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Rare Sugar Syrup Containing d-Allulose but Not High-Fructose Corn Syrup Maintains Glucose Tolerance and Insulin Sensitivity Partly via Hepatic Glucokinase Translocation in Wistar Rats
- Tomoya Shintani
- ,
- Takako Yamada
- ,
- Noriko Hayashi
- ,
- Tetsuo Iida
- ,
- Yasuo Nagata
- ,
- Nobuaki Ozaki
- , and
- Yukiyasu Toyoda
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† Research and Development, Matsutani Chemical Industry Company, Limited, 5-3 Kita-Itami, Itami, Hyogo 664-8508, Japan
‡ Center for Industry, University and Government Cooperation, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-9521, Japan
§ Japanese Red Cross Nagoya Daiichi Hospital, 3-35 Michishita, Nakamuraku-ku, Nagoya, Aichi 453-8511, Japan
∥ Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Aichi468-8503, Japan
*Telephone: +81-72-771-2052. Fax: +81-72-771-2023. E-mail: [email protected]
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Abstract
Ingestion of high-fructose corn syrup (HFCS) is associated with the risk of both diabetes and obesity. Rare sugar syrup (RSS) has been developed by alkaline isomerization of HFCS and has anti-obesity and anti-diabetic effects. However, the influence of RSS on glucose metabolism has not been explored. We investigated whether long-term administration of RSS maintains glucose tolerance and whether the underlying mechanism involves hepatic glucokinase translocation. Wistar rats were administered water, RSS, or HFCS in drinking water for 10 weeks and then evaluated for glucose tolerance, insulin tolerance, liver glycogen content, and subcellular distribution of liver glucokinase. RSS significantly suppressed body weight gain and abdominal fat mass (p < 0.05). The glucose tolerance test revealed significantly higher blood glucose levels in the HFCS group compared to the water group, whereas the RSS group had significantly lower blood glucose levels from 90 to 180 min (p < 0.05). At 30, 60, and 90 min, the levels of insulin in the RSS group were significantly lower than those in the water group (p < 0.05). The amount of hepatic glycogen was more than 3 times higher in the RSS group than that in the other groups. After glucose loading, the nuclear export of glucokinase was significantly increased in the RSS group compared to the water group. These results imply that RSS maintains glucose tolerance and insulin sensitivity, at least partly, by enhancing nuclear export of hepatic glucokinase.
Introduction
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High-fructose corn syrup (HFCS) is commercially produced by isomerizing glucose to fructose. The taste of HCFS is similar to that of sucrose, and its price is affordable. Thus, HFCS has been used in various foods, such as beverages, desserts, and confectionery and bakery products. However, the consumption of HFCS has been reported to be one of the risk factors for developing diabetes and obesity. (1) Although there is no cure for diabetes at present, lifestyle changes, such as eating healthy foods, exercising regularly, and maintaining a healthy body weight, are advised to prevent high blood sugar levels and delay the onset of complications. From a preventative point of view, it is advisible to reduce sugar intake or to replace sugar with other low-calorie sweeteners. Thus, the development of new types of sweeteners is awaiting.
d-Allulose, a C3 epimer of d-fructose, is one of the rare sugars that are present in a limited quantity in nature. Studies have shown that d-allulose has various functions, such as reducing postprandial blood glucose elevation. (2, 3) In addition, d-allulose was observed to decrease body weight gain and adipose tissue weight. (4-6) Clinical trials using a maltodextrin diet or standard meal have confirmed that d-allulose suppresses postprandial blood glucose levels. (7, 8) Two mechanisms have been suggested for the glucose-lowering effect of d-allulose. One is via inhibition of α-glucosidase; d-allulose inhibits the activity of α-glucosidase in vitro and in vivo, resulting in decreased absorption of glucose. (3) The other is the effect on glycemic response in the liver; d-allulose promotes the conversion of blood glucose to glycogen in the liver via glucokinase (GK). (9, 10) In addition to these mechanisms, another mechanism might be proposed: competitive inhibition of glucose absorption by d-allulose in the digestive tract delays an increment in blood sugar because glucose, fructose, and d-allulose have a common transporter, GLUT 2, at the basolateral membrane in Caco-2 cells. (11) Collectively, these mechanisms might have contributed to decreased postprandial blood glucose in humans. (7, 8)
The liver plays an important role in maintaining glucose homeostasis. Glucose internalized by hepatocytes is phosphorylated to glucose 6-phosphate by GK, which is a key step of glycolysis, glycogen synthesis, and the pentose phosphate pathway. (12, 13) GK (also called hexokinase IV) compared to other hexokinases (I–III) has a relatively low affinity for glucose and does not undergo an inhibition by glucose 6-phosphate. (12) Thus, GK increases the amount of glycogen in the liver, suppressing postprandial blood glucose elevation. (14) GK in the liver is regulated by glucokinase regulatory protein (GKRP) that inhibits the activity of GK by binding to it. (15) When the affinity of GK and GKRP is increased by fructose 6-phosphate, GK remains in the nucleus in an inactive form. However, when its affinity is reduced by fructose 1-phosphate or high glucose concentration, GK is transported from the nucleus to the cytoplasm (14-20) via an active process. GK increases glucose utilization in the liver, thus resulting in increased glycogen content or reduced blood glucose levels. d-Allulose 1-phosphate, similar to fructose 1-phosphate, reduces affinity between GKRP and GK, leading to GK activation. (2, 9)
Rare sugar syrup (RSS) has been developed by alkaline isomerization of HFCS. (21) RSS is a mixed syrup containing 45% glucose, 29% fructose, 5% allulose, 5% sorbose, 2% tagatose, 1% allose, and 13% other sugars. Therefore, RSS containing d-allulose may activate GK, probably resulting in improved glycemic control.
The anti-obesity effect of RSS has also been confirmed in both humans and animals; (22, 23) in a clinical trial, the daily intake of 40 g of RSS for 3 months led to a significant reduction (1.8 kg) in body weight compared to that observed after HFCS intake. (22) Furthermore, our previous study has shown that RSS inhibits the activity of intestinal α-glucosidase in vitro and is expected to reduce postprandial blood glucose elevation. (23) It is therefore of interest to assess whether RSS, a new sweetener derived from HFCS, maintains glucose tolerance and insulin sensitivity and, if so, whether anti-hyperglycemic action of RSS is mediated by exporting GK from the nucleus to the cytoplasm. To this end, glucose tolerance and the degree of GK translocation in rats administered water, HFCS, or RSS in drinking water were investigated in the present study.
Materials and Methods
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Experimental Animals
All animal experiments were approved by the Meijo University Faculty of Animal Care and Use Committee. Five-week-old Wistar male rats were purchased (CLEA Japan, Tokyo, Japan), fed a commercial diet (AIN93-G, Oriental Yeast Co., Ltd., Tokyo, Japan), and placed in stainless-steel cages under controlled atmospheric conditions (i.e., 22 ± 2 °C with a 12 h light/dark cycle). After 1 week of acclimation, animals were divided into three groups of 12 animals each. Rats were then fed a commercial diet ad libitum and administered water, HFCS (HFCS42, Nihon Shokuhin Kakou Co., Ltd., Tokyo, Japan), or RSS (Matsutani Chemical Industry Co., Ltd., Itami, Japan) in drinking water for 10 weeks. We diluted HFCS and RSS to provide 7% fructose solution, because a fructose solution of approximately 10% has generally been used in studies to induce insulin resistance. (24) Before administration to animals, we measured the concentration of total sugar and the composition of sugar by a conventional method using high-performance liquid chromatography. The total sugar concentration of the RSS and HFCS solutions was approximately 25 and 15%, respectively.
Experimental Design
At 8 weeks, the oral glucose tolerance test was carried out with 2 g of glucose/kg of body weight by oral gavage after 16 h of fasting. Blood was collected from the tail vein before and 30, 60, 90, 120, and 180 min after glucose loading. For insulin tolerance test at 8 weeks, a dose of 0.5 IU of insulin/kg of body weight (Humulin R, Eli Lilly, Indianapolis, IN, U.S.A.) was subcutaneously administered to rats. Blood was collected from the tail vein before and after 30, 60, 90, 120, and 180 min after insulin loading. The blood was then centrifuged, and the plasma was used for measurement of the levels of blood glucose by a commercial kit (C-II test Wako, Wako Pure Chemical Industries, Osaka, Japan). Insulin levels were measured using an enzyme-linked immunoassay kit (Morinaga Institute of Biological Science, Kanagawa, Japan). The area under the curve (AUC) was calculated using the trapezoidal method.
To elucidate the involvement of GK in RSS-induced anti-hyperglycemic action, an oral glucose tolerance test was carried out again at 10 weeks and GK translocation and the level of hepatic glycogen were determined, as described below. Four rats of each group were sacrificed before and 30 min after a glucose load. The liver was then dissected and used for GK translocation. For glycogen content, an additional four rats from each group underwent laparotomy under anesthesia and the rat livers were perfused through inferior vena cava with saline, excised, and stored at −80 °C before analysis.
Immunohistochemical Staining of GK
An aliquot of the excised liver was immobilized with 4% paraformaldehyde. The immobilized liver was infiltrated in 30% sucrose solution for 48 h at 4 °C. Finally, the liver tissue was infiltrated with OCT compound (Sakura Finetek, Tokyo, Japan) and frozen in liquid nitrogen. Cryosections were subjected to immunostaining using an anti-GK antibody, prepared as described previously. (17, 20)
Analysis of a Distribution of Liver GK in the Nucleus and Cytoplasm
GK translocation from the nucleus to the cytoplasm was analyzed through fluorescence imaging. The intensity of fluorescent–antibody staining in the liver tissue was examined using a fluorescence microscope and confocal laser microscopy (LSM 510 META, Zeiss, Oberkochen, Germany) (25) and quantified by software ImageJ [National Institutes of Health (NIH), Bethesda, MD, U.S.A.).
Analysis of Liver Glycogen
The liver was homogenized with 0.6 M perchloric acid. (26) The homogenate was then added to 1 M potassium bicarbonate followed by 0.2 M acetate buffer to dissolve 1 mg/mL glucoamylase (Oriental Yeast Co., Ltd., Tokyo, Japan). The reaction solution was incubated for 2 h at 40 °C. Next, the enzymatic reaction was stopped by adding 500 μL of 0.6 M perchloric acid and then centrifuged. The supernatant was used for glucose measurement. The glycogen content was then calculated as glucose equivalent after converting glucose milligrams to micromolar.
Statistical Analysis
Data are expressed as the mean ± standard deviation (SD). Data were analyzed using the multiple comparisons of Fisher’s protected least significant difference (PLSD) test. All analyses were performed with a statistical package (Excel Statistics 2010, SSRI, Co., Ltd., Tokyo, Japan). Values were considered to be significantly different when the p value was <0.05.
Results
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Body weight, calorie intake, and abdominal fat weight were examined throughout the experiment, as shown in Figure 1. There was no difference in body weight gain between the water and HFCS groups, whereas that in the RSS group was significantly suppressed throughout the experiment (p < 0.05) (Figure 1A). Average food intake of the HFCS group (15 ± 2 g/day) was significantly lower (p < 0.05) than that of the other two groups (19 ± 2 in the RSS group and 19 ± 4 g/day in the water group), while average fluid intake of the HFCS group (42 ± 6 g/day) was significantly higher (p < 0.05) than that of the other two groups (23 ± 3 and 19 ± 2 g/day in the water and RSS groups, respectively). Therefore, calorie intake from food and fluid was not significantly different in the HFCS and RSS groups, although the daily difference between the water and other two groups was significant from time to time (Figure 1B). The weight of the liver and kidney was not influenced by sugars at 10 weeks (data not shown). The total amount of abdominal fat, including perirenal, epididymal, and mesenteric fat, was significantly higher in the HFCS group than that in the water group, whereas it was significantly lower in the RSS group than that in the other two groups (Figure 1C).
Figure 1
Figure 1. Changes in (A) body weight, (B) total calorie intake, and (C) abdominal fat weight in rats administrated water, RSS, and HFCS. Data are expressed as the mean ± SD (n = 12 for A and B, and n = 4–5 for C). Different letters (a, b, and c) show a significant difference at p < 0.05.
In the oral glucose tolerance test at 8 weeks, the levels of blood glucose were determined for 180 min after a load of glucose (Figure 2A). Although no difference was observed between the blood glucose levels of the water and RSS groups before a glucose load (0 min), the levels of blood glucose in RSS rats were significantly lower than those in the HFCS group. Blood glucose levels in the HFCS group from 0 to 180 min were higher than those in the water group, except at 90 min. Glucose levels at 90, 120, and 180 min were significantly lower in the RSS group than those in the water group. The AUC of blood glucose response in the HFCS group was higher than that in the water and RSS groups (Figure 2B).
Figure 2
Figure 2. Effects of water, RSS, and HFCS on plasma glucose and insulin levels during the oral glucose tolerance test at 8 weeks: (A) plasma glucose, (B) AUC of plasma glucose, (C) insulin, and (D) AUC of insulin. Data are expressed as the mean ± SD (n = 4). Different letters (a, b, and c) show a significant difference at p < 0.05.
The levels of insulin were significantly higher in the HFCS group at baseline than in the water and RSS groups. The HFCS group had higher values of insulin during the oral glucose tolerance test than those in the water group. On the other hand, insulin levels before and during the glucose tolerance test were lower in the RSS group than those in the HFCS group (Figure 2C). The AUC of insulin response was significantly lower in the RSS group than in the water and HFCS groups (Figure 2D).
The insulin tolerance test showed that the reduction in blood glucose in the RSS group was significantly higher than that in the HFCS group (Figure 3).
Figure 3
Figure 3. Effects of water, RSS, and HFCS on glucose levels during the insulin tolerance test at 8 weeks. Data are expressed as a percentage of values at 0 min. Data are expressed as the mean ± SD (n = 4). Different letters (a, b, and c) show a significant difference at p < 0.05.
Before and 30 min after a glucose load at 10 weeks, the HFCS group showed significantly higher levels of glucose than those in the water and RSS groups (Figure 4A). Similarly, insulin levels in the HFCS group were higher than those in the water and RSS groups at 0 min. At 30 min after a glucose loading, a lower insulin level was found in rats administered RSS than that in rats receiving water (Figure 4B). We also examined the hepatic glycogen content before and at 30 min after a glucose loading (Figure 4C). The glycogen content in the RSS group was 3 times higher than that in the water and HFCS groups at 0 min. After a glucose loading, the glycogen content in the HFCS group was significantly lower than in the water and RSS groups.
