**7. Insulin resistance**

Fructose consumption can result in insulin resistance, an effect that is similar to glucose [13]. In rats, high fructose consumption resulted in increased visceral adipose tissue, insulin resistance and hypertension [100, 101]. A higher C-peptide is often associated with insulin resistance [102]. A study was conducted to evaluate the link between fructose intake and C-peptide level in women, and it found that the serum C-peptide concentration of the subjects with the highest intake of fructose was 13.9% higher than those with the lowest intake [103]. In rats fed with HFrD resulted in a complete metabolic syndrome including hyperinsulinemia [43].

Fructose also sensitized pancreatic beta cells to TNF-alpha induced necroptosis [104]. Fructose showed increased insulin resistance in both obese men and women, more notable in males [58]. Fructose increased visceral adipose tissue, plasma insulin, blood triglyceride level, and HOMA index. There was a decreased stimulation of protein kinase B signaling in fructose fed rats. Insulin induced GLUT4 presence on plasma membranes of cardiac cells was decreased by fructose diet [105].

The body's use of insulin may be impaired by increased resistance in peripheral tissues, it is important to assess the effects of fructose on the insulin and the pancreatic beta cells. It is well known that hyperglycemia is detrimental to beta-cell

viability, which is a large part of the pathophysiology of development for diabetes mellitus. One factor in the beta cell death is a mitochondrial channel called the permeability transition pore (PTP, or MTP). PTP is associated with mitochondrial dysfunction and directly involved in insulin resistance [106]. There is evidence that PTP inhibitors prevent the pancreatic β cell death induced by hyperglycemia [107]. Comparing the effects of fructose and glucose on PTP, the results show that even low concentration of fructose (2.5 mM) can induce PTP open, similar to 30 mM glucose [108]. This indicated that the possible role of fructose on PTP and in the development of beta cell damage.

## **8. Diabetes**

In healthy people, acute increases in plasma glucose concentration inhibit endogenous glucose production. This regulation is disrupted in type 2 diabetes patients, causing inappropriate endogenous glucose production and hyperglycemia [109]. Hyperglycemia inhibits glucose production when an intracellular influx of glucose is catalyzed to glucose-6-phosphate via glucokinase [110]. In healthy individuals, there is an autoregulatory mechanism in which glucose phosphorylation suppresses glucose production, primarily by inhibiting glycogenolysis [111].

Studies show that fructose may have an impact on glucose level. In one study, dogs were fasted for 42 hours, then they were administered different amounts of IV fructose. Fructose exposure caused an increase in net hepatic glucose uptake, glycogen synthesis and hepatic lactate output, the experiments show that about 70% of H3- labeled glucose captured by the liver is incorporated into glycogen and deposited in liver [112]. This is significant because glucokinase is known to activate the glycogen synthase enzyme [113]. Fructose has a role in determining glucokinase activity, glucokinase has a major role in determining hepatic glucose uptake [112].

Other animal studies have shown that after two weeks of high fructose intake, blood glucose levels were significantly increased in healthy rats [114]. A study in humans has shown small amounts of fructose stimulated hepatic glucose uptake and hepatic glycogen synthesis. Under euglycemic hyperinsulinemia, low-dose fructose infusion increased net hepatic glycogen synthesis by 3 times via stimulating glycogen synthase flux [115]. Glucose-fructose co-ingestion will significantly increase hepatic glycogen repletion rates compared with glucose ingestion alone [116].

It is important to understand that although insulin resistance and pancreatic cell damage may develop in rats fed with HFrD as reported by some studies, the presentations might not always mimic type 2 diabetes found in humans or rats. For example, HFrD combined with high fat diet to induce T2D in rodents. These animals only developed early stage of diabetes but did not develop β-cell failure as seen in the late stages of T2D in humans [117, 118]. The animal could develop a nutritional tolerance after eating a fructose diet for 3 months, but these animals could be not used as suitable fructose-fed animal model for diabetes study due to no signs of insulin resistance and β-cell dysfunction [119]. A new and alternative rat model was created by using a 10% fructose-fed diet followed by 40 mg/kg of streptozotocin to induce beta cell toxicity. In this animal model, rats developed both insulin resistance and pancreatic β-cell dysfunction [120].

