*Article* **The Spatiotemporal Distribution of Flash Floods and Analysis of Partition Driving Forces in Yunnan Province**

**Junnan Xiong 1 , Chongchong Ye 1 , Weiming Cheng 2,\* , Liang Guo 3 , Chenghu Zhou 2 and Xiaolei Zhang 3**

Received: 10 April 2019; Accepted: 20 May 2019; Published: 23 May 2019

**Abstract:** Flash floods are one of the most serious natural disasters, and have a significant impact on economic development. In this study, we employed the spatiotemporal analysis method to measure the spatial–temporal distribution of flash floods and examined the relationship between flash floods and driving factors in different subregions of landcover. Furthermore, we analyzed the response of flash floods on the economic development by sensitivity analysis. The results indicated that the number of flash floods occurring annually increased gradually from 1949 to 2015, and regions with a high quantity of flash floods were concentrated in Zhaotong, Qujing, Kunming, Yuxi, Chuxiong, Dali, and Baoshan. Specifically, precipitation and elevation had a more significant effect on flash floods in the settlement than in other subregions, with a high *r* (Pearson's correlation coefficient) value of 0.675, 0.674, 0.593, 0.519, and 0.395 for the 10 min precipitation in 20-year return period, elevation, 60 min precipitation in 20-year return period, 24 h precipitation in 20-year return period, and 6 h precipitation in 20-year return period, respectively. The sensitivity analysis showed that the Kunming had the highest sensitivity (*S* = 21.86) during 2000–2005. Based on the research results, we should focus on heavy precipitation events for flash flood prevention and forecasting in the short term; but human activities and ecosystem vulnerability should be controlled over the long term.

**Keywords:** flash flood; driving factor; sensitivity analysis; subregion of landcover; Yunnan Province

### **1. Introduction**

Flash floods are one of the most severe natural disasters to try to prevent and deal with in the aftermath. They are responsible for loss of life and serious destruction to property and infrastructure, severely affecting a region's economic development [1–3]. According to an investigation by the World Meteorological Organization, the loss of property resulting from flash floods ranks in the top 10 among a range of natural disasters in 75% of countries [4]. As an economically developed country, flash floods in the United States ranked first in causes of death, with approximately 100 lives lost each year [5]. In addition, a total of 28,826 flash floods occurred between 2015 and 2017, and 10% of these flash floods resulted in property losses exceeding \$100,000 (US dollars) per flash flood disaster [6]. In Europe, 40% of flood-related casualties during 1950–2006 were due to flash floods [7], which is already more than 80% in southern Europe [8]. China is one of the countries that experiences the most flash floods, and about 4.63 million km2 of land tend to be impacted by flash floods, which have threatened 560 million

people [3]. Yunnan is one of the most important areas of ecological value in the world [9] where flash floods are rapidly increasing, causing serious threat to people's lives and property [10].

In recent years, the vast majority of studies conducted on flash floods have indicated that flash floods are the combined result of various spatiotemporal factors [11–13]. Existing studies on flash floods have focused primarily on the following aspects: (1) the risk assessment [14–16]; (2) the occurrence, development, and influence studied from the perspective of a disaster mechanism [3,17,18]; and (3) the spatial–temporal distribution and influencing factors [19–21]. Further, risk assessment of flash floods has been used to classify a region as low risk, mid risk, or high risk and this is primarily based on the county and province scale [22]. The formation of flash floods is very complicated and has led to many such studies being carried out only in typical watersheds [23]. Regarding the spatiotemporal pattern and driving factors of flash floods, most of the research uses the global spatial autocorrelation, kernel density estimation, hot spot (Getis-Ord Gi\*) analysis, standard deviational ellipse, and spatial gravity center migration to explore the spatial and temporal characteristics of flash floods [24–26]. The driving force analysis of flash floods is primarily based on geographical detectors, and the driving factors selected by the researchers have included precipitation, terrain, and human activities, et al., which were dominated by static indices [27–29]. Such research generally selects the province (or country) as the research object.

