How are non-glucose sugars metabolized in the body?

How are non-glucose sugars metabolized in the body?

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In my biology book's section on disaccharide metabolism and glycolysis, it states that sugars other than glucose must be acted upon to enter glycolysis. Let's take sucrose as an example. Sucrose is hydrolyzed in the small intestine by sucrase. The resulting fructose and glucose are absorbed and transported to the liver via the portal vein. My question concerns the fate of fructose.

To undergo glycolysis, the book states that fructose is converted into either fructose-6-phosphate (F6P) or fructose-1-phosphate (F1P). Let's say it is converted to F1P. Aldolase splits this into dihydroxyacetone phosphate and D-glyceraldehyde. Triose kinase then converts D-glyceraldehyde to glyceraldehyde-3-phosphate, a glycolytic intermediate. Where is this occurring in the body? Are we still in the liver? I can't imagine that all the fructose we consume is undergoing glycolysis in the liver. To leave the liver as a sugar, it would have had to been converted to glucose, right?

In classes I've taken, I've been told that sugars that enter the liver are pretty much all converted to glucose. Once they are converted to glucose, they can be distributed to the rest of the body, stored as glycogen, etc. If we are going straight from fructose to F1P to a glycolytic intermediate, we couldn't have left the liver. How is such a transformation even useful? Anyone care to shed some light on this?

Where is this occurring in the body?

Almost totally in the liver.

To leave the liver as a sugar, it would have had to been converted to glucose, right?

Correct, but it's not a direct conversion.

Fructose is metabolized almost completely in the liver in humans, and is directed toward replenishment of liver glycogen and triglyceride synthesis … Increased concentrations of DHAP and glyceraldehyde-3-phosphate in the liver drive the gluconeogenic pathway toward glucose-6-phosphate, glucose-1-phosphate and glycogen formation. It appears that fructose is a better substrate for glycogen synthesis than glucose and that glycogen replenishment takes precedence over triglyceride formation. Once liver glycogen is replenished, the intermediates of fructose metabolism are primarily directed toward triglyceride synthesis.

So, Fructose is almost entirely made into something else first, and then that something (Glycogen or the Glycerol from triglycerides) gets broken down into Glucose or an intermediate.

Fructose stays in the liver because Fructokinase has a pretty low Km (0.5 mM) compared to Glucokinase (12mM) for Fructose, so almost all of the Fructose that enters the liver is phosphorylated into F1P - which cannot leave.

Sugar consumption, metabolic disease and obesity: The state of the controversy

The impact of sugar consumption on health continues to be a controversial topic. The objective of this review is to discuss the evidence and lack of evidence that allows the controversy to continue, and why resolution of the controversy is important. There are plausible mechanisms and research evidence that supports the suggestion that consumption of excess sugar promotes the development of cardiovascular disease (CVD) and type 2 diabetes (T2DM) both directly and indirectly. The direct pathway involves the unregulated hepatic uptake and metabolism of fructose, leading to liver lipid accumulation, dyslipidemia, decreased insulin sensitivity and increased uric acid levels. The epidemiological data suggest that these direct effects of fructose are pertinent to the consumption of the fructose-containing sugars, sucrose and high fructose corn syrup (HFCS), which are the predominant added sugars. Consumption of added sugar is associated with development and/or prevalence of fatty liver, dyslipidemia, insulin resistance, hyperuricemia, CVD and T2DM, often independent of body weight gain or total energy intake. There are diet intervention studies in which human subjects exhibited increased circulating lipids and decreased insulin sensitivity when consuming high sugar compared with control diets. Most recently, our group has reported that supplementing the ad libitum diets of young adults with beverages containing 0%, 10%, 17.5% or 25% of daily energy requirement (Ereq) as HFCS increased lipid/lipoprotein risk factors for CVD and uric acid in a dose-response manner. However, un-confounded studies conducted in healthy humans under a controlled, energy-balanced diet protocol that enables determination of the effects of sugar with diets that do not allow for body weight gain are lacking. Furthermore, recent reports conclude that there are no adverse effects of consuming beverages containing up to 30% Ereq sucrose or HFCS, and the conclusions from several meta-analyses suggest that fructose has no specific adverse effects relative to any other carbohydrate. Consumption of excess sugar may also promote the development of CVD and T2DM indirectly by causing increased body weight and fat gain, but this is also a topic of controversy. Mechanistically, it is plausible that fructose consumption causes increased energy intake and reduced energy expenditure due to its failure to stimulate leptin production. Functional magnetic resonance imaging (fMRI) of the brain demonstrates that the brain responds differently to fructose or fructose-containing sugars compared with glucose or aspartame. Some epidemiological studies show that sugar consumption is associated with body weight gain, and there are intervention studies in which consumption of ad libitum high-sugar diets promoted increased body weight gain compared with consumption of ad libitum low- sugar diets. However, there are no studies in which energy intake and weight gain were compared in subjects consuming high or low sugar, blinded, ad libitum diets formulated to ensure both groups consumed a comparable macronutrient distribution and the same amounts of fiber. There is also little data to determine whether the form in which added sugar is consumed, as beverage or as solid food, affects its potential to promote weight gain. It will be very challenging to obtain the funding to conduct the clinical diet studies needed to address these evidence gaps, especially at the levels of added sugar that are commonly consumed. Yet, filling these evidence gaps may be necessary for supporting the policy changes that will help to turn the food environment into one that does not promote the development of obesity and metabolic disease.