In humans, the epidemic of T2D and diabetes-related metabolic complications have been linked to fructose consumption [121–125]. Indeed, fructose as a highly lipogeneic monosaccharide, fructose intake increases the risk of impairing

**103**

**Figure 4.**

*Fructose Intake: Metabolism and Role in Diseases DOI: http://dx.doi.org/10.5772/intechopen.95754*

in retinopathy, nephropathy, and neuropathy [22].

with type 2 diabetes [127].

NADPD/NADP<sup>+</sup>

**9. Hyperuricemia**

level [53, 132].

gluocse metabolism [63, 126]. However, results are conflicting. An excessive rate of endogenous glucose production is a major contributor to fasting hyperglycemia in diabetes. A study on human showed that infusion of small amounts of fructose during hyperglycemia partially corrected the regulation of glucose production and partially restored the ability of glucose to suppress glucose production in subjects

In diabetes mellitus, hyperglycemic condition increases the activity of polyol

ratio, leading to NO production decrease, ROS production

pathway; approximately 30% glucose can be converted to fructose via the polyol pathway. Persistent hyperglycemia increases fructose level and decreases

increase, oxidative stress, and protein glycation increase. These events damage the microvascular system and are implicated in diabetic complications, especially

Hyperuricemia (HP) can cause metabolic, cardiovascular, and renal diseases [68]. Elevated level of uric acid can inhibit NO bioavailability; it also can promote smooth muscle cell proliferation and can activate the inflammation cascade, which can lead to damage of the endothelium of vessels [128, 129]. During fructose metabolism intracellular phosphate (PO4) is decreased, there is an activation of adenosine monophosphate deaminase which increases inosine monophosphate. Inosine monophosphate is further degraded to xanthine and hypoxanthine by xanthine oxidase (XO). The end product of these processes is uric acid [130, 131] (**Figure 4**). Furthermore, the increased insulin levels due to fructose intake lead to renal reuptake of urate, resulting in reducing the excretion of uric acid through the kidneys and further increases the serum uric acid

*Fructose stimulates hepatic uric acid synthesis. Fructose is transported into liver via hepatic GLUT2 and is phosphorylated by fructokinase (F-K) to fructose-1-phosphate (F-1-P), which uses ATP as a phosphate donor and results in intracellular phosphate (PO4) depletion. Intracellular phosphate levels decrease stimulates the activity of hepatic AMP deaminase (AMPD). AMPD catalyzes AMP to inosine monophosphate (IMP). IMP is converted to inosine by 5′ nucleotidase (5′NT) and then inosine is further degraded to hypoxanthine by purine nucleotide phosphorylase (PNP). Hypoxanthine is degraded into xanthine by xanthine oxidase (XO),* 

*and finally produced uric acid is released into circulation.*

*Fructose Intake: Metabolism and Role in Diseases DOI: http://dx.doi.org/10.5772/intechopen.95754*

gluocse metabolism [63, 126]. However, results are conflicting. An excessive rate of endogenous glucose production is a major contributor to fasting hyperglycemia in diabetes. A study on human showed that infusion of small amounts of fructose during hyperglycemia partially corrected the regulation of glucose production and partially restored the ability of glucose to suppress glucose production in subjects with type 2 diabetes [127].

In diabetes mellitus, hyperglycemic condition increases the activity of polyol pathway; approximately 30% glucose can be converted to fructose via the polyol pathway. Persistent hyperglycemia increases fructose level and decreases NADPD/NADP<sup>+</sup> ratio, leading to NO production decrease, ROS production increase, oxidative stress, and protein glycation increase. These events damage the microvascular system and are implicated in diabetic complications, especially in retinopathy, nephropathy, and neuropathy [22].

## **9. Hyperuricemia**

*Sugar Intake - Risks and Benefits and the Global Diabetes Epidemic*

development of beta cell damage.

