Vacation!

Fun with Graphs

For the next few weeks, I will be on an overseas vacation. In the meantime, I've been searching on Google and have come up with a set of graphs that should be interesting to look at and consider in the context of low-carbing. Most, but not all, of the data comes from the United States. These graphs are provided without any context to describe how the data was collected or how valid it might be. They just provide something to think about. If you want to enlarge any graph, just click on it, and it will open in a larger version.

One of the more interesting graphs shows that there is not much of a relationship between average cholesterol and rates of death from heart disease. Ancel Keys used seven carefully selected countries to "prove" the opposite, but the countries used for this graph tell another story.



Here's a graph that should be completely unsurprising to a low-carber. It shows a steadily increasing consumption of sugar in the United Kingdom and the United States and, beginning about 1900, a dramatic increase in rates of obesity.



Starting in about 1970, people in the United States began substituting high fructose corn syrup (HFCS) for table sugar. Interestingly, there was also an increase in the incidence of diabetic end stage renal disease during that time. Correlation is not causation, but the values do increase in a similar manner.



End stage renal disease is one of the complications of diabetes, which has also been increasing in the United States.



Sugar consumption, and in recent years HFCS consumption, has been increasing. Has anything else been increasing? Yes, we have been using more wheat flour per capita in the United States.



We are also eating more carbohydrates as a percentage of our total calories.



Not only are we eating a higher percentage of carbs, we are also eating more total calories per person every day.



All of these observations are consistent with (but do not prove) the hypothesis that eating refined carbohydrates can result in the diseases of civilization. However, other factors may also contribute to the increase in metabolic diseases during the past century, and here are some more graphs to consider in that regard.

It is possible that insufficient fiber can be blamed for an increase in health problems. I couldn't find a graph that described fiber consumption over time, but did find one on vegetable consumption. It appears that we are eating more vegetables (and presumably more fiber) than we used to.



It's possible that products that are subject to "sin taxes" could contribute to health problems. Although the introduction of cigarette smoking could be associated with the arrival of Western civilization and its diseases, it is interesting to note that the per capita consumption of cigarettes has actually declined since 1977.



Total alcohol consumption has decreased, too.



As discussed in a previous post, a high intake of omega-6 fats promotes the formation of inflammatory intermediates. Another possible explanation for the increased incidence of the diseases of Western civilization is the increased use of omega-6 rich vegetable oils in place of animal fats. As usual, correlation is not causation, but as shown in the graph below, the production of soybean oil for food consumption went from close to zero in 1935 to 25 pounds person per year in 1999.



Consumption of canola oil has also increased dramatically, from zero in 1984 to seven pounds per person per year in 2004, while the consumption of olive oil went to about two pounds per person per year and the consumption of butter declined.



What do all of these graphs prove? Not a thing. Although they show associations, they cannot prove causation. But I present them for your consideration because they do give us some things to think about as we enjoy a low-carb summer. Have a happy, healthy June!

Cortisol Versus Insulin

The man in the picture has insulin resistance and what the Heart Scan Blog" calls "wheat belly," right? Wrong. He has a hormone problem, but in this case the hormone isn't insulin, it's cortisol.

Insulin, which we discuss frequently on this blog, is a storage hormone. In response to ingestion of carbohydrates, and to a lesser degree of amino acids, the pancreas releases insulin. As a result, within minutes to hours, carbohydrates, amino acids and fats are stored after each meal.

Cortisol is a glucocorticoid hormone that is released from the adrenal glands in response to stress. The stress can be physical or emotional. The effects of cortisol in the body occur over hours to days and include suppression of the immune system, suppression of inflammation and an increase in blood glucose. When people survived by hunting, or when they were involved in combat, elevated cortisol would allow a person to ignore pain and illness in order to concentrate on the task at hand. It would also provide excess glucose in the blood, allowing the person additional energy to fuel the brain and muscles in extreme situations.

Both insulin and cortisol are powerful hormones. Too much insulin for too long will eventually result in insulin resistance, a condition in which more and more insulin must be secreted to produce normal insulin responses in tissues such as muscle, brain and liver. Too much cortisol for too long produces an increased risk of infection, reduced bone density, increased muscle weakness and excess glucose in the blood. Cushing's syndrome is the result of having excessively high cortisol for several years. Take another look at the picture at the beginning of this post. The patient looks like a person with metabolic syndrome, doesn't he? But this person actually has Cushing's syndrome.

Cushing's syndrome can be caused by an adrenal or pituitary tumor, or it may be the result of taking high doses of glucocorticoids for a long period of time. People who do not have these tumors and who do not take exogenous glucocorticoids do not have to worry about Cushing's syndrome, but the man in the picture does illustrate the point that there may be metabolic side effects from stress-induced hypercortisolism.