Figure 4
Figure 4. Effects of water, RSS, and HFCS on (A) plasma glucose levels, (B) insulin levels, and (C) hepatic glycogen levels during the oral glucose tolerance test at 10 weeks. Data are expressed as the mean ± SD (n = 4). Different letters (a, b, and c) show a significant difference at p < 0.05 among the three groups at 0 or 30 min. (∗) Significant difference at p < 0.05 compared to the corresponding group at 0 min.
The nuclear export rate of GK in the perivenous and periportal zones in the liver before and after glucose loading was analyzed (panels A–D of Figure 5). Panels A and B of Figure 5 show that the nuclear immunofluorescence in hepatocytes from HFCS-fed rats is still evident; however, the cytoplasmic immunofluorescence in hepatocytes from RSS-fed rats is brighter than that from HFCS-fed rats. When the distribution in the perivenous zone before a glucose loading was quantified using an image analyzer, the distribution of GK in the cytoplasm in the RSS group was higher (46%) than that in the water group (28%) and that in the HFCS group (21%) (Figure 5C). After glucose loading, the distribution in the cytoplasm remained lower in the HFCS group (30%) compared to the water group (46%) and the RSS group (68%). The same tendency was observed in the periportal zone; the translocation of GK in the RSS group was higher (59%) than that in the water group (39%) and that in the HFCS group (27%) (Figure 5D). After glucose loading, the distribution in the cytoplasm was significantly lower in the HFCS group (37%) than that in the water group (55%) and that in the RSS group (78%).
Figure 5
Figure 5. Effects of water, RSS, and HFCS on nuclear export of GK in the perivenous and periportal zones in the liver: (A) representative picture of immunohistochemical staining of GK in the perivenous (PV) and periportal (PP) zones from rats administered water (upper), HFCS (middle), and RSS (lower) at 0 min, (B) representative picture of immunohistochemical staining of GK in the PV and PP zones from rats administered water (upper), HFCS (middle), and RSS (lower) at 30 min after glucose loading, (C) distribution of GK in the cytoplasm in the perivenous zone at 0 and 30 min after glucose loading, and (D) distribution of GK in the cytoplasm in the periportal zone at 0 and 30 min after glucose loading. Data are expressed as the mean ± SD (n = 4). Different letters (a, b, and c) show a significant difference at p < 0.05 among the three groups at 0 or 30 min. (∗) Significant difference at p < 0.05 compared to the corresponding group at 0 min.
Discussion
ARTICLE SECTIONS
We have previously administered RSS to rats and found that RSS is associated with lower body weight, abdominal fat, and fasting insulin levels in rats compared to feeding with starch and HFCS. (22) In this study, rats were administered water, RSS, or HFCS in drinking water for 10 weeks to understand the effect of RSS on glucose metabolism. We observed that glucose tolerance and insulin sensitivity in rats in the RSS group were similar or even better than in animals in the water group, whereas they deteriorated in the HFCS group, indicating that RSS may be beneficial in maintaining glucose homeostasis.
As shown in Figure 1B, no difference in total calorie intake was observed between the HFCS and RSS groups. However, the former group had a significantly higher average body weight than the latter throughout the experiment. The levels of food efficiency for the water, HFCS, and RSS groups were 0.67, 0.57, and 0.44, respectively, with the difference between the water and RSS groups being significant. In addition, administration of HFCS was associated with a greater total adipose tissue weight than that of water or RSS (Figure 1C), confirming its anti-obese action, as seen in our previous clinical study (23) and animal studies. (22) One of the rare sugars in the RSS, d-allulose, has been well-studied. The mechanisms behind the anti-obese activity of it have been proposed; d-allulose decreases hepatic lipogenic enzymes and enhances energy expenditure. (5, 6) We also calculated the amount of d-allulose ingested in the RSS group as 900 mg kg–1 of body weight day–1. It is unlikely that this amount of d-allulose affects body weight gain as a result of the findings from our previous study that 1500–3000 mg of d-allulose a day did not increase body weight gain. (27) Therefore, it is possible that other rare sugars in RSS, such as d-sorbose and d-tagatose, contributed to decreasing body weight. On the basis of these findings, we have concluded that RSS has anti-obesity activity. However, studies on the detailed mechanism of RSS-induced anti-obese action are needed in the future.
As shown in Figure 2, oral glucose tolerance testing performed at 8 weeks revealed that RSS favorably altered glucose metabolism; the levels of blood glucose in the RSS group were the lowest among the three groups. Administration of water or RSS showed a significantly lower AUC of insulin, per the results of oral glucose tolerance testing (Figure 2D), implying that RSS maintains insulin sensitivity. This finding was further supported by an insulin tolerance test, as shown in Figure 3. The decrease in glucose levels after a subcutaneous injection of insulin was markedly greater in the RSS group than in the water or HFCS group at 30 and 60 min. Matsuo et al. have also shown that, after feeding d-allulose, one of the rare sugars in RSS, to rats for 8 weeks, the levels of plasma glucose and insulin were significantly lower relative to fructose. (3) This anti-hyperglycemic activity of d-allulose was also observed in db/db mice (28) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats. (10) In clinical studies, when a varying amount of d-allulose was co-administered with 75 g of maltodextrin, the AUC for glucose and insulin during glucose tolerance testing decreased in a dose-dependent manner. (7) Furthermore, subjects with a fasting plasma glucose level of 100–126 mg/dL who received a single dose of 5 g of d-allulose in tea and a standard meal containing 84.5 g of carbohydrate exhibited significantly lower plasma glucose levels at 30 and 60 min than those who received a standard meal alone. (8) Previous studies have shown that d-tagatose (one of the rare sugars in RSS) exerts anti-hyperglycemic action. The level of glucagon-like peptide-1, which is involved in secretion of insulin in the pancreas, is augmented by d-tagatose. (29) In addition, d-sorbose, one of the rare sugars in RSS, has been reported to reduce fasting plasma insulin levels. (30) One of the mechanisms underlying the anti-hyperglycemic activity of RSS may be due to an inhibitory effect of α-glucosidase because d-allulose, d-tagatose, and d-sorbose exert α-glucosidase inhibitory action. (3, 21, 31) Furthermore, because glucose, fructose, and d-allulose share a common transporter at the basolateral membrane in Caco-2 cells, as suggested by Hishiike et al., (11) the competitive and suppressive effect of d-allulose in RSS on glucose absorption may provide another conceivable mechanism. On the basis of these studies, RSS containing d-allulose, d-sorbose, and d-tagatose also appears to have anti-hyperglycemic activity.
A glucose load was carried out at 10 weeks to determine the glycogen content and GK translocation. The levels of blood glucose, insulin, and hepatic glycogen were also measured before and 30 min after the glucose load. Administration of water and RSS exhibited lower glucose and insulin levels than HFCS, as shown in Figure 4, while the glycogen content in the liver was higher, which probably implies an anti-hyperglycemic action of RSS. Next, we tried to see if GK translocation is responsible for the improvement of glucose metabolism induced by RSS, because GK plays a critical role in glucose metabolism, shuttling between the nucleus and the cytoplasm and phosphorylating glucose to glucose 6-phosphate, the rate-limiting step in glycolysis. (14-20) Studies have shown that impaired GK activities in the liver may lead to hyperglycemia. (32) In addition, Toyoda et al. have found that GK translocation is malfunctioned in Goto-Kakizaki rats, which are models for diabetes. (24) Decreased GK activities were also observed in patients with impaired glucose tolerance. (33) Thus, these results indicate that GK translocation from the nucleus to the cytoplasm may be a good marker of glucose homeostasis. GK activity is 1.7 times higher in the perivenous zone than in the periportal zone. (34) In this study, the liver was sectioned into two zones, the periportal and perivenous zones, and the translocation of GK from the nucleus to the cytoplasm was measured in each zone. As shown in panels A and B of Figure 5, the area surrounding the nucleus (green spot) is brighter in RSS than in HFCS, indicating that more GK exists in the cytoplasm in the liver of RSS-fed rats. This was confirmed by quantifying fluorescence intensity (panels C and D of Figure 5). The ratio of GK distributed in the cytoplasm (active form) in the RSS group was highest in both the perivenous and periportal zones among the three groups, implying that RSS intake results in a more active form of GK, regardless of the zone. Thus, glucose homeostasis modulated by RSS is at least due to stimulated translocation of GK out of the nucleus. Hossain et al. also observed that d-allulose stimulated GK translocation in OLETF rats, resulting in improved glucose tolerance and insulin sensitivity. (10) The anti-hyperglycemic action of d-tagatose has also been known to enhance the translocation of GK. (35) Interestingly, these rare sugars have been reported to increase hepatic glycogen. (4, 9) Given that GK activity is related to glycogen synthesis, (14) our results suggest for the first time that RSS containing rare sugars may exert anti-hyperglycemic activity partially through activated GK and increased glycogen content. In addition, the protective effect of d-allulose on pancreas β islets, as shown in OLETF rats, (10) may also contribute to the maintenance of glucose tolerance and the enhancement of insulin sensitivity in rats fed RSS. Because GK promotes glycolysis and enhances energy metabolism when overexpressed in the liver, (36) it is of interest to investigate the relation between the mechanism underlying RSS-mediated glucose metabolism and energy metabolism, in future studies.
Although HFCS has been reported to impair glucose homeostasis and cause obesity and diabetes worldwide, reducing its consumption to prevent these lifestyle-related diseases is difficult. This report indicates that RSS, which contains a small amount of d-allulose, d-sorbose, and d-tagatose, has the potential to maintain glucose homeostasis. The underlying mechanisms could be in part due to inhibited or delayed glucose absorption in the small intestine and enhanced GK translocation in the liver. Further studies are needed to confirm the RSS role in maintaining glucose metabolism and to expand on its applicability in the food industry.
Author Information
ARTICLE SECTIONS
- Tomoya Shintani - Research and Development, Matsutani Chemical Industry Company, Limited, 5-3 Kita-Itami, Itami, Hyogo 664-8508, Japan;http://orcid.org/0000-0002-8959-8875;
We acknowledge funding from the Matsutani Chemical Industry Co. and Meijo University.
| AUC | area under the curve |
| GK | glucokinase |
| GKRP | glucokinase regulatory protein |
| OLETF | Otsuka Long-Evans Tokushima Fatty |
| RRS | rare sugar syrup |
| HFCS | high-fructose corn syrup |
References
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This article references 36 other publications.
- 1Gross, S.; Li, L.; Ford, S.; Liu, S. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: An ecologic assessment Am. J. Clin. Nutr. 2004, 79, 774– 779Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXjs1ygsLo%253D&md5=ccd568b6a9b3f699342dcf1e9240d65dIncreased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: An ecologic assessmentGross, Lee S.; Li, Li; Ford, Earl S.; Liu, SiminAmerican Journal of Clinical Nutrition (2004), 79 (5), 774-779CODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)Type 2 diabetes mellitus is an epidemic affecting ever-increasing proportions of the US population. Although consumption of refined carbohydrates has increased and may be related to the increased risk of type 2 diabetes, the ecol. impact of changes in the quality of carbohydrates in the food supply on the risk of type 2 diabetes remains to be quantified. Correlations between consumption of refined carbohydrates and prevalence of type 2 diabetes in US were examd. In this ecol. correlation study, the per capita nutrient consumption in US between 1909 and 1997 obtained from the US Department of Agriculture was compared with the prevalence of type 2 diabetes obtained from the Centers for Disease Control and Prevention. In univariate anal., a correlation with diabetes prevalence was obsd. for dietary fat (r = 0.84), carbohydrate (r = 0.55), protein (r = 0.71), fiber (r = 0.16), corn syrup (r = 0.83), and total energy (r = 0.75) intakes. In multivariate nutrient-d. model, in which total energy intake was accounted for, corn syrup was pos. assocd. with the prevalence of type 2 diabetes (β = 0.0132). Dietary fiber (β = - 13.86) was neg. assocd. with the prevalence of type 2 diabetes. Dietary protein and fat were not assocd. with the prevalence of type 2 diabetes when total energy was controlled for. Thus, increasing dietary intakes of refined carbohydrates (corn syrup) concomitant with decreasing intakes of fiber paralleled the upward trend in the prevalence of type 2 diabetes mellitus obsd. in US during the 20th century.
- 2Hossain, M. A.; Yamaguchi, F.; Matsuo, T.; Tsukamoto, I.; Toyoda, Y.; Ogawa, M.; Nagata, Y.; Tokuda, M. Rare sugar d-allulose: Potential role and therapeutic monitoring in maintaining obesity and type 2 diabetes mellitus Pharmacol. Ther. 2015, 155, 49– 59 DOI: 10.1016/j.pharmthera.2015.08.004Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlylsL7I&md5=26026310302d36825f08f1e8c5f04ccfRare sugar D-allulose: Potential role and therapeutic monitoring in maintaining obesity and type 2 diabetes mellitusHossain, Akram; Yamaguchi, Fuminori; Matsuo, Tatsuhiro; Tsukamoto, Ikuko; Toyoda, Yukiyasu; Ogawa, Masahiro; Nagata, Yasuo; Tokuda, MasaakiPharmacology & Therapeutics (2015), 155 (), 49-59CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Obesity and type 2 diabetes mellitus (T2DM) are the leading worldwide risk factors for mortality. The inextricably interlinked pathol. progression from excessive wt. gain, obesity, and hyperglycemia to T2DM, usually commencing from obesity, typically originates from overconsumption of sugar and high-fat diets. Although most patients require medications, T2DM is manageable or even preventable with consumption of low-calorie diet and maintaining body wt. Medicines like insulin, metformin, and thiazolidinediones that improve glycemic control; however, these are assocd. with wt. gain, high blood pressure, and dyslipidemia. These situations warrant the attentive consideration of the role of balanced foods. Recently, we have discovered advantages of a rare sugar, D-allulose, a zero-calorie functional sweetener having strong anti-hyperlipidemic and anti-hyperglycemic effects. Study revealed that after oral administration in rats D-allulose readily entered the blood stream and was eliminated into urine within 24 h. Cell culture study showed that D-allulose enters into and leaves the intestinal enterocytes via glucose transporters GLUT5 and GLUT2, resp. In addn. to D-allulose's short-term effects, the characterization of long-term effects has been focused on preventing commencement and progression of T2DM in diabetic rats. Human trials showed that D-allulose attenuates postprandial glucose levels in healthy subjects and in borderline diabetic subjects. The anti-hyperlipidemic effect of D-allulose, combined with its anti-inflammatory actions on adipocytes, is beneficial for the prevention of both obesity and atherosclerosis and is accompanied by improvements in insulin resistance and impaired glucose tolerance. Therefore, this review presents brief discussions focusing on physiol. functions and potential benefits of D-allulose on obesity and T2DM.
