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Gelidium elegans Regulates Blood Glucose Homeostasis in ICR Mice

Jia Choi, Kui-Jin Kim, Eun-Jeong Koh, Young-Jin Seo, Boo-Yong Lee*

Department of Food Science and Biotechnology, College of Life Science, CHA University, Seongnam, Kyonggi, Republic of Korea

Abstract: Gelidium elegans has been reported to improve metabolic function, but it has not been studied in non-obese mice with glucose tolerance. To evaluate the effect of Gelidium elegans (50 or 200 mg/kg doses) on glucose homeostasis, an oral glucose tolerance test (OGTT), oral maltose tolerance test (OMTT), and insulin tolerance test (ITT) were performed. The non-obese group of mice that was administered 200 mg/kg Gelidium elegans had significantly lowered blood glucose levels. By revealing that Gelidium elegans may improve glucose homeostasis, this study expands our understanding of the anti-diabetic effect of Gelidium elegans and its biological importance.

Keywords: Gelidium elegans, Gelidium amansii, Hyperglycemia, Diabetes, Glucose absorption

Citation: Jia Choi, Kui-Jin Kim, Eun-Jeong Koh, Young-Jin Seo, Boo-Yong Lee, Gelidium elegans Regulates Blood Glucose Homeostasis in ICR Mice. Journal of Food and Nutrition Research, 5 (4). 274-280. January 2017. doi:10.12691/jfnr-5-4-9

1. Introduction

Hyperglycemia is characterized by an excessive amount of blood glucose and is often observed in obese and diabetic patients [1,2]. Hyperglycemia is known to cause numerous hematogenous-associated complications, such as cardiovascular disease (CVD), oxidative stress, and ketoacidosis [3,4,5]. To maintain the homeostasis of hyperglycemic conditions outside of the cells, glucose moves into the cell via sodium-dependent glucose co-transporter (SGLT) and facilitative glucose transporters (GLUTs) [6]. SGLT works against an electrochemical gradient in which glucose is transported from the intestines or nephrons by the Na+-K+ ATPase pump [7,8]. GLUTs act as glucose carriers and are mediated by an energy-independent glucose transport process that is common to almost all cell [9,10]. GLUT4 is the most abundant type in muscle and adipose tissues and is essential for glucose-stimulated insulin secretion to control blood glucose homeostasis [11,12]. Stimulation of GLUT4 mediates glucose translocation to the plasma membrane; hence, it mediates glucose uptake in muscles.

For many decades, several pharmaceutical compounds have been developed to prevent the development of hyperglycemia and its associated diseases, including obesity and diabetes. Pioglitazone, metformin, and rosiglitazone are well known Food and Drug Administration (FDA)-approved anti-hyperglycemic pharmaceutical compounds [13]. These anti-hyperglycemic compounds decrease excessive amounts of blood glucose through the peripheral cell recognition of insulin as well as activation of the GLUT4 signaling pathway [14,15]. Although anti-hyperglycemic compounds have a beneficial effect on the regulation of blood glucose homeostasis, pioglitazone, metformin, and rosiglitazone have been shown to have a number of adverse effects, such as liver toxicity, lactic acidosis, and diarrhea [16]. Increasing the impact of novel therapy strategies and/or developing effective anti-hyperglycemic compounds without adverse effects is therefore necessary.

Recently, several studies reported that the phytochemicals and polyphenols extracted from fruits, vegetables, and edible seaweeds stimulate glucose uptake via modulation of the GLUT4 signaling pathway and insulin sensitivity both in vitro and in human clinical trials [17,18,19]. In particular, previous studies revealed that seaweed-derived phytochemicals and dietary seaweed attenuate blood glucose levels in vivo [20,21], indicating that seaweed might be a suitable resource for ameliorating blood glucose levels without adverse effects.

Gelidium elegans, previously known as Gelidium amansii, is an edible seaweed native to the Asian Pacific Region [22,23]. Along with other group, we have reported the bioactivity of Gelidium elegans, including its anti-oxidative stress, anti-lipogenesis, and anti-obesity properties [23,24,25]. In addition, Kang et al. suggested the potential effect of Gelidium elegans on blood glucose regulation in vivo [25]. Although these reports potentially indicate that Gelidium elegans regulates the level of hematogenous-circulating glucose and diabetes, they have not yet been studied. In the present study, we therefore investigated the potential effect of Gelidium elegans on anti-diabetes activity in vivo. To determine the anti-diabetic effect of Gelidium elegans, we performed three independent assays, including an oral glucose tolerance test (OGTT), oral maltose tolerance test (OMTT), and insulin tolerance test (ITT).