**8. Diabetes**

uptake [112].

alone [116].

and pancreatic β-cell dysfunction [120].

viability, which is a large part of the pathophysiology of development for diabetes mellitus. One factor in the beta cell death is a mitochondrial channel called the permeability transition pore (PTP, or MTP). PTP is associated with mitochondrial dysfunction and directly involved in insulin resistance [106]. There is evidence that PTP inhibitors prevent the pancreatic β cell death induced by hyperglycemia [107]. Comparing the effects of fructose and glucose on PTP, the results show that even low concentration of fructose (2.5 mM) can induce PTP open, similar to 30 mM glucose [108]. This indicated that the possible role of fructose on PTP and in the

In healthy people, acute increases in plasma glucose concentration inhibit endogenous glucose production. This regulation is disrupted in type 2 diabetes patients, causing inappropriate endogenous glucose production and hyperglycemia [109]. Hyperglycemia inhibits glucose production when an intracellular influx of glucose is catalyzed to glucose-6-phosphate via glucokinase [110]. In healthy individuals, there is an autoregulatory mechanism in which glucose phosphorylation suppresses glucose production, primarily by inhibiting glycogenolysis [111].

Studies show that fructose may have an impact on glucose level. In one study, dogs were fasted for 42 hours, then they were administered different amounts of IV fructose. Fructose exposure caused an increase in net hepatic glucose uptake, glycogen synthesis and hepatic lactate output, the experiments show that about 70% of H3- labeled glucose captured by the liver is incorporated into glycogen and deposited in liver [112]. This is significant because glucokinase is known to activate the glycogen synthase enzyme [113]. Fructose has a role in determining glucokinase activity, glucokinase has a major role in determining hepatic glucose

Other animal studies have shown that after two weeks of high fructose intake, blood glucose levels were significantly increased in healthy rats [114]. A study in humans has shown small amounts of fructose stimulated hepatic glucose uptake and hepatic glycogen synthesis. Under euglycemic hyperinsulinemia, low-dose fructose infusion increased net hepatic glycogen synthesis by 3 times via stimulating glycogen synthase flux [115]. Glucose-fructose co-ingestion will significantly increase hepatic glycogen repletion rates compared with glucose ingestion

It is important to understand that although insulin resistance and pancreatic cell damage may develop in rats fed with HFrD as reported by some studies, the presentations might not always mimic type 2 diabetes found in humans or rats. For example, HFrD combined with high fat diet to induce T2D in rodents. These animals only developed early stage of diabetes but did not develop β-cell failure as seen in the late stages of T2D in humans [117, 118]. The animal could develop a nutritional tolerance after eating a fructose diet for 3 months, but these animals could be not used as suitable fructose-fed animal model for diabetes study due to no signs of insulin resistance and β-cell dysfunction [119]. A new and alternative rat model was created by using a 10% fructose-fed diet followed by 40 mg/kg of streptozotocin to induce beta cell toxicity. In this animal model, rats developed both insulin resistance

In humans, the epidemic of T2D and diabetes-related metabolic complications have been linked to fructose consumption [121–125]. Indeed, fructose as a highly lipogeneic monosaccharide, fructose intake increases the risk of impairing

**102**

Hyperuricemia (HP) can cause metabolic, cardiovascular, and renal diseases [68]. Elevated level of uric acid can inhibit NO bioavailability; it also can promote smooth muscle cell proliferation and can activate the inflammation cascade, which can lead to damage of the endothelium of vessels [128, 129]. During fructose metabolism intracellular phosphate (PO4) is decreased, there is an activation of adenosine monophosphate deaminase which increases inosine monophosphate. Inosine monophosphate is further degraded to xanthine and hypoxanthine by xanthine oxidase (XO). The end product of these processes is uric acid [130, 131] (**Figure 4**). Furthermore, the increased insulin levels due to fructose intake lead to renal reuptake of urate, resulting in reducing the excretion of uric acid through the kidneys and further increases the serum uric acid level [53, 132].