- 3Matsuo, T.; Izumori, K. d-Psicose inhibits intestinal α-glucosidase and suppresses the glycemic response after Ingestion of carbohydrates in rats J. Clin. Biochem. Nutr. 2009, 45, 202– 206 DOI: 10.3164/jcbn.09-36Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlWrsbjM&md5=4f3063a08f0f09f314cf3cfdbd05e1caD-psicose inhibits intestinal α-glucosidase and suppresses the glycemic response after ingestion of carbohydrates in ratsMatsuo, Tatsuhiro; Izumori, KenJournal of Clinical Biochemistry and Nutrition (2009), 45 (2), 202-206CODEN: JCBNER; ISSN:0912-0009. (Society for Free Radical Research Japan)D-psicose is one of the rare sugars present in small quantities in com. carbohydrates and agricultural products. In this study, we investigated the effects of D-psicose on the activities of α-amylases and α-glucosidases in vitro, and evaluated the effects of D-psicose on the in vivo postprandial glycemic response using rats. In the in vitro study, D-psicose potently inhibited the intestinal sucrase and maltase, however, slightly inhibited the intestinal and salivary α-amylase activities. Male Wistar rats (6 mo old) were administrated 2 g/kg of sucrose, maltose or sol. starch together with 0.2 g/kg of D-psicose or D-fructose. The D-psicose significantly inhibited the increment of plasma glucose concn. induced by sucrose or maltose. The starch-induced glycemic response tended to be suppressed by D-psicose, however the suppression was not significant. These results suggest that D-psicose inhibits intestinal sucrase and maltase activities and suppresses the plasma glucose increase the normally occurs after sucrose and maltose ingestion. Thus, D-psicose may be useful in preventing postprandial hyperglycemia in diabetic patients when foods contg. sucrose and maltose are ingested.
- 4Ochiai, M.; Nakanishi, Y.; Yamada, T.; Iida, T.; Matsuo, T. Inhibition by dietary d-psicose of body fat accumulation in adult rats fed a high-sucrose diet Biosci., Biotechnol., Biochem. 2013, 77, 1123– 1126 DOI: 10.1271/bbb.130019Google ScholarThere is no corresponding record for this reference.
- 5Ochiai, M.; Onishi, K.; Yamada, T.; Iida, T.; Matsuo, T. d-Psicose increases energy expenditure and decreases body fat accumulation in rats fed a high-sucrose diet Int. J. Food Sci. Nutr. 2014, 65, 245– 250 DOI: 10.3109/09637486.2013.845653Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisF2mt7c%253D&md5=bc40d3a508649668407e9246ca394591D-Psicose increases energy expenditure and decreases body fat accumulation in rats fed a high-sucrose dietOchiai, Masaru; Onishi, Kana; Yamada, Takako; Iida, Tetsuo; Matsuo, TatsuhiroInternational Journal of Food Sciences and Nutrition (2014), 65 (2), 245-250CODEN: IJFNEH; ISSN:0963-7486. (Informa Healthcare)We investigated the anti-obesity effects of D-psicose by increasing energy expenditure in rats pair-fed the high-sucrose diet (HSD). Wistar rats were divided into two dietary groups: HSD contg. 5% cellulose (C) and 5% D-psicose (P). The C dietary group was further subdivided into two groups: rats fed the C diet ad libitum (C-AD) and pair-fed the C diet along with those in the P group (C-PF). Resting energy expenditure during darkness and lipoprotein lipase activity in the soleus muscle were significantly higher in the P group than in the C-PF group. Serum levels of glucose, leptin and adiponectin; glucose-6-phosphate dehydrogenase activities in the liver and perirenal adipose tissue; and body fat accumulation were all significantly lower in the P group than in the C-PF group. The anti-obesity effects of D-psicose could be induced not only by suppressing lipogenic enzyme activity but also by increasing EE in rats.
- 6Nagata, Y.; Kanasaki, A.; Tamaru, S.; Tanaka, K. d-Psicose, an epimer of d-fructose, favorably alters lipid metabolism in Sprague-Dawley rats J. Agric. Food Chem. 2015, 63, 3168– 3176 DOI: 10.1021/jf502535pGoogle Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjvFymtLc%253D&md5=ac59ebda95507cb4888eb9b3754f7f91D-Psicose, an Epimer of D-Fructose, Favorably Alters Lipid Metabolism in Sprague-Dawley RatsNagata, Yasuo; Kanasaki, Akane; Tamaru, Shizuka; Tanaka, KazunariJournal of Agricultural and Food Chemistry (2015), 63 (12), 3168-3176CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)D-Psicose, a C3 epimer of D-fructose, is known to lower body wt. and adipose tissue wt. and affect lipid metab. The precise mechanism remains unknown. It has been reported that D-psicose has a short half-life and is not metabolized in the body. To det. how D-psicose modifies lipid metab., rats were fed diets with or without 3% D-psicose for 4 wk. Rats were decapitated without fasting every 6 h over a period of 24 h. Changes in serum and liver lipid levels, liver enzyme activity, and gene expression were quantified in expt. 1. Rats fed D-psicose had significantly lower serum insulin and leptin levels. Liver enzyme activities involved in lipogenesis were significantly lowered by the D-psicose diet, whereas gene expression of a transcriptional modulator of fatty acid oxidn. was enhanced. In expt. 2, feeding the D-psicose diet gave significantly lower body wt. (389 ± 3 vs 426 ± 6 g, p < 0.05) and food intake (23.8 ± 0.2 vs 25.7 ± 0.4 g/day, p < 0.05) compared to the control diet. Rats fed the D-psicose diet gave significantly higher energy expenditure in the light period and fat oxidn. in the dark period compared to rats fed the control diet, whereas carbohydrate oxidn. was lower. In summary, these results indicate that the D-psicose diet decreases lipogenesis, increases fatty acid oxidn., and enhances 24 h energy expenditure, leading to D-psicose's potential for wt. management.
- 7Iida, T.; Kishimoto, Y.; Yoshikawa, Y.; Hayashi, N.; Okuma, K.; Tohi, M.; Yagi, K.; Matsuo, T.; Izumori, K. Acute d-psicose administration decreases the glycemic responses to an oral maltodextrin tolerance test in normal adults J. Nutr. Sci. Vitaminol. 2008, 54, 511– 514 DOI: 10.3177/jnsv.54.511Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhvVSqsA%253D%253D&md5=14e8d491e8a18da4eff0f662a8ded7d4Acute D-psicose administration decreases the glycemic responses to an oral maltodextrin tolerance test in normal adultsIida, Tetsuo; Kishimoto, Yuka; Yoshikawa, Yuko; Hayashi, Noriko; Okuma, Kazuhiro; Tohi, Mikiko; Yagi, Kanako; Matsuo, Tatsuhiro; Izumori, KenJournal of Nutritional Science and Vitaminology (2008), 54 (6), 511-514CODEN: JNSVA5; ISSN:0301-4800. (Center for Academic Publications Japan)An examn. was conducted to verify D-psicose suppressed the elevation of blood glucose and insulin concn. in a dose-dependent manner under the concurrent administration of maltodextrin and D-psicose to healthy humans. Twenty subjects aged 20-39 yr, 11 males and 9 females were recruited. A load test of oral maltodextrin was conducted as a randomized single blind study. The subjects took one of five test beverages (7.5 g D-psicose alone, 75 g maltodextrin alone, 75 g maltodextrin +2.5, 5 or 7.5 g D-psicose). Blood was collected before an intake and at 30, 60, 90 and 120 min after an intake. Intervals of administration were at least 1 wk. The load test with 75 g maltodextrin showed significant suppressions of the elevation of blood glucose and insulin concn. under the doses of 5 g or more D-psicose with dose dependency. An independent administration of 7.5 g D-psicose had no influence on blood glucose or insulin concn. D-Psicose is considered efficacious in the suppression of the elevation of blood glucose concn. after eating in humans.
- 8Hayashi, N.; Iida, T.; Yamada, T.; Okuma, K.; Takehara, I.; Yamamoto, T.; Yamada, K.; Tokuda, M. Study on the postprandial blood glucose suppression effect of d-psicose in borderline diabetes and the safety of long-term ingestion by normal human subjects Biosci., Biotechnol., Biochem. 2010, 74, 510– 519 DOI: 10.1271/bbb.90707Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXks1Cntbg%253D&md5=eadbaa0613167bc64b8316411e980d0dStudy on the postprandial blood glucose suppression effect of D-psicose in borderline diabetes and the safety of long-term ingestion by normal human subjectsHayashi, Noriko; Iida, Tetsuo; Yamada, Takako; Okuma, Kazuhiro; Takehara, Isao; Yamamoto, Takashi; Yamada, Koji; Tokuda, MasaakiBioscience, Biotechnology, and Biochemistry (2010), 74 (3), 510-519CODEN: BBBIEJ; ISSN:0916-8451. (Japan Society for Bioscience, Biotechnology, and Agrochemistry)This clin. study was conducted to investigate the safety and effect of D-psicose on postprandial blood glucose levels in adult men and women, including borderline diabetes patients. A randomized double-blind placebo-controlled crossover expt. of single ingestion was conducted on 26 subjects who consumed zero or 5 g of D-psicose in tea with a std. meal. The blood glucose levels at fasting and 30, 60, 90, and 120 min after the meal were compared. The blood glucose level was significantly lower 30 and 60 min after the meal with D-psicose (p < 0.01, p < 0.05), and a significant decrease was also shown in the area under the curve (p < 0.01). The results suggest that D-psicose had an effect to suppress the postprandial blood glucose elevation mainly in borderline diabetes cases. A randomized double-blind placebo-controlled parallel-group expt. of long-term ingestion was conducted on 17 normal subjects who took 5 g of D-psicose or D-glucose with meals three times a day for 12 continuous weeks. Neither any abnormal effects nor clin. problems caused by the continuous ingestion of D-psicose were found.
- 9Toyoda, Y.; Mori, S.; Umemura, N.; Futamura, N.; Inoue, H.; Hata, T.; Miwa, I.; Murao, K.; Nishiyama, A.; Tokuda, M. Suppression of blood glucose levels by d-psicose in glucose tolerance test in diabetic rats Jpn. Pharmacol. Ther. 2010, 38, 261– 269Google ScholarThere is no corresponding record for this reference.
- 10Hossain, M. A.; Kitagaki, S.; Nakano, D.; Nishiyama, A.; Funamoto, Y.; Matsunaga, T.; Tsukamoto, I.; Yamaguchi, F.; Kamitori, K.; Dong, Y.; Hirata, Y.; Murao, K.; Toyoda, Y.; Tokuda, M. Rare sugar d-psicose improves insulin sensitivity and glucose tolerance in type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats Biochem. Biophys. Res. Commun. 2011, 405, 7– 12 DOI: 10.1016/j.bbrc.2010.12.091Google ScholarThere is no corresponding record for this reference.
- 11Hishiike, T.; Ogawa, M.; Hayakawa, S.; Nakajima, D.; O’Charoen, S.; Ooshima, H.; Sun, Y. Transepithelial transports of rare sugar d-psicose in human intestine J. Agric. Food Chem. 2013, 61, 7381– 7386 DOI: 10.1021/jf401449mGoogle ScholarThere is no corresponding record for this reference.
- 12Printz, R. L.; Magnuson, M. A.; Granner, D. K. Mammalian glucokinase Annu. Rev. Nutr. 1993, 13, 463– 496 DOI: 10.1146/annurev.nu.13.070193.002335Google ScholarThere is no corresponding record for this reference.
- 13Matschinsky, F. M. Assessing the potential of glucokinase activators in diabetes therapy Nat. Rev. Drug Discovery 2009, 8, 399– 416 DOI: 10.1038/nrd2850Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXks1Shtro%253D&md5=148b05095b483e91a3898bbd6f31ba21Assessing the potential of glucokinase activators in diabetes therapyMatschinsky, Franz M.Nature Reviews Drug Discovery (2009), 8 (5), 399-416CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Glucokinase, a unique isoform of the hexokinase enzymes, which are known to phosphorylate D-glucose and other hexoses, was identified during the past three to four decades as a new, promising drug target for type 2 diabetes. Glucokinase serves as a glucose sensor of the insulin-producing pancreatic islet β-cells, controls the conversion of glucose to glycogen in the liver and regulates hepatic glucose prodn. Guided by this fundamental knowledge, several glucokinase activators are now being developed, and have so far been shown to lower blood glucose in several animal models of type 2 diabetes and in initial trials in humans with the disease. Here, the scientific basis and current status of this new approach to diabetes therapy are discussed.
- 14Agius, L.; Peak, M.; Newgard, C. B.; Gomez-Foix, A. M.; Guinovart, J. J. Evidence for a role of glucose-induced translocation of glucokinase in the control of hepatic glycogen synthesis J. Biol. Chem. 1996, 271, 30479– 30486 DOI: 10.1074/jbc.271.48.30479Google ScholarThere is no corresponding record for this reference.
- 15Detheux, M.; Vandercammen, A.; Van Schaftigen, E. Effectors of the regulatory protein acting on liver glucokinase: A kinetic investigation Eur. J. Biochem. 1991, 200, 553– 561 DOI: 10.1111/j.1432-1033.1991.tb16218.xGoogle Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXltlSms7s%253D&md5=92e18723d700cb557903203d660774d9Effectors of the regulatory protein acting on liver glucokinase: a kinetic investigationDetheux, Michel; Vandercammen, Annick; Van Schaftingen, EmileEuropean Journal of Biochemistry (1991), 200 (2), 553-61CODEN: EJBCAI; ISSN:0014-2956.In the absence of fructose 6-phosphate, the regulatory protein of rat liver glucokinase (hexokinase IV or D) inhibited this enzyme, though with a much (15-fold) lower potency than in the presence of a satg. concn. of fructose 6-phosphate. Evidence is provided that this inhibition is not due to contaminating fructose 6-phosphate. In the presence of regulatory protein, sorbitol 6-phosphate, a potent analog of fructose 6-phosphate, exerted a hyperpbolic, partial inhibition on glucokinase, the degree of which increased with the concn. of regulatory protein. Plots of the reciprocal of the difference between the rates in the absence and in the presence of sorbitol 6-phosphate vs. 1/[sorbitol 6-phosphate] at various concns. of regulatory protein were linear, and demonstrated that the apparent affinity of sorbitol 6-phosphate increased with the concn. of regulatory protein. Plots of the reciprocal of the difference between 1/v in the presence and in the absence of sorbitol 6-phosphate vs. 1/[sorbitol 6-phosphate] were also linear and crossed the axis at a value independent of the concn. of regulatory protein. Fructose 1-phosphate released the inhibition exerted by the regulatory protein in a hyperbolic fashion. The concn. of this effector required for a half-maximal effect increased linearly with the concn. of sorbitol 6-phosphate and of regulatory protein. These results are consistent with a model in which the regulatory protein exists under two conformations, one form which binds inhibitors and glucokinase, and the other which binds activators, although not glucokinase. Sorbitol 6-phosphate, 2-deoxysorbitol 6-phosphate and mannitol 1-phosphate, all analogs of the open-chain configuration of fructose 6-phosphate, inhibited glucokinase in the presence of regulatory protein at lower concns. than fructose 6-phosphate, whereas fixed analogs of the furanose form of fructose 6-phosphate were inactive or behaved as activators. This indicated that fructose 6-phosphate in its open-chain configuration is recognized by the regulatory protein. A series of compds. exerted an activating effect. These included, in order of decreasing potency: fructose 1-phosphate, psicose 1-phosphate, ribitol 5-phosphate, analogs of fructose 1-phosphate and of ribitol 5-phosphate and, at much higher concns., inorg. phosphate.