2. Materials and Methods

2.1. Reagents

Gelidium elegans extract was provided by NEWTREE Inc. (Seongnam, Kyonggi, South Korea). The composition of the Gelidium elegans extract is described in Table 1. Glucose, insulin, and methylcellulose were purchased from Sigma-Aldrich (St, Louis, MO, USA). Metformin was purchased from Cayman Chemical (Ann Arbor, MI, USA).

Table 1. The composition of Gelidium elegans extract [26]

2.2. Animals and Treatment

All mice were housed in a specific pathogen-free facility at CHA University, Seongnam, Republic of Korea. The project was approved by the Institutional Animal Care and Use Committee of CHA University (IACUC Approval Number 150075). Five-week-old male ICR mice were purchased from Orient Bio Co. (Kapyong, Republic of Korea).

Mice were provided a NIH-07 rodent chow diet (Zeigler Brothers, Gardners, PA, USA). Animals were acclimated to temperature (20-24C) and humidity (44.5-51.8 %) with a 12-h light/dark cycle for 1 week prior to use. After the 1-week adaptation period, mice were randomly divided into twelve group. Each group consisted of 6 mice. Gelidium elegans and/or metformin were provided through oral administration.

2.3. Oral Glucose Tolerance Test

After 5 weeks, mice were randomly divided into four group (n=6 per group). An OGTT was performed following a 12-h fast. There were four group of mice. The first group was orally administered 1.5 g/kg glucose. Two group were administered 1.5 g/kg glucose and 50 or 200 mg/kg Gelidium elegans. The fourth group (positive control) was orally administered 1.5 g/kg glucose and 140 mg/kg metformin. Tail-vein blood samples were collected at 0 (before the glucose challenge), 30, 60, 90, 120, and 150 min.

2.4. Oral Maltose Tolerance Test

After 5 weeks, mice were randomly divided into four group (n=6 per group). An OMTT was performed following a 12 h fast. There were four group of mice. The first group was orally administered 3 g/kg maltose. Two group were administered 3 g/kg maltose and 50 or 200 mg/kg Gelidium elegans. The fourth group (positive control) was orally administered 3 g/kg maltose and 140 mg/kg metformin. Tail-vein blood samples were collected at 0 (before the glucose challenge), 30, 60, 90, and 120 min.

2.5. Insulin Tolerance Test

After 5 weeks, mice were randomly divided into four group (n=6 per group). An ITT was performed following a 12 h fast. There were four group of mice. The first group was intraperitoneally challenged with 0.05 U/kg insulin. Two group were intraperitoneally challenged with 0.05 U/kg insulin, and three min afterwards, they were orally administered 50 or 200 mg/kg Gelidium elegans. As a negative control (fourth group), we used mice that did not receive insulin. Tail-vein blood samples were collected at 0 (before the glucose challenge), 30, 60, 90, 120, and 150 min.

2.6. Statistical Analysis

All statistical analyses were performed using the Statistical Package for Social Sciences version 12.0 (SPSS, Chicago, IL, USA). A one-way analysis of variance (ANOVA) was used for comparisons among the group. Significant differences between the mean values were assessed using Duncan’s test. p values less than 0.05 were considered statistically significant.

3. Results and Discussion

3.1. Oral Glucose Tolerance Test

Hyperglycemia is a metabolic disorder characterized by an excessive amount of circulating glucose in the blood plasma [27,28]. OGTT reflects the degree of glucose tolerance and can be used to diagnose hyperglycemia and diabetes [29,30]. Therefore, we performed OGTT to evaluate the effects of Gelidium elegans on hyperglycemia.

All mice were fasted for 12 h. The control group was administered 1.5 g/kg glucose. Each of the two independent group (n=6) received oral administrations of 50 or 200 mg/kg Gelidium elegans in addition to 1.5 g/kg glucose. The positive control group was orally administered 1.5 g/kg glucose and 140 mg/kg metformin.