#### **Figure 4.**

*Fructose stimulates hepatic uric acid synthesis. Fructose is transported into liver via hepatic GLUT2 and is phosphorylated by fructokinase (F-K) to fructose-1-phosphate (F-1-P), which uses ATP as a phosphate donor and results in intracellular phosphate (PO4) depletion. Intracellular phosphate levels decrease stimulates the activity of hepatic AMP deaminase (AMPD). AMPD catalyzes AMP to inosine monophosphate (IMP). IMP is converted to inosine by 5′ nucleotidase (5′NT) and then inosine is further degraded to hypoxanthine by purine nucleotide phosphorylase (PNP). Hypoxanthine is degraded into xanthine by xanthine oxidase (XO), and finally produced uric acid is released into circulation.*

A meta-analysis of animal research showed that there is a significant relationship between fructose feeding and HP [133]. Research has also shown that when rats fed with HFrD, elevated uric acid blocked acetylcholine-mediated arterial dilation [53]. Human can also develop HP after high fructose consumption [11, 40, 129]. SSB consumption was significantly associated with increased uric acid concentration in adult population [134]. However, a meta-analysis showed that uric acid concentration was reduced by using glucose instead of fructose [135].

### **10. Retinopathy**

Chronic uncontrolled hyperglycemia can cause microvascular damage which can manifest as diabetic retinopathy (DR). Pathological retinal findings include microaneurysms, capillary abnormalities, hyperpermeability, hypoperfusion, and neo-angiogenesis, which eventually can lead to loss of vision [136, 137].

Animal studies have showed that animals can develop metabolic syndrome while on fructose diet and can also develop choroidal neovascularization which can lead to exudative age-related macular degeneration [137–139]. The retinal neovascularization occurs as part of oxidative stress resulting in an activation and infiltration of phagocytic cells in the retina. High fructose diet can also modulate gene expression in the retina [138]. The genes are involved in the development of diabetic retinopathy [140]. Melatonin plays an important role in the maintenance of disc shedding, function of rod photoreceptors [141], and elongation of cone photoreceptors in the retina [142]. Melatonin also blocks apoptosis of retinal cells after experimentally induced ischemia [143]. Excessive fructose consumption leads to down regulation of melatonin, and decrease the effects of melatonin on anti-inflammation and antioxidative stress in the retina [144, 145].

The premature death of retinal pericytes is a pathophysiological hallmark of DR. One study showed that advanced glycosylated end-products (AGEs) can cause retinal pericytes dysfunction and death by reducing survival signals mediated by platelet-derived growth factor [146]. DR is also caused oxidative stress because of increased ROS production and antioxidant depletion [147]. Protein kinase C (PKC) also has an important role in diabetic retinopathy, PKC activation leads to upregulation of pro-inflammatory genes, loss of capillary pericytes and generation of ROS [148, 149].

#### **11. Cancer**

Research studies have provided clinical and experimental evidence that fructose intake is associated with development of cancer, especially if consumed in large amounts [150]. Adenomatous polyposis coli (APC) genes can develop biallelic mutations and in combination with fructose intake can trigger or promote the colorectal cancer [151, 152]. The fructose transporter GLUT5 receptors are expressed on the cancer cells like colorectal and breast cancers indicated that fructose can be used as fuel by several types of cancers [153, 154]. Excessive intake of fructose can lead to increased formation of RDS production via formation of glycolaldehyde [155]. Glyoxal is an autoxidation product during fructose metabolism and also a contaminant in the food processing promoted intestinal tumor growth in mouse model.

Fructose was shown to be carcinogenic even if it was only 3% of total daily caloric intake which are mediated through activation of GLUT5 and phosphofructokinase. If fructokinase (ketohexokinase) which is the first enzyme involved in fructose is knocked out in mice the cancer growth can be suppressed [156, 157].

**105**

*Fructose Intake: Metabolism and Role in Diseases DOI: http://dx.doi.org/10.5772/intechopen.95754*

and hepatocellular carcinoma [158, 159].

proliferation is stopped [162, 163].

proliferation and metabolism [172].

cancer prevention and treatment [175].

potential dietary intervention to reduce disease.

The authors declare that there is no conflict of interest.

pyruvate [167].