- 16Toyoda, Y.; Miwa, I.; Satake, S.; Anai, M.; Oka, Y. Nuclear location of the regulatory protein of glucokinase in rat liver and the translocation of the regulator to the cytoplasm response to high glucose Biochem. Biophys. Res. Commun. 1995, 215, 467– 473 DOI: 10.1006/bbrc.1995.2488Google ScholarThere is no corresponding record for this reference.
- 17Toyoda, Y.; Miwa, I.; Kamiya, M.; Ogiso, S.; Nonogaki, T.; Aoki, S.; Okuda, J. Evidence for glucokinase translocation by glucose in rat hepatocytes Biochem. Biophys. Res. Commun. 1994, 204, 252– 256 DOI: 10.1006/bbrc.1994.2452Google ScholarThere is no corresponding record for this reference.
- 18Toyoda, Y.; Miwa, I.; Kamiya, M.; Ogiso, S.; Nonogaki, T.; Aoki, S.; Okuda, J. Tissue and subcellular distribution of glucokinase in rat liver and their changes during fasting-refeeding Histochemistry 1995, 103, 31– 38 DOI: 10.1007/BF01464473Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjs1Kgtbo%253D&md5=126f4a38c3e692dc5f7981993bd145a3Tissue and subcellular distribution of glucokinase in rat liver and their changes during fasting-refeedingToyoda, Y.; Miwa, I.; Kamiya, M.; Ogiso, S.; Nonogaki, T.; Aoki, S.; Okuda, J.Histochemistry and Cell Biology (1995), 103 (1), 31-8CODEN: HCBIFP ISSN:. (Springer)The distribution of glucokinase in rat liver under both normal feeding and fasting-refeeding conditions was investigated immunohistochem. Under normal feeding conditions, glucokinase immunoreactivity was obsd. in both nuclei and cytoplasm of parenchymal cells. The nuclei were stained intensely and evenly, whereas the cytoplasm showed weak immunoreactivity of different degrees of staining intensity depending on the location of the cells. The cytoplasm of perivenous hepatocytes was stained more intensely, though not so much more, than that of periportal hepatocytes. The cytoplasm of hepatocytes surrounding the terminal hepatic venule (THV), of hepatocytes surrounding the portal triad, and of some other hepatocytes showed a stronger immunoreactivity than that of residual hepatocytes. The nuclear immunoreactivity in hepatocytes surrounding the portal triad and in some other hepatocytes was weak or absent, and pos. immunoreactivity was detected at the plasma membrane of some of these cells. After 72 h of fasting, glucokinase immunoreactivity was markedly decreased in all hepatocytes. After the start of refeeding, the cytoplasmic immunoreactivity began to increase first in the parenchymal cells surrounding the THV and extended to those in the intermediate zone followed by those in the periportal zone. In contrast, the increase in nuclear immunoreactivity started in hepatocytes situated in the intermediate zone adjacent to the perivenous zone and then extended to those in the perivenous zone followed by those in the perivenous zone followed by those in the periportal zone. Hepatocytes surrounding either THV or portal triad showed a distinctive change in immunoreactivity during the refeeding period. After 10 h of refeeding, strong immunoreactivity was obsd. in both the cytoplasm and the nuclei of all hepatocytes, and appreciable glucokinase immunoreactivity was detected at the plasma membrane of some hepatocytes. These findings are discussed from the standpoint of a functional role of glucokinase in hepatic glucose metab.
- 19Toyoda, Y.; Ito, Y.; Miwa, I.; Yoshie, S. Shuttling of glucokinase between nucleus and cytoplasm in primary cultures of rat hepatocytes: Possible involvement in the regulation of the glucose metabolism Arch. Histol. Cytol. 1997, 60, 307– 316 DOI: 10.1679/aohc.60.307Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmsVektro%253D&md5=268a6a8c308d39cf51324fafa4eda2e9Shuttling of glucokinase between the nucleus and the cytoplasm in primary cultures of rat hepatocytes: possible involvement in the regulation of the glucose metabolismToyoda, Yaukyasu; Ito, Yuki; Yoshie, Sumio; Miwa, IchitomoArchives of Histology and Cytology (1997), 60 (3), 307-316CODEN: AHCYEZ; ISSN:0914-9465. (International Society of Histology and Cytology)Glucokinase (GK) is believed to play a key role in the control of the hepatic glucose metab. To address the mechanism of the regulation of glucose metab. through GK action, we immunohistochem. studied changes in GK distribution in primary cultures of rat hepatocytes. In hepatocyte monolayers incubated in 5 mM glucose, GK staining by the immunoperoxidase method was obsd. predominantly in the nucleus. When cultured hepatocytes were incubated for 30 min in various concns. (5-45 mM) of glucose, there was an appreciable decrease in nuclear GK immunoreactivity, even at 10 mM compared with that at 5 mM. After the shift of glucose concn. from 5 mM to 25 mM, the GK distribution changes time-dependently over 1 h. A time-dependent change in GK distribution was also obsd. when the glucose concn. was shifted from 25 mM to 5 mM. Reversal of GK distribution in response to the change in glucose concn. from 5 to 25 mM and vice versa was shown to repeatedly occur. Lower concns. (0.05-5 mM) of fructose, which is known to stimulate glucose phosphorylation in GK, in combination with 5 mM glucose, induced the translocation of GK from the nucleus to the cytoplasm. Mannose (20 mM), a substrate of GK, and sorbitol (1 mM), a stimulator of glucose phosphorylation by GK, induced the translocation of GK from the nucleus to the cytoplasm in the presence of 5 mM glucose. L-Glucose, galactose, 3-O methylglucose, and 2-deoxyglucose at 20 mM each did not affect the GK distribution obsd. in the presence of 5 mM glucose. The results suggest that GK is present mainly in the nuclear under conditions where GK action is not much needed, whereas the enzyme exists mainly in the cytoplasm under conditions where it must function extensively. Our findings indicate that the shuttling of GK between the nucleus and the cytoplasm is essential for the regulation of the glucose metab. in the liver.
- 20Toyoda, Y.; Tsuchida, A.; Iwami, E.; Shironoguchi, I.; Miwa, I. Regulation of hepatic glucose metabolism by translocation of glucokinase between the nucleus and the cytoplasm in hepatocytes Horm. Metab. Res. 2001, 33, 329– 336 DOI: 10.1055/s-2001-15418Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlvVSms7w%253D&md5=1d232027f2885bbfe0cff4cfed7c72ceRegulation of hepatic glucose metabolism by translocation of glucokinase between the nucleus and the cytoplasm in hepatocytesToyoda, Y.; Tsuchida, A.; Iwami, E.; Shironoguchi, H.; Miwa, I.Hormone and Metabolic Research (2001), 33 (6), 329-336CODEN: HMMRA2; ISSN:0018-5043. (Georg Thieme Verlag)The authors studied the role of glucokinase translocation between the nucleus and the cytoplasm in hepatocytes. In cultured hepatocytes, both the translocation of glucokinase from the nucleus to the cytoplasm and the rate of glucose phosphorylation were increased when cells were incubated with high concns. of glucose. The addn. of low concns. of fructose, which is known to stimulate glucose phosphorylation, stimulated both glucokinase translocation and glucose phosphorylation. There was a good correlation between the increase in cytoplasmic glucokinase induced by fructose and that in the glucose phosphorylation rate induced by fructose. Furthermore, the authors obsd. a linear relationship between cytoplasmic glucokinase activity and rate of glucose phosphorylation over various glucose concns. in the absence or presence of fructose. These results indicate that glucose phosphorylation in hepatocytes depended on glucokinase in the cytoplasmic compartment - i.e., the increase in the rate of glucose phosphorylation was due to the increase in translocation of glucokinase out of the nucleus. Also, oral administration of glucose, fructose, or glucose plus fructose to 24-h fasted rats induced translocation of glucokinase in the liver. All of these results indicate that hepatic glucose metab. is regulated by the translocation of glucokinase.
- 21Takamine, S.; Nakamura, M.; Iida, T.; Okuma, K.; Izumori, K. Manufacturing method of rare sugar syrup through alkali isomerization and its inhibitory effect of α-glucosidase Bull. Appl. Glycosci. 2015, 5, 44– 49Google ScholarThere is no corresponding record for this reference.
- 22Iida, T.; Yamada, T.; Hayashi, N.; Okuma, K.; Izumori, K.; Ishii, R.; Matsuo, T. Reduction of abdominal fat accumulation in rats by 8-week ingestion of a newly developed sweetener made from high fructose corn syrup Food Chem. 2013, 138, 781– 785 DOI: 10.1016/j.foodchem.2012.11.017Google ScholarThere is no corresponding record for this reference.
- 23Hayashi, N.; Yamada, T.; Takamine, S.; Iida, T.; Okuma, K.; Tokuda, M. Weight reducing effect and safety evaluation of rare sugar syrup by a randomized double-blind, parallel-group study in human J. Funct. Foods 2014, 11, 152– 159 DOI: 10.1016/j.jff.2014.09.020Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslGrs7%252FO&md5=8634c359d54565fdac6205724649633bWeight reducing effect and safety evaluation of rare sugar syrup by a randomized double-blind, parallel-group study in humanHayashi, Noriko; Yamada, Takako; Takamine, Satoshi; Iida, Tetsuo; Okuma, Kazuhiro; Tokuda, MasaakiJournal of Functional Foods (2014), 11 (), 152-159CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)Rare sugar syrup is a sweetener obtained from high-fructose corn syrup under slightly alk. conditions, which promotes the formation of rare sugars. Here, the physiol. impact and safety of rare sugar syrup in humans was investigated by a randomized double-blind parallel expt. Thirty-four subjects with an av. body mass index of 25.6 kg/m2 were divided into two groups. Subjects consumed either a test drink contg. rare sugar syrup or an isocaloric control drink contg. high-fructose corn syrup on a daily basis for 12 wk. Results showed significant decreases in body wt., body fat percentage and waist circumference in the rare sugar syrup group compared to the control. No adverse events with regard to hepatic and renal function or blood parameters were obsd. Our study conclusively suggests, for the first time, that rare sugar syrup is a safe sweetener, and that continuous consumption of this syrup could help wt. management.
- 24Jürgens, H.; Haass, W.; Castañeda, T. R.; Schürmann, A.; Koebnick, C.; Dombrowski, F.; Otto, B.; Nawrocki, A. R.; Scherer, P. E.; Spranger, J.; Ristow, M.; Joost, H. G.; Havel, P. J.; Tschöp, M. H. Consuming fructose-sweetened beverages increases body adiposity in mice Obes. Res. 2005, 13, 1146– 56 DOI: 10.1038/oby.2005.136Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVSltrrI&md5=5b1981f7f2184c9cefec2c34929d8a51Consuming fructose-sweetened beverages increases body adiposity in miceJuergens, Hella; Haass, Wiltrud; Castaneda, Tamara R.; Schuermann, Annette; Koebnick, Corinna; Dombrowski, Frank; Otto, Baerbel; Nawrocki, Andrea R.; Scherer, Philipp E.; Spranger, Jochen; Ristow, Michael; Joost, Hans-Georg; Havel, Peter J.; Tschoep, Matthias H.Obesity Research (2005), 13 (7), 1146-1156CODEN: OBREFR; ISSN:1071-7323. (North American Association for the Study of Obesity)The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To det. if and how fructose might promote obesity in an animal model, we measured body compn., energy intake, energy expenditure, substrate oxidn., and several endocrine parameters related to energy homeostasis in mice consuming fructose. We compared the effects of ad libitum access to fructose (15% soln. in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metab. in mice. Results showed that exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased RQ, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic peri-central pattern. Therefore, a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.
- 25Toyoda, Y.; Ito, Y.; Tanigawa, K.; Miwa, I. Impairment of glucokinase translocation in cultured hepatocytes from OLETF and GK rats, animal models of type 2 diabetes Arch. Histol. Cytol. 2000, 63, 243– 248 DOI: 10.1679/aohc.63.243Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXms1OhsL8%253D&md5=94dfca708dbe394cac875e52d3f76e2aImpairment of glucokinase translocation in cultured hepatocytes from OLETF and GK rats, animal models of type 2 diabetesToyoda, Yukiyasu; Ito, Yuki; Tanigawa, Keiichiro; Miwa, IchitomoArchives of Histology and Cytology (2000), 63 (3), 243-248CODEN: AHCYEZ; ISSN:0914-9465. (International Society of Histology and Cytology)We examd. sugar-induced translocation of glucokinase in cultured hepatocytes from Otsuka Long-Evans Tokushima Fatty and Goto-Kakizaki rats, animal models of type 2 diabetes, and compared this with that in Long-Evans Tokushima Otsuka and Wistar rats, resp., as control strains. When hepatocytes from the four strains were incubated with 5 mM glucose, glucokinase was present predominantly in the nuclei. Higher concns. of glucose, 5 mM glucose plus 1 mM fructose, and 5 mM glucose plus 1 mM sorbitol all induced the translocation of glucokinase from the nucleus to the cytoplasm in hepatocytes from these rats. The extent of glucokinase translocation under these conditions, however, was less marked in both diabetic rat types than in the control rats. The extent of the phosphorylation of glucose as estd. by the release of 3H2O from [2-3H]glucose is significantly lower in Goto-Kakizaki rats than in Wistar rats. The results indicate that the translocation of glucokinase is impaired in the hepatocytes of diabetic rats. They also suggest that the impaired translocation of glucokinase is assocd. with abnormal hepatic glucose metab. in type 2 diabetes.
- 26Keppler, D.; Decker, K. Glycogen. Determination with amylglucosidase. In Methods of Enzymatic Analysis, 2nd ed.; Bergmeyer, H. U., Ed.; Academic Press: New York, 1974; Vol. 3, pp 1127– 1131.Google ScholarThere is no corresponding record for this reference.