To evaluate the effect of Gelidium elegans on glucose tolerance, blood samples were collected from the tail veins. Blood glucose levels were measured over 2 h. As shown in Figure 1A, all group had glucose levels within the normal range of 106.0 ± 14.0 mg/dL at 0 min.

Insulin release in response to a glucose load occurs within the first 15-30 min and is responsible for limiting the initial rise in glucose levels upon meal ingestion [31]. The glucose-only control group reached a glucose level of 176.0 ± 20.2 mg/dL at 30 min. On the other hand, the group that received 50 or 200 mg/kg Gelidium elegans had a significantly suppressed rise in blood glucose, with glucose levels of 149.0 ± 18.5 mg/dL and 136.0 ± 36.3 mg/dL at 30 min, respectively. In comparison with the control group, the group that was administered 200 mg/kg Gelidium elegans significantly decreased their blood glucose levels by approximately 10.4 % at 30 min.

At 60 min, the glucose level of the control group reached 172.2 ± 31.4 mg/dL. On the other hand, the group that received 50 or 200 mg/kg Gelidium elegans had a significantly suppressed the rise in blood glucose, with glucose levels of 154.7 ± 13.7 mg/dL and 141.8 ± 23.4 mg/dL, respectively, when compared to the control group at 60 min.

The group that were administered 50 or 200 mg/kg of Gelidium elegans exhibited glucose levels of 143.7 ± 19.6 mg/dL and 135.8 ± 28.9 mg/dL at 90 min, respectively. In comparison with the control group, the group that received 200 mg/kg Gelidium elegans had blood glucose levels that were significantly decreased by approximately 12.9 % at 90 min.

At 120 min, the group that were administered 50 or 200 mg/kg Gelidium elegans had significant attenuation of blood glucose (glucose levels of 126.2 ± 28.9 mg/dL and 132.3 ± 27.7 mg/dL, respectively) when compared to the control group. The group that received 140 mg/kg metformin displayed significant attenuation at 30, 60, 90, 120, and 150 min when compared to the control group. By the 150-min time period, the glucose levels of all group had declined to within the normal fasting range of 114.3 ± 30.2 mg/dL. When compared with the control group, the group that received 200 mg/kg Gelidium elegans showed glucose levels that were significantly decreased from their fasting level at 30, 60, 90, and 120 min.

Area under the curve (AUC) is a useful measure for identifying the average concentration over a time interval [32]. We therefore calculated the AUC by the trapezoidal rule to evaluate the OGTT of Gelidium elegans. As shown Figure 1B, AUC glucose levels also correlated with Figure 1A.

In the current study, we found that Gelidium elegans can impact glucose homeostasis in ICR mice. In particular, the group that was administered 200 mg/kg Gelidium elegans had a significant decrease in blood glucose levels after glucose loading. Several studies have reported that phytochemical compounds, such as those found in flavonoid-rich foods, have the potential to regulate glucose homeostasis [33].

To maintain the level of blood glucose within a normal range, there are two major strategies involving the regulation of insulin resistance in peripheral tissues and the regulation of insulin production in pancreatic tissue. When the proper concentration of insulin is insufficient to stimuli the glucose uptake from blood stream into peripheral tissues causes insulin resistance [34]. The critical initial steps in the development of insulin resistance include inactivation of insulin receptor, insulin receptor substrate 1 (IRS1), and IRS2 [35].

It have been shown that flavonoid-rich foods ameliorate insulin resistance in diabetes model [36,37,38,39]. In particular, blue berry has been used traditional medicine for diabetic patients due to its biological activity that promote to decrease insulin resistance in peripheral tissues [40]. In addition, curcumin decreased the level of blood glucose through the suppression of glucose production in hepatic tissue or the attenuation of insulin resistance peripheral tissues [41].

Oral administrations of 50 or 200 mg/kg Gelidium elegans with glucose had significant attenuation of blood glucose when compared to control group. These results indicate that Gelidium elegans may be expected to increase the peripheral and hepatic insulin sensitivity through activating IRS expression.

Flavonoid-rich foods can also reduce glucose uptake by modifying the activity of other carbohydrate-digestive enzymes, such as α-glucosidase [42,43]. Therefore, we performed an OMTT to indirectly investigate whether Gelidium elegans inhibits α-glucosidase.