Some research has been conducted on the spatiotemporal distribution and driving factors of flash floods, although some problems still remain. First, Yunnan has a complex number of characteristics, including its mountain range, human activity, precipitation, and ecosystems. In such complicated conditions, the characteristics of flash floods there remain unknown. Second, Yunnan is one of the most important ecological areas in the world, and the species diversity has been acknowledged by the International Union and the World Wildlife Fund for the Conservation of Nature [9]. There are differences in the weather, landform, and background conditions in each subregion of landcover. As a result, the nonpartitioned approach no longer applies in such a complex ecosystem region. Additionally, the study area is divided into different subregions of landcover, which reflect well the extent of environmental damage caused by human activities. For example, the human activity in the settlement is significantly greater than in other subregions. Third, previous studies have explored how driving factors interact based on two factors that use geographical detectors [30,31], which cannot reflect the contribution rate of multiple factor interactions on the flash floods. Finally, most studies have revealed the influence of human activity on the occurrence of flash floods [32,33], but the response of flash floods on economic development is not well understood in Yunnan. Hence, it is necessary to explore the spatiotemporal variations and driving factors (in different subregions of the landcover, which include grassland, settlement, farmland, and forest) of flash floods and to conduct a sensitivity analysis of the response of flash floods on economic development in Yunnan Province.

The objectives of this study were to (1) measure the spatial–temporal variation of flash floods using the changepoint, kernel density estimation, spatial mismatch analysis, standard deviational ellipse (SDE), and spatial gravity center model; (2) analyze the driving factors for the spatial pattern of flash floods in different subregions of the landcover using the Pearson correlation coefficient, multiple linear regression, and principal component analysis; and (3) conduct a sensitivity analysis to investigate the response of flash floods on economic development. The results can provide references for the prevention of flash floods.

#### **2. Materials and Methods**

#### *2.1. Study Area*

Yunnan Province (21◦–29◦ N, 97◦–106◦ E) is located in southwestern China and is situated on the eastern edge of the collision zone between the Eurasian and Indian continental plates. This region is characterized by some of the most complicated and neotectonic activity and tectonic movements on the Chinese mainland (Figure 1) [34]. Yunnan follows the spatial extent of the land area for this region and covers roughly 394,100 km2 ; the population was 47.7 million at the end of 2016 (http://www.yn.gov.cn/yn\_yngk/gsgk/index.html). Economic activities are gradually gaining momentum, and the yearly economy has exceeded 1.63 trillion yuan (RMB; http://www.stats.gov.cn/) since 2017 in Yunnan. Although Yunnan's economy has made significant progress, the level of urbanization remains lows, and the township density is relatively sparse [35]. Yunnan is located in the Yunnan–Guizhou Plateau; and most of the areas are dominated by high mountains, deep valleys, and dense mountain streams where vertical differentiation in heat and water occurs as a result of changes in landform and altitude [36]. In addition, the precipitation in northwestern and central Yunnan has increased in recent years [37]. All of these conditions have contributed to making this study area one of the most geophysical hazard-prone regions in China. movements on the Chinese mainland (Figure 1) [34]. Yunnan follows the spatial extent of the land area for this region and covers roughly 394,100 km2; the population was 47.7 million at the end of 2016 (http://www.yn.gov.cn/yn\_yngk/gsgk/index.html). Economic activities are gradually gaining momentum, and the yearly economy has exceeded 1.63 trillion yuan (RMB; http://www.stats.gov.cn/) since 2017 in Yunnan. Although Yunnan's economy has made significant progress, the level of urbanization remains lows, and the township density is relatively sparse [35]. Yunnan is located in the Yunnan–Guizhou Plateau; and most of the areas are dominated by high mountains, deep valleys, and dense mountain streams where vertical differentiation in heat and water occurs as a result of changes in landform and altitude [36]. In addition, the precipitation in northwestern and central Yunnan has increased in recent years [37]. All of these conditions have contributed to making this study area one of the most geophysical hazard-prone regions in China.