**12. Summary**

**Conflict of interest**

Fructose can also promote cancer growth via pentose phosphate and increases protein synthesis and also cause hepatic inflammation, nonalcoholic fatty liver disease

Fructose promotes cancer growth by formation of lactate, which is an endproduct of fructose metabolism. Lactate is likely needed at several steps during the cancer growth including escape from the immune system, cell migration, metastasis and self-sustenance [160]. Lactate levels were found to be 40-fold high in glycolytic tumors and it correlates with cancer cell metastasis and poor survival [161]. Lactate also promotes angiogenesis in the tumors by inducing vascular endothelial growth factor (VEGF) in endothelial cells. If the lactate production is blocked by a chemical inhibitor or gene deletion, the angiogenesis and cancer cell

Fructose and uric acid have been shown to stimulate mitochondrial ROS production which is needed for tumor cell growth [164, 165]. During the rapid cell division cancer cells can suffer from hypoxic conditions and have to tolerate them to maintain viability and growth [166]. Fructose metabolism is useful in rapidly dividing cancer cells since during the glycolytic pathway it can use one molecule of ATP to generate 4 molecules of ATP from fructose-1,6-bisphosphate through

Fructose consumption may promote breast cancer cell line MDA-MB-468 to an aggressive type [168]. Fructose intake is associated with more aggressive cancer behavior and may promote metastasis [168–170]. Fructose also has a role in pancreatic cancer growth via the induction of transketolase flux [171]. Prostate cancer cell may also use fructose as the preferred energy source to support the cell

Human cells have the ability to produce fructose endogenously, which is also possible in the cancer cells [173]. Endogenous fructose production takes place through the polyol pathway by utilizing aldolase reductase. This enzyme is found in an activated state in various types of human cancers, including liver, breast, ovarian, cervical, and rectal cancers and helps in synthesizing fructose from glucose [174]. Fructose can promote cancer cell growth by providing fuel to make nucleotides,

lipids, and energy, especially for cancers that express GLUT5 receptors. Low fructose diet and fructokinase inhibitors can be novel techniques to treat cancers. Furthermore, blocking uric acid and lactate production could also be targets of

The past decade of research on fructose has expanded our understanding of role of fructose in disease. The imbalance between high fructose intake and low physical energy consumption is a possible reason of the deleterious health effect of fructose. The consumption of excess fructose may promote the development of metabolic disorders directly or indirectly. Dietary fructose intake has been linked with some human diseases, including hypertension, obesity, dyslipidemia, diabetes, nonalcoholic fatty liver syndrome, and certain type of cancers. Further investigation to gain a better understanding about fructose metabolism will be important to define a

#### *Fructose Intake: Metabolism and Role in Diseases DOI: http://dx.doi.org/10.5772/intechopen.95754*

*Sugar Intake - Risks and Benefits and the Global Diabetes Epidemic*

tion was reduced by using glucose instead of fructose [135].

**10. Retinopathy**

of ROS [148, 149].

**11. Cancer**

oxidative stress in the retina [144, 145].

A meta-analysis of animal research showed that there is a significant relationship between fructose feeding and HP [133]. Research has also shown that when rats fed with HFrD, elevated uric acid blocked acetylcholine-mediated arterial dilation [53]. Human can also develop HP after high fructose consumption [11, 40, 129]. SSB consumption was significantly associated with increased uric acid concentration in adult population [134]. However, a meta-analysis showed that uric acid concentra-

Chronic uncontrolled hyperglycemia can cause microvascular damage which can manifest as diabetic retinopathy (DR). Pathological retinal findings include microaneurysms, capillary abnormalities, hyperpermeability, hypoperfusion, and

Animal studies have showed that animals can develop metabolic syndrome while on fructose diet and can also develop choroidal neovascularization which can lead to exudative age-related macular degeneration [137–139]. The retinal neovascularization occurs as part of oxidative stress resulting in an activation and infiltration of phagocytic cells in the retina. High fructose diet can also modulate gene expression in the retina [138]. The genes are involved in the development of diabetic retinopathy [140]. Melatonin plays an important role in the maintenance of disc shedding, function of rod photoreceptors [141], and elongation of cone photoreceptors in the retina [142]. Melatonin also blocks apoptosis of retinal cells after experimentally induced ischemia [143]. Excessive fructose consumption leads to down regulation of melatonin, and decrease the effects of melatonin on anti-inflammation and anti-