- 27Yamada, T.; Iida, T.; Hayashi, N.; Oga, H.; Okuma, K.; Izumori, K. Effects of d-psicose on Body Fat Accumulation and High Fructose Corn Syrup Diets in Rats Nippon Shokuhin Kagaku Kogaku Kaishi 2010, 57, 263– 267 DOI: 10.3136/nskkk.57.263Google ScholarThere is no corresponding record for this reference.
- 28Baek, S. H.; Park, S. J.; Lee, H. G. d-Psicose, a sweet monosaccharide, ameliorate hyperglycemia, and dyslipidemia in C57BL/6J db/db mice J. Food Sci. 2010, 75, H49– 53 DOI: 10.1111/j.1750-3841.2009.01434.xGoogle Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjslCru7g%253D&md5=81aa750f71e9d152fd7e7d9244e9971eD-psicose, a sweet monosaccharide, ameliorate hyperglycemia, and dyslipidemia in C57BL/6J db/db miceBaek, S. H.; Park, S. J.; Lee, H. G.Journal of Food Science (2010), 75 (2), H49-H53CODEN: JFDSAZ; ISSN:0022-1147. (Wiley-Blackwell)D-psicose has been implicated in glycemic control in recent animal and human studies. In this study, the effects of D-psicose on glycemic responses, insulin release, and lipid profiles were compared with those of D-glucose and D-fructose in a genetic diabetes model. C57BL/6J db/db mice were orally supplemented with 200 mg/kg BW of D-psicose, D-glucose, or D-fructose, resp., while diabetes control or wild type mice were supplemented with water instead. D-psicose sustained wt. gain by about 10% compared to other groups. The initial blood glucose level maintained from 276 to 305 mg/dL during 28 d in the D-psicose group, whereas a 2-fold increase was found in other groups (P < 0.05) among diabetic mice. D-psicose significantly improved glucose tolerance and the areas under the curve (AUC) for glucose among diabetes (P < 0.05), but had no effect on serum insulin concn. The plasma lipid profile was not changed by supplemental monosaccharides, although the ratio of LDL-cholesterol/HDL-cholesterol was ameliorated by D-psicose. The administration of D-psicose reversed hepatic concns. of triglyceride (TG) and total cholesterol (TC) by 37.88% and 62.89%, resp., compared to the diabetes control (P < 0.05). The current findings suggest that D-psicose shows promise as an antidiabetic and may have antidyslipidemic effects in type 2 diabetes.
- 29Buemann, B.; Toubro, S.; Holst, J. J.; Rehfeld, J. F.; Bibby, B. M.; Astrup, A. d-Tagatose, a stereoisomer of d-fructose, increases blood uric acid concentration Metab., Clin. Exp. 2000, 49, 969– 976 DOI: 10.1053/meta.2000.7724Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtFShtrk%253D&md5=572209053ce452342f41f50f8c177de0D-tagatose, a stereoisomer of D-fructose, increases blood uric acid concentrationBuemann, Benjamin; Toubro, Soren; Holst, Jens Juul; Rehfeld, Jens F.; Bibby, Bo Martin; Astrup, ArneMetabolism, Clinical and Experimental (2000), 49 (8), 969-976CODEN: METAAJ; ISSN:0026-0495. (W. B. Saunders Co.)Dietary D-fructose increases uric acid prodn. by accelerating the degrdn. of purine nucleotides, probably via hepatocellular depletion of inorg. phosphate (Pi) and accumulation of D-fructose-1-phosphate. The hyperuricemic effect of D-tagatose may be greater than that of D-fructose, as the subsequent degrdn. of D-tagatose-1-phosphate is slower than the degrdn. of D-fructose-1-phosphate. We tested the effects of 30 g oral doses of D-tagatose and D-fructose on blood serum uric acid levels and other metabolic parameters in 8 men. Both the peak concns. and 4-h areas under the curve (AUC) of serum uric acid were higher after D-tagatose compared with D-fructose or plain water. The decline in serum Pi concns. was greater at 50 min after D-tagatose vs. D-fructose. The thermogenic and lactacidemic responses to D-tagatose were blunted compared with D-fructose. D-Tagatose attenuated the glycemic and insulinemic responses to a meal consumed 255 min after tagatose administration. Both fructose and D-tagatose increased plasma concns. of cholecystokinin and glucagon-like peptide-1 (GLP-1). The metabolic effects of D-tagatose occurred despite its putative poor absorption.
- 30Yamada, T.; Hayashi, N.; Iida, T.; Takamine, S.; Okuma, K.; Matsuo, T. Dietary d-sorbose decreases serum insulin levels in growing Sprague-Dawley rats J. Nutr. Sci. Vitaminol. 2014, 60, 297– 299 DOI: 10.3177/jnsv.60.297Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFaksr7K&md5=1e00dd062fcd35f272cbecc237285df0Dietary D-sorbose decreases serum insulin levels in growing Sprague-Dawley ratsYamada, Takako; Hayashi, Noriko; Iida, Tetsuo; Takamine, Satoshi; Okuma, Kazuhiro; Matsuo, TatsuhiroJournal of Nutritional Science and Vitaminology (2014), 60 (4), 297-299CODEN: JNSVA5; ISSN:0301-4800. (Center for Academic Publications Japan)D-Sorbose is naturally occurring rare sugar. In this study, we examd. the effects of dietary D-sorbose in rats. Four-week-old male Sprague-Dawley rats were fed either an AIN-93G-based control diet or a 3% D-sorbose diet for 28 d. Body wt. and body fat accumulation were not different between the two diet groups. Dietary supplementation of D-sorbose lowered the serum insulin level (*p<0.05) significantly compared to the control, although the glucose was not changed. In addn., the relative wt. of the cecum increased significantly in the D-sorbose group (**p<0.01). These findings suggest that intake of D-sorbose may improve the glucose metab. by reducing insulin secretion, and D-sorbose can be used as a food ingredient.
- 31Oku, T.; Murata-Takenoshita, Y.; Yamazaki, Y.; Shimura, F.; Nakamura, S. d-Sorbose inhibits disaccharidase activity and demonstrates suppressive action on postprandial blood levels of glucose and insulin in the rat Nutr. Res. (N. Y., NY, U. S.) 2014, 34, 961– 967 DOI: 10.1016/j.nutres.2014.09.009Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslCitLrK&md5=af2c5cc0fa5f863c702f77dc3c05e01aD-Sorbose inhibits disaccharidase activity and demonstrates suppressive action on postprandial blood levels of glucose and insulin in the ratOku, Tsuneyuki; Murata-Takenoshita, Yoko; Yamazaki, Yuko; Shimura, Fumio; Nakamura, SadakoNutrition Research (New York, NY, United States) (2014), 34 (11), 961-967CODEN: NTRSDC; ISSN:0271-5317. (Elsevier)In an attempt to develop D-sorbose as a new sweetener that could help in preventing lifestyle-related diseases, we investigated the inhibitory effect of D-sorbose on disaccharidase activity, using the brush border membrane vesicles of rat small intestines. The inhibitory effect was compared with that of L-sorbose and other rare sugars, and the small intestinal disaccharidases in rats was compared with that of humans as well. In humans and the small intestines of rats, D-sorbose strongly inhibited sucrase activity and weakly inhibited maltase activity. Inhibition by D-sorbose of sucrase activity was similar to that of L-arabinose, and the Ki of D-sorbose was 7.5 mM. Inhibition by D-sorbose was very strong in comparison with that of L-sorbose (Ki, 60.8 mM), whereas inhibition of D-tagatose was between that of D-sorbose and L-sorbose. The inhibitory mode of D-sorbose for sucrose and maltase was uncompetitive, and that of L-sorbose was competitive. To det. a suppressive effect on postprandial blood levels of glucose and insulin via inhibition of sucrase activity, sucrose soln. with or without D-sorbose was administered to rats. Increments in the blood levels of glucose and insulin were suppressed significantly after administration of sucrose soln. with D-sorbose to rats, in comparison to administration of sucrose soln. without D-sorbose. In contrast, the suppressive effect of L-sorbose on postprandial blood levels of glucose and insulin was very weak. These results suggest that D-sorbose may have an inhibitory effect on disaccharidase activity and could be used as a sweetener to suppress the postprandial elevation of blood levels of glucose and insulin. The use of D-sorbose as a sweetener may contribute to the prevention of lifestyle-related diseases, such as type 2 diabetes mellitus.
- 32Hawkins, M.; Gabriely, I.; Wozniak, R.; Vilcu, C.; Shamoon, H.; Rossetti, L. Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes Diabetes 2002, 51, 606– 614 DOI: 10.2337/diabetes.51.3.606Google ScholarThere is no corresponding record for this reference.
- 33Perreault, L.; Færch, K.; Kerege, A. A.; Bacon, S. D.; Bergman, B. C. Hepatic glucose sensing is impaired, but can be normalized, in people with impaired fasting glucose J. Clin. Endocrinol. Metab. 2014, 99, E1154– 1162 DOI: 10.1210/jc.2013-3248Google ScholarThere is no corresponding record for this reference.
- 34Trus, M.; Zawalich, H.; Gaynor, D.; Matschinsky, F. Hexokinase and glucokinase distribution in the liver lobule J. Histochem. Cytochem. 1980, 28, 579– 581 DOI: 10.1177/28.6.7391551Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXksVagsr4%253D&md5=30616655b68e752c21c8b8649d75ef4cHexokinase and glucokinase distribution in the liver lobuleTrus, Michael; Zawalich, Kathleen; Gaynor, Deborah; Matschinsky, FranzJournal of Histochemistry and Cytochemistry (1980), 28 (6), 579-81CODEN: JHCYAS; ISSN:0022-1554.Zone 1 and zone 3 of rat livers were identified by differential staining for succinate dehydrogenase, and their hexokinase (I) and glucokinase (II) contents were examd. The activities of I and II exhibited gradients in opposite directions. The I content of zones 1 and 3 was 116 mmol/kg dry wt./h and 61.6 mmol/kg/h, resp., whereas the II content was 210 mmol/kg/h and 349 mmol/kg/h, resp. The av. II activity from both regions was 76% of the total glucose phosphorylating activity measured in lyophilized liver specimens.
- 35Agius, L. Control of glucokinase translocation in rat hepatocytes by sorbitol and the cytosolic redox state Biochem. J. 1994, 298, 237– 243 DOI: 10.1042/bj2980237Google ScholarThere is no corresponding record for this reference.
- 36Wu, C.; Kang, J. E.; Peng, L. J.; Li, H.; Khan, S. A.; Hillard, C. J.; Okar, D. A.; Lange, A. J. Enhancing hepatic glycolysis reduces obesity: Differential effects on lipogenesis depend on site of glycolytic modulation Cell Metab. 2005, 2, 131– 140 DOI: 10.1016/j.cmet.2005.07.003Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXps12ht7k%253D&md5=4bde4bc418fe21dc25f27b42736f79e7Enhancing hepatic glycolysis reduces obesity: Differential effects on lipogenesis depend on site of glycolytic modulationWu, Chaodong; Kang, Johnthomas E.; Peng, Li-Jen; Li, Honggui; Khan, Salmaan A.; Hillard, Christopher J.; Okar, David A.; Lange, Alex J.Cell Metabolism (2005), 2 (2), 131-140CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)Reducing obesity requires an elevation of energy expenditure and/or a suppression of food intake. Here we show that enhancing hepatic glycolysis reduces body wt. and adiposity in obese mice. Overexpression of glucokinase or 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is used to increase hepatic glycolysis. Either of the two treatments produces similar increases in rates of fatty acid oxidn. in extrahepatic tissues, i.e., skeletal muscle, leading to an elevation of energy expenditure. However, only 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase overexpression causes a suppression of food intake and a decrease in hypothalamic neuropeptide Y expression, contributing to a more pronounced redn. of body wt. with this treatment. Furthermore, the two treatments cause differential lipid profiles due to opposite effects on hepatic lipogenesis, assocd. with distinct phosphorylation states of carbohydrate response element binding protein and AMP-activated protein kinase. The step at which hepatic glycolysis is enhanced dramatically influences overall whole-body energy balance and lipid profiles.
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Abstract
Figure 1
Figure 1. Changes in (A) body weight, (B) total calorie intake, and (C) abdominal fat weight in rats administrated water, RSS, and HFCS. Data are expressed as the mean ± SD (n = 12 for A and B, and n = 4–5 for C). Different letters (a, b, and c) show a significant difference at p < 0.05.
Figure 2
Figure 2. Effects of water, RSS, and HFCS on plasma glucose and insulin levels during the oral glucose tolerance test at 8 weeks: (A) plasma glucose, (B) AUC of plasma glucose, (C) insulin, and (D) AUC of insulin. Data are expressed as the mean ± SD (n = 4). Different letters (a, b, and c) show a significant difference at p < 0.05.
Figure 3
Figure 3. Effects of water, RSS, and HFCS on glucose levels during the insulin tolerance test at 8 weeks. Data are expressed as a percentage of values at 0 min. Data are expressed as the mean ± SD (n = 4). Different letters (a, b, and c) show a significant difference at p < 0.05.
Figure 4
Figure 4. Effects of water, RSS, and HFCS on (A) plasma glucose levels, (B) insulin levels, and (C) hepatic glycogen levels during the oral glucose tolerance test at 10 weeks. Data are expressed as the mean ± SD (n = 4). Different letters (a, b, and c) show a significant difference at p < 0.05 among the three groups at 0 or 30 min. (∗) Significant difference at p < 0.05 compared to the corresponding group at 0 min.
Figure 5
Figure 5. Effects of water, RSS, and HFCS on nuclear export of GK in the perivenous and periportal zones in the liver: (A) representative picture of immunohistochemical staining of GK in the perivenous (PV) and periportal (PP) zones from rats administered water (upper), HFCS (middle), and RSS (lower) at 0 min, (B) representative picture of immunohistochemical staining of GK in the PV and PP zones from rats administered water (upper), HFCS (middle), and RSS (lower) at 30 min after glucose loading, (C) distribution of GK in the cytoplasm in the perivenous zone at 0 and 30 min after glucose loading, and (D) distribution of GK in the cytoplasm in the periportal zone at 0 and 30 min after glucose loading. Data are expressed as the mean ± SD (n = 4). Different letters (a, b, and c) show a significant difference at p < 0.05 among the three groups at 0 or 30 min. (∗) Significant difference at p < 0.05 compared to the corresponding group at 0 min.