Keywords: Cardiovascular disease diet high fructose corn syrup metabolic syndrome sucrose triglyceride type 2 diabetes uric acid.

Conflict of interest statement

Dr. Stanhope has no conflicts of interest to report.

The studies conducted by Drs. Havel and Stanhope’s research group were supported with funding from NIH grants R01 HL-075675, 1R01 HL-091333, 1R01 HL-107256 and a Multi-campus Award from the University of California, Office of the President (UCOP #142691). These projects also received support from Grant Number UL1 RR024146 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Dr. Stanhope is supported by a Building Interdisciplinary Research Careers in Women’s Health award (K12 HD051958) funded by the National Institute of Child Health and Human Development (NICHD), Office of Research on Women’s Health (ORWH), Office of Dietary Supplements (ODS), and the National Institute of Aging (NIA).


Cells need to make decisions when faced with multiple options. It is of general interest to understand principles which guide cell decision making, and to understand whether the decisions made are optimal in some sense [1]-[3]. To address this, we focus on the choices that E. coli makes when presented with more than one carbon source.

When multiple carbon sources are available bacteria can either co-metabolize them or preferentially use one of the carbon sources before the others. The best known example of preferential carbon utilization comes from the work of Monod on the glucose-lactose diauxic shift in E. coli [4]. Bacteria first utilized only glucose, and when glucose ran out, switched to lactose.

Subsequent studies revealed that glucose is the preferred carbon source for many organisms [5]. The presence of glucose often prevents the use of secondary carbon sources. This phenomena is termed glucose repression or more generally carbon catabolic repression (CCR) [6]. CCR is a central regulatory mechanism that affects 5-10% of all genes in many bacterial species ([5],[7]-[10] for reviews).

CCR is believed to be important in natural environments to allow the bacteria to grow rapidly on its preferred sugar. On the other hand, in industrial processes such as biofuel production from sugar mixtures (such as agricultural byproducts), CCR is one of the barriers for increased yield of fermentation processes [11].

The molecular mechanism underlying CCR in E. coli has been worked out for the class of sugars transported by the phosphotransferase system (PTS) sugars, including glucose and mannose. The transport pathway leads to reduced levels of a key signaling molecule, cyclic AMP (cAMP). cAMP, in turn, binds the global regulator CRP which activates most carbon utilization promoters. Thus, PTS sugars lower CRP activity, and lead to inactivation of alternative carbon systems. In addition, transport through PTS transporters leads to direct inhibition of several sugar pumps ([5],[7]-[10], for reviews). Recently, post transcriptional control by small regulatory RNA (sRNA) has also been discovered to play a role in CCR [12],[13].

