**6. Suppression of postprandial blood glucose level**

Diabetics may develop serious complications such as retinopathy, nephropathy and neuropathy, in addition to myocardial infarction, cerebral infarction and so on [27, 30], even though the initial subjective symptoms may be minor. Ca-Alg is known to suppress the postprandial increase of blood glucose, and therefore may be helpful in preventing lifestyle-related diseases such as diabetes. Starch is initially decomposed to maltose in the gastrointestinal tract, mainly by α-amylase, before decomposition by α-glucosidase (maltase) to glucose. Transporters located on the cell membrane surface absorb glucose. Ca-Alg should inhibit at least one of these processes to suppress blood glucose levels since it is not absorbed from the gastrointestinal tract. We therefore chose to investigate which of these processes is inhibited by Ca-Alg, and the optimal amount and particle size of Ca-Alg in the diet required to suppress the postprandial increase of blood glucose in rats [25].

We first examined the effect of Ca-Alg concentration on α-glucosidase activity, and observed no significant change compared to the control. On the other hand, the amount of glucose adsorbed on Ca-Alg increased with increasing initial glucose concentration until it reached saturation. The direct binding affinity of glucose for

Ca-Alg was low, and the values of the permeation coefficient of glucose showed no significant change. Moreover, it has been reported that the addition of Alg (polysaccharides) increases the viscosity of starch suspension, and there is a positive correlation between apparent viscosity and the decrease of starch digestion [26]. We speculate that Ca-Alg interferes physically with contact between α-glucosidase and maltose by increasing the viscosity of the intestinal contents. It was our assumption that blood glucose suppression by Ca-Alg is the result of decreased efficiency in starch digestion due to the inhibition of α-glucosidase. This may be as a result of increased viscosity of the gastrointestinal contents. We next aimed to define the optimum amount and particle size of Ca-Alg in the diet for the suppression of postprandial blood glucose levels in rats [25]. A diet containing starch together with varying amounts and particle sizes of Ca-Alg was orally administered to rats randomized into five groups: starch with no Ca-Alg (control), or with Ca-Alg (3%; 270 mesh pass, 5%; 270 mesh pass, 5%; 150 mesh pass, or 5%; 80 mesh pass) (*n* = 3–4 each). Blood was sampled and the glucose level was measured before administration (Co). Water was added to the five types of starch with or without Ca-Alg and the mixtures were orally administered to conscious rats. Blood glucose levels were measured and the change in blood glucose level (ΔCn) was calculated. Starch containing 5% Ca-Alg (particle size; 270 mesh pass) significantly decreased the ΔCmax and ΔAUC, compared to starch containing no Ca-Alg. However, 3% 270-mesh-pass Ca-Alg, or 5% 150- or 80-mesh-pass Ca-Alg produced no significant difference in ΔCmax or ΔAUC compared with the 0% Ca-Alg diet (**Figure 7**) [25].

The in vivo study determined 5% of 270-mesh-pass Ca-Alg to be the most efficient combination of amount and particle size in the suppression of postprandial increases in blood glucose. Compared with 0% Ca-Alg, significant decreases were observed in both ΔCmax and ΔAUC, confirming a decrease in both postprandial peak glucose level and the full amount of glucose absorbed within 2 hours of ingestion. It seems likely that the magnitude of action would depend on the surface area of Alg.

Our results support the idea that Ca-Alg increases the viscosity of the gastrointestinal contents, depending upon the surface area of the administered gel. The gel is expected to interfere with the interaction between α-glucosidase and maltose, thereby suppressing the production of glucose, and preventing a sharp rise in blood glucose level. Various products have been reported to moderate glucose absorption; for example, indigestible dextrin has been confirmed to suppress the postprandial increase in blood glucose level by inhibiting α-glucosidase activity [28]. It seems

#### **Figure 7.**

*Effect of starch diets containing Ca-Alg on blood glucose level in rats [25]. Circles: ΔCmax, the difference between the maximum blood glucose level Cmax and the pre-feeding blood glucose level C0. Bars: ΔAUC, the difference between the area under the blood glucose level-time curve from 0 to 120 min after ingestion and the baseline value C0. The data represent means ± S.D., n = 3 or 4. \* p < 0.05, compared with control.*

**29**

grading system (**Figure 9**).