The premature death of retinal pericytes is a pathophysiological hallmark of DR. One study showed that advanced glycosylated end-products (AGEs) can cause retinal pericytes dysfunction and death by reducing survival signals mediated by platelet-derived growth factor [146]. DR is also caused oxidative stress because of increased ROS production and antioxidant depletion [147]. Protein kinase C (PKC) also has an important role in diabetic retinopathy, PKC activation leads to upregulation of pro-inflammatory genes, loss of capillary pericytes and generation

Research studies have provided clinical and experimental evidence that fructose intake is associated with development of cancer, especially if consumed in large amounts [150]. Adenomatous polyposis coli (APC) genes can develop biallelic mutations and in combination with fructose intake can trigger or promote the colorectal cancer [151, 152]. The fructose transporter GLUT5 receptors are expressed on the cancer cells like colorectal and breast cancers indicated that fructose can be used as fuel by several types of cancers [153, 154]. Excessive intake of fructose can lead to increased formation of RDS production via formation of glycolaldehyde [155]. Glyoxal is an autoxidation product during fructose metabolism and also a contaminant in the food processing promoted intestinal tumor growth in mouse model. Fructose was shown to be carcinogenic even if it was only 3% of total daily caloric intake which are mediated through activation of GLUT5 and phosphofructokinase. If fructokinase (ketohexokinase) which is the first enzyme involved in fructose is knocked out in mice the cancer growth can be suppressed [156, 157].

neo-angiogenesis, which eventually can lead to loss of vision [136, 137].

**104**

Fructose can also promote cancer growth via pentose phosphate and increases protein synthesis and also cause hepatic inflammation, nonalcoholic fatty liver disease and hepatocellular carcinoma [158, 159].

Fructose promotes cancer growth by formation of lactate, which is an endproduct of fructose metabolism. Lactate is likely needed at several steps during the cancer growth including escape from the immune system, cell migration, metastasis and self-sustenance [160]. Lactate levels were found to be 40-fold high in glycolytic tumors and it correlates with cancer cell metastasis and poor survival [161]. Lactate also promotes angiogenesis in the tumors by inducing vascular endothelial growth factor (VEGF) in endothelial cells. If the lactate production is blocked by a chemical inhibitor or gene deletion, the angiogenesis and cancer cell proliferation is stopped [162, 163].

Fructose and uric acid have been shown to stimulate mitochondrial ROS production which is needed for tumor cell growth [164, 165]. During the rapid cell division cancer cells can suffer from hypoxic conditions and have to tolerate them to maintain viability and growth [166]. Fructose metabolism is useful in rapidly dividing cancer cells since during the glycolytic pathway it can use one molecule of ATP to generate 4 molecules of ATP from fructose-1,6-bisphosphate through pyruvate [167].

Fructose consumption may promote breast cancer cell line MDA-MB-468 to an aggressive type [168]. Fructose intake is associated with more aggressive cancer behavior and may promote metastasis [168–170]. Fructose also has a role in pancreatic cancer growth via the induction of transketolase flux [171]. Prostate cancer cell may also use fructose as the preferred energy source to support the cell proliferation and metabolism [172].

Human cells have the ability to produce fructose endogenously, which is also possible in the cancer cells [173]. Endogenous fructose production takes place through the polyol pathway by utilizing aldolase reductase. This enzyme is found in an activated state in various types of human cancers, including liver, breast, ovarian, cervical, and rectal cancers and helps in synthesizing fructose from glucose [174].

Fructose can promote cancer cell growth by providing fuel to make nucleotides, lipids, and energy, especially for cancers that express GLUT5 receptors. Low fructose diet and fructokinase inhibitors can be novel techniques to treat cancers. Furthermore, blocking uric acid and lactate production could also be targets of cancer prevention and treatment [175].

#### **12. Summary**

The past decade of research on fructose has expanded our understanding of role of fructose in disease. The imbalance between high fructose intake and low physical energy consumption is a possible reason of the deleterious health effect of fructose. The consumption of excess fructose may promote the development of metabolic disorders directly or indirectly. Dietary fructose intake has been linked with some human diseases, including hypertension, obesity, dyslipidemia, diabetes, nonalcoholic fatty liver syndrome, and certain type of cancers. Further investigation to gain a better understanding about fructose metabolism will be important to define a potential dietary intervention to reduce disease.

## **Conflict of interest**

The authors declare that there is no conflict of interest.