The contribution of each of these mechanisms to CCR is probably different for different carbon sources and is debated even for the best studied CCR example of the glucose-lactose diauxie shift [14],[15]. The level of cAMP in the cell is also determined by the metabolic and energetic state of the cell [16],[17]. Central carbon metabolites (α-ketoacids) can negatively affect cAMP levels when nitrogen availability is low, thus forming an integral feedback loop that can control carbon uptake to match cell needs between anabolism and catabolism [10],[18],[19].

In contrast to the extensive knowledge on the preferential utilization of glucose [7], much less is known about the utilization of glucose-free sugar mixtures, especially on mixtures of non-PTS sugars. These non-PTS sugars are often found in the environmental niches of E. coli. Sugars found in the intestinal habitat of E coli have been characterized, and cases of sequential and simultaneous utilization of these sugars have been reported in complex mixtures of these sugars [20],[21]. This hints at the existence of a secondary hierarchy of sugar utilization.

The mechanism for a non-PTS sugar hierarchy was directly addressed in E. coli for the mixture of arabinose and xylose. These sugars, together with glucose, are the main components of lignocelluloses, which is a substrate for bacterial biofuel production. Desai et al. [22] showed that arabinose consumption precedes xylose consumption, and that xylose utilization genes are partially inhibited in the presence of arabinose and xylose. They further proposed that the xylose utilization promoters are directly repressed by the arabinose specific transcription factor AraC [22]. There is need for further systematic study of sugar secondary hierarchies and their mechanism, in order to better understand the decisions that E. coli makes in complex nutrient conditions.

Here, we combine experiments and theory to map the sugar utilization hierarchy of E. coli for 6 different non-PTS carbon sources. We find a defined hierarchy in the activation of sugar systems, where the promoter of the less dominant sugar system has reduced activity. The ranking of the sugars in the hierarchy is the same as the ranking of the growth rate supported by the sugars as sole carbon sources. The hierarchy can be quantitatively explained by differential CRP-cAMP activation of the promoters. Both sequential and simultaneous expression of sugar systems is found when one of the sugars is at low concentration, suggesting a multi-objective optimization strategy for decision making in sugar mixtures.

How does the body metabolize sugar?

The fruit has fructose and glucose in it—just like processed sugar. Most fruit has 40-55 percent fructose, and table sugar is 50 percent fructose and 50 percent glucose. Why does this matter? According to Nicole Osinga, a registered dietitian and founder of Osinga Nutrition, the body metabolizes fructose differently than glucose.

“Fructose is primarily metabolized in the liver. There are pros and cons to this,” she says. “The pro is that eating fructose doesn’t raise blood glucose or insulin levels, both of which—when elevated above the normal range—are thought to contribute to a variety of diseases ranging from heart disease to obesity to several forms of cancer.”

The disadvantage, Osinga says, is that when fructose is metabolized in the liver, it’s typically used to make fats. However, because “fructose is almost never eaten by itself and is usually consumed with equal parts glucose,” she adds.

Glucose, on the other hand, breaks down in the stomach and needs insulin to get into the bloodstream, so it can be metabolized. “The glucose our body doesn’t need right then is stored to try to keep our glucose levels as stable as possible all day long,” Fleming says.

Gluconeogenesis Pathway

  1. Gluconeogenesis begins in either the mitochondria or cytoplasm of the liver or kidney. First, two pyruvate molecules are carboxylated to form oxaloacetate. One ATP (energy) molecule is needed for this.
  2. Oxaloacetate is reduced to malate by NADH so that it can be transported out of the mitochondria.
  3. Malate is oxidized back to oxaloacetate once it is out of the mitochondria.
  4. Oxaloacetate forms phosphoenolpyruvate using the enzyme PEPCK.
  5. Phosphoenolpyruvate is changed to fructose-1,6-biphosphate, and then to fructose-6-phosphate. ATP is also used during this process, which is essentially glycolysis in reverse.
  6. Fructose-6-phosphate becomes glucose-6-phosphate with the enzyme phosphoglucoisomerase.
  7. Glucose is formed from glucose-6-phosphate in the cell’s endoplasmic reticulum via the enzyme glucose-6-phosphatase. To form glucose, a phosphate group is removed, and glucose-6-phosphate and ATP becomes glucose and ADP.