**Figure 8.**

*Pharmacological Effects and Utility as a Food Additive of Calcium Alginate*

reasonable to consider that Ca-Alg works similarly. Moreover, it was found that 5% of 270-mesh-pass Ca-Alg was the most effective combination of amount and particle size to suppress the postprandial increase of blood glucose (**Figure 8**). To analyze the effect of Ca-Alg on the postprandial increase of blood glucose, a prospective, randomized, double-blind, 3-group, 3-phase crossover study was undertaken among healthy Japanese adult subjects [29]. Traditional Japanese udon noodles were selected, and blood glucose levels were measured after ingestion of Ca-Alg-free udon, and noodles containing 5 or 8% Ca-Alg. We also examined the effect of Ca-Alg on other chemical parameters in plasma or serum. Healthy male and female volunteers of 20 years of age or older were divided into three groups so that the average BMI values in the groups were similar. Each group ingested one of the three types of noodles containing 0 (control), 5 or 8% Ca-Alg (weight % to flour and modified starch). Blood was collected by fingertip puncture for blood glucose measurement prior to feeding and after ingestion. The blood glucose level was measured twice at each point using a simple blood glucose meter, and the average value was calculated. After eating the noodles, subjects were given a tasting questionnaire to evaluate "chewiness", "thickness" and "favorability" of the noodles in a 5-point

*A possible mechanism of blood glucose level-lowering effect of Ca-Alg [25].*

Noodles containing 5 or 8% Ca-Alg caused a significant decrease in ΔCmax compared to control noodles. Moreover, ΔAUC also showed a significant decrease in both groups. No significant difference in the time of maximum blood glucose level (Tmax) was observed among the three groups. This is consistent with previous findings [31] and is similar to findings with α-glucosidase inhibitors, [32, 33] except miglitol [34]. These results indicate that Ca-Alg suppresses the postprandial increase in blood glucose and reduces the total absorption amount of glucose, but without delaying the absorption. Thus, our previous finding that 5% Ca-Alg had a

blood glucose-suppressing effect in rats [25] was reproduced in humans.

As for blood biochemical parameters, no significant difference in the amount of Ca change at 30 min after noodle feeding (ΔCa30min) was found between the 5 and 8% Ca-Alg groups compared to the control, but ΔCa at 120 min (ΔCa120 min) showed a significant increase in both groups. In addition, ΔT-Cho30 min showed a slight tendency to decrease in both groups, and ΔT-Cho120 min was slightly decreased in the 8% Ca-Alg group. There was no significant change in other blood test values. We found that the blood Ca concentration at 120 min after eating 5 or 8% Ca-Alg-containing noodles remained within the normal range, 8.5–10.4 mg/dL, [35]

*DOI: http://dx.doi.org/10.5772/intechopen.86861*

*Pharmacological Effects and Utility as a Food Additive of Calcium Alginate DOI: http://dx.doi.org/10.5772/intechopen.86861*

