What Causes Insulin Resistance? Part V

Previously in this series, we've discussed the role of cellular energy excess, inflammation, brain insulin resistance, and micronutrient status in insulin resistance.  In this post, I'll explore the role of macronutrients and sugar in insulin sensitivity.

Carbohydrate and Fat

There are a number of studies on the effect of carbohydrate:fat ratios on insulin sensitivity, but many of them are confounded by fat loss (e.g., low-carbohydrate and low-fat weight loss studies), which almost invariably improves insulin sensitivity.  What interests me the most is to understand what effect different carbohydrate:fat ratios have on insulin sensitivity in healthy, weight stable people.  This will get at what causes insulin resistance in someone who does not already have it.

The first study to address this question was published in 1935 by Dr. H.P. Himsworth (Himsworth HP. Clin Sci 2:67. 1935).  He found that insulin sensitivity was increased by feeding a high-carbohydrate diet and decreased by feeding a low-carbohydrate diet, but these effects were only observed at very high (70-80%) and very low (less than 10%) carbohydrate intakes, respectively.

Studies since then have been somewhat equivocal, with some showing higher insulin sensitivity on high-carbohydrate diets (1, 2), and others unable to replicate the finding (3).  One potential explanation is that the difference in carbohydrate:fat ratios was not sufficient to see a difference in the studies that did not confirm the effect.  As per Dr. Himsworth's finding, reduced insulin sensitivity seems to require a very low carbohydrate intake.  Qualitative differences between the fat and carbohydrate sources may also have played a role-- unrefined carbohydrates improve insulin sensitivity more than refined carbohydrates.

Although very low-carbohydrate diets can reduce insulin sensitivity (and this squares with the poor glucose tolerance of many people who have followed very low-carbohydrate diets long-term), I think it is fair to ask whether this is harmful or simply adaptive (pathological vs. physiological).  When glucose is scarce in the diet, the body initiates a metabolic program to spare glucose for the brain, which is more dependent on glucose than other organs.  Since insulin signals tissues to increase glucose uptake, it is logical to think that insulin resistance might be a way of reducing glucose use by peripheral tissues so that the brain gets a larger share.  It's not clear whether or not this type of adaptive mechanism can fully account for the insulin resistance on such diets.  In rodents, insulin resistance on purified high-fat diets rapidly becomes pathological (i.e. it is clearly not an adaptive response because it leads to health problems), but I think we have to be cautious about extrapolating that finding to humans eating a mixed diet.  I would call this question unresolved. 

Much has been made of the glycemic index (speed of absorption) of carbohydrate as a determinant of insulin sensitivity, but a comprehensive review of controlled trials reveals that the glycemic index of carbohydrate generally has no measurable impact on insulin sensitivity (4). 

I think a simple principle that can explain these findings is that a healthy body increases insulin sensitivity in response to increased demand for glucose disposal.  In other words, the more carbohydrate in the diet, the more the body increases insulin sensitivity to appropriately metabolize it. This is particularly apparent at the extremes of carbohydrate intake. 

Sugar and Fructose

For the purposes of this discussion, I'm defining sugar as sucrose (table sugar, cane sugar), its close cousin high-fructose corn syrup, and natural sugars derived from fruit and honey.  When referring to fructose and glucose, I'll refer to them specifically.  Starch is made up of long chains of glucose that are released upon digestion.  Sucrose is composed of 50% glucose, and 50% fructose, linked together.  The form of high-fructose corn syrup that is typically used in soft drinks is roughly 55% fructose and 42% glucose, and the form that is used in most other foods is roughly 42% fructose and 53% glucose.

Sugar consumption per se has not been consistently linked to insulin resistance or diabetes risk in observational studies (update 1/20/12: fructose intake has just been associated with insulin resistance in adolescents.  The association seems to be mediated by increased visceral fat).  Most of the research on insulin resistance has focused on the role of fructose, because there is not much evidence that glucose or starch themselves are involved.  A number of studies have investigated the role of fructose consumption in insulin sensitivity.  Fructose or sucrose feeding consistently causes insulin resistance in rodents, but the effect requires unnaturally large amounts if given in the context of a low-fat diet (5, 6). 