3.2. Oral Maltose Tolerance Test

Maltose is added to a wide variety of foods, including candies, cereal bars, bagels, pies, sweet potatoes, and honey [44]. Maltose is a disaccharide composed of two glucose molecules and is obtained from beverages [45]. After food intake, the enzymes maltase and α-glucosidase break down maltose into two glucose molecules, which results in an increased blood glucose concentration in the small intestine [46,47,48]. α-glucosidase inhibitor, such as miglitol, lower blood glucose levels after a meal by interfering with the conversion of disaccharides to monosaccharides in the small intestine [48,49,50]. Therefore, we performed OMTT to investigate whether Gelidium elegans inhibits the α-glucosidase activity.

Prior to performing the OMTT, all mice were fasted for 12 h [51,52]. Four group were tested: a control group that received 3 g/kg maltose, a reference drug group that received 3 g/kg maltose and 140 mg/kg metformin, and group that received 3 g/kg maltose and two different doses of Gelidium elegans (oral administrations of 50 or 200 mg/kg). Blood samples were collected from the tail veins at 0, 30, 60, 90, and 120 min after maltose loaded. All group showed the glucose levels within the normal range of 114.3 ± 12.1 mg/dL at 0 min. As shown Figure 2A, the group that received 50 or 200 mg/kg Gelidium elegans exhibited glucose levels of 134.0 ± 11.9 mg/dL and 122.4 ± 7.5 mg/dL at 60 min, respectively. In comparison to the control group, the group that received 3 g/kg maltose with 200 mg/kg Gelidium elegans had a significant decrease in blood glucose levels of approximately 10.4 % at 60 min. The group that received 50 or 200 mg/kg Gelidium elegans exhibited glucose levels of 127.4 ± 10.6 mg/dL and 123.6 ± 14.7 mg/dL at 120 min, respectively. In comparison with the control group, the group that received 200 mg/kg Gelidium elegans had a significant decrease in blood glucose levels of approximately 12.9 % at 120 min. The group that was administered 140 mg/kg metformin showed significant attenuation at 30, 60, 90, and 120 min compared to the control group. Therefore, we calculated the area above the axis minus the area below the axis (in their respective coordinates) to evaluate the OMTT of Gelidium elegans. As shown Figure 2B, AUC maltose levels also correlated with Figure 2A.

The group that were administered 50 or 200 mg/kg Gelidium elegans had significant attenuation of blood glucose in OMTT when compared to control group. Certainly, 50 mg/kg Gelidium elegans was sufficient to reduce the level of blood glucose. These results indicate that Gelidium elegans may be expected to inhibit the activity of α-glucosidase in the intestines.

Although we sought that Gelidium elegans might suppress the insulin resistance and α-glucosidase activity (Figure 1A, Figure 1B, Figure 2A, and Figure 2B) however it is still remain unclear whether Gelidium elegans stimulates the production or sensitivity of insulin in vivo. To examine whether Gelidium elegans affect the sensitivity or production of insulin in vivo, we therefore performed an ITT.

Figure 1. Gelidium elegans improves glucose tolerance in ICR mice

Figure 2. Plasma glucose during oral maltose tolerance test in ICR mice with Gelidium elegans supplement

3.3. Insulin Tolerance Test

Hyperglycemia and diabetic patients with insulin resistance occur with critical metabolic syndromes, including visceral obesity, hypertension, dyslipidemia, and IGT [53,54]. Metformin, a representative insulin-sensitizing drug, improves insulin sensitivity [55,56]. An ITT is the most commonly used method for estimating insulin resistance by measuring blood glucose levels [57,58,59]. Therefore, we performed an ITT to investigate whether Gelidium elegans improves insulin resistance in blood glucose levels.