**Figure 1.** The study area: (**a**) the distribution of flash floods in Yunnan Province; (**b**): the geographical position of Yunnan in China; (**c**): the different subregions of landcover in Yunnan **Figure 1.** The study area: (**a**) the distribution of flash floods in Yunnan Province; (**b**): the geographical position of Yunnan in China; (**c**): the different subregions of landcover in Yunnan Province.

Province.

#### *2.2. Selection and Pretreatment of Data*

*2.2. Selection and Pretreatment of Data*  The flash flood data used in this research are from the National Flash Flood Investigation and Evaluation Project, which was launched in 2013 to research the historical flash floods that occurred from 1949 to 2015 on a national scale, and the disaster areas were assumed as a point for collection [29]. In Yunnan, the number of flash floods was 3166, which we derived from the above-mentioned project. Current research has shown that the occurrence of flash flood is closely related to precipitation, topography, and human influence [14,21,29]. To explore the relationship between flash floods and the driving factors of flash floods, we selected the following factors: precipitation factors (unit: mm), elevation (ELE, unit: m), topographic relief (TR, unitless), slope (SLP, unit: °), normalized difference vegetation index (NDVI, unitless), population density (PD, unit: person/km2), and GDP (unit: yuan/km2). The precipitation factors included the 10 min precipitation (M10\_20), 60 min precipitation (M60\_20), 6 h precipitation (H6\_20), and 24 h precipitation (H24\_20) in 20-year return period, which reflect the impact of various precipitation intensities on flash floods. In addition, the station data of annual mean precipitation used to calculate the gravity center in The flash flood data used in this research are from the National Flash Flood Investigation and Evaluation Project, which was launched in 2013 to research the historical flash floods that occurred from 1949 to 2015 on a national scale, and the disaster areas were assumed as a point for collection [29]. In Yunnan, the number of flash floods was 3166, which we derived from the above-mentioned project. Current research has shown that the occurrence of flash flood is closely related to precipitation,topography, and human influence [14,21,29]. To explore the relationship between flash floods and the driving factors of flash floods, we selected the following factors: precipitation factors (unit:mm), elevation (ELE, unit: m), topographic relief (TR, unitless), slope (SLP, unit: ◦ ), normalized difference vegetation index (NDVI, unitless), population density (PD, unit: person/km2 ), and GDP (unit: yuan/km2 ). The precipitation factors included the 10 min precipitation (M10\_20), 60 min precipitation (M60\_20), 6 h precipitation (H6\_20), and 24 h precipitation (H24\_20) in 20-year return period, which reflect the impact of various precipitation intensities on flash floods. In addition, the station data of annual mean precipitation used to calculate the gravity center in Yunnan Province were acquired from the National Weather Service of China (http://www.cma.gov.cn/). Table 1 shows the source and resolution of all raw data sets.

Yunnan Province were acquired from the National Weather Service of China

(http://www.cma.gov.cn/). Table 1 shows the source and resolution of all raw data sets.

In this study, we interpolated precipitation raster data by the Inverse Distance Weighted in ArcGIS10.2 (ESRI, Inc., Redlands, CA, USA), which was based on the vector data of precipitation factors, and the final resolution was 1 km × 1 km. We calculated topographic relief using focal statistics in the ArcGIS 10.2 software, which was represented by elevation standard deviation based on the DEM data; the SLP also was generated by this data.

