Does increased consumption of fructose cause increased insulin resistance in humans?

Question

As far as I understand it, diabetes is a disease that is composed of essentially two issues:

1. The pancreas' insulin production capabilities
2. The body's sensitivity to insulin

and I'm asking a rather basic question whose answer would seem like common sense to most people, that is:

"Does the increased intake of fructose cause increased insulin resistance?"

as in, as you increase this specific sugar's intake, does insulin resistance also go up? to determine this, a scientist would have to measure insulin resistance which I certainly have no idea how to do.

But assuming it is done, and these two variables are appropriately isolated, what kind of correlations have been found between these two??

The background for asking this is that I have known some friends who hopped onto the frugivore fad last year, and their diets are extremely high in sugar from fruit. They still have no sign of diabetes. Although I understand fruits contain many other nutrients and chemicals that may influence insulin resistance, so maybe I should ask

"Does high fructose consumption from fruit cause insulin resistance?" in a separate question.

this question is relevant, and I have noted the reviews and studies mentioned by the answer. The thing is, i'm only interested strictly with the statistical and mechanistic relationships between fructose intake and insulin resistance.

in the first study linked

Consumption of sweet beverages and type 2 diabetes incidence in European adults: results from EPIC-InterAct - Romaguera (and others)

it seems they had very few control variables ?

they just searched for a correlation between sugary drinks and type 2 diabetes in existing patient records. I speak as a layman but that sounds like very weak evidence, I think a method like this should be strictly used to identify potentially worthwhile directions of study, rather than used as evidence.

And in their second source, the journal's review relies rather extensively on rodent studies which i could not be more disinterested in because I have no idea how reliable they are as evidence for humans.

But they did mention this old 1980 human study in which a statistical relationship between fructose intake and insulin resistance was found:

Impaired cellular insulin binding and insulin sensitivity induced by high fructose feeding in normal subjects

but it's an old study, i have not evaluated the methods of measurement they used and they have a sample size of seven people which is much too small though thats not a problem for me as numbers can be corroborated with other studies. Bad study designs are more difficult to corroborate.

I understand there's not many studies of the well controlled design i am looking for on this subject, probably due to ethical concerns but whatever there is, please tell me. thank you

Answer 1

TL;DR;

Fructose's biochemistry indicates it may lead to increased triglyceride levels in the blood, which can lead to insulin resistance. Data on humans has not yet shown fructose, as a replacement for other simple sugars in the diet, to increase insulin resistance. However, excess fructose has been associated with weight gain and insulin resistance.

Biochemistry

Fructose metabolism

Glucose and fructose consumed in food first go to the liver by the portal vein. Fructose, unlike glucose, is metabolized almost entirely to intermediates that can eventually lead to glucose production (termed 'gluconeogenesis') or, more commonly, energy and fatty acid production. (1)

Glucose is primarily stored and metabolized in the liver, adipose (fat) tissue, and skeletal muscle. Increased blood glucose concentrations lead to a peak of insulin secretion after meals, while fructose typically leads to a peak of triglyceride levels in Very Low Density Lipoproteins (VLDLs) produced and secreted in the liver. (2)

Insulin resistance

Insulin signaling in the cells is rather complicated and not fully understood. Its principal action in glucose metabolism is to cause glucose transporters (GLUT4), that are sequestered in the cytoplasm, to move to cell surface, allowing glucose to enter the cell in high levels.

Free Fatty Acids (FFAs) and triglycerides (TG) can activate intracellular proteins that deactivate the molecules involved in insulin signaling. Hence, the number of GLUT4 on the membrane does not increase as much, and this is referred to as 'insulin resistance'. (3)

In conclusion, fructose, on principle, leads to increased circulating FFA and TG, unlike glucose; hence, resistance to insulin's effects may occur in the cells. It has been clinically established that weight gain and increased circulating levels of TG lead to insulin resistance. (4) Whether this is of clinical significance needs to be observed and analyzed in humans.