In a May 2010 review in the American Journal of Physiology-Endocrinology and Metabolism, Dake Qi and Brian Rodrigues described the effects of glucocorticoids on insulin-responsive tissues. Many of the studies in the review used dexamethasone, a synthetic glucocorticoid that is about 50 times as potent as cortisol and produces robust reactions in a short period of time. However, clinical experience with excess cortisol secretion supports these observations. At any rate, excess glucocorticoids will produce:

• Decreased glucose uptake and utilization in muscle and adipose tissue.
  
• Increased gluconeogenesis and glucose output by the liver.
  
• Increased triglyceride storage in the liver.
  
• Increased fatty acid uptake, fat synthesis and fat storage in adipose cells.

Readers of the previous post will recognize that these symptoms are consistent with insulin resistance. What makes it complicated is that there are many different molecules involved in insulin signaling, and each of these can be regulated on several levels. Any of the signaling intermediates can be synthesized more slowly or more rapidly, degraded more slowly or more rapidly, and activated or inactivated through phosphorylation or dephosphorylation by various kinases or phosphatases at numerous sites. These multiple levels of regulation mean that insulin resistance can be achieved through one mechanism when excess cortisol is involved and through another mechanism when excess insulin is involved. Consequently it is possible that both hormones working together can achieve more damage to insulin signaling pathways than one hormone acting alone.

Stress is able to produce a ten-fold increase in cortisol secretion. If the stress is chronic, it is possible that this alone could result in insulin resistance and eventually in the symptoms of the metabolic syndrome. This has been postulated by Anagnostis et al. in The Pathogenetic Role of Cortisol in the Metabolic Syndrome: A Hypothesis.

As we have noted, when primitive cultures adopt Western lifestyles, within about twenty years they can expect to begin experiencing the chronic diseases of Western civilization. While the carbohydrate hypothesis postulates that a diet of refined carbohydrates is the chief cause of insulin resistance and ultimately of the metabolic syndrome, it is also possible that the stress associated with the Western lifestyle is a contributor to insulin resistance. Stress and cortisol secretion are unavoidable, but in the absence of mammoth hunts and hand-to-hand warfare, those of us who wish to avoid the symptoms of insulin resistance would do well to avoid stress while also minimizing our intake of refined carbohydrates.

Insulin Resistance and the Metabolic Syndrome

The metabolic syndrome is a symptom set that includes the following: increased truncal obesity, high blood pressure, high blood glucose, low HDL cholesterol and high triglycerides. As anyone who has observed adults and even children in Western countries can confirm, the metabolic syndrome is becoming more and more prevalent. In Good Calories Bad Calories, Gary Taubes uses several lines of argument to show that one unifying explanation for the development of the metabolic syndrome is the prior development of insulin resistance.

Interestingly, one of the arguments Taubes does not use for his hypothesis is something called the "knockout mouse." The knockout mouse is not a small pugilist with boxing gloves. Instead, it is a genetically engineered mouse in which one or more genes have been turned off (knocked out) through targeted deletions. If we want to know what the effect of insulin is on a particular tissue, one approach is to delete the expression of the insulin receptor in that tissue.

The first attempt at an insulin receptor knockout mouse was to remove insulin receptor expression from the entire mouse. These mice were smaller than normal but were born alive at term. Shortly after birth they developed diabetic ketoacidosis and died. This was not helpful to the investigation of the relationship of insulin receptor signaling to various metabolic conditions, and the investigators moved on.

Because muscle insulin resistance is thought to be important in the development of type 2 diabetes, the next group of knockout studies involved mice that lacked insulin receptors specifically on muscle tissue. These mice had normal levels of blood glucose and plasma insulin. However, they had a 74% decrease in insulin-stimulated glucose transport into their muscle tissue. This caused blood glucose to be preferentially taken up by adipose tissue. Although these mice did not develop overt symptoms of diabetes, they demonstrated two of the features of the metabolic syndrome: increased fat mass and high triglycerides.

Another tissue targeted for insulin receptor deletion was the liver. By two months of age, the mice lacking liver insulin receptors had high levels of serum insulin but were were hyperglycemic in the fed state. To a great extent this was found to be attributable to the fact that insulin was unable to suppress the production of glucose by the liver. This suggests that hepatic insulin resistance is necessary for the onset of overt diabetes.

Because insulin receptors are widely distributed in the brain, investigators also developed a neural insulin receptor knockout mouse. The brains of these mice were normally developed, but the mice showed increased food intake and moderate diet-dependent obesity. It is known that the brain is able to regulate hepatic glucose production. When these neural-knockout mice were given exogenous insulin, they were only about half as effective as normal mice at suppressing hepatic glucose output.

Finally, the insulin receptor was uniquely deleted in the pancreatic beta cells of another group of mice. The investigators were expecting the pancreas to sense glucose concentrations directly rather than to use insulin signaling as an intermediary. To their surprise, mice that lacked pancreatic beta cell insulin receptors showed both a decreased ability to sense glucose and an insufficient secretion of insulin in response to glucose. Some, but not all, of the mice developed diabetes.