References
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- 2Hossain, M. A.; Yamaguchi, F.; Matsuo, T.; Tsukamoto, I.; Toyoda, Y.; Ogawa, M.; Nagata, Y.; Tokuda, M. Rare sugar d-allulose: Potential role and therapeutic monitoring in maintaining obesity and type 2 diabetes mellitus Pharmacol. Ther. 2015, 155, 49– 59 DOI: 10.1016/j.pharmthera.2015.08.004Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlylsL7I&md5=26026310302d36825f08f1e8c5f04ccfRare sugar D-allulose: Potential role and therapeutic monitoring in maintaining obesity and type 2 diabetes mellitusHossain, Akram; Yamaguchi, Fuminori; Matsuo, Tatsuhiro; Tsukamoto, Ikuko; Toyoda, Yukiyasu; Ogawa, Masahiro; Nagata, Yasuo; Tokuda, MasaakiPharmacology & Therapeutics (2015), 155 (), 49-59CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Obesity and type 2 diabetes mellitus (T2DM) are the leading worldwide risk factors for mortality. The inextricably interlinked pathol. progression from excessive wt. gain, obesity, and hyperglycemia to T2DM, usually commencing from obesity, typically originates from overconsumption of sugar and high-fat diets. Although most patients require medications, T2DM is manageable or even preventable with consumption of low-calorie diet and maintaining body wt. Medicines like insulin, metformin, and thiazolidinediones that improve glycemic control; however, these are assocd. with wt. gain, high blood pressure, and dyslipidemia. These situations warrant the attentive consideration of the role of balanced foods. Recently, we have discovered advantages of a rare sugar, D-allulose, a zero-calorie functional sweetener having strong anti-hyperlipidemic and anti-hyperglycemic effects. Study revealed that after oral administration in rats D-allulose readily entered the blood stream and was eliminated into urine within 24 h. Cell culture study showed that D-allulose enters into and leaves the intestinal enterocytes via glucose transporters GLUT5 and GLUT2, resp. In addn. to D-allulose's short-term effects, the characterization of long-term effects has been focused on preventing commencement and progression of T2DM in diabetic rats. Human trials showed that D-allulose attenuates postprandial glucose levels in healthy subjects and in borderline diabetic subjects. The anti-hyperlipidemic effect of D-allulose, combined with its anti-inflammatory actions on adipocytes, is beneficial for the prevention of both obesity and atherosclerosis and is accompanied by improvements in insulin resistance and impaired glucose tolerance. Therefore, this review presents brief discussions focusing on physiol. functions and potential benefits of D-allulose on obesity and T2DM.
- 3Matsuo, T.; Izumori, K. d-Psicose inhibits intestinal α-glucosidase and suppresses the glycemic response after Ingestion of carbohydrates in rats J. Clin. Biochem. Nutr. 2009, 45, 202– 206 DOI: 10.3164/jcbn.09-36Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlWrsbjM&md5=4f3063a08f0f09f314cf3cfdbd05e1caD-psicose inhibits intestinal α-glucosidase and suppresses the glycemic response after ingestion of carbohydrates in ratsMatsuo, Tatsuhiro; Izumori, KenJournal of Clinical Biochemistry and Nutrition (2009), 45 (2), 202-206CODEN: JCBNER; ISSN:0912-0009. (Society for Free Radical Research Japan)D-psicose is one of the rare sugars present in small quantities in com. carbohydrates and agricultural products. In this study, we investigated the effects of D-psicose on the activities of α-amylases and α-glucosidases in vitro, and evaluated the effects of D-psicose on the in vivo postprandial glycemic response using rats. In the in vitro study, D-psicose potently inhibited the intestinal sucrase and maltase, however, slightly inhibited the intestinal and salivary α-amylase activities. Male Wistar rats (6 mo old) were administrated 2 g/kg of sucrose, maltose or sol. starch together with 0.2 g/kg of D-psicose or D-fructose. The D-psicose significantly inhibited the increment of plasma glucose concn. induced by sucrose or maltose. The starch-induced glycemic response tended to be suppressed by D-psicose, however the suppression was not significant. These results suggest that D-psicose inhibits intestinal sucrase and maltase activities and suppresses the plasma glucose increase the normally occurs after sucrose and maltose ingestion. Thus, D-psicose may be useful in preventing postprandial hyperglycemia in diabetic patients when foods contg. sucrose and maltose are ingested.
- 4Ochiai, M.; Nakanishi, Y.; Yamada, T.; Iida, T.; Matsuo, T. Inhibition by dietary d-psicose of body fat accumulation in adult rats fed a high-sucrose diet Biosci., Biotechnol., Biochem. 2013, 77, 1123– 1126 DOI: 10.1271/bbb.130019Google ScholarThere is no corresponding record for this reference.
- 5Ochiai, M.; Onishi, K.; Yamada, T.; Iida, T.; Matsuo, T. d-Psicose increases energy expenditure and decreases body fat accumulation in rats fed a high-sucrose diet Int. J. Food Sci. Nutr. 2014, 65, 245– 250 DOI: 10.3109/09637486.2013.845653Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXisF2mt7c%253D&md5=bc40d3a508649668407e9246ca394591D-Psicose increases energy expenditure and decreases body fat accumulation in rats fed a high-sucrose dietOchiai, Masaru; Onishi, Kana; Yamada, Takako; Iida, Tetsuo; Matsuo, TatsuhiroInternational Journal of Food Sciences and Nutrition (2014), 65 (2), 245-250CODEN: IJFNEH; ISSN:0963-7486. (Informa Healthcare)We investigated the anti-obesity effects of D-psicose by increasing energy expenditure in rats pair-fed the high-sucrose diet (HSD). Wistar rats were divided into two dietary groups: HSD contg. 5% cellulose (C) and 5% D-psicose (P). The C dietary group was further subdivided into two groups: rats fed the C diet ad libitum (C-AD) and pair-fed the C diet along with those in the P group (C-PF). Resting energy expenditure during darkness and lipoprotein lipase activity in the soleus muscle were significantly higher in the P group than in the C-PF group. Serum levels of glucose, leptin and adiponectin; glucose-6-phosphate dehydrogenase activities in the liver and perirenal adipose tissue; and body fat accumulation were all significantly lower in the P group than in the C-PF group. The anti-obesity effects of D-psicose could be induced not only by suppressing lipogenic enzyme activity but also by increasing EE in rats.
- 6Nagata, Y.; Kanasaki, A.; Tamaru, S.; Tanaka, K. d-Psicose, an epimer of d-fructose, favorably alters lipid metabolism in Sprague-Dawley rats J. Agric. Food Chem. 2015, 63, 3168– 3176 DOI: 10.1021/jf502535pGoogle Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjvFymtLc%253D&md5=ac59ebda95507cb4888eb9b3754f7f91D-Psicose, an Epimer of D-Fructose, Favorably Alters Lipid Metabolism in Sprague-Dawley RatsNagata, Yasuo; Kanasaki, Akane; Tamaru, Shizuka; Tanaka, KazunariJournal of Agricultural and Food Chemistry (2015), 63 (12), 3168-3176CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)D-Psicose, a C3 epimer of D-fructose, is known to lower body wt. and adipose tissue wt. and affect lipid metab. The precise mechanism remains unknown. It has been reported that D-psicose has a short half-life and is not metabolized in the body. To det. how D-psicose modifies lipid metab., rats were fed diets with or without 3% D-psicose for 4 wk. Rats were decapitated without fasting every 6 h over a period of 24 h. Changes in serum and liver lipid levels, liver enzyme activity, and gene expression were quantified in expt. 1. Rats fed D-psicose had significantly lower serum insulin and leptin levels. Liver enzyme activities involved in lipogenesis were significantly lowered by the D-psicose diet, whereas gene expression of a transcriptional modulator of fatty acid oxidn. was enhanced. In expt. 2, feeding the D-psicose diet gave significantly lower body wt. (389 ± 3 vs 426 ± 6 g, p < 0.05) and food intake (23.8 ± 0.2 vs 25.7 ± 0.4 g/day, p < 0.05) compared to the control diet. Rats fed the D-psicose diet gave significantly higher energy expenditure in the light period and fat oxidn. in the dark period compared to rats fed the control diet, whereas carbohydrate oxidn. was lower. In summary, these results indicate that the D-psicose diet decreases lipogenesis, increases fatty acid oxidn., and enhances 24 h energy expenditure, leading to D-psicose's potential for wt. management.
- 7Iida, T.; Kishimoto, Y.; Yoshikawa, Y.; Hayashi, N.; Okuma, K.; Tohi, M.; Yagi, K.; Matsuo, T.; Izumori, K. Acute d-psicose administration decreases the glycemic responses to an oral maltodextrin tolerance test in normal adults J. Nutr. Sci. Vitaminol. 2008, 54, 511– 514 DOI: 10.3177/jnsv.54.511Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhvVSqsA%253D%253D&md5=14e8d491e8a18da4eff0f662a8ded7d4Acute D-psicose administration decreases the glycemic responses to an oral maltodextrin tolerance test in normal adultsIida, Tetsuo; Kishimoto, Yuka; Yoshikawa, Yuko; Hayashi, Noriko; Okuma, Kazuhiro; Tohi, Mikiko; Yagi, Kanako; Matsuo, Tatsuhiro; Izumori, KenJournal of Nutritional Science and Vitaminology (2008), 54 (6), 511-514CODEN: JNSVA5; ISSN:0301-4800. (Center for Academic Publications Japan)An examn. was conducted to verify D-psicose suppressed the elevation of blood glucose and insulin concn. in a dose-dependent manner under the concurrent administration of maltodextrin and D-psicose to healthy humans. Twenty subjects aged 20-39 yr, 11 males and 9 females were recruited. A load test of oral maltodextrin was conducted as a randomized single blind study. The subjects took one of five test beverages (7.5 g D-psicose alone, 75 g maltodextrin alone, 75 g maltodextrin +2.5, 5 or 7.5 g D-psicose). Blood was collected before an intake and at 30, 60, 90 and 120 min after an intake. Intervals of administration were at least 1 wk. The load test with 75 g maltodextrin showed significant suppressions of the elevation of blood glucose and insulin concn. under the doses of 5 g or more D-psicose with dose dependency. An independent administration of 7.5 g D-psicose had no influence on blood glucose or insulin concn. D-Psicose is considered efficacious in the suppression of the elevation of blood glucose concn. after eating in humans.
- 8Hayashi, N.; Iida, T.; Yamada, T.; Okuma, K.; Takehara, I.; Yamamoto, T.; Yamada, K.; Tokuda, M. Study on the postprandial blood glucose suppression effect of d-psicose in borderline diabetes and the safety of long-term ingestion by normal human subjects Biosci., Biotechnol., Biochem. 2010, 74, 510– 519 DOI: 10.1271/bbb.90707Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXks1Cntbg%253D&md5=eadbaa0613167bc64b8316411e980d0dStudy on the postprandial blood glucose suppression effect of D-psicose in borderline diabetes and the safety of long-term ingestion by normal human subjectsHayashi, Noriko; Iida, Tetsuo; Yamada, Takako; Okuma, Kazuhiro; Takehara, Isao; Yamamoto, Takashi; Yamada, Koji; Tokuda, MasaakiBioscience, Biotechnology, and Biochemistry (2010), 74 (3), 510-519CODEN: BBBIEJ; ISSN:0916-8451. (Japan Society for Bioscience, Biotechnology, and Agrochemistry)This clin. study was conducted to investigate the safety and effect of D-psicose on postprandial blood glucose levels in adult men and women, including borderline diabetes patients. A randomized double-blind placebo-controlled crossover expt. of single ingestion was conducted on 26 subjects who consumed zero or 5 g of D-psicose in tea with a std. meal. The blood glucose levels at fasting and 30, 60, 90, and 120 min after the meal were compared. The blood glucose level was significantly lower 30 and 60 min after the meal with D-psicose (p < 0.01, p < 0.05), and a significant decrease was also shown in the area under the curve (p < 0.01). The results suggest that D-psicose had an effect to suppress the postprandial blood glucose elevation mainly in borderline diabetes cases. A randomized double-blind placebo-controlled parallel-group expt. of long-term ingestion was conducted on 17 normal subjects who took 5 g of D-psicose or D-glucose with meals three times a day for 12 continuous weeks. Neither any abnormal effects nor clin. problems caused by the continuous ingestion of D-psicose were found.
- 9Toyoda, Y.; Mori, S.; Umemura, N.; Futamura, N.; Inoue, H.; Hata, T.; Miwa, I.; Murao, K.; Nishiyama, A.; Tokuda, M. Suppression of blood glucose levels by d-psicose in glucose tolerance test in diabetic rats Jpn. Pharmacol. Ther. 2010, 38, 261– 269Google ScholarThere is no corresponding record for this reference.
- 10Hossain, M. A.; Kitagaki, S.; Nakano, D.; Nishiyama, A.; Funamoto, Y.; Matsunaga, T.; Tsukamoto, I.; Yamaguchi, F.; Kamitori, K.; Dong, Y.; Hirata, Y.; Murao, K.; Toyoda, Y.; Tokuda, M. Rare sugar d-psicose improves insulin sensitivity and glucose tolerance in type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats Biochem. Biophys. Res. Commun. 2011, 405, 7– 12 DOI: 10.1016/j.bbrc.2010.12.091Google ScholarThere is no corresponding record for this reference.
- 11Hishiike, T.; Ogawa, M.; Hayakawa, S.; Nakajima, D.; O’Charoen, S.; Ooshima, H.; Sun, Y. Transepithelial transports of rare sugar d-psicose in human intestine J. Agric. Food Chem. 2013, 61, 7381– 7386 DOI: 10.1021/jf401449mGoogle ScholarThere is no corresponding record for this reference.
- 12Printz, R. L.; Magnuson, M. A.; Granner, D. K. Mammalian glucokinase Annu. Rev. Nutr. 1993, 13, 463– 496 DOI: 10.1146/annurev.nu.13.070193.002335Google ScholarThere is no corresponding record for this reference.
- 13Matschinsky, F. M. Assessing the potential of glucokinase activators in diabetes therapy Nat. Rev. Drug Discovery 2009, 8, 399– 416 DOI: 10.1038/nrd2850Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXks1Shtro%253D&md5=148b05095b483e91a3898bbd6f31ba21Assessing the potential of glucokinase activators in diabetes therapyMatschinsky, Franz M.Nature Reviews Drug Discovery (2009), 8 (5), 399-416CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Glucokinase, a unique isoform of the hexokinase enzymes, which are known to phosphorylate D-glucose and other hexoses, was identified during the past three to four decades as a new, promising drug target for type 2 diabetes. Glucokinase serves as a glucose sensor of the insulin-producing pancreatic islet β-cells, controls the conversion of glucose to glycogen in the liver and regulates hepatic glucose prodn. Guided by this fundamental knowledge, several glucokinase activators are now being developed, and have so far been shown to lower blood glucose in several animal models of type 2 diabetes and in initial trials in humans with the disease. Here, the scientific basis and current status of this new approach to diabetes therapy are discussed.