#### **Figure 8.**

*Alginates - Recent Uses of This Natural Polymer*

Ca-Alg was low, and the values of the permeation coefficient of glucose showed no significant change. Moreover, it has been reported that the addition of Alg (polysaccharides) increases the viscosity of starch suspension, and there is a positive correlation between apparent viscosity and the decrease of starch digestion [26]. We speculate that Ca-Alg interferes physically with contact between α-glucosidase and maltose by increasing the viscosity of the intestinal contents. It was our assumption that blood glucose suppression by Ca-Alg is the result of decreased efficiency in starch digestion due to the inhibition of α-glucosidase. This may be as a result of increased viscosity of the gastrointestinal contents. We next aimed to define the optimum amount and particle size of Ca-Alg in the diet for the suppression of postprandial blood glucose levels in rats [25]. A diet containing starch together with varying amounts and particle sizes of Ca-Alg was orally administered to rats randomized into five groups: starch with no Ca-Alg (control), or with Ca-Alg (3%; 270 mesh pass, 5%; 270 mesh pass, 5%; 150 mesh pass, or 5%; 80 mesh pass) (*n* = 3–4 each). Blood was sampled and the glucose level was measured before administration (Co). Water was added to the five types of starch with or without Ca-Alg and the mixtures were orally administered to conscious rats. Blood glucose levels were measured and the change in blood glucose level (ΔCn) was calculated. Starch containing 5% Ca-Alg (particle size; 270 mesh pass) significantly decreased the ΔCmax and ΔAUC, compared to starch containing no Ca-Alg. However, 3% 270-mesh-pass Ca-Alg, or 5% 150- or 80-mesh-pass Ca-Alg produced no significant difference in ΔCmax or ΔAUC compared with the 0% Ca-Alg diet (**Figure 7**) [25]. The in vivo study determined 5% of 270-mesh-pass Ca-Alg to be the most efficient combination of amount and particle size in the suppression of postprandial increases in blood glucose. Compared with 0% Ca-Alg, significant decreases were observed in both ΔCmax and ΔAUC, confirming a decrease in both postprandial peak glucose level and the full amount of glucose absorbed within 2 hours of ingestion. It seems likely that the magnitude of action would depend on the surface area of Alg. Our results support the idea that Ca-Alg increases the viscosity of the gastrointestinal contents, depending upon the surface area of the administered gel. The gel is expected to interfere with the interaction between α-glucosidase and maltose, thereby suppressing the production of glucose, and preventing a sharp rise in blood glucose level. Various products have been reported to moderate glucose absorption; for example, indigestible dextrin has been confirmed to suppress the postprandial increase in blood glucose level by inhibiting α-glucosidase activity [28]. It seems

*Effect of starch diets containing Ca-Alg on blood glucose level in rats [25]. Circles: ΔCmax, the difference between the maximum blood glucose level Cmax and the pre-feeding blood glucose level C0. Bars: ΔAUC, the difference between the area under the blood glucose level-time curve from 0 to 120 min after ingestion and the* 

*p < 0.05, compared with control.*

*baseline value C0. The data represent means ± S.D., n = 3 or 4. \**

**28**

**Figure 7.**

*A possible mechanism of blood glucose level-lowering effect of Ca-Alg [25].*

reasonable to consider that Ca-Alg works similarly. Moreover, it was found that 5% of 270-mesh-pass Ca-Alg was the most effective combination of amount and particle size to suppress the postprandial increase of blood glucose (**Figure 8**).

To analyze the effect of Ca-Alg on the postprandial increase of blood glucose, a prospective, randomized, double-blind, 3-group, 3-phase crossover study was undertaken among healthy Japanese adult subjects [29]. Traditional Japanese udon noodles were selected, and blood glucose levels were measured after ingestion of Ca-Alg-free udon, and noodles containing 5 or 8% Ca-Alg. We also examined the effect of Ca-Alg on other chemical parameters in plasma or serum. Healthy male and female volunteers of 20 years of age or older were divided into three groups so that the average BMI values in the groups were similar. Each group ingested one of the three types of noodles containing 0 (control), 5 or 8% Ca-Alg (weight % to flour and modified starch). Blood was collected by fingertip puncture for blood glucose measurement prior to feeding and after ingestion. The blood glucose level was measured twice at each point using a simple blood glucose meter, and the average value was calculated. After eating the noodles, subjects were given a tasting questionnaire to evaluate "chewiness", "thickness" and "favorability" of the noodles in a 5-point grading system (**Figure 9**).