In humans, high-dose refined fructose feeding can cause insulin resistance in as little as a week (7), however this requires an amount of fructose that far exceeds what can be obtained in a normal diet.  Somewhat lower, but still very high (~100 g/d) fructose intakes do not lead to insulin resistance in healthy, lean adults when fed for four weeks (8).  I think it is notable that in Dr. Lynda Frassetto's Paleo diet study, the diet was fairly high in sugar from fruit, fruit juice and carrot juice, yet participants experienced impressive improvements in insulin sensitivity (9).  This shows that naturally sourced sugars from fruit and vegetables are compatible with high insulin sensitivity in the context of a healthy diet.  As another example, the inhabitants of the island of Kitava eat a diet rich in fruit and thus unrefined sugar, yet in the context of a traditional diet and lifestyle, they do not develop insulin resistance (10). 

However, in overweight and obese people, a high intake of refined fructose can exacerbate insulin resistance.  Dr. Peter Havel showed this in a thorough study in 2009 (11).  After 10 weeks of drinking fructose- or glucose-sweetened beverages for 25% of calories, both groups gained the same amount of body fat (~3%), yet the fructose group gained it disproportionately in the abdominal (belly) region, and also showed a decrease in insulin sensitivity of 17%.  Another interesting study showed that a very high fructose intake (200 g/d) caused insulin resistance and increased blood pressure in overweight and obese volunteers, and that these effects were partially blocked by allopurinol, a drug that lowers circulating uric acid (12).  This supports the hypothesis that fructose exerts some of its effects by increasing uric acid, but it seems to take a lot of fructose to significantly increase plasma uric acid levels.

In another interesting study, Dr. Judith Hallfrisch and colleagues fed insulin resistant and normal men diets containing 0%, 7.5% and 15% fructose for 5 weeks (13).  None of the diets influenced fasting insulin, but the 15% diet increased the insulin response to a sucrose drink.  There was no glucose control group, so we don't know if the same response would have been observed with glucose or other sugars.  The level of sweetness of the different diets was not matched.

In a more realistic study, Dr. Maria Maersk and colleagues showed that adding one liter (equivalent to 2.75 12 oz cans; 106 g/d of sugar or 53 g/d of fructose) of cola to the habitual diet for 6 months resulted in an increase in liver and visceral fat, but no change in fasting insulin or estimated insulin sensitivity in overweight volunteers, relative to the same volume of water, milk or diet cola (14).  There was no significant effect on body fatness, although there was a trend toward an increase in the soda group.  I suspect that if these trends continued, insulin resistance would have developed eventually, but that may simply have been secondary to increased fat mass. In any case, regardless of its effects on insulin sensitivity, this study supports the idea that sweetened soda is not healthy! 

Overall, these studies show that very high fructose intakes can worsen insulin resistance in people who carry excess fat, but they do not offer strong support to the idea that normal intakes of fructose cause insulin resistance in those who are lean (particularly when the sugar comes from natural sources).  It is possible that insulin resistance would develop over a longer period of refined sugar consumption, particularly if visceral and liver fat continued to accumulate, but this has not been demonstrated to my knowledge.  Although some uncertainty remains, the evidence I've seen does not convince me that sugar intake within the typical range causes insulin resistance through an inherent metabolic effect of fructose, and I have seen nothing that suggests we should avoid eating whole fresh fruit.  However, since added sugar increases the energy density and palatability/reward value of food, it can contribute to insulin resistance indirectly via increased food intake and body fatness in susceptible people.  To be clear, I still think refined sugar is unhealthy and should be largely avoided.  In a future post, I'll explore the effect of sugar on body fatness in more detail.