- 14Agius, L.; Peak, M.; Newgard, C. B.; Gomez-Foix, A. M.; Guinovart, J. J. Evidence for a role of glucose-induced translocation of glucokinase in the control of hepatic glycogen synthesis J. Biol. Chem. 1996, 271, 30479– 30486 DOI: 10.1074/jbc.271.48.30479Google ScholarThere is no corresponding record for this reference.
- 15Detheux, M.; Vandercammen, A.; Van Schaftigen, E. Effectors of the regulatory protein acting on liver glucokinase: A kinetic investigation Eur. J. Biochem. 1991, 200, 553– 561 DOI: 10.1111/j.1432-1033.1991.tb16218.xGoogle Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3MXltlSms7s%253D&md5=92e18723d700cb557903203d660774d9Effectors of the regulatory protein acting on liver glucokinase: a kinetic investigationDetheux, Michel; Vandercammen, Annick; Van Schaftingen, EmileEuropean Journal of Biochemistry (1991), 200 (2), 553-61CODEN: EJBCAI; ISSN:0014-2956.In the absence of fructose 6-phosphate, the regulatory protein of rat liver glucokinase (hexokinase IV or D) inhibited this enzyme, though with a much (15-fold) lower potency than in the presence of a satg. concn. of fructose 6-phosphate. Evidence is provided that this inhibition is not due to contaminating fructose 6-phosphate. In the presence of regulatory protein, sorbitol 6-phosphate, a potent analog of fructose 6-phosphate, exerted a hyperpbolic, partial inhibition on glucokinase, the degree of which increased with the concn. of regulatory protein. Plots of the reciprocal of the difference between the rates in the absence and in the presence of sorbitol 6-phosphate vs. 1/[sorbitol 6-phosphate] at various concns. of regulatory protein were linear, and demonstrated that the apparent affinity of sorbitol 6-phosphate increased with the concn. of regulatory protein. Plots of the reciprocal of the difference between 1/v in the presence and in the absence of sorbitol 6-phosphate vs. 1/[sorbitol 6-phosphate] were also linear and crossed the axis at a value independent of the concn. of regulatory protein. Fructose 1-phosphate released the inhibition exerted by the regulatory protein in a hyperbolic fashion. The concn. of this effector required for a half-maximal effect increased linearly with the concn. of sorbitol 6-phosphate and of regulatory protein. These results are consistent with a model in which the regulatory protein exists under two conformations, one form which binds inhibitors and glucokinase, and the other which binds activators, although not glucokinase. Sorbitol 6-phosphate, 2-deoxysorbitol 6-phosphate and mannitol 1-phosphate, all analogs of the open-chain configuration of fructose 6-phosphate, inhibited glucokinase in the presence of regulatory protein at lower concns. than fructose 6-phosphate, whereas fixed analogs of the furanose form of fructose 6-phosphate were inactive or behaved as activators. This indicated that fructose 6-phosphate in its open-chain configuration is recognized by the regulatory protein. A series of compds. exerted an activating effect. These included, in order of decreasing potency: fructose 1-phosphate, psicose 1-phosphate, ribitol 5-phosphate, analogs of fructose 1-phosphate and of ribitol 5-phosphate and, at much higher concns., inorg. phosphate.
- 16Toyoda, Y.; Miwa, I.; Satake, S.; Anai, M.; Oka, Y. Nuclear location of the regulatory protein of glucokinase in rat liver and the translocation of the regulator to the cytoplasm response to high glucose Biochem. Biophys. Res. Commun. 1995, 215, 467– 473 DOI: 10.1006/bbrc.1995.2488Google ScholarThere is no corresponding record for this reference.
- 17Toyoda, Y.; Miwa, I.; Kamiya, M.; Ogiso, S.; Nonogaki, T.; Aoki, S.; Okuda, J. Evidence for glucokinase translocation by glucose in rat hepatocytes Biochem. Biophys. Res. Commun. 1994, 204, 252– 256 DOI: 10.1006/bbrc.1994.2452Google ScholarThere is no corresponding record for this reference.
- 18Toyoda, Y.; Miwa, I.; Kamiya, M.; Ogiso, S.; Nonogaki, T.; Aoki, S.; Okuda, J. Tissue and subcellular distribution of glucokinase in rat liver and their changes during fasting-refeeding Histochemistry 1995, 103, 31– 38 DOI: 10.1007/BF01464473Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2MXjs1Kgtbo%253D&md5=126f4a38c3e692dc5f7981993bd145a3Tissue and subcellular distribution of glucokinase in rat liver and their changes during fasting-refeedingToyoda, Y.; Miwa, I.; Kamiya, M.; Ogiso, S.; Nonogaki, T.; Aoki, S.; Okuda, J.Histochemistry and Cell Biology (1995), 103 (1), 31-8CODEN: HCBIFP ISSN:. (Springer)The distribution of glucokinase in rat liver under both normal feeding and fasting-refeeding conditions was investigated immunohistochem. Under normal feeding conditions, glucokinase immunoreactivity was obsd. in both nuclei and cytoplasm of parenchymal cells. The nuclei were stained intensely and evenly, whereas the cytoplasm showed weak immunoreactivity of different degrees of staining intensity depending on the location of the cells. The cytoplasm of perivenous hepatocytes was stained more intensely, though not so much more, than that of periportal hepatocytes. The cytoplasm of hepatocytes surrounding the terminal hepatic venule (THV), of hepatocytes surrounding the portal triad, and of some other hepatocytes showed a stronger immunoreactivity than that of residual hepatocytes. The nuclear immunoreactivity in hepatocytes surrounding the portal triad and in some other hepatocytes was weak or absent, and pos. immunoreactivity was detected at the plasma membrane of some of these cells. After 72 h of fasting, glucokinase immunoreactivity was markedly decreased in all hepatocytes. After the start of refeeding, the cytoplasmic immunoreactivity began to increase first in the parenchymal cells surrounding the THV and extended to those in the intermediate zone followed by those in the periportal zone. In contrast, the increase in nuclear immunoreactivity started in hepatocytes situated in the intermediate zone adjacent to the perivenous zone and then extended to those in the perivenous zone followed by those in the perivenous zone followed by those in the periportal zone. Hepatocytes surrounding either THV or portal triad showed a distinctive change in immunoreactivity during the refeeding period. After 10 h of refeeding, strong immunoreactivity was obsd. in both the cytoplasm and the nuclei of all hepatocytes, and appreciable glucokinase immunoreactivity was detected at the plasma membrane of some hepatocytes. These findings are discussed from the standpoint of a functional role of glucokinase in hepatic glucose metab.
- 19Toyoda, Y.; Ito, Y.; Miwa, I.; Yoshie, S. Shuttling of glucokinase between nucleus and cytoplasm in primary cultures of rat hepatocytes: Possible involvement in the regulation of the glucose metabolism Arch. Histol. Cytol. 1997, 60, 307– 316 DOI: 10.1679/aohc.60.307Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXmsVektro%253D&md5=268a6a8c308d39cf51324fafa4eda2e9Shuttling of glucokinase between the nucleus and the cytoplasm in primary cultures of rat hepatocytes: possible involvement in the regulation of the glucose metabolismToyoda, Yaukyasu; Ito, Yuki; Yoshie, Sumio; Miwa, IchitomoArchives of Histology and Cytology (1997), 60 (3), 307-316CODEN: AHCYEZ; ISSN:0914-9465. (International Society of Histology and Cytology)Glucokinase (GK) is believed to play a key role in the control of the hepatic glucose metab. To address the mechanism of the regulation of glucose metab. through GK action, we immunohistochem. studied changes in GK distribution in primary cultures of rat hepatocytes. In hepatocyte monolayers incubated in 5 mM glucose, GK staining by the immunoperoxidase method was obsd. predominantly in the nucleus. When cultured hepatocytes were incubated for 30 min in various concns. (5-45 mM) of glucose, there was an appreciable decrease in nuclear GK immunoreactivity, even at 10 mM compared with that at 5 mM. After the shift of glucose concn. from 5 mM to 25 mM, the GK distribution changes time-dependently over 1 h. A time-dependent change in GK distribution was also obsd. when the glucose concn. was shifted from 25 mM to 5 mM. Reversal of GK distribution in response to the change in glucose concn. from 5 to 25 mM and vice versa was shown to repeatedly occur. Lower concns. (0.05-5 mM) of fructose, which is known to stimulate glucose phosphorylation in GK, in combination with 5 mM glucose, induced the translocation of GK from the nucleus to the cytoplasm. Mannose (20 mM), a substrate of GK, and sorbitol (1 mM), a stimulator of glucose phosphorylation by GK, induced the translocation of GK from the nucleus to the cytoplasm in the presence of 5 mM glucose. L-Glucose, galactose, 3-O methylglucose, and 2-deoxyglucose at 20 mM each did not affect the GK distribution obsd. in the presence of 5 mM glucose. The results suggest that GK is present mainly in the nuclear under conditions where GK action is not much needed, whereas the enzyme exists mainly in the cytoplasm under conditions where it must function extensively. Our findings indicate that the shuttling of GK between the nucleus and the cytoplasm is essential for the regulation of the glucose metab. in the liver.
- 20Toyoda, Y.; Tsuchida, A.; Iwami, E.; Shironoguchi, I.; Miwa, I. Regulation of hepatic glucose metabolism by translocation of glucokinase between the nucleus and the cytoplasm in hepatocytes Horm. Metab. Res. 2001, 33, 329– 336 DOI: 10.1055/s-2001-15418Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXlvVSms7w%253D&md5=1d232027f2885bbfe0cff4cfed7c72ceRegulation of hepatic glucose metabolism by translocation of glucokinase between the nucleus and the cytoplasm in hepatocytesToyoda, Y.; Tsuchida, A.; Iwami, E.; Shironoguchi, H.; Miwa, I.Hormone and Metabolic Research (2001), 33 (6), 329-336CODEN: HMMRA2; ISSN:0018-5043. (Georg Thieme Verlag)The authors studied the role of glucokinase translocation between the nucleus and the cytoplasm in hepatocytes. In cultured hepatocytes, both the translocation of glucokinase from the nucleus to the cytoplasm and the rate of glucose phosphorylation were increased when cells were incubated with high concns. of glucose. The addn. of low concns. of fructose, which is known to stimulate glucose phosphorylation, stimulated both glucokinase translocation and glucose phosphorylation. There was a good correlation between the increase in cytoplasmic glucokinase induced by fructose and that in the glucose phosphorylation rate induced by fructose. Furthermore, the authors obsd. a linear relationship between cytoplasmic glucokinase activity and rate of glucose phosphorylation over various glucose concns. in the absence or presence of fructose. These results indicate that glucose phosphorylation in hepatocytes depended on glucokinase in the cytoplasmic compartment - i.e., the increase in the rate of glucose phosphorylation was due to the increase in translocation of glucokinase out of the nucleus. Also, oral administration of glucose, fructose, or glucose plus fructose to 24-h fasted rats induced translocation of glucokinase in the liver. All of these results indicate that hepatic glucose metab. is regulated by the translocation of glucokinase.
- 21Takamine, S.; Nakamura, M.; Iida, T.; Okuma, K.; Izumori, K. Manufacturing method of rare sugar syrup through alkali isomerization and its inhibitory effect of α-glucosidase Bull. Appl. Glycosci. 2015, 5, 44– 49Google ScholarThere is no corresponding record for this reference.
- 22Iida, T.; Yamada, T.; Hayashi, N.; Okuma, K.; Izumori, K.; Ishii, R.; Matsuo, T. Reduction of abdominal fat accumulation in rats by 8-week ingestion of a newly developed sweetener made from high fructose corn syrup Food Chem. 2013, 138, 781– 785 DOI: 10.1016/j.foodchem.2012.11.017Google ScholarThere is no corresponding record for this reference.
- 23Hayashi, N.; Yamada, T.; Takamine, S.; Iida, T.; Okuma, K.; Tokuda, M. Weight reducing effect and safety evaluation of rare sugar syrup by a randomized double-blind, parallel-group study in human J. Funct. Foods 2014, 11, 152– 159 DOI: 10.1016/j.jff.2014.09.020Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslGrs7%252FO&md5=8634c359d54565fdac6205724649633bWeight reducing effect and safety evaluation of rare sugar syrup by a randomized double-blind, parallel-group study in humanHayashi, Noriko; Yamada, Takako; Takamine, Satoshi; Iida, Tetsuo; Okuma, Kazuhiro; Tokuda, MasaakiJournal of Functional Foods (2014), 11 (), 152-159CODEN: JFFOAX; ISSN:1756-4646. (Elsevier Ltd.)Rare sugar syrup is a sweetener obtained from high-fructose corn syrup under slightly alk. conditions, which promotes the formation of rare sugars. Here, the physiol. impact and safety of rare sugar syrup in humans was investigated by a randomized double-blind parallel expt. Thirty-four subjects with an av. body mass index of 25.6 kg/m2 were divided into two groups. Subjects consumed either a test drink contg. rare sugar syrup or an isocaloric control drink contg. high-fructose corn syrup on a daily basis for 12 wk. Results showed significant decreases in body wt., body fat percentage and waist circumference in the rare sugar syrup group compared to the control. No adverse events with regard to hepatic and renal function or blood parameters were obsd. Our study conclusively suggests, for the first time, that rare sugar syrup is a safe sweetener, and that continuous consumption of this syrup could help wt. management.
- 24Jürgens, H.; Haass, W.; Castañeda, T. R.; Schürmann, A.; Koebnick, C.; Dombrowski, F.; Otto, B.; Nawrocki, A. R.; Scherer, P. E.; Spranger, J.; Ristow, M.; Joost, H. G.; Havel, P. J.; Tschöp, M. H. Consuming fructose-sweetened beverages increases body adiposity in mice Obes. Res. 2005, 13, 1146– 56 DOI: 10.1038/oby.2005.136Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtVSltrrI&md5=5b1981f7f2184c9cefec2c34929d8a51Consuming fructose-sweetened beverages increases body adiposity in miceJuergens, Hella; Haass, Wiltrud; Castaneda, Tamara R.; Schuermann, Annette; Koebnick, Corinna; Dombrowski, Frank; Otto, Baerbel; Nawrocki, Andrea R.; Scherer, Philipp E.; Spranger, Jochen; Ristow, Michael; Joost, Hans-Georg; Havel, Peter J.; Tschoep, Matthias H.Obesity Research (2005), 13 (7), 1146-1156CODEN: OBREFR; ISSN:1071-7323. (North American Association for the Study of Obesity)The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To det. if and how fructose might promote obesity in an animal model, we measured body compn., energy intake, energy expenditure, substrate oxidn., and several endocrine parameters related to energy homeostasis in mice consuming fructose. We compared the effects of ad libitum access to fructose (15% soln. in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metab. in mice. Results showed that exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased RQ, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic peri-central pattern. Therefore, a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.