Prior to an ITT, mice were fasted for 12 h [51,52]. Four group were tested: a negative control (non-insulin) group, a control group that received 0.05 U/kg insulin, and two group that received 0.05 U/kg insulin along with dose dependent of 50 or 200 mg/kg Gelidium elegans by oral administration. Blood samples were collected from the tail veins at 0, 30, 60, 90, 120, and 150 min. Prior to performing the ITT, all mice were fasted for 12 h. All group showed glucose levels within the normal range of 107.3 ± 13.1 mg/dL. As shown in Figure 3A, the group that were administered 50 or 200 mg/kg Gelidium elegans exhibited glucose levels of 70.6 ± 16.9 mg/dL and 67.6 ± 3.2 mg/dL at 60 min, respectively. In comparison to the control group, the group that received 0.05 U/kg insulin with 200 mg/kg Gelidium elegans had a significant decrease in blood glucose levels of approximately 18.4 % at 60 min. The group that received 50 or 200 mg/kg Gelidium elegans exhibited glucose levels of 69.0 ± 14.8 mg/dL and 69.4 ± 6.5 mg/dL at 90 min, respectively. In comparison with the control group, the group that was administered 0.05 U/kg insulin with 200 mg/kg Gelidium elegans had a significant decrease in blood glucose levels of approximately 24.7 % at 90 min. The group that was administered 50 or 200 mg/kg of Gelidium elegans exhibited glucose levels of 80.8 ± 10.3 mg/dL and 84.0 ± 8.7 mg/dL at 120 min, respectively. In comparison to the control group, the group that received 0.05 U/kg insulin with 200 mg/kg Gelidium elegans had a significant decrease in blood glucose levels of approximately 14.3 % at 120 min. The group that received 50 or 200 mg/kg Gelidium elegans exhibited glucose levels of 92.6 ± 21.1 mg/dL and 91.6 ± 14.5 mg/dL at 150 min, respectively. In comparison with the control group, the group that received 0.05 U/kg insulin with 200 mg/kg Gelidium elegans had a significantly decrease in blood glucose levels of approximately 26.6 % at 150 min. There was no significant difference in the negative control group’s glucose attenuation at 30, 60, 90, and 120 min. This study has shown that insulin sensitivity can be attributed to Gelidium elegans. We therefore calculated the area above the axis minus the area below the axis (in their respective coordinates) to evaluate the ITT of Gelidium elegans. As shown Figure 3B, AUCinsulin levels also correlated with Figure 3A.

Figure 3. Plasma glucose during insulin tolerance test in ICR mice with Gelidium elegans supplement

Flavonoids may exert beneficial effects in diabetes by enhancing insulin secretion and suppressing hyperglycemia through regulation of glucose metabolism. Resveratrol attenuate hyperglycemia through the stimulation of IRS and GLUT4 proteins in diabetes model [60].

Administered insulin with 50 or 200 mg/kg Gelidium elegans had significant attenuation of blood glucose in ITT when compared to control group. These results indicate that Gelidium elegans may partially reflect an increase in the production of insulin from pancreatic tissues or the stimulation of protein kinase B (Akt) and GLUT4 protein in peripheral tissues. In addition, this experiment might imply that Gelidium elegans has anti-hyperglycemic effects. Further experiments are necessary to clarify the actual mechanisms involved.

4. Conclusion

Taken together, these results from the OMTT, OGTT, and ITT showed that Gelidium elegans decreased blood glucose levels when compared to the control. More specifically, the group that was administered 200 mg/kg Gelidium elegans had a significant decrease in blood glucose levels. Insulin is one of the well-known hormones that can reduce blood glucose levels by promoting insulin release or improving insulin sensitivity. Gelidium elegans is widely distributed in Asia and is commonly used as an edible item, with a known lack of toxicity. Gelidium elegans therefore represents a potentially useful dietary addition for the treatment of diabetes.

Acknowledgements

This research was partially supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education (20161D1A1A09917209). This research was a part of the project titled “Development of functional ingredient approved by KFDA and global finished product of improving metabolic syndrome using

Gelidium elegans” which was funded by the Ministry of Oceans and Fisheries, Korea. The funders has no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

