL cholesterol.  In fact, it was the only predictor that remained statistically significant.  This shows that insulin resistance has major predictive value for cardiovascular disease risk, and it also raises the possibility that insulin resistance could be a powerful driver of cardiovascular disease.  From the paper:
These data provide substantial support for the view that the presence of insulin resistance identifies a subset of the population who will develop CVD over a relatively short time period.
Am I insulin resistant?

The test Reaven's group used to accurately measure insulin sensitivity is labor-intensive and it's only available for research purposes.  Yet there are a few simple questions you can ask yourself that will give you a pretty good idea of whether or not you're insulin resistant.

  1. What's your body weight?  If you're overweight, you may be insulin resistant.  If you're obese, there's an 80-90 percent chance you're insulin resistant.  If you're lean, that doesn't necessarily mean you're insulin sensitive, but the likelihood is higher.
  2. What's your body fat distribution?  If you're moderately overweight but you carry your fat evenly all over your body, there's a good chance you're insulin sensitive.  If you carry most of your fat in your abdominal region (belly), you're probably insulin resistant.
  3. How physically active are you?  If you have a high level of physical activity and you aren't obese, you're probably insulin sensitive.  If you're sedentary, particularly sedentary and overweight or obese, you're probably insulin resistant.
If you think you're insulin resistant, the fastest effective way to begin addressing the problem is to exercise regularly.  Play basketball, swim, jog, hike, cycle, lift weights, walk-- it doesn't matter what activity you choose-- just get moving!  Controlling your weight and eating a healthy, whole-food-based diet will also help over the long term.

* I would argue that leptin resistance is equally important.
** Insulin suppression test.


Unknown said...
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RLL said...

There is also a correlation with A1Cs and heart disease in diabetics. Keeping A1Cs below 6 seems to greatly reduce heart disease. It likely does not reduce insulin resistance.

Robert Andrew Brown said...

Thanks Stephan :)

Fascinating if not altogether surprising.

The study conclusion.

"In conclusion, approximately one of every five healthy, nonobese subjects in the most insulin-resistant tertile, followed for approximately 5 yr, had a serious clinical event. These data highlight the importance of insulin resistance as a predictor of CVD."

I would suggest dietary related oxidative stress increases, combined with genetic predisposition, result in the early onset of noncommunicable western diseases generally. Many of the related underlying pathways interconnect and interlink. The pancreatic beta cells are particularly susceptible to oxidative stress, inherently having low antioxidant production capacity. Oxidative stress is in common also key to vascular damage.

Unknown said...

Does this lend credence to the idea that some form of carbohydrate control in modern, industrialized societies (not necessarily Blue Zones, traditional societies) is CVD risk reductive?

Stephan Guyenet said...

Hi William,

Despite the fact that you commonly hear the claim that carb restriction increases insulin sensitivity, that does not seem to actually be the case. It does reduce fasting insulin, which reduces the indirect HOMA-IR estimate of insulin sensitivity, but when researchers actually measure insulin sensitivity directly, it hasn't changed. The only exceptions are that extremely low-carb diets (<10% CHO) reduce insulin sensitivity, while extremely high-carb, low-fat diets increase insulin sensitivity. Everything in the middle seems to be a wash.

Gudmundur J said...

"but when researchers actually measure insulin sensitivity directly, it hasn't changed."
Very interesting. Could you point me to the references?
Great post btw.

Gretchen said...

Stephan, It makes sense to me that very LC diets increase IR, because the IR is a way of keeping the muscles from grabbing the scarce glucose so it can be used by the brain.

The crucial question is whether IR in the setting of a very LC diet has the same effect as IR on a higher-carb diet. For anyone with diabetes, the very high carb diets that reduce IR also increase blood glucose levels, and higher blood glucose is also a risk factor for heart disease.

About 50% of IR is genetic, and there's not much a person can do about that.

fff said...

Hi Stephan

Glad you found the Reaven article interesting. Can you please post link from your above comment on IS though? It would be very interesting if the researchers were using hyperinsulinemic euglycemic clamp method, and properly interpreting as per the unparalleled experience of Dr. Kraft - via the 5 physiological responses to this 'gold-standard' test? Dr. Kraft verified that low carb regime often generated the pattern V response, which is entirely reasonable, and healthy for that matter (otherwise you are likely Type 1 Diabetic with this V response - not good). Do you have full data from their research to verify that this is the case - if it was it would be very interesting indeed :-)


Stephan Guyenet said...

Hi Gudmundur and Ivor,

I cited a few of the relevant refs in this post:

Hi Gretchen,

I agree with your comments.

aluchko said...

You emphasized the benefit of physical activity. Where you talking about activity in the context of weight loss or is physical activity and fitness important to insulin sensitivity independent of weight?

Stephan Guyenet said...

Hi aluchko,

Independent of weight. Physical activity has a large and rapid impact on insulin sensitivity in people of all weights.

Mechelle said...

Thank you, Stephan, for a well-written blog.

Question for a future blog: What is known about the impact of the total amount of insulin secreted in a lifetime on one's health--especially for folks who are somewhat insulin resistant? In other words, if I am somewhat insulin resistant (even though I exercise a lot), is eating carbs and thus making more insulin, better than avoiding carbs and too much protein so that I make less insulin in my lifetime? After spending the last 3 years VLC, my A1c is 5.3, but my fasting glucose runs between 100 and 120. I feel awesome, but worry about that high fasting glucose (physiological insulin resistance?). I assume adding carbs will lower my fasting glucose at the expense of increasing the amount of insulin I produce… Do you have any thoughts about this? Would love to read one of your posts on this subject...

Aegirsson said...

Hello Mechelle,

I am not an expert but I read enough to tell you with a certain confidence that if you up your carbs intake, and I mean natural carb sources (those that generally come with fibers like tubers and legumes), and decrease fat significantly at the same time, you will regain insulin sensitivity. Physical activity is also a great thing, regardless of your insulin sensitivity or lack thereof. A rather famous example of this is the Kempner diet. Type 2 diabetic can also cure their condition with high carb very low fat, limited calorie diets, not like low-carb diets where they can only manage blood sugar without curing the disease.

Chris said...


Did you type that correctly when you stated that a very high carb, low fat diet is better for people with insulin resistance? Is this along the same lines of Denise Minger's presentation where she stated a low-carb diet keeps blood glucose low as long as you follow it while a high carb, low fat diet actually cures diabetes?

This goes against everything I thought I knew.

Stephan Guyenet said...

Hi Chris,

I didn't say it's better-- what I said is that a very high-carb, very low-fat diet increases insulin sensitivity. To clarify, what I'm referring to is the effect of the diet independent of weight loss. Weight loss tends to increase insulin sensitivity, and that's an additional layer of complexity to consider.

There is a commonly held idea that carb restriction increases insulin sensitivity and high-carb diets reduce it, but the evidence does not support that. It's a misunderstanding that arose due to a quirk of one of the methods that is sometimes used to estimate insulin sensitivity. That doesn't mean low-carb diets aren't useful in certain contexts, and in fact if they cause enough weight loss they can increase insulin sensitivity.