Noodles containing 5 or 8% Ca-Alg caused a significant decrease in ΔCmax compared to control noodles. Moreover, ΔAUC also showed a significant decrease in both groups. No significant difference in the time of maximum blood glucose level (Tmax) was observed among the three groups. This is consistent with previous findings [31] and is similar to findings with α-glucosidase inhibitors, [32, 33] except miglitol [34]. These results indicate that Ca-Alg suppresses the postprandial increase in blood glucose and reduces the total absorption amount of glucose, but without delaying the absorption. Thus, our previous finding that 5% Ca-Alg had a blood glucose-suppressing effect in rats [25] was reproduced in humans.

As for blood biochemical parameters, no significant difference in the amount of Ca change at 30 min after noodle feeding (ΔCa30min) was found between the 5 and 8% Ca-Alg groups compared to the control, but ΔCa at 120 min (ΔCa120 min) showed a significant increase in both groups. In addition, ΔT-Cho30 min showed a slight tendency to decrease in both groups, and ΔT-Cho120 min was slightly decreased in the 8% Ca-Alg group. There was no significant change in other blood test values. We found that the blood Ca concentration at 120 min after eating 5 or 8% Ca-Alg-containing noodles remained within the normal range, 8.5–10.4 mg/dL, [35]

#### **Figure 9.**

*Changes in blood glucose level (ΔC) after eating test noodles to volunteers [30]. The data represent means ± S.D., n = 15.*

but was significantly increased compared with the value in the control noodle group, suggesting that Ca derived from Ca-Alg was absorbed into the body.

The recommended amount of Ca intake in adults to help prevent diseases such as osteoporosis is 600–900 mg/day.[35] Since the amounts of Ca in noodles containing 8% Ca-Alg and 5% Ca-Alg would be 500 and 320 mg, respectively, about half of the recommended daily intake might be provided by these noodles. The upper limit of tolerable daily Ca intake for Japanese adults is 2500 mg, [35] so even if these noodles were eaten three times a day, the upper limit would not be reached. Thus, the likelihood of excessive Ca intake appears to be low.

Many substances are known to suppress glucose absorption; for example, indigestible dextrin has been shown to inhibit α-glucosidase. Our work showed that Ca-Alg also inhibits α-glucosidase activity [25], and its effect on blood glucose level was similar to or more potent than that of indigestible dextrin [36]. On the other hand, α-glucosidase inhibitors have side effects such as abdominal distention and flatus. Ingestion of noodles containing 8% Ca-Alg was expected to show an α-glucosidaseinhibitory effect equal to about 1/40th that of a single dose of acarbose [21]. Therefore, it is considered that the likelihood of side effects arising from α-glucosidase inhibition due to ingestion of noodles containing Ca-Alg is extremely low.

Our results raise the interesting possibility that the introduction of food ingredients containing Ca-Alg into the regular diet may be helpful in preventing lifestylerelated diseases, particularly diabetes and osteoporosis, without adversely affecting individual eating habits.

### **7. Conclusion**

Alg, especially Ca-Alg, has a number of beneficial physiological effects. For example, we have shown that Ca-Alg increases excretion and reduces the absorption of toxic heavy metals such as Sr. and Cs in rats. Moreover, Ca-Alg decreases the blood Cho and TG levels, as well as reducing plasma levels of uric acid, allantoin and BUN levels in rats. Further, Ca-Alg moderated the postprandial increase of blood glucose level in rats and humans. Ca-Alg has been confirmed as safe for use as a food additive, and is superior to Na-Alg, because there is no risk of hypertension

**31**

food (**Figure 10**).

**Figure 10.**

**Acknowledgements**

**Conflict of interest**

Research (KAKENHI) Grant Number 25560062.

*Revealed functions and future development of Ca-Alg.*

have no potential conflicts of interest.