[1]   | Laakso, M., Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999, 48, 937-942.
[2]   | Ikemoto, S., Takahashi, M., Tsunoda, N., Maruyama, K., et al., High-fat diet-induced hyperglycemia and obesity in mice: differential effects of dietary oils. Metabolism 1996, 45, 1539-1546.
[3]   | Palsamy, P., Subramanian, S., Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. Biomedicine & Pharmacotherapy 2008, 62, 598-605.
[4]   | Cetin, M., Yetgin, S., Kara, A., Tuncer, A. M., et al., Hyperglycemia, ketoacidosis and other complications of L-asparaginase in children with acute lymphoblastic leukemia. Journal of medicine 1993, 25, 219-229.
[5]   | Kelly, T. N., Bazzano, L. A., Fonseca, V. A., Thethi, T. K., et al., Systematic review: glucose control and cardiovascular disease in type 2 diabetes. Annals of internal medicine 2009, 151, 394-403.
[6]   | De Vos, A., Heimberg, H., Quartier, E., Huypens, P., et al., Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression. J Clin Invest 1995, 96, 2489-2495.
[7]   | Zhao, F.-Q., Keating, A. F., Functional properties and genomics of glucose transporters. Current genomics 2007, 8, 113-128.
[8]   | Wright, E. M., Renal Na+-glucose cotransporters. American Journal of Physiology-Renal Physiology 2001, 280, F10-F18.
[9]   | Scheepers, A., Joost, H.-G., Schurmann, A., The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. Journal of Parenteral and Enteral Nutrition 2004, 28, 364-371.
[10]   | Carruthers, A., Facilitated diffusion of glucose. Physiol Rev 1990, 70, 1135-1176.
[11]   | Ohtsubo, K., Takamatsu, S., Minowa, M. T., Yoshida, A., et al., Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes. Cell 2005, 123, 1307-1321.
[12]   | Katz, E. B., Stenbit, A. E., Hatton, K., DePinhot, R., Charron, M. J., Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. 1995.

[13]  
Pantalone, K. M., Kattan, M. W., Yu, C., Wells, B. J., et al., The risk of developing coronary artery disease or congestive heart failure, and overall mortality, in type 2 diabetic patients receiving rosiglitazone, pioglitazone, metformin, or sulfonylureas: a retrospective analysis. Acta diabetologica 2009, 46, 145-154.

[14]   | Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., et al., The hormone resistin links obesity to diabetes. Nature 2001, 409, 307-312.

[15]  
Al-Khalili, L., Forsgren, M., Kannisto, K., Zierath, J., et al., Enhanced insulin-stimulated glycogen synthesis in response to insulin, metformin or rosiglitazone is associated with increased mRNA expression of GLUT4 and peroxisomal proliferator activator receptor gamma co-activator 1. Diabetologia 2005, 48, 1173-1179.

