One of the more important hypotheses on what causes obesity is the insulin hypothesis. According to this hypothesis, obesity is not driven so much by the amount of calories we eat, but rather by whether the food we eat stimulates the release of the hormone, insulin. Insulin drives glucose into our muscle and liver where it is used as a fuel, but also can be stored as fat. According to the insulin hypothesis, obesity results from eating carbohydrates that stimulate the release of insulin. Specifically, this occurs when we eat carbohydrates that cause a rise in blood glucose (carbohydrates with a high glycemic index). This includes rice, potatoes, breads and cereals. Sugar also has a high glycemic index because sugar contains both glucose and fructose, and the glucose component of sugar results in high glucose levels.
The hypothesis explains many things, including why high glycemic carbs and sugar are strongly linked with the development of obesity and diabetes, and why low carb diets are so effective at weight loss. However, a problem with the insulin hypothesis is fructose does not raise blood glucose (it is low glycemic). Another problem is that one would predict that if excessive insulin drives obesity, that conditions that increase insulin release should cause obesity, while insulin resistant states should protect against obesity. Yet obesity is associated with insulin resistance. Furthermore, one of the most effective new therapies for obesity is wegovy (semaglutide), which is a glucagon-like peptide-1 agonist that stimulates insulin release. One would expect the opposite if insulin was the cause of obesity.
Our work provided the key information to explain how high glycemic carbohydrates work. When these carbs raise glucose levels, they do stimulate insulin, but they also stimulate the conversion of glucose to fructose. When enough fructose is made, it triggers the survival switch that causes insulin resistance and obesity. The proof came when we gave glucose to mice that had an intact insulin system but could not metabolize fructose. These mice could eat all the glucose they wanted, and while they did gain some fat, they were completely protected from both fatty liver and insulin resistance, and they also were much less obese than regular mice. Later we did the same type of experiment in which we gave soft drinks containing high fructose corn syrup. This latter syrup contains both fructose and glucose. When mice that could not metabolize fructose were given soft drinks, they were completely protected from obesity and diabetes.
High glycemic carbs do cause obesity and diabetes, and obesity is associated with high insulin levels (which occurs when one is insulin resistant). But it is not the insulin that is causing obesity. Insulin is a good guy. Rather, it is the fructose that is responsible. The problem is not with stimulating insulin, but rather with the creation of insulin resistance and activating the swith. The insulin hypothesis, despite being attractive, is incorrect.
References
- Lanaspa, M.A., Ishimoto, T., Li, N., Cicerchi, C., Orlicky, D.J., Ruzycki, P., Rivard, C., Inaba, S., Roncal-Jimenez, C.A., Bales, E.S., Diggle, C.P., Asipu, A., Petrash, J.M., Kosugi, T., Maruyama, S., Sanchez-Lozada, L.G., McManaman, J.L., Bonthron, D.T., Sautin, Y.Y. and Johnson, R.J. (2013) Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun 4: 2434.
- Andres-Hernando, A., Orlicky, D.J., Kuwabara, M., Ishimoto, T., Nakagawa, T., Johnson, R.J. and Lanaspa, M.A. (2020) Deletion of Fructokinase in the Liver or in the Intestine Reveals Differential Effects on Sugar-Induced Metabolic Dysfunction. Cell Metab 32: 117-127 e113.