This diagram shows the gluconeogenesis pathway.

2. Gluconeogenesis is a(n) ______ process.
A. Endogenous
B. Exogenous
C. Neither endogenous nor exogenous

3. What is the main body organ where gluconeogenesis takes place?
A. Kidney
B. Brain
C. Liver
D. Mitochondria

Lifestyle Risk Factors

Diet plays a significant role in the development of high blood sugar. Excess consumption of sugar- and carbohydrate-containing foods raise blood sugar levels after eating as the food is broken down into glucose molecules that enter the bloodstream.

In a healthy person, the presence of more glucose molecules in the blood signals the pancreas to release insulin, which helps uptake glucose from the blood and transports it to the muscles and liver to be used for energy and storage. As blood sugar decreases, the signals to the pancreas to release more insulin stop, and blood sugar levels should return to a stable baseline.

When levels of blood sugar continually become elevated with repeat and excessive sugar and carbohydrate consumption, the excess glucose in the bloodstream stimulates the pancreas to release a lot of insulin. Over time, the body stops responding to insulin due to chronic high blood sugar, causing insulin resistance and keeping blood sugar high.

Managing a healthy and balanced diet with proteins, fats, and fiber-rich foods while limiting sugar and processed and refined carbohydrates can help control blood sugar levels.

Excess alcohol consumption can also affect your blood sugar by interfering with your liver’s ability to regulate the production and release of glucose and negatively impact your body’s response to insulin.

Lack of Physical Activity

Lack of physical activity can increase your blood sugar, as skeletal muscles are a main part of the body that uses glucose for energy or stores extra glucose as glycogen for later use. With low levels of physical activity, the muscles become inactive and do not remove glucose efficiently from the blood.

Regular exercise can help lower blood sugar levels by increasing the need for muscles to remove glucose from the blood to use for energy.

Sugar and Weight Gain

Hundreds of studies point to sugar consumption as a leading cause of obesity, heart disease and diabetes. According to a July 2017 review published in Translational Medicine, high sugar intakes contribute to dental caries, weight gain and obesity-related diseases. Researchers recommend limiting sugar to 10 percent of total calories to prevent these health issues. One gram of sugar has approximately 4 calories, meaning that a 2,000-calorie diet should provide no more than 50 grams of sugar per day.

This sneaky ingredient may lead to weight gain and affect your heart and metabolism. In a large-scale study, participants who consumed 17 to 21 percent of their daily calories from sugar had a nearly 40 percent higher risk of dying from heart disease than those eating less sugar (8 percent of their daily calories). The odds of cardiovascular disease mortality were more than double in subjects who ate 21 percent or more of their calories from sugar.

As the scientists point out, soft drinks, fruit drinks and grain-based desserts are the primary sources of added sugar in the American diet. When consumed regularly, sugary foods and beverages may contribute to diabetes, obesity, elevated triglycerides, high cholesterol and inflammation. They also promote fat accumulation in the liver and may increase blood pressure. These findings were published in April 2014 in JAMA Internal Medicine.

Sugar is harmful to adults and children alike. According to a research paper featured in the journal Circulation in August 2016, added sugar may raise heart disease risk in children even when consumed in lower doses than the maximum daily recommended amount. Furthermore, this food ingredient may lead to non-alcoholic fatty liver disease, liver inflammation and insulin resistance in people of all ages.


The primary results of the pathway are:

  • The generation of reducing equivalents, in the form of NADPH, used in reductive biosynthesis reactions within cells (e.g. fatty acid synthesis).
  • Production of ribose 5-phosphate (R5P), used in the synthesis of nucleotides and nucleic acids.
  • Production of erythrose 4-phosphate (E4P) used in the synthesis of aromatic amino acids.

Aromatic amino acids, in turn, are precursors for many biosynthetic pathways, including the lignin in wood. [ citation needed ]

Dietary pentose sugars derived from the digestion of nucleic acids may be metabolized through the pentose phosphate pathway, and the carbon skeletons of dietary carbohydrates may be converted into glycolytic/gluconeogenic intermediates.