[16]   | Schuster, D. P., Duvuuri, V., Diabetes mellitus. Clin Podiatr Med Surg 2002, 19, 79-107.
[17]   | Stull, A. J., Cash, K. C., Johnson, W. D., Champagne, C. M., Cefalu, W. T., Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. The Journal of nutrition 2010, 140, 1764-1768.
[18]   | Ding, L., Jin, D., Chen, X., Luteolin enhances insulin sensitivity via activation of PPARγ transcriptional activity in adipocytes. The Journal of nutritional biochemistry 2010, 21, 941-947.
[19]   | Yu, H., Zhen, J., Yang, Y., Gu, J., et al., Ginsenoside Rg1 ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress-induced apoptosis in a streptozotocin-induced diabetes rat model. J Cell Mol Med 2016, 20, 623-631.
[20]   | Cho, Y., Bang, M., Effects of dietary seaweed on blood glucose, lipid and glutathione enzymes in streptozotocin-induced diabetic rats. Journal of The Korean Society of Food Science and Nutrition 2004.
[21]   | Maeda, H., Hosokawa, M., Sashima, T., Miyashita, K., Dietary combination of fucoxanthin and fish oil attenuates the weight gain of white adipose tissue and decreases blood glucose in obese/diabetic KK-Ay mice. J. of Agricultural and Food Chemistry 2007, 55, 7701-7706.
[22]   | Kim, K. M., Hoarau, G. G., Boo, S. M., Genetic structure and distribution of Gelidium elegans (Gelidiales, Rhodophyta) in Korea based on mitochondrial cox1 sequence data. Aquatic botany 2012, 98, 27-33.
[23]   | Jeon, H. J., Seo, M. J., Choi, H. S., Lee, O. H., Lee, B. Y., Gelidium elegans, an edible red seaweed, and hesperidin inhibit lipid accumulation and production of reactive oxygen species and reactive nitrogen species in 3T3-L1 and RAW264.7 cells. Phytother Res 2014, 28, 1701-1709.
[24]   | Choi, J., Kim, K.-J., Koh, E.-J., Lee, B.-Y., Altered Gelidium elegans Extract-stimulated Beige-like Phenotype Attenuates Adipogenesis in 3T3-L1 Cells. Journal of Food and Nutrition Research 2016, 4, 448-453.
[25]   | Kang, M.-C., Kang, N., Kim, S.-Y., Lima, I. S., et al., Popular edible seaweed, Gelidium amansii prevents against diet-induced obesity. Food and Chemical Toxicology 2016, 90, 181-187.
[26]   | Kim, K.-J., Choi, J., Lee, B.-Y., Evaluation of the Genotoxicity of a <i>Gelidium elegans</i> Extract in Vitro and in Vivo. Journal of Food and Nutrition Research 2016, 4, 653-657.
[27]   | Martyn, J. A. J., Kaneki, M., Yasuhara, S., Obesity-induced Insulin Resistance and HyperglycemiaEtiologic Factors and Molecular Mechanisms. The Journal of the American Society of Anesthesiologists 2008, 109, 137-148.
[28]   | Association, A. D., Diagnosis and classification of diabetes mellitus. Diabetes care 2006, 29, S43.
[29]   | Schmidt, M. I., Duncan, B. B., Reichelt, A. J., Branchtein, L., et al., Gestational diabetes mellitus diagnosed with a 2-h 75-g oral glucose tolerance test and adverse pregnancy outcomes. Diabetes care 2001, 24, 1151-1155.
[30]   | Stern, M. P., Williams, K., Haffner, S. M., Identification of persons at high risk for type 2 diabetes mellitus: do we need the oral glucose tolerance test? Annals of Internal Medicine 2002, 136, 575-581.
[31]   | Ernsberger, P., Koletsky, R. J., The glucose tolerance test as a laboratory tool with clinical implications, INTECH Open Access Publisher 2012.
[32]   | Pruessner, J. C., Kirschbaum, C., Meinlschmid, G., Hellhammer, D. H., Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology 2003, 28, 916-931.
[33]   | Seo, K. I., Choi, M. S., Jung, U. J., Kim, H. J., et al., Effect of curcumin supplementation on blood glucose, plasma insulin, and glucose homeostasis related enzyme activities in diabetic db/db mice. Molecular nutrition & food research 2008, 52, 995-1004.

[34]  
Paz, K., Hemi, R., LeRoith, D., Karasik, A., et al., A Molecular Basis for Insulin Resistance elevated serine/threonine phosphorylation of irs-1 and irs-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. Journal of Biological Chemistry 1997, 272, 29911-29918.

[35]   | Cho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., et al., Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001, 292, 1728-1731.
[36]   | Derave, W., Eijnde, B. O., Verbessem, P., Ramaekers, M., et al., Combined creatine and protein supplementation in conjunction with resistance training promotes muscle GLUT-4 content and glucose tolerance in humans. Journal of Applied Physiology 2003, 94, 1910-1916.
[37]   | Agyemang, K., Han, L., Liu, E., Zhang, Y., et al., Recent advances in Astragalus membranaceus anti-diabetic research: pharmacological effects of its phytochemical constituents. Evidence-Based Complementary and Alternative Medicine 2013, 2013.
[38]   | Pari, L., Satheesh, M. A., Effect of pterostilbene on hepatic key enzymes of glucose metabolism in streptozotocin-and nicotinamide-induced diabetic rats. Life sciences 2006, 79, 641-645.
[39]   | Tunnicliffe, J. M., Shearer, J., Coffee, glucose homeostasis, and insulin resistance: physiological mechanisms and mediators. Applied Physiology, Nutrition, and Metabolism 2008, 33, 1290-1300.

[40]  
Vuong, T., Martineau, L. C., Ramassamy, C., Matar, C., Haddad, P. S., Fermented Canadian lowbush blueberry juice stimulates glucose uptake and AMP-activated protein kinase in insulin-sensitive cultured muscle cells and adipocytes This article is one of a selection of papers published in this special issue (part 1 of 2) on the Safety and Efficacy of Natural Health Products. Canadian journal of physiology and pharmacology 2007, 85, 956-965.