**Table 1.** Source and resolution of the raw data sets.


**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+

**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+ 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.


*4.3.4 Treatment*

*Visual Impairment and Blindness - What We Know and What We Have to Know*

Surgical debridement of the epithelium and base of the fungal keratitis is crucial in the management because it debulks the organisms and enhances drug penetration into cornea [79]. Surgery for fungal keratitis, ranging from lamellar or penetrating keratoplasty to evisceration or enucleation, plays a role as an adjunct to medical therapy for initial management and when medical therapy fails or impending corneal perforation [51, 61, 79]. The prognosis of fungal keratitis is worse than bacterial keratitis [80]. The course is favorable with medical treatment in 50—70% of cases. A surgery is required in 30 to 54% of cases [80]. These infections may lead to loss of the globe in 10 to 25% of cases [80]. High risk of developing corneal perforation and the need to undergo therapeutic penetrating keratoplasty (TPK) are due to infiltrate size of more than 6.6 mm, an infiltrate involving the posterior one-third of the stroma, and the presence of a hypopyon [73]. Unfortunately, recurrence keratitis can occur approximately 6–7% after therapeutic keratoplasty [81]. Hypopyon, corneal perforation, and corneal infection expanding to limbus and lens infection are predominant risk factors for the recurrence of fungal keratitis after corneal transplantation [81]. After therapeutic keratoplasty, systemic and topical antifungal treatments should be used for 2 weeks routinely and possibly for 6 to 8 weeks in high-risk cases [81]. Generally, if no typical signs of recurrence were present 2 weeks after surgery, low-concentration topical steroids may be adminis-

Herpes simplex virus (HSV) is a common cause of viral keratitis and the most common cause of unilateral infectious corneal blindness in the world [5, 9]. Varicellazoster and cytomegalovirus can also cause viral keratitis but are much less common [9]. The prevalence of viral keratitis was 0.11% in a recent population-based study [5]. The majority of corneal HSV-1 infection is not the outcome of primary ocular infection, but in response to reactivation of latent virus from the trigeminal ganglion [82]. However, recurrent corneal epithelial infection with HSV-1 can have stromal involvement known as herpes stromal keratitis (HSK), which can be necrotizing, nonnecrotizing, or a mix of both [82, 83]. One study with HSV stromal keratitis reported that disease was of the necrotizing type in 7%, nonnecrotizing in 88%, and a mix of the two in 5% [84]. In this review, we address only the herpes necrotizing stromal keratitis that may mimic infectious keratitis from other organisms.

Viral keratitis differs from bacterial and fungal keratitis in that it can become recurrent and chronic [9]. In necrotizing HSV stromal keratitis, necrosis, ulceration, and dense leukocytic infiltration of the stroma are present and often associated with an overlying epithelial defect and neovascularization [18, 83, 85]. The viral keratitis diagnosis is usually based on clinical findings [43] and diagnosis by exclusion. However, in atypical cases, the investigations such as tissue culture,

The risk of HSV reactivation can occur after excimer laser refractive surgery such as LASIK or PRK. The exposure to ultraviolet light during corneal collagen cross-linking

ELISA, and PCR may aid in the diagnostic confirmation [43].

**14**

tered with caution [81].

**4.3 Viral keratitis**

*4.3.1 Epidemiology*

*4.3.2 Manifestations*

*4.3.3 Risk factors*

Both immune and active viral replications are responsible for the disease pathogenesis [83]. In contrast to nonnecrotizing stromal keratitis where topical corticosteroid is the mainstay treatment, oral acyclovir is used to control the viral invasion and replication in cornea, while low-dose topical corticosteroids are given to control inflammation in necrotizing stromal keratitis [18]. Topical CsA administration can resolve stromal inflammation and neovascularization in 50 and 64% of cases, respectively [83]. Without timely and effective treatment, necrotizing HSV stromal keratitis can rapidly lead to corneal perforation [83]. Amniotic membrane transplantation onto the ocular surface promotes corneal epithelial healing and reduces stromal inflammation, angiogenesis, and scarring [83]. Various oral antiviral agents to treat active viral replication and prevent recurrences are available as mentioned below [86]:

1.Acyclovir: 800 mg, 3–5 times/day, 7–10 days

2.Valacyclovir: 1 g, 3 times per day, 7–10 days

3.Famciclovir: 500 mg, 2 times/day, 7–10 days

Data from the Herpetic Eye Disease (HEDS) study concluded that the HSV stromal keratitis patients who received 400 mg oral acyclovir twice per day for 12 months had reduced rate of recurrent HSV stromal keratitis by about 50%. The research about HSV vaccination is underway, and no vaccine is currently available [83, 86, 88].