In mammals, the PPP occurs exclusively in the cytoplasm. In humans, it is found to be most active in the liver, mammary glands, and adrenal cortex. [ citation needed ] The PPP is one of the three main ways the body creates molecules with reducing power, accounting for approximately 60% of NADPH production in humans. [ citation needed ]

One of the uses of NADPH in the cell is to prevent oxidative stress. It reduces glutathione via glutathione reductase, which converts reactive H2O2 into H2O by glutathione peroxidase. If absent, the H2O2 would be converted to hydroxyl free radicals by Fenton chemistry, which can attack the cell. Erythrocytes, for example, generate a large amount of NADPH through the pentose phosphate pathway to use in the reduction of glutathione.

Hydrogen peroxide is also generated for phagocytes in a process often referred to as a respiratory burst. [5]

Oxidative phase Edit

In this phase, two molecules of NADP + are reduced to NADPH, utilizing the energy from the conversion of glucose-6-phosphate into ribulose 5-phosphate.

The entire set of reactions can be summarized as follows:

Reactants Products Enzyme Description
Glucose 6-phosphate + NADP+ → 6-phosphoglucono-δ-lactone + NADPH glucose 6-phosphate dehydrogenase Dehydrogenation. The hydroxyl on carbon 1 of glucose 6-phosphate turns into a carbonyl, generating a lactone, and, in the process, NADPH is generated.
6-phosphoglucono-δ-lactone + H2O → 6-phosphogluconate + H + 6-phosphogluconolactonase Hydrolysis
6-phosphogluconate + NADP + → ribulose 5-phosphate + NADPH + CO2 6-phosphogluconate dehydrogenase Oxidative decarboxylation. NADP + is the electron acceptor, generating another molecule of NADPH, a CO2, and ribulose 5-phosphate.

The overall reaction for this process is:

Glucose 6-phosphate + 2 NADP + + H2O → ribulose 5-phosphate + 2 NADPH + 2 H + + CO2

Non-oxidative phase Edit

Net reaction: 3 ribulose-5-phosphate → 1 ribose-5-phosphate + 2 xylulose-5-phosphate → 2 fructose-6-phosphate + glyceraldehyde-3-phosphate

Regulation Edit

Glucose-6-phosphate dehydrogenase is the rate-controlling enzyme of this pathway. It is allosterically stimulated by NADP + and strongly inhibited by NADPH. [6] The ratio of NADPH:NADP + is normally about 100:1 in liver cytosol [ citation needed ] . This makes the cytosol a highly-reducing environment. An NADPH-utilizing pathway forms NADP + , which stimulates Glucose-6-phosphate dehydrogenase to produce more NADPH. This step is also inhibited by acetyl CoA. [ citation needed ]

G6PD activity is also post-translationally regulated by cytoplasmic deacetylase SIRT2. SIRT2-mediated deacetylation and activation of G6PD stimulates oxidative branch of PPP to supply cytosolic NADPH to counteract oxidative damage or support de novo lipogenesis. [7] [8]

Several deficiencies in the level of activity (not function) of glucose-6-phosphate dehydrogenase have been observed to be associated with resistance to the malarial parasite Plasmodium falciparum among individuals of Mediterranean and African descent. The basis for this resistance may be a weakening of the red cell membrane (the erythrocyte is the host cell for the parasite) such that it cannot sustain the parasitic life cycle long enough for productive growth. [9]

Triglycerides, a form of long-term energy storage in animals, are made of glycerol and three fatty acids. Animals can make most of the fatty acids they need. Triglycerides can be both made and broken down through parts of the glucose catabolism pathways. Glycerol can be phosphorylated to glycerol-3-phosphate, which continues through glycolysis.

Fatty acids are catabolized in a process called beta-oxidation that takes place in the matrix of the mitochondria and converts their fatty acid chains into two carbon units of acetyl groups, while producing NADH and FADH2. The acetyl groups are picked up by CoA to form acetyl CoA that proceeds into the citric acid cycle as it combines with oxaloacetate. The NADH and FADH2 are then used by the electron transport chain.

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