[41]   | Jiménez‐Osorio, A. S., Monroy, A., Alavez, S., Curcumin and insulin resistance—Molecular targets and clinical evidences. Biofactors 2016, 42, 561-580.
[42]   | Ademiluyi, A. O., Oboh, G., Soybean phenolic-rich extracts inhibit key-enzymes linked to type 2 diabetes (α-amylase and α-glucosidase) and hypertension (angiotensin I converting enzyme) in vitro. Experimental and Toxicologic Pathology 2013, 65, 305-309.
[43]   | Yilmazer-Musa, M., Griffith, A. M., Michels, A. J., Schneider, E., Frei, B., Grape seed and tea extracts and catechin 3-gallates are potent inhibitors of α-amylase and α-glucosidase activity. Journal of agricultural and food chemistry 2012, 60, 8924-8929.
[44]   | Louie, J. C. Y., Moshtaghian, H., Boylan, S., Flood, V. M., et al., A systematic methodology to estimate added sugar content of foods. European journal of clinical nutrition 2015, 69, 154-161.
[45]   | Anderson, G., Sugars-containing beverages and post-prandial satiety and food intake. International Journal of Obesity 2006, 30, S52-S59.
[46]   | Murao, S., Nagano, H., Ogura, S., Nishino, T., Enzymatic synthesis of trehalose from maltose. Agricultural and biological chemistry 1985, 49, 2113-2118.
[47]   | Fernández-Arrojo, L., Marin, D., De Segura, A. G., Linde, D., et al., Transformation of maltose into prebiotic isomaltooligosaccharides by a novel α-glucosidase from Xantophyllomyces dendrorhous. Process Biochemistry 2007, 42, 1530-1536.
[48]   | Lebovitz, H. E., Alpha-glucosidase inhibitors. Endocrinology and metabolism clinics of North America 1997, 26, 539-551.
[49]   | Joubert, P., Venter, H., Foukaridis, G., The effect of miglitol and acarbose after an oral glucose load: a novel hypoglycaemic mechanism? British journal of clinical pharmacology 1990, 30, 391-396.
[50]   | Van de Laar, F. A., Lucassen, P. L., Akkermans, R. P., Van de Lisdonk, E. H., et al., Alpha‐glucosidase inhibitors for type 2 diabetes mellitus. The Cochrane Library 2005.
[51]   | Tchamgoue, A. D., Tchokouaha, L. R., Domekouo, U. L., Atchan, A. P., et al., Effect of Costus afer on Carbohydrates Tolerance Tests and Glucose Uptake.
[52]   | Cheng, D. M., Roopchand, D. E., Poulev, A., Kuhn, P., et al., High phenolics Rutgers Scarlet Lettuce improves glucose metabolism in high fat diet‐induced obese mice. Molecular Nutrition & Food Research 2016.
[53]   | Reaven, G. M., Role of insulin resistance in human disease. Diabetes 1988, 37, 1595-1607.
[54]   | Lann, D., LeRoith, D., Insulin resistance as the underlying cause for the metabolic syndrome. Medical Clinics of North America 2007, 91, 1063-1077.
[55]   | Mayerson, A. B., Hundal, R. S., Dufour, S., Lebon, V., et al., The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002, 51, 797-802.
[56]   | Gelato, M. C., Mynarcik, D. C., Quick, J. L., Steigbigel, R. T., et al., Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study. Journal of acquired immune deficiency syndromes (1999) 2002, 31, 163-170.
[57]   | Hirst, S., Phillips, D., Vines, S., Clark, P., Hales, C., Reproducibility of the short insulin tolerance test. Diabetic medicine 1993, 10, 839-842.
[58]   | Lindheim, S. R., Presser, S. C., Ditkoff, E. C., Vijod, M. A., et al., A possible bimodal effect of estrogen on insulin sensitivity in postmenopausal women and the attenuating effect of added progestin. Fertility and sterility 1993, 60, 664-667.
[59]   | Abrams, R. L., Grumbach, M. M., Kaplan, S. L., The effect of administration of human growth hormone on the plasma growth hormone, cortisol, glucose, and free fatty acid response to insulin: evidence for growth hormone autoregulation in man. Journal of Clinical Investigation 1971, 50, 940.
[60]   | Timmers, S., Hesselink, M. K., Schrauwen, P., Therapeutic potential of resveratrol in obesity and type 2 diabetes: new avenues for health benefits? Annals of the New York Academy of Sciences 2013, 1290, 83-89.