Clinical data

An orange typically has fewer than 10 grams of fructose. Estimates on the internet seem to be from 2.4 g to 6 g for an average orange. In a normal diet of 1600 to 2000 Cal, roughly every percent of calorie intake corresponds to 4 g of fructose. 30 g would correspond to 7.5 % of daily calorie intake. Most individuals are unlikely to derive this amount of fructose from consuming fruit during the day. (1)

The studies on fructose effects on blood markers and weight gain have severe limitations, as mentioned in the respective meta-analyses. The most prominent possible flaws are:

1. The duration of follow-up is often two weeks, so longstanding effects remain to be seen. There are some instances of longer, 4- to 10-week follow-up.
2. Especially in studies where adverse effects were visible, a high dose of fructose, well beyond normal daily consumption, was used.
3. Many studies did not have blinding or were of poor design.

• In diets with the same amount of calories ('isocaloric') where other simple sugars were replaced by fructose, no adverse effects on blood lipids were seen. In diets with 21-35 % excess calories derived from fructose, it did lead to increased lipid biomarkers. (5)
• Fructose effects on weight gain follow a similar pattern. It had no significant effects on weight gain in isocaloric diets, while diets with excess calories dervied mainly from fructose were associated with significant weight gain. (6)
• Sweet beverages sweetened with high-fructose corn syrup (HFCS) were associated with more weight gain than sweet beverages sweetened with glucose, and with higher blood TG levels, after two weeks.
• Diets with varying amounts of HFCS, compared to diets consisting of complex carbohydrates, showed a dose-dependent relationship with increases in weight and blood TG. This suggests that compared to complex carbohydrates, even lower amounts of fructose consumption may lead to weight gain, hence insulin resistance. (1)
• Sweet beverages sweetened with HFCS, compared to glucose, showed higher fat accumulation in the liver and other organs, and less fat accumulation under the skin. The former (visceral fat) is much more detrimental to health than the latter (subcutaneous fat), leading to insulin resistance, fatty liver disease, and vascular lipid abnormalities.(7)

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_{(1): Herman, M. A., & Samuel, V. T. (2016). The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. Trends in endocrinology and metabolism: TEM, 27(10), 719–730. https://doi.org/10.1016/j.tem.2016.06.005
(2): Schaefer, E. J., Gleason, J. A., & Dansinger, M. L. (2009). Dietary fructose and glucose differentially affect lipid and glucose homeostasis. The Journal of nutrition, 139(6), 1257S–1262S. https://doi.org/10.3945/jn.108.098186
(3): Bhattacharya, S., Dey, D., & Roy, S. S. (2007). Molecular mechanism of insulin resistance. Journal of biosciences, 32(2), 405–413. https://doi.org/10.1007/s12038-007-0038-8
(4): Verkouter, I., Noordam, R., le Cessie, S., van Dam, R. M., Lamb, H. J., Rosendaal, F. R., van Heemst, D., & de Mutsert, R. (2019). The Association between Adult Weight Gain and Insulin Resistance at Middle Age: Mediation by Visceral Fat and Liver Fat. Journal of clinical medicine, 8(10), 1559. https://doi.org/10.3390/jcm8101559
(5): Chiavaroli, L., de Souza, R. J., Ha, V., Cozma, A. I., Mirrahimi, A., Wang, D. D., Yu, M., Carleton, A. J., Di Buono, M., Jenkins, A. L., Leiter, L. A., Wolever, T. M., Beyene, J., Kendall, C. W., Jenkins, D. J., & Sievenpiper, J. L. (2015). Effect of Fructose on Established Lipid Targets: A Systematic Review and Meta-Analysis of Controlled Feeding Trials. Journal of the American Heart Association, 4(9), e001700. https://doi.org/10.1161/JAHA.114.001700
(6): Sievenpiper, J. L., de Souza, R. J., Mirrahimi, A., Yu, M. E., Carleton, A. J., Beyene, J., Chiavaroli, L., Di Buono, M., Jenkins, A. L., Leiter, L. A., Wolever, T. M., Kendall, C. W., & Jenkins, D. J. (2012). Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis. Annals of internal medicine, 156(4), 291–304. https://doi.org/10.7326/0003-4819-156-4-201202210-00007
(7): Ma, J., Sloan, M., Fox, C. S., Hoffmann, U., Smith, C. E., Saltzman, E., Rogers, G. T., Jacques, P. F., & McKeown, N. M. (2014). Sugar-sweetened beverage consumption is associated with abdominal fat partitioning in healthy adults. The Journal of nutrition, 144(8), 1283–1290. https://doi.org/10.3945/jn.113.188599}