As part of this ongoing metabolism series, I’d be remiss if I didn’t discuss fructose. This is a molecule that sees a spike in controversy from time to time. Sucrose, or table sugar, is a molecule of glucose connected to a molecule of fructose, so its consumption is widespread in the Western Diet. There’s an assertion that fructose or fructose-containing foods (such as high-fructose corn syrup) lends itself to disease because fructose is metabolized differently than other sugars in the liver – its breakdown bypasses the enzyme phosphofructokinase. This enzyme’s isoforms act somewhat as a pacemaker for glycolysis, regulating its activity via insulin’s stimulation. As such, the fear that fructose has the potential to lead to obesity and diabetes is understandable. Is it the fructose in of itself that’s linked to these metabolic diseases? Or is it that fructose often comes in the form of easily accessible, nutrient-poor, and calorie-dense foods and beverages. This is a topic that seems to have everyone (including myself) a bit confused. Let’s see if we can figure it out, starting with the metabolism of fructose.
In muscle, fructose metabolism is handled the same as with glucose. Hexokinase in muscle can act on fructose directly and phosphorylate it to make fructose-6-phosphate. If you remember from the First Half of Glycolysis post, this is an early intermediate in glycolytic process. Muscle can utilize this sugar as if it was glucose, so there really nothing too different here.
If you recall, the liver has a different isoform of hexokinase – it uses glucokinase instead. Glucokinase does not recognize fructose as a substrate. As such, the liver uses a different enzyme to initiate the metabolism of fructose – fructokinase. Unlike hexokinase in the muscle, fructokinase does not phosphorylate the 6 position of fructose. Rather it phosphorylates the 1 position, forming fructose-1-phosphate. This molecule is off the glycolytic pathway and thus, handled differently.
A different aldolase from glycolysis, fructose-1-phosphate aldolase, breaks the molecule into two 3-carbon units. One of these fragments is different than what we saw in glycolysis. Glyceraldehyde (not glycercaldehyde-3-phosphate) and dihydroxyacetone phosphate are formed.
Generally speaking, aldehydes are toxic. These are highly reactive molecules, reacting with amines on proteins and mutagenic to nucleic acids. So, they need to be handled accordingly. Here, glyceraldehyde is reduced to glycerol via alcohol dehydrogenase.
There’re two pressing issues that distinguish fructose from glucose metabolism:
1) The enzyme fructokinase is not under the same regulation as phosphofructokinase is. So, when fructose enters the liver, its metabolism moves forward whether the liver is in a “fed” or “fasted” state.
2) Glycerol is a component of di- and triacylglycerol – fat. The rate limiting step in the production of triacylglycerol is, in fact, the amount of glycerol available. That is, if you’re making a bunch of glycerol, you’re sending a strong signal to the liver to make fat.
As you can see, the assertion that fructose contributes to metabolic disorders and organ-specific diseases is understandable. There’s a bit more to this story that I’ll discuss shortly, but first let’s see what happens to the glyceraldehyde, glycerol, and dihydroxyacetone phosphate we have.
Glycerol can be phosphorylated through the action of glycerol kinase to form glycerol-3-phosphate. This can then be oxidized to dihydroxyacetone phosphate which can then be fed into the glycolytic pathway as I’ve discussed in the past two posts. Fructose metabolism is certainly much more involved than glucose metabolism (in the liver, at least) which raises the concern about the prevalence of high-fructose corn syrup (which has unsuccessfully tried to rename itself to “corn sugar”) in our diets. For that matter, what about fructose found in fruit? It’s all the same molecule and gets metabolized in the liver the same, right? So why would the source of fructose matter? Let’s discuss.
Applying the Biochemistry to the Real World
While the fructose molecule, in of itself, is identical, fruit-derived fructose is quite different from the high-fructose corn syrup. Metabolism, as I’ve described, can be a bit misleading. As complicated as it’s been up until this point, I’ve only depicted a very simplistic overview of what’s occurring when you eat something. See, we never are just metabolizing one nutrient at a time – when we eat a meal, a mixture of macro- and micronutrients interact with one another, affecting digestion, absorption, and utilization. There’re different levels of regulation that can all affect the response your body has to a particular food. Moreover, the composition of the food itself contributes to degree of post-prandial glucose spikes and insulin response. A blueberry, for example, is a semi-solid fibrous food that greatly slows its digestion when compared with say, a high-fructose corn syrup-filled soda. Same molecule, different response.
In fact, fruit can actually lower the postprandial glucose spike that comes from eating high glycemic foods. When glucose levels are low, it’s absorbed into the blood stream through passive diffusion by the action of the active transporter, sodium-dependent glucose transporter 1 (SGLT1). As glucose concentrations rise a different transporter, GLUT2, moves to the surface of the enterocyte. This then becomes the predominant transporter for glucose into the blood stream. Polyphenols and phenolic acids, micronutrients loaded with antioxidants, can substantially inhibit these transporter’s actions, preventing blood sugar spikes.