*Pharmacological Effects and Utility as a Food Additive of Calcium Alginate*

due to increased sodium intake. In addition, Ca-Alg may also have a preventive effect on osteoporosis. Ca-Alg is convenient to take, because it is effective in solid form, and it appears to be suitable for long-term use as an additive or functional

Lifestyle-related diseases associated with high calorie intake and insufficient exercise have become a significant social problem [37, 38], and may lead to the development of cancer, heart disease and cerebrovascular disease, which are major causes of death [13–17, 23, 39, 40]. It will be interesting to examine further whether Ca-Alg may also offer potential benefits in relation to lifestyle-related diseases [36].

This work was supported by JSPS Grant-in-Aid for Challenging Exploratory

Fumiyoshi Kasahara is an employee of Kimica Corporation. The other authors

*DOI: http://dx.doi.org/10.5772/intechopen.86861*

*Pharmacological Effects and Utility as a Food Additive of Calcium Alginate DOI: http://dx.doi.org/10.5772/intechopen.86861*

*Alginates - Recent Uses of This Natural Polymer*

but was significantly increased compared with the value in the control noodle group,

The recommended amount of Ca intake in adults to help prevent diseases such as osteoporosis is 600–900 mg/day.[35] Since the amounts of Ca in noodles containing 8% Ca-Alg and 5% Ca-Alg would be 500 and 320 mg, respectively, about half of the recommended daily intake might be provided by these noodles. The upper limit of tolerable daily Ca intake for Japanese adults is 2500 mg, [35] so even if these noodles were eaten three times a day, the upper limit would not be reached. Thus, the likeli-

Many substances are known to suppress glucose absorption; for example, indigestible dextrin has been shown to inhibit α-glucosidase. Our work showed that Ca-Alg also inhibits α-glucosidase activity [25], and its effect on blood glucose level was similar to or more potent than that of indigestible dextrin [36]. On the other hand, α-glucosidase inhibitors have side effects such as abdominal distention and flatus. Ingestion of noodles containing 8% Ca-Alg was expected to show an α-glucosidaseinhibitory effect equal to about 1/40th that of a single dose of acarbose [21]. Therefore, it is considered that the likelihood of side effects arising from α-glucosidase inhibition

Our results raise the interesting possibility that the introduction of food ingredients containing Ca-Alg into the regular diet may be helpful in preventing lifestylerelated diseases, particularly diabetes and osteoporosis, without adversely affecting

Alg, especially Ca-Alg, has a number of beneficial physiological effects. For example, we have shown that Ca-Alg increases excretion and reduces the absorption of toxic heavy metals such as Sr. and Cs in rats. Moreover, Ca-Alg decreases the blood Cho and TG levels, as well as reducing plasma levels of uric acid, allantoin and BUN levels in rats. Further, Ca-Alg moderated the postprandial increase of blood glucose level in rats and humans. Ca-Alg has been confirmed as safe for use as a food additive, and is superior to Na-Alg, because there is no risk of hypertension

suggesting that Ca derived from Ca-Alg was absorbed into the body.

*Changes in blood glucose level (ΔC) after eating test noodles to volunteers [30]. The data represent* 

due to ingestion of noodles containing Ca-Alg is extremely low.

hood of excessive Ca intake appears to be low.

individual eating habits.

**7. Conclusion**

**Figure 9.**

*means ± S.D., n = 15.*

**30**

**Figure 10.** *Revealed functions and future development of Ca-Alg.*

due to increased sodium intake. In addition, Ca-Alg may also have a preventive effect on osteoporosis. Ca-Alg is convenient to take, because it is effective in solid form, and it appears to be suitable for long-term use as an additive or functional food (**Figure 10**).

Lifestyle-related diseases associated with high calorie intake and insufficient exercise have become a significant social problem [37, 38], and may lead to the development of cancer, heart disease and cerebrovascular disease, which are major causes of death [13–17, 23, 39, 40]. It will be interesting to examine further whether Ca-Alg may also offer potential benefits in relation to lifestyle-related diseases [36].