For those who would like to read more about these experiments, additional information can be found here and here. The use of insulin receptor knockout mice is a rather blunt instrument to determine whether insulin resistance can be implicated as the cause of the development of the metabolic syndrome. And mice are not people. Nonetheless, it is interesting to note that the deletion of insulin signaling in various tissues can produce obesity, high triglycerides, poor suppression of glucose output by the liver and both impaired pancreatic production of insulin and insufficient release of insulin in response to glucose.

The Fiber Hypothesis

Today's question is: What if you know that the dietary-saturated-fat-and-cholesterol hypothesis doesn't work very well to explain heart disease, but at the same time you don't want to admit that eating too many refined carbohydrates might be the cause?

Answer: You put the blame on fiber. Or rather on not eating enough fiber.

In 1972, Peter Cleave tried to explain to a U.S. Senate Select Committee that when primitive cultures adopted Western eating patterns, they also began to experience the diseases of Western civilization, including diabetes, heart disease and hypertension. Cleave pointed out that the fat and cholesterol hypothesis of heart disease did not explain this transition, but that the adoption of a diet rich in refined carbohydrates did account for it rather elegantly. The Senators reached the only logical conclusion. They refused to believe Dr. Cleave. Dr. Ancel Keys had so completely won the argument that dietary fat was the cause of heart disease, that any alternative hypothesis had to be rejected out of hand.

The Senators were left with the problem of how to explain the increased incidence of heart disease in transitioning cultures. Enter a famous medical missionary, Denis Burkitt. While working in Uganda, Dr. Burkitt had noticed that Africans produced several times more feces than people in Western countries. He hypothesized that the presence of dietary fiber produced the absence of the diseases of Western civilization. Burkitt collected over 800 anectodal reports showing that primitive peoples ate high fiber foods, while Westernized cultures tended to eat foods that were nutritionally dense and low in bulk, not providing enough volume to allow the intestines to remain healthy. This idea made sense to the granola-eating counterculturalists of the time. More importantly, it did not contradict Ancel Keys' diet-heart hypothesis.

Forty years later, the need for high fiber in the diet has become received wisdom. Some studies show that eating more dietary fiber is associated with lower all-cause mortality, for example Dietary fiber intake in relation to coronary heart disease and all-cause mortality over 40 y: the Zutphen Study. Other studies show no relationship between fiber intake and all-cause mortality, including this one, The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART).

For the purposes of low-carbers, several of the studies on the relationship of glycemic load with the risk of type 2 diabetes may be instructive. The glycemic load is the glycemic index of each food eaten, multiplied by the number of carbohydrate grams of that food eaten, summed for all items consumed during a day. In two studies (here in women and here in men), Salmerón et al. showed that the combination of a high glycemic load and a low cereal fiber intake increased the risk of type 2 diabetes when compared with a low glycemic load and high cereal fiber intake. The figure below is taken from the women's study.Looking at the X axis, at all levels of intake of cereal fiber, the relative risk of diabetes decreases as the glycemic load goes from high to medium to low. On the Z axis, at all levels of glycemic load the relative risk of diabetes decreases as the cereal fiber intake goes from low to medium to high.

Let's say that two low-carbers eat an identical number of carbs. One eats high-glycemic foods and has a high glycemic load. The other eats low-glycemic foods and has a low glycemic load. Both of them will need to release insulin to dispose of the carbs, but the first low-carber will have to release insulin in spikes to counteract the rapid rise of his blood glucose, while the second low-carber will be able to get by with a more gradual release of insulin. As Sullivan et al. have shown here, there is reason to believe that insulin spikes contribute to the development of insulin resistance.

How does fiber fit into the equation? The traditional explanation is that fiber fills us up. However, experiments done with caloric dilution show that when low-calorie foods are subsituted for higher-calorie ones, humans are well able to adjust their consumption of food to maintain their customary caloric intake. Another function of fiber is that it slows the absorption of nutrients from food. In other words, the addition of fiber can be expected to lower the effective glycemic index of high-, medium- and low-glycemic index carbohydrates. The relationship of the total amount of fiber to the total number of carbs to the glycemic index is probably quite complex, which may explain why many of the fiber-health studies do not show clearcut relationships between fiber intake and outcomes such as heart disease, type 2 diabetes, obesity and cancer.

In other words, if low-carb is good and low-glycemic index carb is good, the addition of fiber to all of that might be better. Low-glycemic-index foods like broccoli and nuts do tend to contain more fiber, so perhaps the point is moot for low-carbers who are careful about the type of carbs they consume. In any case, there is good evidence that lowering carbohydrate intake and lowering the glycemic index of those carbs is protective against the diseases of Western civilization. The data on the benefits of fiber intake is not overwhelming, so use your own judgment to decide what level of fiber intake might be right for you.