High Fructose Corn Syrup. What Does the Research Say?
What about fructose coming from high-fructose corn syrup? Given that I’ve told you that fructose metabolism lacks the regulation glucose has and it produces the rate-limiting component of fat, I wouldn’t hold it against you to pin fructose as the culprit for say, Type 2 diabetes. It’s not a wrong train of thought, but context matters. The detriments of high-fructose corn syrup appear to only take place in when in a caloric surplus.
The research finding a relationship between fructose and diabetes uses extreme conditions. It’s not uncommon to see research designs utilizing unrealistic amounts of fructose or, even more impractical, using only fructose as the diet. It’s not difficult to imagine that some abnormal health parameters would be witnessed in a diet designed as such. In recent studies using moderate intakes of fructose (and not contributing to calorie excess), there have not been any findings to suggest it as a risk factor for diabetes.
- A randomized controlled trial by Heden et al. didn’t find any change in fasting status, insulin sensitivity and resistance, cholesterol, triglycerides, or glucose in adolescents (ages 15-20) given either a 50 gram fructose/15 gram glucose beverage or a 50 gram glucose/15 gram fructose beverage daily for 2 weeks.
- Another randomized controlled trial by Hokayem et al. investigated the effect grape polyphenols would have on mitigating the metabolic detriments high fructose consumption would have on those at risk for Type 2 diabetes. Interestingly, the control group – the group consuming high fructose (3 grams of fructose per kilogram of fat-free mass) without grape polyphenols – actually saw an average 19% reduction in fasting insulin sensitivity.
These studies reinforce the idea that fructose consumption, in of itself, isn’t harmful. Rather, the harm presents itself when in a calorie excess. For example:
When fructose was consumed as 25% of a calorie excess (the actual calorie intake was not determined), Stanhope et al. found, among weight gain, increases in postprandial serum triglycerides and slight impairment in insulin response after 10 weeks. There was no change in fasting triglyceride levels. A natural question arises – are these effects the result of fructose alone? With the exception of fructose content, this study design allowed participants to choose their own diet composition and amount. Thus, it’s possible that the increased calories (which were enough to increase fat mass by 2.8% over the study period) could be part, equally, or more responsible than fructose alone. When in a calorie excess it’s difficult to distinguish what’s responsible for the observed effect.
To Conclude, Context Matters
Rarely is disease caused by a single variable. Typically, it’s a culmination of many factors going awry over a period of time, despite the body’s efforts at maintaining homeostasis. In this context, diabetes has many risk factors – increased adiposity, inactivity, family history, blood pressure, etc. To pin fructose as the scapegoat mistakenly over-simplifies a highly complex issue. Given that the current evidence is not in its favor, blaming fructose as a culprit in the onset and progression of diabetes without context may have unintended consequences. Further research is warranted to assess how (or, if) high fructose consumption alongside overfeeding may contribute as a diabetic risk factor.
Heden, T. D., Liu, Y., Park, Y. M., Nyhoff, L. M., Winn, N. C., & Kanaley, J. A. (2014). Moderate amounts of fructose- or glucose-sweetened beverages do not differentially alter metabolic health in male and female adolescents. The American journal of clinical nutrition, 100(3), 796–805. doi:10.3945/ajcn.113.081232
Hokayem, M., Blond, E., Vidal, H., Lambert, K., Meugnier, E., Feillet-Coudray, C., … Avignon, A. (2013). Grape polyphenols prevent fructose-induced oxidative stress and insulin resistance in first-degree relatives of type 2 diabetic patients. Diabetes care, 36(6), 1454–1461. doi:10.2337/dc12-1652
Khan, T. A., & Sievenpiper, J. L. (2016). Controversies about sugars: results from systematic reviews and meta-analyses on obesity, cardiometabolic disease and diabetes. European journal of nutrition, 55(Suppl 2), 25–43. doi:10.1007/s00394-016-1345-3
Macdonald I. A. (2016). A review of recent evidence relating to sugars, insulin resistance and diabetes. European journal of nutrition, 55(Suppl 2), 17–23. doi:10.1007/s00394-016-1340-8
Manzano, S., & Williamson, G. (2010). Polyphenols and phenolic acids from strawberry and apple decrease glucose uptake and transport by human intestinal Caco-2 cells. Molecular Nutrition & Food Research, 54(12), 1773–1780. doi: 10.1002/mnfr.201000019
Sánchez-Lozada, L. G., Mu, W., Roncal, C., Sautin, Y. Y., Abdelmalek, M., Reungjui, S., … Johnson, R. J. (2010). Comparison of free fructose and glucose to sucrose in the ability to cause fatty liver. European journal of nutrition, 49(1), 1–9. doi:10.1007/s00394-009-0042-x
Stanhope, K. L., Schwarz, J. M., Keim, N. L., Griffen, S. C., Bremer, A. A., Graham, J. L., … Havel, P. J. (2009). Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. The Journal of clinical investigation, 119(5), 1322–1334. doi:10.1172/JCI37385