- 25Toyoda, Y.; Ito, Y.; Tanigawa, K.; Miwa, I. Impairment of glucokinase translocation in cultured hepatocytes from OLETF and GK rats, animal models of type 2 diabetes Arch. Histol. Cytol. 2000, 63, 243– 248 DOI: 10.1679/aohc.63.243Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXms1OhsL8%253D&md5=94dfca708dbe394cac875e52d3f76e2aImpairment of glucokinase translocation in cultured hepatocytes from OLETF and GK rats, animal models of type 2 diabetesToyoda, Yukiyasu; Ito, Yuki; Tanigawa, Keiichiro; Miwa, IchitomoArchives of Histology and Cytology (2000), 63 (3), 243-248CODEN: AHCYEZ; ISSN:0914-9465. (International Society of Histology and Cytology)We examd. sugar-induced translocation of glucokinase in cultured hepatocytes from Otsuka Long-Evans Tokushima Fatty and Goto-Kakizaki rats, animal models of type 2 diabetes, and compared this with that in Long-Evans Tokushima Otsuka and Wistar rats, resp., as control strains. When hepatocytes from the four strains were incubated with 5 mM glucose, glucokinase was present predominantly in the nuclei. Higher concns. of glucose, 5 mM glucose plus 1 mM fructose, and 5 mM glucose plus 1 mM sorbitol all induced the translocation of glucokinase from the nucleus to the cytoplasm in hepatocytes from these rats. The extent of glucokinase translocation under these conditions, however, was less marked in both diabetic rat types than in the control rats. The extent of the phosphorylation of glucose as estd. by the release of 3H2O from [2-3H]glucose is significantly lower in Goto-Kakizaki rats than in Wistar rats. The results indicate that the translocation of glucokinase is impaired in the hepatocytes of diabetic rats. They also suggest that the impaired translocation of glucokinase is assocd. with abnormal hepatic glucose metab. in type 2 diabetes.
- 26Keppler, D.; Decker, K. Glycogen. Determination with amylglucosidase. In Methods of Enzymatic Analysis, 2nd ed.; Bergmeyer, H. U., Ed.; Academic Press: New York, 1974; Vol. 3, pp 1127– 1131.Google ScholarThere is no corresponding record for this reference.
- 27Yamada, T.; Iida, T.; Hayashi, N.; Oga, H.; Okuma, K.; Izumori, K. Effects of d-psicose on Body Fat Accumulation and High Fructose Corn Syrup Diets in Rats Nippon Shokuhin Kagaku Kogaku Kaishi 2010, 57, 263– 267 DOI: 10.3136/nskkk.57.263Google ScholarThere is no corresponding record for this reference.
- 28Baek, S. H.; Park, S. J.; Lee, H. G. d-Psicose, a sweet monosaccharide, ameliorate hyperglycemia, and dyslipidemia in C57BL/6J db/db mice J. Food Sci. 2010, 75, H49– 53 DOI: 10.1111/j.1750-3841.2009.01434.xGoogle Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjslCru7g%253D&md5=81aa750f71e9d152fd7e7d9244e9971eD-psicose, a sweet monosaccharide, ameliorate hyperglycemia, and dyslipidemia in C57BL/6J db/db miceBaek, S. H.; Park, S. J.; Lee, H. G.Journal of Food Science (2010), 75 (2), H49-H53CODEN: JFDSAZ; ISSN:0022-1147. (Wiley-Blackwell)D-psicose has been implicated in glycemic control in recent animal and human studies. In this study, the effects of D-psicose on glycemic responses, insulin release, and lipid profiles were compared with those of D-glucose and D-fructose in a genetic diabetes model. C57BL/6J db/db mice were orally supplemented with 200 mg/kg BW of D-psicose, D-glucose, or D-fructose, resp., while diabetes control or wild type mice were supplemented with water instead. D-psicose sustained wt. gain by about 10% compared to other groups. The initial blood glucose level maintained from 276 to 305 mg/dL during 28 d in the D-psicose group, whereas a 2-fold increase was found in other groups (P < 0.05) among diabetic mice. D-psicose significantly improved glucose tolerance and the areas under the curve (AUC) for glucose among diabetes (P < 0.05), but had no effect on serum insulin concn. The plasma lipid profile was not changed by supplemental monosaccharides, although the ratio of LDL-cholesterol/HDL-cholesterol was ameliorated by D-psicose. The administration of D-psicose reversed hepatic concns. of triglyceride (TG) and total cholesterol (TC) by 37.88% and 62.89%, resp., compared to the diabetes control (P < 0.05). The current findings suggest that D-psicose shows promise as an antidiabetic and may have antidyslipidemic effects in type 2 diabetes.
- 29Buemann, B.; Toubro, S.; Holst, J. J.; Rehfeld, J. F.; Bibby, B. M.; Astrup, A. d-Tagatose, a stereoisomer of d-fructose, increases blood uric acid concentration Metab., Clin. Exp. 2000, 49, 969– 976 DOI: 10.1053/meta.2000.7724Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtFShtrk%253D&md5=572209053ce452342f41f50f8c177de0D-tagatose, a stereoisomer of D-fructose, increases blood uric acid concentrationBuemann, Benjamin; Toubro, Soren; Holst, Jens Juul; Rehfeld, Jens F.; Bibby, Bo Martin; Astrup, ArneMetabolism, Clinical and Experimental (2000), 49 (8), 969-976CODEN: METAAJ; ISSN:0026-0495. (W. B. Saunders Co.)Dietary D-fructose increases uric acid prodn. by accelerating the degrdn. of purine nucleotides, probably via hepatocellular depletion of inorg. phosphate (Pi) and accumulation of D-fructose-1-phosphate. The hyperuricemic effect of D-tagatose may be greater than that of D-fructose, as the subsequent degrdn. of D-tagatose-1-phosphate is slower than the degrdn. of D-fructose-1-phosphate. We tested the effects of 30 g oral doses of D-tagatose and D-fructose on blood serum uric acid levels and other metabolic parameters in 8 men. Both the peak concns. and 4-h areas under the curve (AUC) of serum uric acid were higher after D-tagatose compared with D-fructose or plain water. The decline in serum Pi concns. was greater at 50 min after D-tagatose vs. D-fructose. The thermogenic and lactacidemic responses to D-tagatose were blunted compared with D-fructose. D-Tagatose attenuated the glycemic and insulinemic responses to a meal consumed 255 min after tagatose administration. Both fructose and D-tagatose increased plasma concns. of cholecystokinin and glucagon-like peptide-1 (GLP-1). The metabolic effects of D-tagatose occurred despite its putative poor absorption.
- 30Yamada, T.; Hayashi, N.; Iida, T.; Takamine, S.; Okuma, K.; Matsuo, T. Dietary d-sorbose decreases serum insulin levels in growing Sprague-Dawley rats J. Nutr. Sci. Vitaminol. 2014, 60, 297– 299 DOI: 10.3177/jnsv.60.297Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFaksr7K&md5=1e00dd062fcd35f272cbecc237285df0Dietary D-sorbose decreases serum insulin levels in growing Sprague-Dawley ratsYamada, Takako; Hayashi, Noriko; Iida, Tetsuo; Takamine, Satoshi; Okuma, Kazuhiro; Matsuo, TatsuhiroJournal of Nutritional Science and Vitaminology (2014), 60 (4), 297-299CODEN: JNSVA5; ISSN:0301-4800. (Center for Academic Publications Japan)D-Sorbose is naturally occurring rare sugar. In this study, we examd. the effects of dietary D-sorbose in rats. Four-week-old male Sprague-Dawley rats were fed either an AIN-93G-based control diet or a 3% D-sorbose diet for 28 d. Body wt. and body fat accumulation were not different between the two diet groups. Dietary supplementation of D-sorbose lowered the serum insulin level (*p<0.05) significantly compared to the control, although the glucose was not changed. In addn., the relative wt. of the cecum increased significantly in the D-sorbose group (**p<0.01). These findings suggest that intake of D-sorbose may improve the glucose metab. by reducing insulin secretion, and D-sorbose can be used as a food ingredient.
- 31Oku, T.; Murata-Takenoshita, Y.; Yamazaki, Y.; Shimura, F.; Nakamura, S. d-Sorbose inhibits disaccharidase activity and demonstrates suppressive action on postprandial blood levels of glucose and insulin in the rat Nutr. Res. (N. Y., NY, U. S.) 2014, 34, 961– 967 DOI: 10.1016/j.nutres.2014.09.009Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslCitLrK&md5=af2c5cc0fa5f863c702f77dc3c05e01aD-Sorbose inhibits disaccharidase activity and demonstrates suppressive action on postprandial blood levels of glucose and insulin in the ratOku, Tsuneyuki; Murata-Takenoshita, Yoko; Yamazaki, Yuko; Shimura, Fumio; Nakamura, SadakoNutrition Research (New York, NY, United States) (2014), 34 (11), 961-967CODEN: NTRSDC; ISSN:0271-5317. (Elsevier)In an attempt to develop D-sorbose as a new sweetener that could help in preventing lifestyle-related diseases, we investigated the inhibitory effect of D-sorbose on disaccharidase activity, using the brush border membrane vesicles of rat small intestines. The inhibitory effect was compared with that of L-sorbose and other rare sugars, and the small intestinal disaccharidases in rats was compared with that of humans as well. In humans and the small intestines of rats, D-sorbose strongly inhibited sucrase activity and weakly inhibited maltase activity. Inhibition by D-sorbose of sucrase activity was similar to that of L-arabinose, and the Ki of D-sorbose was 7.5 mM. Inhibition by D-sorbose was very strong in comparison with that of L-sorbose (Ki, 60.8 mM), whereas inhibition of D-tagatose was between that of D-sorbose and L-sorbose. The inhibitory mode of D-sorbose for sucrose and maltase was uncompetitive, and that of L-sorbose was competitive. To det. a suppressive effect on postprandial blood levels of glucose and insulin via inhibition of sucrase activity, sucrose soln. with or without D-sorbose was administered to rats. Increments in the blood levels of glucose and insulin were suppressed significantly after administration of sucrose soln. with D-sorbose to rats, in comparison to administration of sucrose soln. without D-sorbose. In contrast, the suppressive effect of L-sorbose on postprandial blood levels of glucose and insulin was very weak. These results suggest that D-sorbose may have an inhibitory effect on disaccharidase activity and could be used as a sweetener to suppress the postprandial elevation of blood levels of glucose and insulin. The use of D-sorbose as a sweetener may contribute to the prevention of lifestyle-related diseases, such as type 2 diabetes mellitus.
- 32Hawkins, M.; Gabriely, I.; Wozniak, R.; Vilcu, C.; Shamoon, H.; Rossetti, L. Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes Diabetes 2002, 51, 606– 614 DOI: 10.2337/diabetes.51.3.606Google ScholarThere is no corresponding record for this reference.
- 33Perreault, L.; Færch, K.; Kerege, A. A.; Bacon, S. D.; Bergman, B. C. Hepatic glucose sensing is impaired, but can be normalized, in people with impaired fasting glucose J. Clin. Endocrinol. Metab. 2014, 99, E1154– 1162 DOI: 10.1210/jc.2013-3248Google ScholarThere is no corresponding record for this reference.
- 34Trus, M.; Zawalich, H.; Gaynor, D.; Matschinsky, F. Hexokinase and glucokinase distribution in the liver lobule J. Histochem. Cytochem. 1980, 28, 579– 581 DOI: 10.1177/28.6.7391551Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaL3cXksVagsr4%253D&md5=30616655b68e752c21c8b8649d75ef4cHexokinase and glucokinase distribution in the liver lobuleTrus, Michael; Zawalich, Kathleen; Gaynor, Deborah; Matschinsky, FranzJournal of Histochemistry and Cytochemistry (1980), 28 (6), 579-81CODEN: JHCYAS; ISSN:0022-1554.Zone 1 and zone 3 of rat livers were identified by differential staining for succinate dehydrogenase, and their hexokinase (I) and glucokinase (II) contents were examd. The activities of I and II exhibited gradients in opposite directions. The I content of zones 1 and 3 was 116 mmol/kg dry wt./h and 61.6 mmol/kg/h, resp., whereas the II content was 210 mmol/kg/h and 349 mmol/kg/h, resp. The av. II activity from both regions was 76% of the total glucose phosphorylating activity measured in lyophilized liver specimens.
- 35Agius, L. Control of glucokinase translocation in rat hepatocytes by sorbitol and the cytosolic redox state Biochem. J. 1994, 298, 237– 243 DOI: 10.1042/bj2980237Google ScholarThere is no corresponding record for this reference.
- 36Wu, C.; Kang, J. E.; Peng, L. J.; Li, H.; Khan, S. A.; Hillard, C. J.; Okar, D. A.; Lange, A. J. Enhancing hepatic glycolysis reduces obesity: Differential effects on lipogenesis depend on site of glycolytic modulation Cell Metab. 2005, 2, 131– 140 DOI: 10.1016/j.cmet.2005.07.003Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXps12ht7k%253D&md5=4bde4bc418fe21dc25f27b42736f79e7Enhancing hepatic glycolysis reduces obesity: Differential effects on lipogenesis depend on site of glycolytic modulationWu, Chaodong; Kang, Johnthomas E.; Peng, Li-Jen; Li, Honggui; Khan, Salmaan A.; Hillard, Christopher J.; Okar, David A.; Lange, Alex J.Cell Metabolism (2005), 2 (2), 131-140CODEN: CMEEB5; ISSN:1550-4131. (Cell Press)Reducing obesity requires an elevation of energy expenditure and/or a suppression of food intake. Here we show that enhancing hepatic glycolysis reduces body wt. and adiposity in obese mice. Overexpression of glucokinase or 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase is used to increase hepatic glycolysis. Either of the two treatments produces similar increases in rates of fatty acid oxidn. in extrahepatic tissues, i.e., skeletal muscle, leading to an elevation of energy expenditure. However, only 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase overexpression causes a suppression of food intake and a decrease in hypothalamic neuropeptide Y expression, contributing to a more pronounced redn. of body wt. with this treatment. Furthermore, the two treatments cause differential lipid profiles due to opposite effects on hepatic lipogenesis, assocd. with distinct phosphorylation states of carbohydrate response element binding protein and AMP-activated protein kinase. The step at which hepatic glycolysis is enhanced dramatically influences overall whole-body energy balance and lipid profiles.